Clinical trial NCT02465528
Conditions: Tumors With Aberrations in ALK Anaplastic Large Cell Lymphoma Inflammatory Myofibroblastic Tumor Glioblastoma
Keywords: ALK GBM hematological malignancy anaplastic lymphoma kinase glioblastoma anaplastic large cell lymphoma IMT inflammatory myofibroblastic tumor
Sponsor: Novartis Pharmaceuticals
Start date: 2016-05-06; Completion date: 2018-08-20
Enrollment: 22 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is Proof-of-Concept (POC) study to assess the preliminary antitumor activity and safety and tolerablity using ceritinib (LDK378) in the treatment of life threatening tumors that are characterized by ALK genetic alteration (and/or overexpression in some diseases).

Detailed description:

Arms: arm 1: Patients diagnosed with IMT with a confirmed translocation involving the ALK gene arm 2: Patients with a diagnosis of ALCL histologically or cytologically confirmed to be ALK-positive arm 3: Patients with GBM with a translocation involving the ALK gene arm 4: Patients with any other ALK-positive tumor. Patients in this arm included adenocarcinoma (n= 2), sarcoma (1) and other (2).
Interventions: intervention 1: Ceritinib (LDK378)
Intervention descriptions: intervention 1: Ceritinib was to be administered orally once daily at a dose of 750 mg (5 capsules of 150 mg) on a continuous dosing schedule. A complete treatment cycle was defined as 28 days of once daily continuous treatment with ceritinib.

Protocol documents:
Prot_000.pdf: 
 
 
 
Global Medical Affairs 
Ceritinib (LDK378) 
Protocol CLDK378A2407 / NCT02465528
A Phase II, open label, multi-center, multi-arm study of 
ceritinib in patients with advanced solid tumors and 
hematological malignancies characterized by genetic 
abnormalities of anaplastic lymphoma kinase (ALK) 
Authors 
 
Document type 
Amended Protocol Version 
EUDRACT number 
2015-000814-23 
Version number 
01 (Clean) 
Development phase 
Phase II 
Document status 
Final 
Release date 
30-Nov-2015
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Template version 17-Nov-2014 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 20 
Protocol No. CLDK378A2407 
 
 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of figures....................................................................................................................... 6 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 12 
Amendment 1 .................................................................................................................... 14 
Protocol Summary ............................................................................................................. 17 
1 
Background ........................................................................................................................ 26 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 26 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 29 
1.2.1 
Overview of ceritinib ............................................................................ 29 
2 
Rationale ............................................................................................................................ 40 
2.1 
Study rationale and purpose ................................................................................... 40 
2.1.1 
Rationale for the use of ceritinib in ALK-driven tumors ...................... 40 
2.2 
Rationale for the study design ............................................................................... 41 
2.3 
Rationale for dose and regimen selection .............................................................. 42 
2.4 
Rationale for choice of combination drugs ............................................................ 42 
2.5 
Rationale for choice of comparators drugs ............................................................ 42 
3 
Objectives and endpoints ................................................................................................... 42 
4 
Study design ...................................................................................................................... 46 
4.1 
Description of study design ................................................................................... 46 
4.1.1 
Duration of treatment ............................................................................ 49 
4.1.2 
End of treatment (EOT)......................................................................... 49 
4.2 
Timing of interim analyses and design adaptations ............................................... 49 
4.3 
End of the study ..................................................................................................... 50 
4.4 
Early study termination .......................................................................................... 50 
5 
Population .......................................................................................................................... 50 
5.1 
Patient population .................................................................................................. 50 
5.2 
Inclusion criteria .................................................................................................... 51 
5.3 
Exclusion criteria ................................................................................................... 53 
6 
Treatment ........................................................................................................................... 55 
6.1 
Study treatment ...................................................................................................... 55 
6.1.1 
Dosing regimen ..................................................................................... 55 
6.1.2 
Ceritinib administration ........................................................................ 55 
6.1.3 
Ancillary treatments .............................................................................. 56 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 30 
Protocol No. CLDK378A2407 
 
6.1.4 
Rescue medication ................................................................................ 56 
6.2 
Dose escalation guidelines ..................................................................................... 56 
6.2.1 
Starting dose rationale ........................................................................... 56 
6.2.2 
Provisional dose levels .......................................................................... 56 
6.2.3 
Guidelines for dose escalation and determination and dose delay ........ 56 
6.2.4 
Dose modification and dose delay ........................................................ 57 
6.2.5 
Treatment interruption and treatment discontinuation .......................... 57 
6.2.6 
Criteria for ceritinib dose modifications ............................................... 58 
6.2.7 
Follow-up for toxicities ......................................................................... 65 
6.2.8 
Anticipated risks and safety concerns of the study treatment ............... 69 
6.3 
Concomitant medications ...................................................................................... 69 
6.3.1 
Permitted concomitant therapy ............................................................. 70 
6.3.2 
Prohibited concomitant therapy ............................................................ 72 
6.4 
Patient numbering, treatment assignment or randomization ................................. 73 
6.4.1 
Patient numbering ................................................................................. 73 
6.4.2 
Treatment assignment ........................................................................... 73 
6.4.3 
Treatment blinding ................................................................................ 74 
6.5 
Study drug preparation and dispensation ............................................................... 74 
6.5.1 
Study drug packaging and labeling ....................................................... 74 
6.5.2 
Drug supply and storage ........................................................................ 74 
6.5.3 
Study drug compliance and accountability ........................................... 74 
6.5.4 
Disposal and destruction ....................................................................... 75 
7 
Visit schedule and assessments ......................................................................................... 75 
7.1 
Study flow and visit schedule ................................................................................ 75 
7.2 
Molecular pre-screening ........................................................................................ 79 
7.2.1 
Screening ............................................................................................... 79 
7.2.2 
Treatment period ................................................................................... 80 
7.2.3 
End of treatment (EOT) visit including study treatment 
discontinuation and premature withdrawal ........................................... 81 
7.2.4 
Follow up period ................................................................................... 82 
7.3 
Assessment types ................................................................................................... 82 
7.3.1 
Efficacy assessments ............................................................................. 82 
7.3.2 
Safety and tolerability assessments ....................................................... 85 
 
 88 
 
 90 
7.3.5 
Resource utilization ............................................................................... 90 
7.3.6 
Patient reported outcomes ..................................................................... 90 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 40 
Protocol No. CLDK378A2407 
8 
Safety monitoring and reporting ........................................................................................ 91 
8.1 
Adverse events ....................................................................................................... 91 
8.1.1 
Definitions and reporting ...................................................................... 91 
8.1.2 
Laboratory test abnormalities ................................................................ 92 
8.1.3 
Adverse events of special interest ......................................................... 92 
8.2 
Serious adverse events ........................................................................................... 93 
8.2.1 
Definitions ............................................................................................. 93 
8.2.2 
Reporting ............................................................................................... 93 
8.3 
Emergency unblinding of treatment assignment ................................................... 94 
8.4 
Pregnancies ............................................................................................................ 94 
8.5 
Warnings and precautions ...................................................................................... 95 
8.6 
Data Monitoring Committee .................................................................................. 95 
8.7 
Steering Committee ............................................................................................... 95 
9 
Data collection and management ....................................................................................... 95 
9.1 
Data confidentiality ............................................................................................... 95 
9.2 
Site monitoring ...................................................................................................... 96 
9.3 
Data collection ....................................................................................................... 96 
9.4 
Database management and quality control ............................................................ 97 
10 Statistical methods and data analysis ................................................................................. 98 
10.1 
Analysis sets .......................................................................................................... 98 
10.1.1 
Full Analysis Set ................................................................................... 98 
10.1.2 
Safety Set............................................................................................... 98 
10.1.3 
Per-Protocol Set .................................................................................... 98 
10.1.4 
Dose-determining analysis set ............................................................... 98 
 
. 98 
 
 98 
10.2 
Patient demographics/other baseline characteristics .............................................. 98 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 99 
10.4 
Primary objective ................................................................................................... 99 
10.4.1 
Variable ................................................................................................. 99 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 99 
10.4.3 
Handling of missing values/censoring/discontinuations ..................... 100 
10.4.4 
Supportive analyses ............................................................................. 100 
10.5 
Secondary objectives ........................................................................................... 101 
10.5.1 
Secondary objective(s) ........................................................................ 101 
10.5.2 
Other secondary efficacy objectives ................................................... 102 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 50 
Protocol No. CLDK378A2407 
 
10.5.3 
Safety objectives ................................................................................. 102 
 
 103 
10.5.5 
Biomarkers .......................................................................................... 104 
10.5.6 
Resource utilization ............................................................................. 104 
10.5.7 
Patient-reported outcomes ................................................................... 104 
 
 104 
 
 104 
10.7 
Interim analysis .................................................................................................... 105 
10.8 
Sample size calculation ........................................................................................ 106 
10.9 
Power for analysis of key secondary variables .................................................... 108 
11 Regulatory and ethical compliance.................................................................................. 108 
11.1 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 108 
11.2 
Informed consent procedures ............................................................................... 108 
11.3 
Discontinuation of the study ................................................................................ 108 
11.4 
Publication of study protocol and results ............................................................. 109 
11.5 
Study documentation, record keeping and retention of documents ..................... 109 
11.6 
Confidentiality of study documents and patient records ..................................... 110 
11.7 
Audits and inspections ......................................................................................... 110 
11.8 
Financial disclosures ............................................................................................ 110 
12 Protocol adherence .......................................................................................................... 110 
12.1 
Amendments to the protocol ................................................................................ 111 
13 References (available upon request) ................................................................................ 112 
14 Appendices ...................................................................................................................... 115 
14.1 
Appendix 1: List of prohibited concomitant medications and concomitant 
medications requiring caution for ceritinib for LDK378 ..................................... 115 
14.2 
Appendix 2: Harmonization of efficacy analysis of solid tumor studies 
(RECIST 1.1) ....................................................................................................... 118 
14.2.1 
Measurability of tumor lesions at baseline .......................................... 118 
14.2.2 
Specification by methods of measurement .......................................... 119 
14.2.3 
Evaluation of best overall response ..................................................... 121 
14.2.4 
References (available upon request) .................................................... 123 
14.3 
Appendix 3: Response assessment in neuro-oncology (RANO) criteria for 
high-grade gliomas .............................................................................................. 124 
14.3.1 
Antitumor effect - definitions .............................................................. 124 
14.3.2 
Response/progression categories ......................................................... 125 
14.3.3 
Methods for evaluation of measurable disease .................................... 127 
14.3.4 
Evaluation of best response ................................................................. 127 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 60 
Protocol No. CLDK378A2407 
 
14.3.5 
Other effect measures .......................................................................... 127 
14.4 
Appendix 4: Guidelines for efficacy evaluation in lymphoma studies (based 
on Cheson response criteria). International Working Group guidelines for 
hematological malignancies ................................................................................. 129 
14.4.1 
Definitions and criteria for normalization ........................................... 129 
14.4.2 
Measurability of tumor lesions at baseline .......................................... 129 
14.4.3 
Specification by methods of measurement ......................................... 130 
14.4.4 
Evaluation of radiological response .................................................... 132 
14.4.5 
References (available upon request) ................................................... 138 
14.5 
Appendix 5: Details statistical methodology ....................................................... 139 
14.5.1 
Prior specification of model parameters .............................................. 139 
14.5.2 
Hypothetic scenario testing ................................................................. 140 
 
 
List of figures 
Figure 4-1 
Study design .......................................................................................... 48 
 
 
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: 31-Oct-2013) ..... 33 
Table 1-2 
Summary of best overall response based on investigator assessment 
in NSCLC patients in the 750 mg dose group, by prior ALK 
inhibitor status (Full Analysis Set NSCLC 750 mg) (Cut-off date: 
31-Oct-2013) ......................................................................................... 35 
Table 3-1 
Objectives and related endpoints........................................................... 44 
Table 4-1 
Tumor types of interest ......................................................................... 46 
Table 4-2 
Locally documented generic alterations of ALK are accepted ............. 47 
Table 6-1 
Dose and treatment schedule ................................................................. 55 
Table 6-2 
Dose reduction steps for ceritinib .......................................................... 58 
Table 6-3 
Criteria for interruption and re-initiation of ceritinib treatment ............ 59 
Table 6-4 
Follow-up evaluations for selected toxicities ........................................ 69 
Table 6-5 
Packaging and labeling.......................................................................... 74 
Table 6-6 
Supply and storage of study treatments ................................................. 74 
Table 7-1 
Visit evaluation schedule ...................................................................... 76 
Table 7-2 
Imaging assessment collection plan ...................................................... 83 
Table 7-3 
WHO performance status scale ............................................................. 86 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 70 
Protocol No. CLDK378A2407 
 
 
Table 7-4 
Clinical laboratory parameters collection plan...................................... 87 
 
. 89 
Table 7-6 
Tumor tissue sample collection plan ..................................................... 90 
Table 10-1 
Type of tumors of interest with definition of being clinically 
meaningful ........................................................................................... 105 
Table 10-2 
Simulation results Scenario 1 (ceritinib inactive for all arms) ............ 107 
Table 10-3 
Simulation results Scenario 2 (ceritinib active for all arms) ............... 107 
Table 10-4 
Simulation results Scenario 3 (certinib active for T1 and T5 arms) .... 107 
Table 14-1 
Prohibited medications that are strong inducers or inhibitors of 
CYP3A, or CYP3A substrates with narrow therapeutic index, or 
sensitive CYP2C9 substrates with narrow therapeutic index** .......... 115 
Table 14-2 
List of medications to be used with caution ........................................ 116 
Table 14-3 
List of prohibited enzyme-inducing anti-epileptic drugs .................... 116 
Table 14-4 
List of prohibited QT prolonging drugs .............................................. 117 
Table 14-5 
Evaluation of target lesions ................................................................. 120 
Table 14-6 
Evaluation of non-target lesions .......................................................... 120 
Table 14-7 
Point response: patients with target (+/- non-target) disease ............... 122 
Table 14-8 
Time point response: patients with non-target disease only ............... 122 
Table 14-9 
Best overall response when confirmation of CR and PR required ...... 122 
Table 14-10 
Summary of the RANO response criteria ........................................... 127 
Table 14-11 
Response definition for lymphoma ..................................................... 133 
Table 14-12 
Radiological status based on SPD calculation for all index lesions .... 134 
Table 14-13 
Radiological response criteria for index extranodal lesions in case 
of CR in index nodal lesions ............................................................... 134 
Table 14-14 
Radiological response for index lesions .............................................. 135 
Table 14-15 
Response criteria for non-index lesions (nodal, splenic and/or 
hepatic nodules and other extranodal lesions) ..................................... 136 
Table 14-16 
Overall radiological response at each assessment ............................... 137 
Table 14-17 
Specifications for model parameters, and prior median (95%- 
interval) for disease specific DCR ...................................................... 140 
Table 14-18 
Hypothetical data scenarios and decision at interim ........................... 141 
Table 14-19 
Hypothetical data scenarios and decision at final................................ 143 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 80 
Protocol No. CLDK378A2407 
 
 
List of abbreviations 
ADME 
Absorption Distribution Metabolism and Excretion 
AE 
Adverse Event 
ALCL 
Anaplastic Large Cell Lymphoma 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
Absolute Neutrophil Count 
AP 
Alkaline Phosphatase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC0-24h 
Area Under the Curve 0-24 h 
b.i.d. 
bis in diem/twice a day 
BLRM 
Bayesian Logistic Regression Model 
BP 
Blood pressure 
BSC 
Best supportive care 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CABG 
Coronary artery bypass graft 
CBC 
Complete blood count 
CHF 
Congestive heart failure 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum Concentration 
CNS 
Central Nervous System 
CPK 
Creatine phosphokinase 
CR 
Complete Response 
CrCl 
Creatinine clearance 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CSR addendum 
An addendum to Clinical Study Report (CSR) that captures all the additional 
information that is not included in the CSR 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
Cerebrovascular accident 
CYP 
Cytochrome P 
DLs 
dose levels 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration of Response 
DS&E 
Drug Safety and Epidemiology 
e.g. 
for example 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 90 
Protocol No. CLDK378A2407 
 
 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FAS 
Full Analysis Set 
FFPE 
Formalin fixed paraffin embedded 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyltranspeptidase 
GI 
Gastrointestinal 
GLP 
Good laboratory practice 
GM-CSF 
Granulocyte macrophage colony-stimulating factor 
GVHD 
Graft-versus-host disease 
HBV 
Hepatitis B Virus 
hCG 
human chorionic gonadotropin 
HCV 
Hepatitis C Virus 
HDL 
High density lipoprotein 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
hr 
hour 
IB 
Investigators Brochure 
IC50 
Half maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
ILD 
Interstitial Lung Disease 
IMT 
Inflammatory Myofibrolastic Tumor 
IMWG 
International Myeloma Working Group 
IN 
Investigator notification 
INR 
International Normalized Ratio 
IUD 
intrauterine device 
IUS 
intrauterine system 
i.v. 
intravenous(ly) 
IWG 
International working group 
KA 
Keratoacanthoma 
KRAS 
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
mg 
milligram 
MI 
Myocardial infarction 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 100 
Protocol No. CLDK378A2407 
 
 
MIGB 
Metaiodobenzylguanidine 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NA 
Not applicable 
Na 
Sodium 
NCI CTC 
National Cancer Institute Common Terminology Criteria 
nM 
Nano molar 
NSCLC 
Non-small cell lung carcinoma 
OC 
Oral contraception 
OR 
Overall response 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD 
Pharmacodynamics 
PE 
Pulmonary embolism 
PET 
Positron emission tomography 
PFS 
Progression –free survival 
PHI 
Protected health information 
PK 
Pharmacokinetics 
PLT 
Platelets 
PR 
Partial Response 
POC 
Proof of Concept 
PT 
Prothrombin time 
QD 
quaque die/once a day 
QTc 
QT corrected 
QTcF 
Q-T interval in the ECG (corrected according to the formula of Fridericia) 
RANO 
Respone assessment in neuro-oncology 
SAP 
Statistical Analysis Plan 
RAS 
RAS oncogene (rat sarcoma viral oncogene homologue) 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
Recommended phase two dose 
RTK 
Receptor tyrosine kinase 
SAE 
Serious Adverse Event 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic 
SOP 
Standard Operating Procedure 
SPEP 
Serum protein electrophoresis 
SUSAR 
Suspected unexpected serious adverse reaction 
TdP 
Torsade de Pointes 
TIA 
Transient ischemic attack 
Tmax 
The time at which the maximum observed concentration (Cmax) occurs 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 110 
Protocol No. CLDK378A2407 
 
 
TSH 
Thyroid stimulating hormone 
ULN 
Upper Limit of Normal 
UPEP 
Urine protein electrophoresis 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WNL 
Within normal limits 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 120 
Protocol No. CLDK378A2407 
 
 
 
Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study subject or study 
patient 
Control drug 
A study treatment used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days) 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.” 
Investigational treatment 
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). 
This also includes approved drugs used outside of their 
indication/approved dosage, or that are tested in a fixed combination. 
Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required 
or allowed by the protocol when used in within approved 
indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which 
is linked to one of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Patient Number 
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study 
Randomization number 
A unique treatment identification code assigned to each randomized 
patient, corresponding to a specific treatment arm assignment 
Stage related to study 
timeline 
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; 
study treatment in this case refers to the investigational and non- 
investigational treatments in combination. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment for 
any reason 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 130 
Protocol No. CLDK378A2407 
 
 
Variable 
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints 
Withdrawal of Consent 
Withdrawal of consent occurs only when a patient does not want to 
participate in the study any longer, and does not want any further 
visits or assessments, and does not want any further study related 
contact 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 140 
Protocol No. CLDK378A2407 
 
 
 
Amendment 1 
Amendment rationale 
This global amendment clarifies the inclusion critieria #2 for ALK positivity. A patient must 
have a histologically or cytologically confirmed diagnosis of one of the tumors that is ALK 
positive (ALK+). The ALK test results must be available at the investigator site before the 
first dose of the study drug. 
The tumor types are described below: 
Anaplastic Large Cell Lymphoma (ALCL), local confirmation of diagnosis of ALK+ 
ALCL is sufficient for eligibility. 
Inflammatory Myofibroblastic Tumor local confirmation of translocation involving the 
ALK gene. 
Glioblastoma, Inflammatory breast cancer and any other locally documented ALK+ 
tumor must carry a locally documented genetic alteration of ALK including any of the 
following: 
• A known activating mutation in the kinase domain of ALK or a point mutation in the 
kinase domain of ALK that results in an amino acid change that has not been reported in 
normal germline DNA, or any other mutation (e.g. insertion or deletion) which results in a 
change in the amino acid sequence of the kinase domain of ALK, 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. 
• An amplification of the ALK gene, defined as ≥ 6 copies per cell, or 3 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 translocation involving the ALK gene. 
• Glioblastoma patients only, overexpression of ALK protein documented locally is also 
acceptable for eligibility 
This amendment also provides follow up evaluations for hepatic toxicities and work-up 
guidelines for potential Drug Induced Liver Injury (DILI) cases. Additioanlly, the following 
changes were made for consistency with other Novartis sponsored clinical studies: 
• Updated the exclusion criteria for contraception use 
• Dose guidance modification for QTcF text was updated to provide clarification on 
monitoring procedure. 
 
Changes to the protocol 
• List of Abbreviations: deleted the duplicate terms: DLT, IB, IC50, ICF, ICH, SD and 
SGOT. Added the term POC, DILI, IMTand MIGB 
• 
 
 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 150 
Protocol No. CLDK378A2407 
 
 
• Protocol Summary: inclusion criteria# 2 has been modified to provide additional 
information for the types of ALK gene activating/alteration (and/or overexpression. 
• Protocol Summary: inclusion criteria #7 ALCL by Cheson for the measurement of a nodal 
has been corrected to ≥ 1.5 cm. 
• Protocol Summary: inclusion criteria #8, calculated creatinine clearance has been 
corrected to ≥ 30 mL/min 
• Protocol Summary: exclusion criteria #10, has been modified to QTcF > 470 msec (as 
means of triplicate ECGs) at screening. 
• Protocol Summary: Updated the interim analysis section. 
• Section 1.2.1: Updated the approval/submission status of certinib. 
• Section 1.2.1.1.4: corrected references to the appropriate inclusion and exclusion criteira. 
• 
 
 
• 
 
 
• Section 4.1: Table 4-2; Deleted reference to FISH in the table heading. 
• Section 4.2: Removed “at least” wording. 
• Section 4.2: Deleted the sentence referring to a separate charter. 
• Section 5.2: inclusion criteria #2 has been modified to provide additional information for 
the types of ALK gene that will be acceptable for the 5 tumor types. 
• Section 5.2: inclusion criteria #7 ALCL by Cheson for the measurement of a nodal has 
been corrected to ≥ 1.5 cm. 
• Section 5.2: inclusion criteria #8 calculated creatinine clearence has been corrected to ≥ 30 
mL/min 
• Section 5.2: exclusion criteria #10, has been modified to QTcF > 470 msec (triplicate 
ECGs) at screening 
• Section 6.2.7.2: added additional guidelines for Hy’s Law for the follow-up of laboratory 
liver abnormalities. 
• Table 6-3: AST and ALT provided a reference to Section 6.2.7.2 
• Table 6-3: provided clarification for pancreatic toxicity. 
• Table 6-3: provided additional guidance for QTc dose modifications. 
• Section 6.3.1.1: clarified corticosteroid treatment guidance. 
• Table 7-1: added a visit name to ensure documentation of local ALK testing results are 
available at screening to the investigator. 
• Table 7-1: included ECG and vital sign measurements at C1 Day 15 and C2 Day 15. 
• Table 7-1: clarified the timing of the radiological tumor assessments (MRI/CT/PET/PET- 
CT). 
• Table 7-1: clarified the need to perform bone marrow aspirate or biopsy at screening and 
EOT. 
• Table 7-2: corrected “follow-up” to EOT. 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 160 
Protocol No. CLDK378A2407 
 
 
• Table 7-2: clarified radiological procedure for GMB patients. 
• Section 7.3.2.2: Corrected “respirations” to respiratory rate. 
• Section 7.3.2.4: Corrected the timing interval. 
• Section 7.3.2.5: Deleted the reference to a central lab for the analysis of out of range urine 
samples. 
• Section 7.3.2.6.1: added the triplicate ECGs at screening 
• Table 7-6: corrected the unit of measure for tumor slides from uM to µm. 
• 10.5.3.3: Changed the reference from “RAP” to “SAP”. 
• 10.5.3.4: Changed the reference from “RAP” to “SAP”. 
• 10.6.1: Removed reference to “PD”. 
• 10.7: Updated this section to include all available data in the interim analysis. 
• Corrected discrepancies, typographical errors or add missing minor information. 
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. 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 170 
Protocol No. CLDK378A2407 
 
 
 
Protocol Summary 
Protocol number 
CLDK378A2407 
Title 
A Phase II, open label, multi-center, multi-arm study of ceritinib in patients 
with advanced solid tumors and hematological malignancies 
characterized by genetic abnormalities of anaplastic lymphoma kinase 
(ALK) 
Brief title 
Ceritinib Rare Indications Study in ALK+ Tumors 
Sponsor and Clinical 
Phase 
Novartis, Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
This Proof-of-Concept (POC) efficacy study will assess the preliminary 
antitumor activity and safety and tolerablity using ceritinib (LDK378) in the 
treatment of life threatening tumors that are characterized by ALK genetic 
alteration (and/or overexpression in some diseases). The tumors selected 
in this study are Anaplastic Large Cell Lymphoma (ALCL), Inflammatory 
Myofibroblastic Tumor (IMT), Glioblastoma (GBM), Inflammatory Breast 
Cancer or any other ALK+ tumor type refractory or intolerant to standard 
therapeutic treatments. The tumor pathogenesis may involve ALK gene 
aberration resulting in potential dysregulation at the protein level. 
Inhibition of dysregulated protein by ALK inhibitors such as ceritinib is a 
rational approach to inhibit ALK-driven proliferation. 
Primary Objective 
To assess the preliminary antitumor activity of ceritinib treatment in 
patients with life threatening diseases other than NSCLC known to be 
associated with ALK dysregulation following failure or intolerance of the 
standard therapy. The antitumor activity will be measured by Disease 
Control Rate (DCR) based on local investigator assessment. 
For patients with solid tumors the assessment criteria will be RECIST 1.1. 
For GBM, RANO and RECIST 1.1 criteria will apply. For hematologic 
tumors, Cheson response criteria will apply. The DCR is defined as the 
proportion of ceritinib treated patients with complete response (CR), 
partial response (PR) or stable disease (SD) at 16 weeks from the start of 
the treatment. The DCR responses will need to be confirmed at least 4 
weeks later by the same method 
Secondary Objectives 
• 
To assess the antitumor activity of ceritinib as measured by ORR, 
DOR, TTR as determined by investigators 
• 
To assess the antitumor activity of ceritinib as measured by PFS 
determined by investigators 
• 
To assess the safety and tolerability of ceritinib. Hematology, 
biochemistry, urinalysis, coagulation, pregnancy test, hormones 
(males only); ECG; Performance status; Physical examination; Vital 
signs; Adverse events will be assessed using CTCAE 4.03. 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 180 
Protocol No. CLDK378A2407 
 
 
Study design 
This is a phase II, open-label, multi-center, multi-arm POC study to 
assess the preliminary anti-tumor activity and safety and tolerability of 
ceritinib in diverse populations of patients suffering from life threatening 
advanced, malignant diseases (solid tumors other than NSCLC) and 
hematological malignancies associated with ALK dysregulation 
contributing to the disease phenotype (see Table 4-2) 
Population 
Approximately 106 male and female patients 18 years and older. 
Inclusion criteria 
1. Written informed consent obtained prior to any screening procedure 
2. Patient must have a histologically or cytologically confirmed diagnosis 
of one of the tumors that is ALK positive (ALK+). The ALK test results 
must be available at the investigator site before the first dose of the 
study drug. The tumor types are described below: 
Anaplastic Large Cell Lymphoma (ALCL), local confirmation of 
diagnosis of ALK+ ALCL is sufficient for eligibility. 
Inflammatory Myofibroblastic Tumor locally documented translocation 
involving the ALK gene, 
Glioblastoma, Inflammatory breast cancer Any other locally 
documented ALK+ tumor. Must carry a locally documented genetic 
alteration of ALK including any of the following (ALK overexpression is 
also acceptable in Gliobalstoma): 
• 
A known activating mutation in the kinase domain of ALK or a 
point mutation in the kinase domain of ALK that results in an 
amino acid change that has not been reported in normal germline 
DNA, or any other mutation (e.g. insertion or deletion) which 
results in a change in the amino acid sequence of the kinase 
domain of ALK, 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. 
• 
An amplification of the ALK gene, defined as ≥ 6 copies per cell, 
or 3 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 translocation involving the ALK gene. 
• 
Glioblastoma patients only, overexpression of ALK protein 
documented locally is also acceptable for eligibility 
3. Patient must provide an archival or fresh tumor tissue before the first 
dose of the study drug for potential retrospective ALK testing at a 
Novartis designated central laboratory by a comparative technology: 
• 
the confirmation of ALK positivity is not required for enrollment if 
other inclusion and exclusion criteria are fulfilled 
4. Patient is 18 years or older at the time of informed consent. 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 190 
Protocol No. CLDK378A2407 
 
 
5. Patient has WHO Performance Status (PS) ≤ 2 
6. Patient must have received at least one line of prior systemic 
treatment for recurrent, locally advanced and/or metastatic disease, 
may have discontinued for: 
• 
Disease progression as defined by RECIST 1.1 for solid tumors; 
by RANO and RECIST for GBM and by Cheson assessment 
criteria for lymphoma 
• 
Intolerance described as any discontinuation due to an AE of any 
grade despite appropriate supportive treatment 
7. Patient must have a wash-out period prior to the first dose of ceritinib: 
• 
Chemotherapy, immunotherapy, stem cell transplant within 4 
weeks 
• 
Radiotherapy and ALK inhibitors must have discontinued within 1 
week 
• 
Recovered from all toxicities related to prior anticancer therapies 
to grade ≤ 1 (CTCAE v4.03). Exception to this criterion: patients 
with any grade of alopecia are allowed to enter the study. 
8. Patient has at least one measurable lesion as defined by appropriate 
guidelines. A lesion at a previously irradiated site may only be 
counted as a target lesion if there is clear sign of progression since 
the irradiation. 
• 
Solid Tumors: by RECIST 1.1 (Section 14.2) 
• 
GBM: by RANO and RECIST (Section 14.3 and Section 14.2) 
• 
ALCL: by Cheson (Section 14.4). Patient has at least one 
measurable nodal lesion (≥1.5). In case where the patient has no 
measurable nodal lesions ≥ 1.5 cm in the long axis at screening, 
then the patient must have at least one measurable extra-nodal 
lesion. 
9. Patient must meet the following laboratory values at the screening 
visit: 
• 
Absolute neutrophil count (ANC) ≥ 1.0 x 109/L; 
• 
Platelets ≥ 75 x 109/L 
• 
Hgb ≥ 8 g/dL 
• 
International Normalized Ratio (INR) ≤ 1.5 
• 
Serum creatinine ≤ 1.5 mg/dL and/or calculated creatinine 
clearance (using Cockcroft-Gault formula) ≥ 30 mL/min; 
• 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN), except for 
patients with Gilbert’s syndrome, who may only be included if 
total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN; 
• 
Aspartate transaminase (or aminotransferase; AST) ≤ 2.5 x ULN, 
except for patients with liver metastasis, who are only included if 
AST ≤ 5 x ULN; 
• 
Alanine transaminase (or aminotransferase; ALT) ≤ 2.5 x ULN, 
except for patients with liver metastasis, who are only included if 
AST ≤ 5 x ULN; 
• 
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) 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 200 
Protocol No. CLDK378A2407 
 
 
10. Patient must have the following laboratory values within ≤ Gr1 
(CTCAE v4.03) at screening: 
• 
Potassium 
• 
Magnesium 
• 
Phosphorus 
• 
Total calcium (corrected for serum albumin) 
11. Patient must be willing and able to comply with scheduled visits, 
treatment plans, laboratory tests and other study procedures. 
Exclusion criteria 
1. Patient with ALK+ lung cancer. 
2. Patient with known hypersensitivity to any of the excipients of ceritinib 
(microcrystalline cellulose, mannitol, crospovidone, colloidal silicon 
dioxide and magnesium stearate). 
3. Patient with symptomatic CNS metastases who are neurologically 
unstable or have required increasing doses of steroids within the 2 
weeks prior to study entry to manage CNS symptoms. 
4. Patient with history of carcinomatous meningitis 
5. Patient with diarrhea CTCAE ≥ grade 2; or patients with neuropathy 
CTCAE ≥ grade 2 
6. Patient with acute or chronic GI disease that may significantly alter 
the absorption of ceritinib 
7. Patient with a history of pancreatitis or history of increased amylase 
or lipase that was due to pancreatic disease 
8. Patient has history of interstitial lung disease or interstitial 
pneumonitis, including clinically significant radiation pneumonitis 
9. Presence or history of a malignant disease other than primary tumor 
under consideration that has been diagnosed and/or required therapy 
within the past 3 years. 
• 
Exceptions to this exclusion include the following: completely 
resected basal cell and squamous cell skin cancers, and 
completely resected carcinoma in situ of any type 
10. Patient has clinically significant, uncontrolled heart disease and/or 
recent cardiac event (within 6 months) such as: 
• 
unstable angina within 6 months prior to screening; 
• 
myocardial infarction within 6 months prior to screening; 
• 
history of documented congestive heart failure (New York Heart 
Association functional classification III-IV); 
• 
uncontrolled hypertension defined by a Systolic Blood Pressure 
(SBP) ≥ 160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 
mm Hg, with or without antihypertensive medication 
• 
initiation or adjustment of antihypertensive medication(s) is 
allowed prior to screening; 
• 
ventricular and atrial arrhythmias; supraventricular and nodal 
arrhythmias not controlled with medication; 
• 
Other cardiac arrhythmia not controlled with medication. 
• 
Corrected QT (QTcF) >470 ms using Fridericia’s correction on 
the screening ECG (as mean of triplicate ECGs). 
11. Evidence of active viral hepatitis, including Hepatitis A, B or C (testing 
for viral hepatitis is not mandatory). 
12. Known diagnosis of human immunodeficiency virus (HIV) infection 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 210 
Protocol No. CLDK378A2407 
 
 
(HIV testing is not mandatory). 
13. Patient receiving treatment with medications that meet one of the 
following criteria and that cannot be discontinued at least 1 week prior 
to the start of treatment with ceritinib and for the duration of the study: 
• 
Strong inhibitors or strong inducers of CYP3A4/5 
• 
Medications with a low therapeutic index that are primarily 
metabolized by CYP3A4/5 and/or CYP2C9 
• 
Medication with a known risk of prolonging the QT interval or 
inducing Torsades de Pointes 
14. Patient who are currently receiving treatment with warfarin sodium 
(Coumadin®) or any other coumarin-derivative anticoagulants. 
15. Patient receiving unstable or increasing doses of corticosteroids. 
• 
If patients are on corticosteroids for endocrine deficiencies or 
tumor-associated symptoms (non-CNS), dose must have been 
stabilized (or decreasing) for at least 5 days before first dose of 
study treatment. 
16. Patient receiving treatment with any enzyme-inducing anticonvulsant 
that cannot be discontinued at least 1 week before first dose of study 
treatment, and for the duration of the study. Patients on non-enzyme- 
inducing anticonvulsants are eligible. 
17. Major surgery (e.g., intrathoracic, intra-abdominal or intra-pelvic) 
within 4 weeks prior (2 weeks for resection of brain metastases) to 
starting study treatment or who have not recovered from side effects 
of such procedures. 
18. Pregnant or nursing (lactating) women 
19. Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless they are using 
highly effective methods of contraception during dosing and for 3 
months after stopping medication. Highly effective contraception 
methods include: 
• 
Total abstinence (when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception 
• 
Female sterilization (have had surgical bilateral oophorectomy 
with or without hysterectomy), total hysterectomy, or tubal ligation 
at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level 
assessment 
• 
Male sterilization (at least 6 months prior to screening). The 
vasectomized male partner should be the sole partner for that 
subject 
• 
Use of oral, injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or 
intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), 
for example hormone vaginal ring or transdermal hormone 
contraception. 
• 
In case of use of oral contraception women should have been 
stable on the same pill for a minimum of 3 months before taking 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 220 
Protocol No. CLDK378A2407 
 
 
study treatment. 
20. Sexually active male unless they use a condom during intercourse 
while taking the drug and for 3 months after the last dose of ceritinib 
treatment. Male patients should not father a child for 3 months after 
the last dose of ceritinib treatment. A condom is required to be used 
also by vasectomized men in order to prevent delivery of the drug via 
seminal fluid 
21. Patient has other severe, acute, or chronic medical or psychiatric 
conditions including uncontrolled diabetes mellitus or laboratory 
abnormalities that in the opinion of the investigator may increase the 
risk associated with study participation, or that may interfere with the 
interpretation of study results. 
Investigational and 
reference therapy 
Ceritinib (LDK378) 750 mg once daily oral. No reference therapy will be 
administered in this trial. 
Efficacy assessments 
Efficacy assessments will be performed every 8 weeks: 
Primary objective: 
To assess Disease Control Rate (DCR) associated with ceritinib 
treatment based on local investigator assessment 
For patients with solid tumors the assessment criteria will be RECIST 1.1. 
For GBM, RANO and RECIST 1.1 criteria will apply. For hematologic 
tumors, Cheson response criteria will apply. DCR will include complete 
response (CR), partial response (PR) or stable disease (SD) at 16 weeks 
since the start of the treatment. The DCR responses will need to be 
confirmed at least 4 weeks later by the same method. 
Secondary objectives: 
• 
To assess Overall Response Rate (ORR) based on local 
investigator assessment 
• 
To assess Duration of Response (DOR) based on local investigator 
assessment 
• 
To assess Time to Response (TTR) based on local investigator 
assessment 
• 
To assess Progression-Free Survival (PFS) based on local 
investigator assessment 
Safety assessments 
Adverse Events (AEs) using Adverse Events CTCAE 4.03 including: 
• 
Serious AEs (SAEs) 
• 
Laboratory profiles 
• 
hematology 
• 
biochemistry 
• 
urinalysis 
• 
coagulation 
• 
pregnancy test (females) 
• 
hormones (males only) 
• 
Physical examination 
• 
Vital signs 
• 
Electrocardiograms (ECG) 
• 
WHO Performance Assessment 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 230 
Protocol No. CLDK378A2407 
 
 
Data analysis 
The primary endpoint of this study is to assess Disease Control Rate 
(DCR) defined as the proportion of patients with CR, PR and stable 
disease (SD) lasting at 16 weeks since the start of treatment based on 
local investigator’s assessment according to RECIST 1.1., RANO or 
Cheson hematological criteria. Responses must be confirmed at least 4 
weeks later by the same method. DCR will be analyzed using Bayesian 
hierarchical model. Posterior summary (point estimate and 95% credible 
interval) and posterior probability of not being clinically meaningful for 
each arm (tumor type) will be calculated. For a specific arm, a POC about 
treatment with ceritinib will be declared if both of the following conditions 
are met: 
• 
Observed DCR > clinically meaningful threshold (Table 1 see 
Section 10 for more details) 
• 
Posterior probability of not being clinically meaningful (Table 1 see 
Section 10 for more details) is less than 20% 
As a sensitivity analysis DCR and its 95% confidence interval will also be 
provided based on exact binomial distribution. 
Statistical analysis of the secondary endpoint: 
The secondary endpoints of this study are: 
ORR (investigator-assessed); defined as the proportion of patients with 
best overall response of complete response (CR) or partial response (PR) 
based on local investigator’s assessment according to RECIST 1.1, 
RANO or Cheson hematological criteria. 
ORR will be analyzed using Bayesian hierarchical model. Posterior 
summary (point estimate and 95% credible intervals) and posterior 
probability of different categories of interests will be provided. 
As a sensitivity analysis ORR and its 95% confidence interval will also be 
provided based on exact binomial distribution. 
For each tumor type, duration of response (DOR) and time to response 
(TTR) will be described in tabular and graphical format using Kaplan- 
Meier methods. The Kaplan-Meier estimate of the distribution function will 
be constructed. The number of patients at risk at certain time points will 
be shown on the plot. The estimated median (in weeks) along with 95% 
CIs, as well as 25th and 75th percentiles will be reported. 
Median PFS which will be estimated using the Kaplan-Meier method and 
will be presented along with 95% confidence interval in each disease 
group. 
Interim Analysis 
Interim analysis for each arm (tumor type) will be performed for decision 
making (early stopping or continuation of recruitment) when a predefined 
number of patients ( 5 for IMT and 10 for all other tumor types) have 
completed 16 weeks of treatment with ceritinib and have their anti-tumor 
activity assessed. Responses observed at week 16 (CR or PR) must be 
confirmed by a subsequent assessment at least 4 weeks later. The 
reduced number of patients (5) in the IMT arm is based on the rare 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 240 
Protocol No. CLDK378A2407 
 
 
incidence of this tumor type. All available data will be used for analysis at 
the interim. However, a decision will be made only for arm with minimum 
number of pre-specified patients (a minimum of 5 patients in IMT arm or a 
minimum of 10 patients for any of the other arm). For a specific arm, a 
decision will be made based on the calculated probability as given below: 
• 
If the posterior probability of being clinically meaningful (Table 1) is 
less then 20% then recruitment will be stopped in that arm 
• 
Otherwise, recruitment will be extended for at least 10 more patients 
in that arm (including IMT). 
Depending on enrollment and follow-up, there may be multiple interim 
analyses. 
Sample size calculation: 
The study will enroll patients in 5 parallel arms from at least 4 tumor 
types, with each tumor type having different cutoff for being clinically 
meaningful as shown on Table 1. The 5th arm will enroll any other ALK+ 
tumor. If there are minimum 5 patients of the same tumor type in the “Any 
other ALK+ tumor” arm, then a separate arm will be opened for that 
specific tumor type. The study plans to enroll a minimum of 5 patients in 
IMT arm and a minimum of 10 patients in each of the other 4 arms. The 
primary analysis will be performed separately for each arm when both 
initial accrual and the accrual following-up the interim analysis are 
complete in an arm. For each of the arm the effect of ceritinib is defined 
as clinically meaningful based on the threshold for observed DCR (Table 
1). 
Table 1: Type of diseases of interest with definition of being 
clinically meaningful 
Disease 
Code 
Arm (Tumor 
Type) 
#Patients† 
at Interim 
DCR Not 
Clinically 
meaningful 
DCR 
Clinically 
meaningful 
T1 
Anaplastic 
large cell 
lymphoma 
(ALCL) 
10 
<40% 
≥50% 
T2 
Inflammatory 
myofibroblastic 
tumor (IMT) 
5 
<20% 
≥30% 
T3 
Glioblastoma 
10 
<10% 
≥20% 
T4 
Inflammatory 
breast cancer 
10 
<10% 
≥20% 
T5 
Any other 
ALK+ tumor 
tumor) 
10 
<10% 
≥20% 
† Extend recruitment for at least 10 more patients in each arm 
according to IA outcome [p(clinically meaningful)>20%]. 
A Bayesian hierarchical model (BHM) will be applied to estimate the 
DCR, for each arm, and its 95% credible interval and posterior probability 
of being clinically meaningful. The proposed model is a modified version 
of standard model which assumes full exchangeability (similarity) 
between the disease-specific response rates. The proposed model is 
robust as it allows for non-exchangeability (non-similarity) for each 
disease group. This approach allows the data to determine the strength of 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 250 
Protocol No. CLDK378A2407 
 
 
borrowing across the strata in a flexible way. 
Allowing for an estimated attrition rate of 10%, a total of approximately 
106 patients will be enrolled in order to get 95 patients for the final 
analysis. 
Key words 
Anaplastic large cell lymphoma (ALCL); Inflammatory myofibroblastic 
tumor (IMT); glioblastoma multiforme (GBM); inflammatory breast cancer 
(IBC); ALK inhibitor; ALK+ tumor, ceritinib 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 260 
Protocol No. CLDK378A2407 
 
 
 
1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Anaplastic lymphoma kinase gene (ALK) has emerged as a strong biomarker and therapeutic 
target for cancer patients who may benefit from ALK-targeting agents. Aberrant ALK has 
oncogenic potential and activates variety of intracellular signaling pathways. The key 
signaling pathways are (1) Janus kinase 3 (JAK3)-STAT3 intracellular pathway; (2) 
phosphoinositide 3-kinase (PI3K)-Akt pathway and (3) RAS extracellular signal regulated 
(ERK) pathway (Enrique 2011). Overexpression and activation of ALK mediate many 
downstream effects that may contribute to transformation, increased proliferation, and 
increased survival. 
Activation of ALK appears to be a molecular oncogenic event that is seen in most diverse 
tumors such as NSCLC, ALCL, IMT, neuroblastoma, or other hematologic and solid tumors. 
All tumors bearing genetic aberrations (e.g. ALK mutations, amplification, translocation) or 
showing overexpression of the ALK protein, might potentially benefit from ALK inhibitors. 
 
Anaplastic large cell lymphoma (ALCL) 
The ALK gene was first described in anaplastic large cell lymphoma (ALCL) an aggressive 
mature T-cell lymphoma that accounts for 10%–15% and 2%–8% of non-Hodgkin 
lymphomas in children and adults, respectively (Merkel 2011). ALK was 
identified as the gene on chromosome 2 fused to the NPM gene in the t(2;5)(p23;Q35) 
translocation. Other fusion partners have been described in ALCL (e.g. TFG, MSN, CLTC 
and ATIC), but NPM-ALK accounts for more than 75-80% of all ALK+ ALCL cases 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 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). 
The first-line therapy for adult patients with systemic ALCL is a multi-agent, anthracycline- 
containing regimen, in most cases CHOP (cyclophosphamide, doxorubicin, vincristine, and 
prednisone). In patients with refractory or relapsed ALCL, there is no established standard 
treatment and therapeutic options are limited, as only a few agents have shown consistent 
activity. Despite various protocols, ALCL in pediatric and adolescent patients still has a 
relapse rate of 25%–30%. The therapies for refractory or relapsed disease are highly variable 
with no established standard (Le Delay 2008). ALCL patients are encouraged to participate in 
clinical trials to establish standard treatment in the setting of refractory or relapsed disease as 
well as to develop new therapeutic strategies (Xueyan 2014) 
ALK activation by translocation, amplification, point mutations, or other genetic 
rearrangements has since been identified in other malignancies. 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 270 
Protocol No. CLDK378A2407 
 
 
Non-small cell lung cancer (NSCLC) 
About 2-8% of non-small cell lung cancers (NSCLC) carry activating translocations of ALK, 
most commonly an EML4-ALK translocation created by an intrachromasomal inversion in 
chromosome 2 (Soda 2007, Scagliotti 2012, Takeuchi 2009). Two ALK inhibitors have been 
developed for treatment of NSCLC. 
• Crizotinib (Xalcori™) was approved in the USA by the Food and Drug Administration 
(FDA) in August 2011 for the treatment of patients with locally advanced or metastatic 
non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)+ as 
detected by an FDA-approved test., primarily based on response rates of 50% from the 
first 136 patients with ALK-rearranged NSCLC enrolled on PROFILE 1005 and 
secondarily on a response rate of 61% from the first 119 patients with ALK-rearranged 
NSCLC enrolled on PROFILE 1001 (Camidge 2011). Crizotinib has since been approved 
in many other countries worldwide. 
• Ceritinib (Zykadia ™) was approved by the FDA in April 2014 for the treatment of 
patients with anaplastic lymphoma kinase-positive (ALK+) metastatic non-small cell lung 
cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approval of 
ceritinib is based on a pivotal trial that included 163 patients with metastatic ALK+ 
NSCLC who progressed on or were intolerant to treatment with crizotinib. Among 
previously-treated patients, ceritinib achieved an overall response rate (ORR) of 54.6% 
[95% CI, 47-62%] and a median duration of response (DOR) of 7.4 months [95% CI, 5.4- 
10.1 months]. (Shaw 2014). Ceritinib has been approved and is undergoing regulatory 
approval in many other countries worldwide. 
 
Inflammatory myofibroblastic tumors (IMT) 
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). Several fusion partners have been 
identified. Two related tropomyosin genes TPM3 and TPM4 are the most common 
translocation partners for ALK in IMT and together with other fusion genes (e.g. CARS-ALK, 
RANBP2, CTLC1-ALK, SEC31L) constitutively activate ALK and induce transformation in 
cell  lines  and  animal  models  (Lawrence  2000,  Ladanyi  2000,  Giuriato  2007).   
Butrynski et al (2010) reported sustained partial response to an ALK inhibitor (PF-02341066, 
crizotinib) in ALK+ IMT patient, whereas no observed activity was found in another patient 
without ALK translocation. Cessna described abnormalites of chromosome 2p23 with 
expression of p80 and ALK1 in up to 40% of IMT’s (Cessna 2002). These tumors may exhibit 
aggressive local behavior and rarely metastasis. 
The primary therapeutic approach for IMT is surgery if the anatomic location is amenable to a 
resection. If surgery is not possible, these lesions are typically treated with a variety of 
regimens including radiation and chemotherapeutic agents. Surgery as the standard of 
treatment, may be followed up by adjuvant chemotherapy and/or radiotherapy depending of 
the tumor aggressivness. Adjuvant therapy targeted at the more aggressive variants may prove 
to be warranted with the better understanding of the underlying genetic alterations. 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 280 
Protocol No. CLDK378A2407 
 
 
Glioblastoma (GBM) 
Human glioblastoma (GBM) is highly invasive and particularly aggressive primary brain 
tumor. Most patients diagnosed with this tumor die within one year from the diagnosis and 
only 5% survive more than 5 years despite aggressive therapies (CBTRUS 2011). Over the 
last decade, a variety of different treatments were explored with very limited success. Major 
challenges in therapy of GBM are associated with the location of the disease, its complex and 
heterogeneous biology and the blood-brain barrier that consequently prevents drug delivery to 
the brain parenchyma and the tumor itself (Kesari 2011). 
ALK overexpression was found in human glioblastoma (GBM) relative to normal brain and 
ALK mRNA was detected in GBM cell lines (Powers 2002). In Glioblastoma the growth 
factor pleiotropin (PTN) activates ALK signaling and the PTN-ALK axis drives tumor growth 
suggesting that inhibition of ALK could be good therapeutic approach. 
After initial therapy fails, therapeutic options are limited and generally not effective. There is 
no standard of care for recurrent GBM. Median time to progression at this stage is about 10 
weeks and overall survival ~30 weeks (Wong et al 1999). Chemotherapy options have been 
and continue to be quite limited. Many agents have been used in this setting with rather 
disappointing results. Bevacizumab, an anti-VEGF inhibitor, has been approved by FDA for 
use in recurrent GBM in 2009 (Cohen et al 2009). The search for new agents and better 
clinical trial designs are highly recommended (Mrugala et al 2013) 
 
Inflammatory breast cancer (IBC) 
Inflammatory breast carcinoma (IBC) is a relatively rare (5% of all cases) form of breast 
cancer with distinct clinicopathologic features (Anderson 2003). IBC is characterized by an 
early age at diagnosis and poor survival outcome due to an aggressive clinical behavior. 
Despite advances in the multidisciplinary treatment, the prognosis is much less favorable than 
for other types of BC, with a 5-year survival ranging from 30% to 50% (Key 2001). There are 
currently no standard IBC-specific treatments for patients with advanced disease; therefore, 
enrollment in available clinical trials, including those of novel targeted therapies, is strongly 
recommended for IBC patients. The usual treatment of IBC is chemotherapy followed by 
surgery to remove the cancer. Radiation follows surgery. The use of anthracyclines (such as 
doxorubicin/Adriamycin® and epirubicin/Ellence®) and taxanes (such as paclitaxel/Taxol® 
and docetaxel/Taxotere®) as chemo drugs for IBC have been shown to improve outcomes. If 
the cancer is HER2-positive trastuzumab (Herceptin®) is given as well. If the cancer is 
hormone-receptor negative and HER2-negative (known as triple negative), the chemo drug 
carboplatin may be added to paclitaxel. 
EML4-ALK fusion was found in 2.4% of breast cancers (Lin 2009). The presence of a mild 
increase in copy numbers has been noted in IBC. This is mostly due to increased copies of 
chromosome 2 rather than ALK gene amplifications (Krishnamurthy 2013). Other studies 
showed that ALK is amplified in most inflammatory breast cancer cases and crizotinib caused 
tumor shrinkage in mouse xenograft IBC (Tuma 2012). Although combined use of 
chemotherapy, surgery, and radiation therapy has somewhat improved disease-free and 
overall survival rates, there is still a strong need for new approaches one of which includes 
targeted systemic therapy. 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 290 
Protocol No. CLDK378A2407 
 
 
Other ALK positive (ALK+) tumors 
ALK activation is found in approximately 10% of neuroblastomas, but in contrast to ALCL 
and NSCLC, ALK activation in neuroblastoma occurs by point mutation (e.g. hotspot and 
gain-of-function  mutations  like  F1174L  and  R1275Q)  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). 
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 embryonal subtype. 
ALK rearrangements were identified in <1% of renal cell cancer (RCC) while ALK copy 
number gain was identified in 10% of RCC (Sukov 2012). ALK gene mutations were found in 
anaplastic thyroid cancer (ATC) with a prevalence of 11% but not in papillary (PTC) and 
follicular thyroid cancers (FTC) (Murugan 2011). TPM4-ALK has been recognized in the 
tumorigenesis of esophageal and other tumor types (Jazzi 2006). Further, translocations 
linking ALK to multiple fusion partners were subsequently identified in other malignancies. 
EML4-ALK fusion was found in 2.4% of colorectal cancer (Lin 2009). 
In summary, the available treatments for the selected ALK+ tumors are scarse, ineffective and 
new treatment modalities to prolong patient’s lives are needed. 
 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of ceritinib 
Ceritinib 
[5-Chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2 
(isopropylsulfonyl) phenyl]-2,4-pyrimidinediamine] is an orally available ALK inhibitor. 
Ceritinib is an approximately 20-fold more potent ALK inhibitor than crizotinib, more 
selective for ALK and does not inhibit MET. 
In addition, ceritinib shows potent antitumor activity in crizotinib-resistant animal models (as 
described below), and the efficacy seen in the Phase I clinical trial in patients (with and 
without previous crizotinib therapy) led to the approval of ceritinib by the FDA under the 
trade name ZYKADIA™ on 29-Apr-2014 for the following indication: 
• “Ceritinib (Zykadia ™) is indicated for the treatment of patients with ALK- 
positive)metastatic non-small cell lung cancer 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: 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 300 
Protocol No. CLDK378A2407 
 
 
ZYKADIA is indicated for the treatment of adult patients with anaplastic lymphoma kinase 
(ALK) positive advanced non-small cell lung cancer (NSCLC) previously treated with 
crizotinib. 
Submissions to other health authorities worldwide have been completed in some countries and 
are underway in others. 
 
1.2.1.1 
Non-clinical experience 
 
1.2.1.1.1 Pharmacology 
Ceritinib inhibits ALK and ALK-mediated signaling pathways in a dose-dependent manner. It 
inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of downstream 
signaling proteins, and proliferation of ALK-dependent cancer cells both in vitro and in vivo. 
Ceritinib is approximately 20-fold more potent than crizotinib in enzymatic inhibition assays 
of ALK kinase activity In a kinase panel of 35 additional enzymes, ceritinib demonstrated a 
high degree of selectivity for ALK inhibition by inhibiting only 2 other kinases (INSR and 
IGF1R) but with approximately 50-fold less potency than ALK inhibition. 
Inhibition of fusion oncogenes NPM-ALK and EML4-ALK in mouse and rat xenograft 
models resulted in inhibition of tumor growth and tumor regression in vivo. Ceritinib was also 
active in cell lines with ALK amplification or expression of activating point mutations. 
 
1.2.1.1.2 Antitumor activity in xenograft models 
Ceritinib is highly active in mouse and rat xenograft models of lung cancer and ALCL that 
carry an ALK rearrangement. In murine xenograft models of H2228 NSCLC and Karpas299 
ALCL cells, ceritinib dosed at 25mg/kg daily, a dose below the maximum tolerated dose 
(MTD) in clinical studies, resulted in complete regression of established tumors. 
Ceritinib also has potent antitumor activity against crizotinib-resistant H2228 NSCLC cell 
lines, including resistant variants carrying I1171T or C1156Y mutations in the ALK kinase 
domain. These data support the hypothesis that ceritinib may be clinically active in ALK- 
rearranged NSCLCs in multiple treatment settings. 
 
1.2.1.1.3 Nonclinical pharmacokinetics (PKs) and metabolism 
In general, ceritinib was moderately absorbed in rats (37%) and monkeys (≥40%). Oral 
bioavailability was complete in fed dogs, suggesting the possible existence of a positive food 
effect. The formulation used in these bioavailability determinations was a 0.5% 
methylcellulose suspension except for the mouse where a solution formulation was used. 
Ceritinib is highly bound to plasma protein (>94%) in all species. Following oral 
administration of [14C] ceritinib to LEH male rats, radioactivity was widely distributed. The 
highest tissue exposures were found in intestine wall, uveal tract, pituitary gland, bile, adrenal 
cortex, harderian gland, liver, spleen, lymph node, lung, kidney, thyroid, bone marrow, 
adrenal medulla and pancreas (25- to 710-fold higher exposure relative to blood). Although 
the brain to blood concentration ratio of drug-related radioactivity was low compared to these 
other tissues with a brain-to-blood exposure (AUCinf) ratio of approximately 15%, it was 
higher than the 3% background associated with brain vasculature at all monitored time points. 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 310 
Protocol No. CLDK378A2407 
 
 
This indicates that drug-related radioactivity crossed the blood-brain barrier. Unchanged 
ceritinib was the major component in feces and bile of intact and bile duct-cannulated rats. In 
the rat, ceritinib underwent oxidation leading to the formation of four oxygenated metabolites 
(designated as M23.6, M30.6, M35.8, and M33.4). In addition, ceritinib underwent sulfation 
leading to M36.8 and oxidation followed by sulfation resulting in the presence of M29.5. 
Ceritinib 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] 
ceritinib, ceritinib -derived radioactivity was excreted predominantly via the fecal route 
(>99%), and renal excretion was a minor pathway for excretion (<1%). Fecal excretion was 
the result of biliary excretion (69%) and gastrointestinal (GI) secretion (31%). Since parent 
drug was the major component in bile and feces after intravenous (i.v.) administration, 
enterohepatic circulation may occur. 
CYP3A4/5 is the major hepatic enzyme metabolizing ceritinib in a human in vitro system. 
The metabolic drug-drug interaction (DDI) potential of ceritinib as an inhibitor was evaluated 
using pooled human liver microsomes. Based on the assessment of clinical significance of in 
vitro results using the appropriate DDI decision tree described in FDA draft DDI guidance 
2012 and EMA DDI guideline 2012, at clinically relevant concentrations, ceritinib is unlikely 
to inhibit CYP1A2, 2B6, 2C8, 2C19 or 2D6. Only CYP2A6, 3A4, 2C9 and possibly CYP2E1 
need to be considered as possible victims of in vivo inhibition by ceritinib. Ceritinib is also a 
time-dependent CYP3A inhibitor (Ki: 1.47 µM and Kinact: 0.0642 min-1), but shows no 
apparent time-dependent inhibition of CYP1A2, 2C9 or 2D6 at ceritinib concentrations of up 
to 50 µM. 
Ceritinib is likely a P-gp, but not BCRP or MRP2 substrate. It does not inhibit P-gp, BCRP or 
MRP2 at concentrations up to 1.5 μM in vitro. 
 
1.2.1.1.4 Safety pharmacology and toxicology 
Ceritinib was evaluated for safety in 2- and 4-week studies in rats and monkeys. The principal 
toxicity induced by ceritinib was a systemic inflammation characterized by increased 
neutrophil counts in the peripheral blood and mixed cell/neutrophilic inflammation of the 
biliopancreatic ducts, pancreas, and/or duodenum. Gastrointestinal toxicity was observed in 
both species characterized by body weight loss, decreased food consumption, emesis 
(monkey), diarrhea, and at high doses, by histopathologic lesions including erosion, mucosal 
inflammation, and foamy macrophages in the duodenal crypts and ampullae of rats and 
monkeys, respectively. The liver (bile duct) was also affected in both species only at the 
highest dose levels studied (100 mg/kg/day in the 2-week studies for both rat and monkeys 
and 50 and 30 mg/kg/day in the 4-week studies in rat and monkeys, respectively), and 
included increases in liver transaminases in a few animals at high doses, and mixed cell 
inflammation, erosion and cytoplasmic vacuolation of the bile duct epithelium. The pancreas 
was a target organ in the rat, but not the monkey, with acinar cell atrophy and mixed cell 
inflammation noted at middle and high doses. Target organ effects showed partial to complete 
recovery during the 4-week non-dosing period. No effects in the rat central nervous system or 
on the respiratory system were observed at single, high doses (100 mg/kg). 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 320 
Protocol No. CLDK378A2407 
 
 
Ceritinib has potent activity on the hERG channel with an IC50 of 0.4 μM. However, there 
were no ceritinib -related effects in vivo in monkeys at doses as high as 100 mg/kg (human 
equivalent dose (HED) of 1950 mg). 
Preclinical studies (in vitro 3T3 NRU assay, refer to [Investigator’s Brochure] indicated a low 
risk of phototoxicity with use of ceritinib. In addition, a preliminary analysis from an in vivo 
ultraviolet local lymph node assay (UV LLNA) demonstrated no phototoxic potential with 
ceritinib. 
 
1.2.1.2 
Clinical experience 
 
1.2.1.2.1 Clinical safety and tolerability 
Ceritinib 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 study [CLDK378X2101], the median 
duration of exposure as of the 31-Oct-2013 cut-off date was 26.9 weeks (range 0.4 to 82.3 
weeks). The most common adverse events (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%). 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 330 
Protocol No. CLDK378A2407 
 
 
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: 31-Oct-2013) 
Ceritinib 
750 mg 
N=255 
Preferred term 
All Grades 
n (%) 
Grade 3/4 
n (%) 
Total 
255 (100.0) 
184 (72.2) 
Diarrhea 
219 (85.9) 
15 (5.9) 
Nausea 
205 (80.4) 
11 (4.3) 
Vomiting 
153 (60.0) 
10 (3.9) 
Alanine Aminotransferase Increased 
110 (43.1) 
68 (26.7) 
Fatigue 
102 (40.0) 
10 (3.9) 
Abdominal Pain 
91 (35.7) 
3 (1.2) 
Decreased Appetite 
87 (34.1) 
2 (0.8) 
Aspartate Aminotransferase Increased 
78 (30.6) 
21 (8.2) 
Constipation 
73 (28.6) 
0 
Cough 
62 (24.3) 
0 
Abdominal Pain Upper 
58 (22.7) 
2 (0.8) 
Dyspnea 
47 (18.4) 
8 (3.1) 
Asthenia 
45 (17.6) 
2 (0.8) 
Blood Alkaline Phosphatase Increased 
45 (17.6) 
13 (5.1) 
Back Pain 
43 (16.9) 
1 (0.4) 
Headache 
41 (16.1) 
3 (1.2) 
Weight Decreased 
39 (15.3) 
4 (1.6) 
Blood Creatinine Increased 
39 (15.3) 
0 
Pyrexia 
38 (14.9) 
0 
Rash 
32 (12.5) 
0 
Insomnia 
31 (12.2) 
0 
Dyspepsia 
26 (10.2) 
1 (0.4) 
Hypokalemia 
26 (10.2) 
11 (4.3) 
Dizziness 
26 (10.2) 
0 
Dose reductions due to AEs occurred in 58.8% of patients treated with ceritinib 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 leading to 
study drug discontinuations occurred in 10.2% of patients treated with ceritinib at the 750 mg 
dose. The most frequent AEs leading to study drug 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 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 340 
Protocol No. CLDK378A2407 
 
 
5% of patients, consisting of: pneumonia (4 patients), respiratory failure, ILD/pneumonitis, 
pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary 
tuberculosis, cardiac tamponade, and sepsis (1 patient each). Adverse events of special  
interest (AESIs) include hepatotoxicity, ILD /pneumonitis, QT interval prolongation, 
bradycardia, hyperglycemia gastrointestinal toxicity (nausea, vomiting and diarrhea) and 
pancreatitis (including lipase and amylase elevations), refer to Section 8.1.3 and 
[Investigator’s Brochure]. 
 
1.2.1.2.2 Clinical efficacy 
As of 31-Oct-2013, data from the [Study CLDK378X2101] demonstrated a high rate of rapid 
and durable responses with ceritinib in 246 ALK-positive  NSCLC  patients  treated in  the 
750 mg dose group (RD). In these patients the overall response rate (ORR) was 58.5% (95% 
CI: 52.1, 64.8) based on investigator assessment (Table 1-2). Among the 144 ALK-positive 
NSCLC patients with a confirmed complete response (CR) or partial response (PR) based on 
investigator assessment, 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 investigator assessment, the median PFS was 8.21 months (95% CI: 6.70, 
10.12) with 53.3% of the patients censored. 
Importantly, ceritinib showed this level of high anti-cancer activity regardless of prior ALK 
inhibitor status(i.e., whether or not the patient received previous treatment with an ALK 
inhibitor). A high ORR of 54.6% and 66.3% was observed in patients treated with a prior 
ALK inhibitor and in ALK inhibitor naïve patients, respectively, by investigator assessment 
(Table 1-2). Rapid responses were observed in patients regardless of prior ALK inhibitor 
status, 6.1 weeks (range: 4.6 to 24.1) in 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 in the latter group was not reached in ALK inhibitor naïve patients, 
however the 12-month DOR rate was 65.2% (95% CI: 46.4, 78.8) The estimated median PFS 
was 6.90 months (95% CI: 5.39, 8.41) in patients treated with a prior ALK inhibitor, while the 
median PFS was not reached in ALK inhibitor naïve patients (95% CI: 8.31, NE) Finally, 
ceritinib demonstrated activity in patients with brain metastase at baseline. Among the 98 
patients with brain metastasis who had received prior ALK-inhibitor treatment, the ORR was 
50% (95% CI: 39.7, 60.3), DOR was 6.9 months (95% CI: 4.8, 8.5), and PFS was 6.7 months 
(95% CI: 4.9, 8.4). For additional details, refer to [Investigator’s Brochure]. 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 350 
Protocol No. CLDK378A2407 
 
 
Table 1-2 
Summary of best overall response based on investigator assessment 
in NSCLC patients in the 750 mg dose group, by prior ALK inhibitor 
status (Full Analysis Set NSCLC 750 mg) (Cut-off date: 31-Oct-2013) 
 
NSCLC with prior 
ALK inhibitor 
NSCLC ALK 
inhibitor naïve 
All NSCLC 
N=163 
N=83 
N=246 
n (%) 
n (%) 
n (%) 
Best overall response 
Complete response (CR) 
2 (1.2) 
1 (1.2) 
3 (1.2) 
Partial response (PR) 
87 (53.4) 
54 (65.1) 
141 (57.3) 
Stable disease (SD) 
32 (19.6) 
19 (22.9) 
51 (20.7) 
Progressive disease (PD) 
16 (9.8) 
0 
16 (6.5) 
Unknown 
26 (16.0) 
9 (10.8) 
35 (14.2) 
Overall response rate (ORR) 
(CR or PR), n (%) 
89 (54.6) 
55 (66.3) 
144 (58.5) 
95% CI 
(46.6-62.4) 
(55.1-76.3) 
(52.1-64.8) 
This table presents data for all patients with ALK-positive NSCLC in the 750 mg treatment dose group, 
FAS-NSCLC 750 mg group 
Best overall response is based on investigators assessment of disease status using RECIST 1.0 
criteria 
CR and PR are confirmed by repeat assessments performed not less than 4 weeks after the criteria for 
response are first met. 
Exact binomial 95% Confidence Interval 
 
 
1.2.1.2.3 Clinical pharmacodynamics 
Data are not available from the ongoing clinical studies. 
 
1.2.1.2.4 Clinical pharmacokinetics 
In  adult  patients  with   tumors   characterized   by   genetic   abnormalities   in   ALK 
([Study CLDK378X2101])   and   in   healthy   subjects   ([Studies CLDK378A2101],    
[Study CLDK378A2104] and [Study CLDK378A2106]), single-dose pharmacokinetics (PK) 
of ceritinib in humans has the following features: (1) ceritinib 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, ceritinib 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 AUC last increased dose- 
proportionally following single oral administration of ceritinib across the 50 to 750 mg dose 
groups in patients. (3) moderate to high variability in ceritinib PK parameters has been 
observed in both healthy subjects and patients. Following single oral doses of 450 to 750 mg 
in healthy subjects when ceritinib 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. 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 360 
Protocol No. CLDK378A2407 
 
 
Multiple-dose PK of ceritinib following repeated daily oral dosing in patients has the 
following features: (1) following ceritinib 750 mg once daily dosing, steady-state was reached 
by approximately 15 days with a geometric mean accumulation ratio (as assessed by AUCtau) 
of 6.2 after 3 weeks; (2) ceritinib 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 ceritinib 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 ceritinib. In contrast with single dose data, Ctrough on Cycle 2 Day 1 after 
repeated daily dosing increased with dose in a greater than dose-proportional manner. 
In the human ADME study [Study CLDK378A2105], the majority of the radioactivity dose in 
humans was eliminated in the feces (mean: 91.0%) with only a minor amount eliminated in 
the urine (mean: 1.3%) following a single oral dose of 750 mg of [14C] ceritinib to healthy 
male subjects. The mean percentage of the dose eliminated in the feces as unchanged ceritinib 
was 68.0% while all the metabolites were present at low levels, with no individual metabolite 
contributing greater than 2.3% to the radioactivity AUC. Hepatic metabolism and potentially 
biliary excretion and GI secretion all contribute to ceritinib elimination in humans while the 
kidney appears to play a negligible role. The primary biotransformation pathways of ceritinib 
that were observed included mono-oxygenation, O-dealkylation, and N-formylation. 
Unchanged ceritinib was the most abundant drug-related component found in both the plasma 
and excreta. 
CYP3A was identified as the major CYP isozyme responsible for the metabolism of ceritinib 
in humans. An inhibition DDI study conducted in healthy subjects 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 ceritinib by 1.2-fold and 2.9-fold, respectively, compared with 
ceritinib alone [Study CLDK378A2104]. These results demonstrated that concurrent use of 
strong CYP3A inhibitors may markedly increase ceritinib exposure and should be avoided. 
An induction DDI study conducted in healthy subjects 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 ceritinib by 44% and  70%,  respectively,  compared  with  ceritinib  alone  
[Study CLDK378A2106]. These results demonstrated that concurrent use of strong CYP3A 
inducers may markedly decrease ceritinib exposure and should be avoided. 
A food effect study was conducted in healthy subjects [Study CLDK378A2101]. Compared to 
the fasted state, a low-fat meal (approximately 330 calories and 9 grams of fat) increased 
Cmax and AUCinf of a single oral dose of ceritinib (500 mg) in healthy subjects by 43% and 
58%, respectively, whereas a high-fat meal (approximately 1000 calories and 58 grams of fat) 
increased Cmax and AUCinf by 41% and 73%, respectively. 
To further clarify if low fat content has an impact on the extent of ceritinib absorption, a food 
effect assessment with a very low-fat light snack (containing approximately 100-300 calories 
and 1.5 grams of fat) was also explored in a relative bioavailability study conducted in healthy 
subjects [Study CLDK378A2108]. PK data from the light snack cohort showed that when a 
single 750 mg oral dose of ceritinib was administered with a light snack, the Cmax and 
AUCinf increased by 45% and 54% respectively, compared to the fasted condition. This 
magnitude of increase is similar to that caused by a low-fat meal as described in Study 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 370 
Protocol No. CLDK378A2407 
 
 
CLDK378A2101, suggesting that even a very low-fat meal could lead to a clinically 
meaningful LDK378 exposure increase. 
Risk and benefits 
Overall benefit-risk 
Ceritinib dosed at 750 mg once daily has remarkable anti-tumor activity and induces a high 
rate of rapid and durable responses and prolonged PFS in patients with advanced, ALK- 
positive NSCLC, regardless of whether they had been previously treated with an ALK 
inhibitor or were ALK inhibitor naïve. The substantial anti-tumor activity and resulting 
clinical benefit combined with the clinically manageable safety profile of ceritinib strongly 
support a positive benefit/risk balance for ALK-positive NSCLC patients. 
 
Efficacy 
Patients with prior ALK inhibitor treatment: ALK-positive NSCLC patients previously 
treated with crizotinib who have progressed and patients intolerant to crizotinib have no 
effective treatment options, have a dismal prognosis, and represent a population with a high 
unmet medical need. In ALK-positive NSCLC patients failing treatment with crizotinib, 
independent from the resistance mechanism involved, ALK translocation is still present and is 
still the oncogenic driver in almost all of the cases. Chemotherapy is not expected to provide a 
meaningful clinical benefit in these patients, as was recently demonstrated in a Phase III study 
(PROFILE 1007) of crizotinib vs. chemotherapy in the second-line setting (Shaw et al 2013). 
In ALK-positive NSCLC patients previously treated with an ALK inhibitor and multiple prior 
lines of anti-neoplastic therapy, based on an independent review of tumor assessments, as of 
31-Oct-2013, the response rate was 45.1% (95% CI: 37.1 - 53.3) and the median DOR was 
7.1 months (95% CI: 5.6 – NE). The median PFS was 6.7 months (95% CI: 5.5 - 7.7) in Study 
[CLDK378X2101]. The median PFS is similar (overlapping 95% CIs) to that reported for 
crizotinib in the second-line setting (7.7 months (95% CI: 6.0 - 8.8)) and similar or better than 
that  reported  for  chemotherapy  (4.2  months  (95%  CI:  2.8  -  5.7)  with  pemetrexed  and 
2.6 months (95% CI: 1.6 - 4.0) with docetaxel) in the PROFILE 1007 study (Shaw et al 2013) 
for patients with locally advanced or metastatic ALK-positive NSCLC who had received prior 
treatment with one platinum-containing chemotherapy regimen. Therefore, ceritinib fulfills an 
existing unmet medical need. 
The efficacy of ceritinib seen in Study [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 ceritinib in ALK-inhibitor naïve patients was not 
evaluable (95% CI: 13.7 - NE) as the majority of patients were ongoing without an event at 
the time of the data cut-off. 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 380 
Protocol No. CLDK378A2407 
 
 
Overall, these data suggest that ceritinib as a first-line ALK inhibitor treatment has 
remarkable anti-tumor activity and induces a consistently high rate of durable responses in 
ALK inhibitor naïve patients. 
 
Safety 
The safety profile of ceritinib is manageable (Section 1.2.1.2), with a low rate of AEs leading 
to discontinuation. Furthermore, patients’ perception of their quality of life was maintained or 
slightly improved with ceritinib treatment. The most common AEs were gastrointestinal 
(diarrhea, nausea, vomiting); increases in transaminases, decreased appetite, fatigue; 
abdominal pain, and constipation were also seen in ≥ 25% of patients. These AEs can be 
managed with symptomatic treatment and/or dose reductions or interruptions; only 8.8% of 
patients discontinued study drug due to an AE. No clinically meaningful differences in the 
safety profile were observed between ALK-positive NSCLC patients previously treated with 
an ALK inhibitor and ALK inhibitor naïve patients. 
The risks identified with ceritinib treatment include hepatotoxicity, interstitial lung disease 
(ILD)/pneumonitis, QT interval prolongation, bradycardia, hyperglycemia, gastrointestinal 
toxicity (nausea, vomiting and diarrhea) and pancreatitis (including lipase and amylase 
elevations) (Section 8.1.3). These risks can be managed and ameliorated by early diagnosis 
and dose adjustment/interruption, or permanent discontinuation. 
 
Risk management during study conduct 
In order to manage the risks associated with ceritinib treatment, specific dose modifications 
and stopping rules during study conduct are described in the protocol. For patients who do not 
tolerate the initial protocol-specified dose, dose adjustments are provided in order to allow the 
patients to continue the study treatment (Section 6.3 and Table 6-2). Patients whose treatment 
is temporarily interrupted or permanently discontinued due to a study drug related AE or an 
abnormal laboratory value must be followed until resolution or stabilization of the event, 
whichever comes first, including all study assessments appropriate to monitor the event. 
In addition, a thorough post-treatment safety follow-up is included (Section 7.2.4.1). Patients 
may voluntarily withdraw from study treatment at any time or on the advice of the 
investigator if he/she believes that continuation would be detrimental to the patient’s well- 
being. When the patient discontinues from study treatment, an End of Treatment (EOT) visit 
must be performed as soon as possible and within 7 days of the last dose of ceritinib. Patients 
will also be contacted for the safety follow-up 30 days after their last dose of ceritinib to 
determine if they have experienced any new AEs and/or to follow resolution of ongoing AEs. 
Detailed information on allowed and prohibited concomitant medications is provided in 
Section 6.3. In vitro drug metabolism studies show that the metabolism of ceritinib is 
mediated by CYP3A4/5. Appendix 1 contains several tables listing medications that are 
prohibited, permitted or to be used with caution during treatment with ceritinib. Prohibited 
medications should be discontinued at least 1 week prior to the start of treatment  with 
ceritinib (see exclusion criteria #13). 
Recommended guidelines for prophylactic or supportive treatment for expected toxicities, 
including management of study-drug induced AEs, are extensively described in Section 6.2.8. 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 390 
Protocol No. CLDK378A2407 
 
 
Furthermore, regarding adverse events of special interest (see Section 8.1.3): 
• Hepatotoxicity: cases of hepatotoxicity occurred in less than 1% of patients treated with 
ceritinib in clinical studies. Increases to grade 3 or 4 ALT elevations were observed in 
25% of patients receiving ceritinib. Concurrent elevations in ALT >3xULN and total 
bilirubin >2xULN, with normal alkaline phosphatase, occurred in less than 1% of patients 
in clinical studies. The majority of cases were manageable with dose interruption and/or 
dose reduction. Few events required discontinuation of ceritinib. Patients will be closely 
monitored by regular laboratory testing and related signs and symptoms. Risk to patients 
will also be minimized by restricting study enrollment to subjects with laboratory values 
for AST, ALT, ALP and bilirubin below certain thresholds (see inclusion criteria #8). 
• Interstitial lung disease/pneumonitis: severe, life-threatening, or fatal interstitial lung 
disease (ILD)/pneumonitis have been observed in patients treated with ceritinib in clinical 
studies. Most cases improved or resolved with interruption of ceritinib. Patients will be 
monitored for symptoms such as shortness of breath, cough or fever. Risk to patients will 
be minimized by excluding from study enrollment any patient with a history of interstitial 
lung disease or interstitial pneumonitis, including clinically significant radiation 
pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention) 
(see exclusion criteria #8). 
• QT interval prolongation: QTc prolongation has been observed in clinical studies in 
patients treated with ceritinib, which may lead to an increased risk for ventricular 
tachyarrhythmias (e.g., Torsade de pointes) or sudden death. A pharmacokinetic analysis 
suggested that ceritinib causes concentration-dependent increases in QTc. Repeated ECG 
tracings will be performed throughout the study to closely monitor cardiovascular safety. 
Risk to patients will also be minimized by excluding from study enrollment those patients 
with clinically significant, uncontrolled heart disease and/or a recent cardiac event (within 
6 months), including a corrected QT (QTcF) > 470 ms using Fridericia’s correction on the 
screening ECG (see exclusion criteria #10). 
• Bradycardia: asymptomatic cases of bradycardia have been observed in patients treated 
with ceritinib in clinical studies. Repeated ECG tracings will be performed throughout the 
study to closely monitor cardiovascular safety. Risk will also be minimized by monitoring 
concomitant use of other agents known to cause bradycardia (e.g., beta-blockers, non- 
dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. 
Heart rate and blood pressure will also be monitored regularly during the study. 
• Hyperglycemia: events of hyperglycemia (all grades) have been reported in less than 10% 
of patients treated with ceritinib in clinical studies; 5% of patients reported a grade 3/4 
event. The risk of hyperglycemia was higher in patients with diabetes mellitus and/or 
concurrent steroid use. Patients will be closely monitored throughout the study for any 
signs and symptoms related to elevated blood glucose levels. Risk will be minimized by 
including subjects with fasting plasma glucose levels ≤ 175 mg/dL (≤ 11.1 mmol/L) at 
screening (see inclusion #8). 
• 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 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 400 
Protocol No. CLDK378A2407 
 
 
managing patients using standards of care, including anti-diarrheals, anti-emetics, or fluid 
replacement, as indicated. 
• Pancreatitis (including lipase and amylase elevations): in most cases, pancreatic enzyme 
elevations have been mild to moderate, and have typically reversed with interruption of 
ceritinib. Few patients have experienced pancreatitis with severe upper abdominal pain. 
Patients will be monitored closely for any related signs and symptoms. In order to 
minimize the risk to patients during the study, patients with a history of pancreatitis or a 
history of increased lipase or amylase levels that was due to pancreatic disease will be 
excluded. In addition, serum amylase must be ≤2 x ULN and serum lipase must be within 
normal limits at screening. 
 
Conclusion 
The outstanding anti-tumor activity and resulting clinical benefit combined with the 
manageable safety profile of ceritinib strongly support a positive benefit-risk balance for 
ALK-positive NSCLC patients, regardless of whether the patients had received prior ALK 
inhibitor treatment or not. 
The risk to subjects in this trial will be minimized and managed by compliance with the 
eligibility criteria, close clinical monitoring, dose modifications/interruptions and permanent 
discontinuation as required. There may be unforeseen risks with LDK378 which could be 
serious. Refer to the [Investigator’s Brochure] for additional information regarding the safety 
profile of ceritinib. 
 
2 
Rationale 
2.1 
Study rationale and purpose 
2.1.1 
Rationale for the use of ceritinib in ALK-driven tumors 
Ceritinib 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 
cancers. Both in vitro and in vivo experiments have demonstrated that neuroblastoma, ALCL, 
and NSCLC models carrying ALK alterations are frequently dependent on ALK for their 
growth, and are responsive to  treatment  with ALK  inhibitors  (Chiarle  2003,  Soda  2007, 
Li 2011, Galkin 2007). Butrynski et al (2010) reported sustained partial response to the ALK 
inhibitor (PF-02341066, crizotinib) in ALK+ IMT patient, whereas no observed activity was 
found in another patient without ALK translocation. The small study suggests potential 
therapeutic benefit for genetically identified patients with aggressive and life threatening 
tumors with limited treatment options while Mosse et al (2012) demonstrated that the ALK 
inhibitor (PF-02341066, crizotinib) has antitumor activity in children with neuroblastoma and 
ALCL. Bang et al (2010) demonstrated that use of an ALK inhibitor (PF-02341066, 
crizotinib) in heavily pretreated EML4-ALK expressing non-small cell lung cancer patients 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 410 
Protocol No. CLDK378A2407 
 
 
resulted in a response rate of >60%. The responses were durable and the safety profile of the 
drug was deemed acceptable. Shaw et al (2014) demonstrated that ALK inhibitor (LDK378, 
ceritinib) was highly active in patients with advanced, ALK-rearranged NSCLC, including 
those who had had disease progression during crizotinib treatment. 
Together, these preclinical and clinical data support evaluation of ceritinib in patients with 
malignancies carrying genetic alterations of ALK. It is therefore reasonable to formulate a 
hypothesis that predefined diverse populations of patients suffering from life threatening 
tumors such as ALCL, IMT, GBM, IBC as well as any other tumor associated with ALK 
dysregulation may be effectively treated with ceritinib. 
 
2.2 
Rationale for the study design 
This is a phase II, open-label, multicenter, parallel multi-arm, clinical trial that will be 
assessing ceritinib as monotherapy in diverse populations of patients with various life 
threatening tumors other than NSCLC. Given the variety of diseases to be treated, the study 
design is exploratory in nature and tumor types have been selected based on the scientific 
rationale of the presence of ALK dysregulation. Antitumor activity of ceritinib in any tumor 
type will be evaluated in a non-comparative single arm to support the POC that inhibition of 
dysregulated ALK activity might prove to be an important antineoplastic intervention for the 
targeted diseases. 
The selected tumors in this study are considered rare based on the low prevalence of the ALK 
dysregulation as recorded in the published literature. Depending on the tumor type, patients 
will be enrolled into one of 5 parallel arms:(Arm 1) ALCL; (Arm 2) IMT; (Arm 3) GBM; 
(Arm 4) Inflammatory Breast Cancer and (Arm 5) Any other ALK+ tumor. If there 5 or more 
patients of the same tumor type in the “Any other ALK+ tumor” arm, then a separate arm will 
be opened for that specific tumor type. Only patients whose tumors harbor ALK genetic 
alteration (and/or overexpression in some diseases) will be enrolled in the study. 
Patients must have received at least one line of prior systemic therapy for recurrent, locally 
advanced and/or metastatic disease and must not be candidates for any alternative therapy. 
They may have progressed or may be intolerant to standard therapy. There will be no 
reference control arm. The study will initially enroll 10 patients in each arm: ALCL; GBM 
and Any other ALK+ tumor. The IMT arm will enroll 5 patients due to the rare incidence of 
this tumor type. 
Interim analysis for an arm will be performed when a predefined number of patients (5 for 
IMT and 10 for all other tumor type) have completed 16 weeks of treatment with ceritinib and 
have their anti-tumor activity assessed. Responses observed at week 16 (CR or PR) must be 
confirmed by a subsequent assessment at least 4 weeks later. An additional 10 patients may be 
enrolled for a given arm (including IMT) subsequent to the interim analysis if the probability 
of the pre-defined clinically meaningful response for the arm is at least 20%. 
Bayesian hierarchical model (BHM) to estimate the DCR for each arm and its 95% credible 
interval and posterior probability of being clinically meaningful will be applied. The proposed 
model is a modified version of standard model (Thall 2003, Chugh 2009) which assumes full 
exchangeability (similarity) between the disease-specific response rates. The total number of 
patients to be enrolled per arm will be based on an adaptive design. The adaptive design will 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 420 
Protocol No. CLDK378A2407 
 
 
be patient-sparing and allow the early closure of non-responding arms and continuation of 
enrollment of arms which show meaningful clinical activity. Approximately 106 patients 18 
years and older are planned to be enrolled. Patients must be diagnosed with a life threatening 
malignancy that have a genetic alteration of ALK (such as a mutation, translocation 
amplification, and/or overexpression in some diseases) and have progressed or are intolerant 
following standard therapy. 
 
2.3 
Rationale for dose and regimen selection 
In the global phase I study CLDK378X2101, where a majority of the patients were diagnosed 
with NSCLC, the MTD and recommended dose for the adult patients 18 years and older for 
the expansion cohorts and future trials was determined to be 750 mg daily (QD). 
The dose escalation phase of the phase I study CLDK378X2101 was completed in May 2012 
(Shaw et al 2014). Fifty-nine patients were treated at the following dose levels: 50 mg (2 
patients), 100 mg (2 patients), 200 mg (3 patients), 300 mg (3 patients), 400 mg (14 patients), 
500 mg (10 patients), 600 mg (10 patients), 700 mg (5 patients), and 750 mg (10 patients). 
DLTs were observed in 6 patients: 
• 400 mg: hypophosphatemia and ALT elevation (1 patient each) 
• 600 mg: diarrhea and dehydration (1 patient each) 
• 750 mg: diarrhea/vomiting (1 patient) and diarrhea/nausea (1 patient) 
Ceritinib 750 mg dose once daily oral is the approved dose and will be used in this study. 
 
2.4 
Rationale for choice of combination drugs 
Not applicable. 
 
2.5 
Rationale for choice of comparators drugs 
Not applicable. 
 
3 
Objectives and endpoints 
This is an efficacy POC study to determine the preliminary anti-tumor activity and safety and 
tolerability of ceritinib in advanced ALK+ solid tumors (other than NSCLC) and ALK+ 
hematologic malignancies. 
 
Primary objective: 
To assess the antitumor activity of ceritinib treatment as measured by Disease Control Rate 
(DCR) based on local investigator assessment. 
Antitumor activity in each arm will be evaluated after 16 weeks of ceritinib treatment and will 
include responses of CR or PR or SD. The primary end point DCR at 16 weeks since the start 
of the treatment is considered clinically meaningful duration of drug activity in the selected 
patient population. 
For patients with solid tumors the assessment criteria will be RECIST 1.1. For GBM, RANO 
and RECIST 1.1 criteria will apply. For hematologic tumors, Cheson response criteria will 


 
 
 
Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 430 
Protocol No. CLDK378A2407 
 
 
apply. DCR will include complete response (CR), partial response (PR) or stable disease (SD) 
at 16 weeks since the start of the treatment. The responses will need to be confirmed at least 4 
weeks later by the same method. 
 
Secondary objectives: 
• To assess the antitumor activity of ceritinib as measured by ORR, DOR, TTR determined 
by investigators 
• To assess the antitumor activity of ceritinib as measured by PFS determined by 
investigators 
• To assess safety and tolerability: 
Hematology, biochemistry, urinalysis, coagulation, pregnancy test and hormones (males 
only); ECG; Performance status; Physical examination, Vital signs; Adverse events 
CTCAE 4.03 will be used to assess events. 
 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 44
4 Protocol No. 
 
 
 
 
 
 
Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
Refer to Section 10.4. 
To assess the antitumor activity of ceritinib as 
measured by DCR determined by investigators 
DCR, defined as the proportion of patients with best overall response of 
CR, PR, or SD ≥ 16 weeks of ceritinib treatment 
Secondary 
Refer to Section 10.5.1. 
1. To assess the antitumor activity of ceritinib 
as measured by ORR determined by 
investigators 
2. To assess the antitumor activity of ceritinib 
as measured by DOR,TTR and PFS 
determined by investigators 
1. ORR, defined as the proportion of patients with a best overall 
response defined as CR or PR; (CR+PR) 
 
2. The following endpoints will be evaluated by investigator assessment 
per RECIST 1.1, RANO and Cheson criteria: 
a. DOR, defined as the time from date of first documented CR or 
PR to date of first documented disease progression or death due 
to any cause 
b. TTR, defined as the time from date of the first dose to date of 
first documented response (CR or PR) 
c. PFS, defined as time from date of the first dose to date of first 
documented disease progression (assessed by investigators per 
RECIST 1.1) or date of death due to any cause 
For GBM, RANO and RECIST 1.1 criteria will apply. For hematologic 
tumors, Cheson response criteria will apply. 
3. To assess the safety profile of ceritinib 
3. ECG, Performance status, Vital signs, Physical examination; AEs 
(assessed by CTCAE 4.03), and laboratory (hematology, 
biochemistry, urinalysis, coagulation, pregnancy test and hormones 
(males only), 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 45
4 Protocol No. 
 
 
 
 
 
Objective 
Endpoint 
Analysis 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 46
8 Protocol No. 
 
 
 
 
 
 
4 
Study design 
4.1 
Description of study design 
This is a Phase II, open-label, multicenter, parallel multi-arm, POC clinical trial that will 
assess anti-tumor activity and safety and tolerability of ceritinib as monotherapy in patients 
with life threatening locally advanced or metastatic solid tumors other than NSCLC and 
hematological malignancies (see Table 4-1) characterized by ALK genetic alteration (and/or 
overexpression in some diseases). 
Patients must have received at least one prior systemic, anti-cancer therapy for locally 
advanced and/or metastatic disease. In addition, patients may have had prior surgery and/or 
radiotherapy and/or adjuvant and/or neoadjuvant systemic therapy. ALCL patients may have 
had a prior autologous stem cell transplant (ASCT). There will be at least 4 different tumor 
types in parallel arms in adult patients: 
 
Table 4-1 
Tumor types of interest 
 
Tumor Types of interest 
1. 
Anaplastic Large Cell Lymphoma (ALCL) 
2. 
Inflammatory Myofibroblastic Tumor (IMT) 
3. 
Glioblastoma (GBM) 
4. 
Inflammatory Breast cancer (IBC) 
5. 
Any other ALK+ tumor 
Locally documented ALK genetic alteration (and/or overexpression in some diseases) 
determined for specific tumor types as by the protocol defined ALK genetic alteration (and/or 
overexpression in some diseases) (see Table 4-2) is acceptable. All patients are required to 
have a pathology report, including the ALK test results, and an archival or fresh tumor tissue 
sample available prior to the first dose of the study treatment for potential retrospective 
confirmation of ALK positivity by a Novartis designated central laboratory if deemed 
necessary. The results from the ALK test report must be entered into the eCRF prior to the 
first dose of the study treatment. 
The confirmation of ALK positivity by the Novartis designated central laboratory is not 
required for enrollment if other inclusion and exclusion criteria are fulfilled Novartis will 
conduct the confirmatory retrospective ALK test if, and at the time considered necessary. The 
tumor samples will be kept in the storage until a decision will be made to perform a 
confirmatory test; at that time selected samples will be shipped to the central laboratory. The 
confirmatory ALK test will be performed before the end of the study. Acceptable archival 
tumor tissue may consist of a formalin fixed paraffin embedded (FFPE) tumor block 
(preferred) or at least 5, or more slides 4-5 μm thick. The minimum number of slides is 
indicated in order to have sufficient material for ALK determination. If a tumor block is 
provided, the remaining tissue will be returned to the site upon request. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 47
8 Protocol No. 
 
 
 
 
 
Table 4-2 
Locally documented generic alterations of ALK are accepted 
 
Tumor type 
Genetic Alteration of ALK 
Translocation 
involving ALK Gene 
ALK Protein over 
expression 
Mutation, amplification 
involving ALK Gene*, ** 
Anaplastic Large Cell 
Lymphoma (ALK+) 
√ 
√ 
√ 
Inflammatory 
Myofibroblastic Tumor 
√ 
- 
- 
Inflammatory breast 
cancer 
√ 
- 
√ 
Glioblastoma 
√ 
√ 
√ 
Any other ALK + tumor 
√ 
- 
√ 
* An amplification of the ALK gene, defined as ≥ 6 copies per cell, or 3 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 known activating mutation in the kinase domain of ALK or a point mutation in the kinase domain of 
ALK that results in an amino acid change that has not been reported in normal germline DNA, or any 
other mutation (e.g. insertion or deletion) which results in a change in the amino acid sequence of the 
kinase domain of ALK, 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. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 48
8 Protocol No. 
 
 
 
 
 
Figure 4-1 
Study design 
 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 49
8 Protocol No. 
 
 
 
 
 
4.1.1 
Duration of treatment 
Patients will continue ceritinib until they experience any of the following: 
• Disease progression (radiologically documented according to RECIST 1.1, RANO and 
RECIST 1.1 for GBM or by Cheson criteria for hematologic malignancies). 
• Unacceptable toxicity that precludes further treatment 
• Start of a new anti-cancer therapy 
• Pregnancy 
• Treatment is discontinued at the discretion of the investigator or patient 
• Lost to follow-up 
• Death 
• Study terminated by Sponsor 
Patients treated with ceritinib who have RECIST, RANO or Cheson -defined progressive 
disease but who, in the opinion of the investigator, have evidence of continuing clinical 
benefit from ceritinib may continue to receive this drug. In such cases, patients must complete 
the EOT visit only after permanent discontinuation of ceritinib. 
 
4.1.2 
End of treatment (EOT) 
Patients will continue to receive study treatment until disease progression (assessed by 
investigator per RECIST 1.1 for solid tumors, RANO and RECIST 1.1 criteria for GBM or 
Cheson criteria for ALCL), unacceptable toxicity, death or discontinuation from study 
treatment for any other reason (e.g., withdrawal of consent, start of a new anti-neoplastic 
therapy or at the discretion of the investigator), otherwise known as End of Treatment. All 
patients who discontinue from study treatment due to disease progression must have their 
progression clearly documented. 
 
4.2 
Timing of interim analyses and design adaptations 
Interim analysis for each arm will be performed for decision making (early stopping or 
continuation of recruitment) when a predefined number of patients ( 5 for IMT and 10 for all 
other arms) have completed 16 weeks of treatment with ceritinib and have their anti-tumor 
activity assessed. Responses observed at week 16 (CR or PR) must be confirmed by a 
subsequent assessment at least 4 weeks later. The reduced number of patients (5) in the IMT 
arm is based on the rare incidence of this tumor type. An additional 10 patients may be 
enrolled for a given arm (including IMT) subsequent to the interim analysis if the probability 
of the pre-defined clinically meaningful response for the arm is at least 20%. 
All available data will be used for analysis at the interim. For a specific arm, a decision will 
be made based on the calculated probability as given below: 
• If the posterior probability of being clinically meaningful (Table 10-1) is less then 20% 
then recruitment will be stopped in that arm 
• Otherwise, recruitment will be extended for 10 more patients in that arm 
All available data will be used for analysis at the interim. However, a decision will be made 
only for arms with a minimum number of pre-specified patients (a minimum of 5 patients in 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 50
8 Protocol No. 
 
 
 
 
 
IMT arm or a minimum of 10 patients for any of the other arm). Depending on enrollment and 
follow-up, there may be multiple interim analyses. Details of the interim analysis is given in 
Section 10.7. 
 
4.3 
End of the study 
The study will end approximately 38 weeks after the last patient started treatment with study 
medication or once at least 75% of patients have died or have been lost to follow-up or 
withdraws consent, or when the study is terminated early. The primary analysis for a given 
arm will occur once all patients in that arm complete at least 16 weeks of treatment with 
ceritinib unless discontinued earlier; have their efficacy evaluation completed at week 16 and 
the responses are confirmed by subsequent visit within 4 weeks and EOT visit completed 30 
days later. The final analysis of study data will be conducted at the end of the study 
Novartis may continue to supply ceritinib to patients who may benefit from continued 
treatment as per the Investigator’s opinion. Novartis will make every effort to provide study 
medication for patients who continue to experience benefit from the treatment. 
 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible for an end of treatment (EOT) visit and the 
assessments for EOT should be performed as described in Section 7 for a prematurely 
withdrawn patient. The investigator may be informed of additional procedures to be followed 
in order to ensure that adequate consideration is given to the protection of the patient’s 
interests. The investigator will be responsible for informing the Institutional Review Board 
(IRB) and/or Ethics Committee (EC) of the early termination of the trial. 
 
5 
Population 
5.1 
Patient population 
This study will be conducted in previously treated male or female patients 18 years and older. 
Approximately 106 patients are planned to be enrolled to have 95 evaluable patients. Patients 
must be diagnosed with one of the per protocol selected ALK+ life threatening malignancy 
that has a dysregulation of ALK (such as a mutation, translocation, amplification or 
overexpression) (see Section 4.1 Table 4-2). In addition, patients must have progressed 
following at least one line of prior systemic treatment for recurrent, locally advanced and or 
metastatic disease or are intolerant to therapy. 
The investigator or designee must ensure that only patients who meet all of the inclusion and 
none of the exclusion criteria are offered treatment in the study. All tumor specific arms will 
enroll patients in parallel. The patient must not receive any additional anti-cancer therapy 
during treatment with ceritinib. 
Written informed consent must be obtained prior to any screening procedures. 
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies while on treatment. Rescreening may be allowed up to 2 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 51
8 Protocol No. 
 
 
 
 
 
times; laboratory parameters and ECGs may be retested within the 28-day screening period 
for an individual patient if such parameters meet an exclusion criterion when initially tested. 
 
5.2 Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Written informed consent for the main study obtained prior to any screening procedure. 
2. Patient must have a histologically or cytologically confirmed diagnosis of one of the 
tumors that is ALK positive (ALK+). The ALK test results must be available at the 
investigator site before the first dose of the study drug. The tumor types are described 
below: 
Anaplastic Large Cell Lymphoma (ALCL), local confirmation of diagnosis of ALK+ 
ALCL is sufficient for eligibility. 
Inflammatory Myofibroblastic Tumor locally documented translocation involving the ALK 
gene, 
Glioblastoma, Inflammatory breast cancer Any other locally documented ALK+ tumor 
must carry a locally documented genetic alteration of ALK including any of the following 
(ALK overexpression is also acceptable in Gliobalstoma): 
• A known activating mutation in the kinase domain of ALK or a point mutation in the 
kinase domain of ALK that results in an amino acid change that has not been reported 
in normal germline DNA, or any other mutation (e.g. insertion or deletion) which 
results in a change in the amino acid sequence of the kinase domain of ALK, 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. 
• An amplification of the ALK gene, defined as ≥ 6 copies per cell, or 3 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 translocation involving the ALK gene. 
• Glioblastoma patients only, an overexpression of the ALK protein (documented 
locally is also acceptable for eligibility). 
3. Patient must provide an archival or fresh tumor tissue before the first dose of the study 
drug for potential retrospective ALK testing at a Novartis designated central laboratory by 
a comparative technology: 
• the confirmation of ALK positivity is not required for enrollment if other inclusion 
and exclusion criteria are fulfilled. 
4. Patient is 18 years or older at the time of informed consent. 
5. Patient has WHO performance status ≤ 2. 
6. Patient must have received at least one line of prior systemic treatment for recurrent, 
locally advanced and/or metastatic disease, may have discontinued for: 
• Disease progression: defined by RECIST 1.1 for solid tumors; by RANO for GBM 
and by Cheson assessment criteria for lymphoma 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 52
8 Protocol No. 
 
 
 
 
 
• Intolerance, described as any discontinuation due to an AE of any grade despite 
appropriate supportive treatment 
7. Patient must have a wash-out period prior to the first dose of ceritinib: 
• Chemotherapy, immunotherapy, stem cell transplant within 4 weeks 
• Radiotherapy and ALK inhibitors must have discontinued within 1 week 
• Recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 
(CTCAE v4.03). Exception to this criterion: patients with any grade of alopecia are 
allowed to enter the study. 
8. Patient must have at least one measurable lesion as defined by appropriate guidelines. A 
lesion at a previously irradiated site may only be counted as a target lesion if there is clear 
sign of progression since the irradiation. 
• Solid Tumors: by RECIST 1.1 (Section 14.2) 
• GBM: by RANO and RECIST 1.1 (Section 14.3 and Section 14.2) 
• ALCL: by Cheson (Section 14.4). Patient has at least one measurable nodal lesion 
(≥1.5 cm). In case where the patient has no measurable nodal lesions ≥ 1.5 cm in the 
long axis at screening, then the patient must have at least one measurable extra-nodal 
lesion. 
9. Patient must meet the following laboratory values at the screening visit: 
• Absolute neutrophil count (ANC) ≥ 1.0 x 109/L; 
• Platelets ≥ 75 x 109/L) 
• Hemoglobin ≥ 8 g/dL 
• International Normalized Ratio (INR) ≤ 1.5 
• Serum creatinine ≤ 1.5 mg/dL and/or calculated creatinine clearance (using 
Cockcroft-Gault formula) ≥ 30 mL/min; 
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN), except for patients with Gilbert’s 
syndrome, who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin 
≤ 1.5 x ULN; 
• Aspartate transaminase (or aminotransferase; AST) ≤ 2.5 x ULN, except for patients 
with liver metastasis, who are only included if AST ≤ 5 x ULN; 
• Alanine transaminase (or aminotransferase; ALT) ≤ 2.5 x ULN, except for patients 
with liver metastasis, who are only included if AST ≤ 5 x ULN; 
• 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) 
10. Patient must have the following laboratory values within ≤ Gr1 (CTCAE v4.03) at 
screening: 
• Potassium 
• Magnesium 
• Phosphorus 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 53
8 Protocol No. 
 
 
 
 
 
• Total calcium (corrected for serum albumin) 
11. Patient must be willing and able to comply with scheduled visits, treatment plans, 
laboratory tests and other study procedures. 
 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patient with ALK+ lung cancer. 
2. Patient with known hypersensitivity to any of the excipients of LDK378 (microcrystalline 
cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate). 
3. Patient with symptomatic CNS metastases who are neurologically unstable or have 
required increasing doses of steroids within the 2 weeks prior to study entry to manage 
CNS symptoms. 
4. History of carcinomatous meningitis, 
5. Patient with diarrhea CTCAE ≥ grade 2; or patients with neuropathy CTCAE ≥ grade 2 
6. Patients with acute or chronic GI disease that may significantly alter the absorption of 
ceritinib 
7. Patient with a history of pancreatitis or history of increased amylase or lipase that was due 
to pancreatic disease 
8. Patient has history of interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis 
9. Presence or history of a malignant disease other than primary tumor under consideration 
that has been diagnosed and/or required therapy within the past 3 years. 
• Exceptions to this exclusion include the following: completely resected basal cell and 
squamous cell skin cancers, and completely resected carcinoma in situ of any type. 
10. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event 
(within 6 months) such as: 
• unstable angina within 6 months prior to screening; 
• myocardial infarction within 6 months prior to screening; 
• history of documented congestive heart failure (New York Heart Association 
functional classification III-IV); 
• uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without 
antihypertensive medication 
• initiation or adjustment of antihypertensive medication(s) is allowed prior to 
screening; 
• ventricular and atrial arrhythmias; supraventricular and nodal arrhythmias not 
controlled with medication; 
• Other cardiac arrhythmia not controlled with medication. 
• Corrected QT (QTcF) >470 ms using Fridericia’s correction on the screening ECG (as 
mean of triplicate ECGs). 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 54
8 Protocol No. 
 
 
 
 
 
11. Evidence of active viral hepatitis, including Hepatitis A, B or C (testing for viral hepatitis 
is not mandatory). 
12. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not 
mandatory). 
13. Patient receiving treatment with medications that meet one of the following criteria and 
that cannot be discontinued at least 1 week prior to the start of treatment with ceritinib and 
for the duration of the study: 
• Strong inhibitors or strong inducers of CYP3A4/5 
• Medications with a low therapeutic index that are primarily metabolized by 
CYP3A4/5 and/or CYP2C9 
• Medication with a known risk of prolonging the QT interval or inducing Torsades de 
Pointes 
14. Patients who are currently receiving treatment with warfarin sodium (Coumadin®) or any 
other coumarin-derivative anticoagulants. 
15. Patient receiving unstable or increasing doses of corticosteroids. 
If patient is on corticosteroids for endocrine deficiencies or tumor-associated symptoms 
(non-CNS), dose must have been stabilized (or decreasing) for at least 5 days before 
first dose of study treatment. 
16. Patient receiving treatment with any enzyme-inducing anticonvulsant that cannot be 
discontinued at least 1 week before first dose of study treatment, and for the duration of 
the study. Patients on non-enzyme-inducing anticonvulsants are eligible. 
17. Major surgery (e.g., intrathoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2 
weeks for resection of brain metastases) to starting study treatment or who have not 
recovered from side effects of such procedures. 
18. Pregnant or nursing (lactating) women 
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 3 months after stopping medication. Highly effective contraception 
methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject 
• Use of oral, injected or implanted hormonal methods of contraception or 
placement of an intrauterine device (IUD) or intrauterine system (IUS), or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 55
8 Protocol No. 
 
 
 
 
 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
20. Sexually active male unless they use a condom during intercourse while taking the drug 
and for 3 months after the last dose of LDK378 treatment. Male patients should not father 
a child for 3 months after the last dose of LDK378 treatment. For male patients treated 
with reference chemotherapy they should not father a child for at least 6 months after the 
last dose of treatment or as per the local label. A condom is required to be used also by 
vasectomized men in order to prevent delivery of the drug via seminal fluid. 
21. Patient has other severe, acute, or chronic medical or psychiatric conditions including 
uncontrolled diabetes mellitus or laboratory abnormalities that in the opinion of the 
investigator may increase the risk associated with study participation, or that may interfere 
with the interpretation of study results. 
 
6 
Treatment 
6.1 
Study treatment 
For this study, the term “investigational treatment” refers to ceritinib (LDK378). 
The ceritinib dose and treatment schedule of the study treatments are listed in Table 6-1. All 
dosages prescribed and dispensed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record eCRF. 
 
6.1.1 
Dosing regimen 
A complete treatment cycle is defined as 28 days of once daily continuous treatment with 
ceritinib. The first dose of study treatment defines Day 1 of the treatment cycle and the last 
day of a complete treatment cycle is Day 28. Those patients without confirmed Progressive 
Disease (i.e., those with CR, PR, SD,) will continue receiving treatment with ceritinib until 
disease progression, unacceptable toxicity or withdrawal from the study for other reasons. 
 
Table 6-1 
Dose and treatment schedule 
 
Study treatments 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or 
Regimen 
Ceritinib 
Hard gelatin capsule for 
oral use 
750 mg (5 x 150 mg 
capsule 
Once daily (28 day cycle) 
 
6.1.2 
Ceritinib administration 
Each study site will be supplied with ceritinib by Novartis. Ceritinib is supplied as individual 
patient supply, packaged in bottles. Medication labels for the globally provided study 
treatment ceritinib will comply with legal regulations of each country and be printed in local 
language. The storage conditions for the study treatment will be described on the medication 
label. 
• Patients will self-administer ceritinib on an outpatient basis. The investigator must instruct 
the patient to take the study drug exactly as prescribed. Patients should take ceritinib once 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 56
8 Protocol No. 
 
 
 
 
 
daily at approximately the same time each day, in the morning, afternoon, or at the bed 
time. 
• 
 
 
 
 
 
 
• Patients should take ceritinib on an empty stomach (i.e. fast from food and drink, except 
water) at least 2 hour before or 2 hours after a light meal. 
• Each dose of ceritinib should be taken with a glass of water and consumed over as short a 
time as possible (i.e. not slower than 1 capsule every 2 minutes). 
• Patients should be instructed to swallow whole capsules and not to chew or open them. 
• If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. 
Patients must be instructed not to make up missed doses or partial doses (i.e., when the entire 
dose is not taken as instructed). A missed or partial dose will be defined as a case when the 
full dose is not taken within 8 hours after the approximate time of the usual daily dosing. That 
day’s dose (or part remaining dose) should be omitted and the patient should continue 
treatment with the next scheduled dose on the following day. 
 
6.1.3 
Ancillary treatments 
Not applicable. 
 
6.1.4 
Rescue medication 
Not applicable. 
 
6.2 
Dose escalation guidelines 
Not applicable. 
 
6.2.1 
Starting dose rationale 
Not applicable. 
 
6.2.2 
Provisional dose levels 
Not applicable. 
 
6.2.3 
Guidelines for dose escalation and determination and dose delay 
Not applicable. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 57
8 Protocol No. 
 
 
 
 
 
6.2.4 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patients to continue the study treatment. Any changes in 
ceritinib administration must be recorded on the Dosage Administration Record eCRF. 
Detailed ceritinib dose modification guidelines for selected toxicities are described  in  
Section 6.2.5 and Table 6-2. All dose modifications, interruptions or discontinuations must be 
based on the worst preceding toxicity as graded by the NCI Clinical Toxicity Criteria (NCI- 
CTCAE version 4.03). 
 
General guidelines for dose modifications for toxicities other than those listed 
in Table 6-2: 
For grade 1 and tolerable grade 2 treatment-related toxicities, patients are encouraged to 
continue at the current dose of study treatment. For intolerable grade 2 treatment-related 
toxicities, dosing should be interrupted until resolution to grade 1 or lower followed by dose 
reduction to the next dose level. 
For grade 3 or grade 4 treatment-related toxicity that is not considered by the investigator to 
be life-threatening, patients should interrupt study treatment until resolution to grade 1 or 
lower; then study treatment may continue following a dose reduction to the next dose level, if, 
in the opinion of the Investigator, the patient continues to experience clinical benefit. For any 
grade 3 or 4 treatment-related toxicity that is considered by the investigator to be life- 
threatening, permanently discontinue study treatment. 
 
6.2.5 
Treatment interruption and treatment discontinuation 
If the administration of ceritinib is temporarily interrupted for reasons other than toxicity then 
treatment with ceritinib will be resumed at the same dose. 
If treatment with ceritinib is withheld due to toxicity, scheduled visits and all assessments will 
continue to be performed (with the exception of the dosing of the withheld study drug), as 
described in Table 7-1. 
If treatment with ceritinib is withheld for more than 28 consecutive days (counting from the 
first day when a dose was missed) due to treatment-related toxicity, then ceritinib should be 
permanently discontinued except in cases where the investigator believes the patient continues 
to derive clinical benefit. In such cases, treatment with ceritinib may be resumed at a lower 
dose. 
Patients whose treatment is temporarily interrupted or permanently discontinued due to an AE 
or abnormal laboratory value must be followed until resolution or stabilization of the event, 
whichever comes first, including all study assessments appropriate to monitor the event. 
Detailed guidelines for follow-up of study drug related AEs or abnormal laboratory values 
must be followed as described in Section 6.2.6. 
All patients will be followed for safety until 30 days after the last dose of ceritinib. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 58
8 Protocol No. 
 
 
 
 
 
6.2.6 
Criteria for ceritinib dose modifications 
A ceritinib dose reduction will follow the guidelines described in Table 6-1. For each patient, 
a maximum of 3 dose reductions will be allowed. All dose reductions will be in 150 mg 
decrements per reduction. The patient must be discontinued from treatment with ceritinib if 
further reduction is necessary. Once the dose of ceritinib has been reduced due to toxicity, it 
cannot be re-escalated. 
 
Table 6-2 
Dose reduction steps for ceritinib 
Ceritinib dose levels 
Dose* and schedule 
 
Starting dose level 
750 mg qd 
 
Dose level – 1 
600 mg qd 
 
Dose level – 2 
450 mg qd 
 
Dose level – 3 
300 mg qd ** 
 
*Dose reduction should be based on the worst preceding toxicity 
**Dose reduction below 300 mg/day is not allowed. If a dose reduction below 300 mg/day is required, 
the patient should be permanently discontinued from ceritinib 
 
Guidelines for dose modification and dose interruption of ceritinib are described in Table 6-2. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 59
9 Protocol No. 
 
 
 
 
 
 
Table 6-3 
Criteria for interruption and re-initiation of ceritinib treatment 
 
Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for ceritinib 
HEMATOLOGICAL 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1.5 x 109/L) 
Grade 2 (ANC <1.5 and ≥1.0 x 109/L) 
Grade 3 (ANC <1.0 and ≥0.5 x 109/L) 
Maintain dose level 
Maintain dose level 
If resolved to ≤ Grade 2, then  1 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 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 60
9 Protocol No. 
 
 
 
 
 
Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for ceritinib 
Grade 2 (>1.5 and ≤3.0 x ULN) with AST or ALT ≤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 AST or ALT ≤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 ceritinib 
Grade 4 (>10.0 x ULN) 
Permanently discontinue patient from ceritinib 
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 (or to baseline), then  1 dose level 
Grade 4 (>20.0 x ULN) without total bilirubin elevation to >2.0 x 
ULN 
Omit dose until resolved to ≤ Grade 1 (or to baseline), then  1 dose level 
AST or ALT and concurrent Total bilirubin 
AST or ALT >3.0 x ULN and total bilirubin >2.0 x ULN in the 
absence of cholestasis or hemolysis 
Permanently discontinue patient from ceritinib. Refer to Section 6.2.7.2 for 
additional follow-up 
PANCREATIC 
Amylase and/or lipase elevations (in the absence of clinical symptoms) 
Grade 1 (> ULN and ≤1.5 x ULN) 
Maintain dose level 
Grade 2 (>1.5 - 2.0 x ULN) 
Maintain dose level 
Grade ≥3 (> 2.0 x ULN) 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Note: Withhold ceritinib for acute onset of new or progressive unexplained abdominal symptoms, such as severe pain or vomiting; perform diagnostic 
procedures (e.g., abdominal CT scan or ultrasound) to exclude pancreatic pathology. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 61
9 Protocol No. 
 
 
 
 
 
Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for ceritinib 
RENAL 
Serum creatinine 
Grade 1 (>1 and ≤1.5 x baseline; > ULN and ≤1.5 x ULN) 
Maintain dose level 
Grade 2 (>1.5 and ≤3.0 x baseline; >1.5 and ≤3.0 x ULN) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤7 days, then maintain dose level 
If resolved in >7 days, then  1 dose level 
Grade 3 (>3.0 x baseline; >3.0 and ≤6.0 x ULN) 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Grade 4 (>6.0 x ULN) 
Permanently discontinue patient from ceritinib 
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 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 62
9 Protocol No. 
 
 
 
 
 
Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for ceritinib 
METABOLIC 
Any Grade hypophosphatemia 
Treatment with phosphate supplements as clinically indicated and maintain dose 
level 
Persistent hyperglycemia (glucose >250 mg/dL) despite optimal 
anti-hyperglycemic therapy 
Omit dose until hyperglycemia is adequately controlled, then resume ceritinib at ↓ 
1 dose level 
If adequate hyperglycemic control cannot be achieved with optimal medical 
management, permanently discontinue patient from ceritinib. 
GENERAL DISORDERS 
Fatigue (asthenia) 
Grade 1 or 2 
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 ceritinib for acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever and during diagnostic 
workup for pneumonitis/ILD. 
• 
During evaluation of potential grade 2, 3, and 4 pneumonitis, if an infectious etiology is confirmed (i.e., pneumonia) and pneumonitis is excluded, and 
then consider resuming ceritinib at current dose level after the pneumonia resolves. 
PNEUMONITIS 
Any Grade treatment-related ILD/pneumonitis 
Permanently discontinue patient from ceritinib 
CARDIAC 
Electrocardiogram QT corrected (QTc) interval prolonged 
Grade 1 (QTc 450-480 ms) 
Grade 2 (QTc 481-500 ms) 
Maintain dose level 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 63
9 Protocol No. 
 
 
 
 
 
Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for ceritinib 
Grade 3 (QTc ≥501 ms on at least two separate ECGs) 
Omit dose until QTc is less than < 481ms, then ↓ 1 dose level 
• 
Assess the quality of the ECG recording and the QT value and repeat if 
needed 
Repeat ECG in 24 hours, or less, as clinically indicated; continue monitoring as 
clinically indicated until QTc < 481 ms 
In addition:-Determine the serum electrolyte levels (in particular hypokalemia, 
hypomagnesemia). If abnormal, correct abnormalities before resuming study drug 
treatment 
• 
Review concomitant medication use for drugs with the potential to increase 
the risk of drug exposure related to QT prolongation 
• 
Consider collecting a time-matched 
 sample and record time and date of 
last study drug intake 
After resumption of dosing: 
• 
Repeat ECGs 7 days after dose resumption for all patients who had therapy 
interrupted due to QTc ≥ 501 ms. 
Grade 4 (QTc ≥501 or >60 ms change from baseline and Torsades 
de pointes or polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia) 
Permanently discontinue patient from ceritinib 
Bradycardia 
Grade 1 or 2 
Omit dose until recovery to asymptomatic bradycardia or to a heart rate ≥60 bpm 
Evaluate concomitant medications known to cause bradycardia, and adjust the 
dose of ceritinib. 
Grade 3 
Grade 4 (in patients taking a concomitant medication also known to 
cause bradycardia or a medication known to cause hypotension) 
Omit dose until recovery to asymptomatic bradycardia or to a heart rate ≥60 bpm 
If the concomitant medication can be adjusted or discontinued, resume ceritinib at 
↓ 1 dose level with frequent monitoring 
Grade 4 (in patients who are not taking a concomitant medication 
also known to cause bradycardia or known to cause hypotension) 
Permanently discontinue ceritinib. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 64
9 Protocol No. 
 
 
 
 
 
Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for ceritinib 
* Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All dose modifications should be based on the worst preceding toxicity. 
** If Grade 3 or 4 hyperbilirubinemia is due to the indirect (non-conjugated) component only, and hemolysis as the etiology has been ruled out as per 
institutional guidelines (e.g., review of peripheral blood smear and haptoglobin determination), then ↓ 1 dose level and continue treatment at the 
discretion of the Investigator. 
***LFTs include albumin, ALT, AST, total bilirubin, alkaline phosphatase and GGT 
**** Dose modifications apply to patients who experience diarrhea despite appropriate antidiarrheal medication. This medication should be started at the 
first sign of abdominal cramping, loose stools or overt diarrhea (see Section 6.2.7.6) 
***** Dose modifications apply to patients who experience nausea and/or vomiting despite appropriate antiemetic medication. This medication should be 
started at the first sign of nausea and/or vomiting (see Section 6.2.7.5) 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 65
5 Protocol No. 
 
 
 
 
 
 
6.2.7 
Follow-up for toxicities 
An unscheduled visit should be performed in all cases below where toxicity monitoring is 
recommended more frequently than defined by the schedule of assessments (Table 7-1). 
 
6.2.7.1 
Guidelines for the follow-up of laboratory hematologic abnormalities 
In case of any occurrence of febrile neutropenia, neutropenia ≥ grade 3, or thrombocytopenia 
≥ grade 3, tests must be performed weekly (or more frequently if clinically indicated) until the 
event resolves to ≤ grade 2. Subsequent monitoring must be performed every 4 weeks. See 
Table 6-3. 
 
6.2.7.2 
Guidelines for the follow-up of laboratory liver abnormalities 
In patients with any clinically relevant laboratory liver abnormality, as defined below, hepatic 
toxicity monitoring must include ALL of the following liver function tests (LFTs): albumin, 
AST, ALT, total bilirubin (fractionated if total bilirubin >2.0 x ULN), alkaline phosphatase 
and GGT). Note: for patients with Gilbert Syndrome, total and direct bilirubin must be 
monitored, but intensified monitoring applies to changes in direct bilirubin only. 
In case of any occurrence of AST/ALT/total bilirubin increase to grade 2, the LFTs must be 
monitored weekly (or more frequently if clinically indicated) until the event resolves to ≤ 
grade 1. Thereafter monitoring must be continued every other week (or more frequently if 
clinically indicated) for two additional cycles (e.g. 8 weeks). If there is no recurrence of grade 
2 AST/ALT/total bilirubin elevations during this period, subsequent monitoring must be 
performed every 4 weeks. For patients with liver metastasis and grade 2 AST/ALT at 
baseline, increased monitoring is required for grade 3/4 AST/ALT; follow guidelines for 
grade 3 or 4 AST/ALT. 
In case of any occurrence of AST/ALT/total bilirubin increase to grade 3 or 4, LFTs must be 
monitored weekly (or more frequently if clinically indicated) until the event resolves to ≤ 
grade 1 (or to baseline). Thereafter monitoring must be continued every other week (or more 
frequently if clinically indicated) for four additional cycles (e.g. 16 weeks). If there is no 
recurrence of ≥ grade 2 AST/ALT/total bilirubin elevations during this period, subsequent 
monitoring must be performed every 4 weeks. 
Patients who discontinue study treatment due to liver toxicity must be monitored weekly (or 
more frequently if clinically indicated) until the event resolves to ≤ grade 1 or stabilization 
occurs (no CTCAE grade change over 4 weeks). Refer to Table 6-4. 
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below: 
• For patients with normal ALT or AST or TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 66
5 Protocol No. 
 
 
 
 
 
• 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 on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented. 
 
6.2.7.3 
Guidelines for the follow-up of laboratory renal abnormalities 
In case of any occurrence of serum creatinine grade ≥2, tests must be performed weekly (or 
more frequently if clinically indicated) until the event resolves to ≤ grade 1. Subsequent 
monitoring must be performed every 4 weeks. 
In case of any occurrence of serum creatinine ≥ grade 3, tests must be performed twice weekly 
(or more frequently if clinically indicated) until the event resolves to ≤ grade 1. Subsequent 
monitoring must be performed every 4 weeks. Refer to Table 6-3. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 67
5 Protocol No. 
 
 
 
 
 
6.2.7.4 
Guidelines for monitoring pneumonitis 
Monitor patients for pulmonary symptoms indicative of pneumonitis. In addition, withhold 
ceritinib for acute onset of new or progressive unexplained pulmonary symptoms, such as 
dyspnea, cough and fever and during diagnostic workup for pneumonitis/ILD. 
See also dose modification guidelines described in Table 6-2. 
 
6.2.7.5 
Guidelines for the treatment of study drug induced nausea and 
vomiting 
Nausea and vomiting are among the most frequently reported AEs following treatment with 
ceritinib and patients must therefore be closely monitored for the appearance of these AEs. 
The investigator should consider/investigate potential concomitant medication, food or 
comorbidity-driven causes of nausea and/or vomiting and remedy these causes if possible 
(e.g., discontinuation of concomitant medication, dietary modification, treatment of 
comorbidity). 
Individualized supportive and anti-emetic treatment should be initiated, as appropriate, at the 
first signs and/or symptoms of these AEs. In patients with vomiting, the patient should be 
monitored for signs of dehydration and instructed to take preventive measures against 
dehydration. 
Concomitant medication for the treatment of nausea and/or vomiting should follow local 
practice and the investigator’s best judgment. For moderate emetogenic drugs, such as 
ceritinib, International Guidelines for anti-emetic treatment recommend early treatment with 
5-HT3-receptor antagonists (5-HT3RAs). 
Dose adaptation of ceritinib in case of treatment related nausea and/or vomiting must follow 
the guidelines presented above in Table 6-2. 
 
6.2.7.6 
Guidelines for the treatment of study drug induced diarrhea 
The investigator should consider/investigate potential concomitant medication, food or 
comorbidity driven causes of diarrhea (including infectious causes) and remedy these causes 
if possible (e.g., discontinuation of concomitant medication, dietary modification, treatment of 
comorbidity). 
The patient should be monitored for signs of dehydration and instructed to take preventive 
measures against dehydration as soon as diarrhea occurs. Antidiarrheal medication must be 
initiated at the first sign of abdominal cramping, loose stools or overt diarrhea. Concomitant 
medication for the treatment of diarrhea should follow local practice and the investigator’s 
best judgment and may follow “the recommended guidelines for the treatment of cancer 
treatment-induced diarrhea” (Benson et al 2004). For example: 
• For uncomplicated diarrhea (grade 1 or 2 without complicating signs or symptoms), 
loperamide given at a standard dose (e.g., initial administration of 4 mg, then 2 mg every 
2-4 hours, maximum of 16 mg/day), along with oral hydration and dietetic measures 
should be considered. Note: complicating signs or symptoms include: moderate to severe 
cramping, decreased performance status, fever, neutropenia, frank bleeding or 
dehydration. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 68
5 Protocol No. 
 
 
 
 
 
• For complicated diarrhea (all grade 3 or 4, grade 1-2 with complicating signs or 
symptoms), management should involve intravenous (IV) fluids, and consider treatment 
with octreotide (at starting dose of 100 to 150 µg SC tid or 25 to 50 µg IV) and antibiotics 
(e.g. fluoroquinolone) should be given. 
Dose adaptation of ceritinib in case of treatment related diarrhea must follow the guidelines 
presented above in Table 6-2. 
 
6.2.7.7 
Guidelines for treatment of hypophosphatemia 
In the phase I study [CLDK378X2101], as of 31-Oct-2013, there were 9 cases of grade 3 
hypophosphatemia in all dose groups, one of which was a DLT that contributed to the MTD 
determination – this patient was able to continue ceritinib at the same dose. One patient in the 
750 mg group had grade 3 hypophosphatemia that resolved after dose adjustment or 
interruption; in the remaining 8 cases, patients were able to continue therapy without dose 
modification. Hypophosphatemia was a commonly reported AE (6.3%), regardless of 
relationship to ceritinib treatment. Therefore, phosphate levels will be checked at baseline and 
during treatment. In cases of hypophosphatemia at baseline, phosphate supplements should be 
started before treatment withceritinib. For any grade of hypophosphatemia during the study, 
treatment with phosphate supplements should be given as clinically indicated, and the 
ceritinib dose can be maintained. 
 
6.2.7.8 
Guidelines for the follow-up of laboratory pancreatic abnormalities 
In case of any occurrence of lipase or amylase increase to grade 3 or 4, both lipase and 
amylase must be monitored weekly (or more frequently if clinically indicated) until the event 
resolves to ≤ grade 1 (or to baseline). 
After resumption of dosing, monitoring must be continued weekly (or more frequently if 
clinically indicated) for one additional cycle (i.e. 4 weeks). If there is no recurrence of ≥ grade 
2 amylase or lipase elevations during this period, subsequent monitoring must be performed 
every 4 weeks. 
Patients who discontinue study treatment due to pancreatic toxicity must be monitored weekly 
(or more frequently if clinically indicated) until the event resolves to ≤ grade 1 or stabilization 
occurs (no CTCAE grade change over 3 weeks). Refer to Table 6-3. 
If amylase and/or lipase elevations are accompanied by new or progressive unexplained 
abdominal symptoms such as severe pain or vomiting, withhold ceritinib, then perform 
diagnostic procedures (e.g., abdominal CT scan or ultrasound) to exclude pancreatic 
pathology. 
See also dose modification guidelines in Table 6-2. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 69
5 Protocol No. 
 
 
 
 
 
Table 6-4 
Follow-up evaluations for selected toxicities 
Toxicity 
Follow-up evaluation* 
Investigations 
(hematologic) 
 
Investigations 
(hepatic) 
 
 
 
 
 
 
 
 
 
 
 
 
Investigations 
(renal) 
 
 
 
 
Investigations 
(pancreatic) 
Febrile neutropenia, neutropenia or thrombocytopenia ≥ CTCAE Grade 3 
Test weekly (or more frequent) until ≤ Grade 2 
Subsequent monitoring must be performed every cycle (4 weeks) 
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 (8 
weeks) 
If no recurrence of ≥ Grade 2 event, continue monitoring every cycle (4 weeks) 
Total bilirubin/ALT/AST ≥ Grade 3: 
Test weekly (or more frequent) until ≤ Grade 1 
Thereafter, continue to test every 2 weeks (or more frequently) for 4 cycles (16 
weeks) 
If no recurrence of ≥ grade 2 event, continue monitoring every cycle (4 weeks) 
Discontinuation due to liver toxicity: 
Test weekly (or more frequent) until ≤ Grade 1 or stabilization 
Serum creatinine Grade 2: 
Test weekly (or more frequent) until Grade 1 
Thereafter, test every cycle (4 weeks) 
Serum creatinine ≥ Grade 3: 
Test twice weekly (or more frequent) until ≤ Grade 1 
Thereafter, test every cycle (4 weeks) 
Amylase/lipase ≥ Grade 3: 
Test weekly (or more frequently) until ≤ Grade 1. After resumption of dosing, 
continue to test weekly for one additional cycle (4 weeks). If no reoccurrence of 
≥ Grade 2 event, continue monitoring every cycle (4 weeks). 
 
*Note: this table refers to the evaluation schedule only. Refer to Table 6-2 for dose modifications 
required for applicable toxicities 
 
6.2.8 
Anticipated risks and safety concerns of the study treatment 
Appropriate eligibility criteria and specific dose modification and stopping rules are included 
in this protocol. Recommended guidelines for prophylactic or supportive treatment for 
expected toxicities, including management of study-drug induced AEs, e.g., diarrhea are 
provided in Section 6.2.4. Refer to preclinical toxicity and or clinical data found in the IB. 
 
6.3 
Concomitant medications 
In general, the use of any concomitant medication/therapy deemed necessary for the care of 
the patient (e.g., anti-emetics, anti-diarrheal) is permitted (see Section 6.3.1), except when 
specifically prohibited (see Section 6.3.2). 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications including herbal/natural medications 
(excluding study treatment and prior antineoplastic treatments and blood transfusions), 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 70
5 Protocol No. 
 
 
 
 
 
surgeries and procedures (including physical therapy) administered within 28 days prior to the 
first dose of administration of ceritinib through 30 days after the last dose of ceritinib will be 
recorded in the Concomitant Medications or Surgical and Medical Procedures eCRF, 
respectively. Medications include not only physician prescribed medications, but also all over-
the counter medications, herbal medications (prohibited, see Section 6.3.2.7), food and or 
vitamin supplements. 
 
6.3.1 
Permitted concomitant therapy 
 
6.3.1.1 
Corticosteroids 
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to induce 
CYP3A enzymes, thereby increasing the risk of reducing ceritinib drug exposure to sub- 
therapeutic levels. 
If possible, systemic corticosteroid treatment should not be given during the study, except for: 
• Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye 
drops or local injections (e.g., intra-articular); 
• 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. 
 
6.3.1.2 
Bisphosphonates 
The use of bisphosphonates is allowed regardless of indication provided patients have been on 
stable doses optimally for at least 4 weeks prior to the start of treatment. Patients requiring 
initiation of bisphosphonate treatment during the course of the study should be discontinued 
due to progressive disease and the result of the evaluation should be clearly documented in the 
patients’ source documentation. 
No drug-drug interaction is expected between ceritinib and bisphosphonates as the two drugs 
are eliminated through different elimination pathways. Bisphosphonates are not inhibitors of 
human CYP450 enzymes involved in the metabolism of ceritinib and do not undergo 
metabolism in vivo. 
The same guidelines apply to the use of denosumab for the treatment of bone metastatic 
disease. 
 
6.3.1.3 
Drugs that are metabolized by CYP450 enzymes 
In vitro drug metabolism studies show that the metabolism of ceritinib is mediated by 
CYP3A4/5. Ceritinib is a time-dependent CYP3A4/5 inhibitor and is also a potent reversible 
inhibitor of CYP2A6, 2E1, 2C9 and 3A4/5 and may consequently increase exposure to drugs 
metabolized by these enzymes at clinically relevant concentrations. Clinical studies have not 
yet been performed to confirm the potential effect of ceritinib on substrate drugs metabolized 
by these enzymes in patients. The risk for CYP2A6 and CYP2E1 is largely mitigated by the 
low potential for drugs metabolized by these enzymes to be co-administered with ceritinib. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 71
5 Protocol No. 
 
 
 
 
 
Concomitant treatment of ceritinib with weak inhibitors or inducers of CYP3A4/5 is 
permitted. Caution is advised when ceritinib is co-administered with drugs that are moderate 
inhibitors or inducers of CYP3A4/5 (Appendix 1, Table 14-2). 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 dose titration or adjustment. Note that co-administration of 
ceritinib  with  strong  inhibitors  or  inducers  of  CYP3A4/5  is  prohibited  (refer  to   
Section 6.3.2.5). 
Concomitant treatment of ceritinib with medications known to be metabolized by CYP2C9 
and CYP3A4 is allowed with caution (Appendix 1, Table 14-2), except for drugs which have 
narrow therapeutic index/sensitive substrates for these CYP isoforms (Appendix 1, Table 14- 
1). 
 
6.3.1.4 
Non-enzyme inducing anti-epileptic drugs 
Non-enzyme inducing anti-epileptic medication (Non-EIAED) is allowed. 
 
6.3.1.5 
Palliative radiotherapy and surgery 
Local radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be carried 
out if required. If a target bone lesion requires palliative radiotherapy, the patient should be 
discontinued from the study. If palliative radiotherapy is initiated after start of study 
treatment, the reason for its use must be clearly documented and progression as per RECIST 
1.1 must be assessed and documented. 
Patients who develop progressive disease but are still deriving clinical benefit from ceritinib 
therapy, as determined by the Investigator may undergo radiotherapy and/or surgical resection 
as palliative localized therapy to treat metastatic lesions. Ceritinib should be held for at least 4 
days prior to radiotherapy and at least 1 day prior to any surgery. Ceritinib may be resumed 
≥3 days after completing radiotherapy or minor surgery, and ≥2 weeks after major surgery. 
 
6.3.1.6 Gastric protection agents 
The use of gastric protection agents including antacids, H2-antagonists, and proton pump 
inhibitors (PPIs) is allowed (Appendix 1). However, PPIs should be used with caution due to 
the theoretical effects of long-acting pH elevating agents (i.e., prolonged acid suppression) on 
reducing ceritinib absorption. When the concurrent use of a H2-antagonist or an antacid with 
ceritinib is necessary, the H2 blocker must be administered 10 hours before or 2 hours after 
the ceritinib dose, and the antacid must be administered 2 hours before or 2 hours after the 
ceritinib dose. Time restrictions for the concurrent use of PPIs and ceritinib are not applicable 
due to the long-acting effects of PPIs on gastric pH (i.e., separation of doses will not likely 
impact this interaction). 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 72
5 Protocol No. 
 
 
 
 
 
6.3.2 
Prohibited concomitant therapy 
 
6.3.2.1 
Other anticancer therapy 
Anticancer therapy (chemotherapy, targeted therapy, biologic therapy or radiation therapy 
[except palliative radiotherapy and palliative surgery as described in Section 6.3.1.5], 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. 
 
6.3.2.2 
Other investigational therapies 
Other investigational therapies must not be used while the patient is on the study. 
 
6.3.2.3 
Warfarin and coumarin derivatives 
Therapeutic doses of warfarin sodium or any other coumarin-derivative anticoagulants are not 
permitted. Ceritinib is an inhibitor of CYP2C9, the major metabolizing enzyme of warfarin. A 
clinically relevant increase in warfarin exposure is possible. 
 
6.3.2.4 
Enzyme inducing anti-epileptic drug 
Use of EIAEDs is not permitted. Refer to Appendix 1, Table 14-3 for a list of prohibited 
EIAED. 
If a patient is currently taking an EIAED, he/she must have discontinued the EIAED therapy 
for at least 1 week prior to starting study drug. 
If a patient was previously on a non-EIAED and needs to permanently change anticonvulsant 
agent but cannot change to another non-EIAED, the patient will be taken off ceritinib. 
 
6.3.2.5 
Strong CYP3A inhibitors and inducers 
In vitro metabolism studies suggest that oxidative metabolism of ceritinib is predominantly 
mediated by CYP3A4/5. 
Strong inhibitors or inducers of CYP3A4/5 are prohibited. Patients receiving concomitant 
medications known to strongly inhibit and/or induce CYP3A4/5 that are deemed medically 
necessary should be excluded from the study. Refer to Appendix 1, Table 14-1 for a list of 
these medications. Please note that this list may not be comprehensive. 
 
6.3.2.6 
Medications that are CYP2C9 and CYP3A4/5 substrates with narrow 
therapeutic index 
Ceritinib is a potent inhibitor of drugs metabolized by CYP2C9 and CYP3A4/5 in vitro. 
Because of the potential risk for drug-drug interactions, using medications known to be 
metabolized by these enzymes and that have a narrow therapeutic index is not permitted 
concomitantly with ceritinib. Refer to Appendix 14-1, Table 14-1 for a list of these 
medications. Please note that this list may not be comprehensive. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 73
5 Protocol No. 
 
 
 
 
 
6.3.2.7 
Herbal medications 
Herbal preparations/medications are not allowed throughout the study, as a potential drug- 
drug interaction is always possible. These herbal medications include, but are not limited to: 
St. John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng. 
Patients should stop using herbal medications at least 7 days prior to first dose of study 
treatment. 
 
6.3.2.8 
Medications that may prolong the QT interval or have a known risk of 
inducing Torsades de Pointes 
Ceritinib has potent activity on the hERG channel with an IC50 of 0.4 μM. There were no 
ceritinib-related effects in vivo in monkeys at doses as high as 100 mg/kg (human equivalent 
dose [HED] of 1950 mg). 
Serial ECGs were collected following a single dose and at steady-state to evaluate the effect 
of ceritinib on the QT interval in an open-label, dose-escalation, and expansion [Study 
CLDK378X2101]. A total of 304 patients were treated with ceritinib doses ranging from 50 to 
750 mg with 255 patients treated with ceritinib 750 mg. One of 304 patients (<1%) was found 
to have a QTc >500 msec and 10 patients (3.3%) had an increase from baseline QTc >60 
msec. A central tendency analysis of the QTc data at average steady-state concentrations 
demonstrated that the upper bound of the 2-sided 90% CI for QTc was 16 msec at ceritinib 
750 mg. A pharmacokinetic/pharmacodynamic analysis suggested concentration-dependent 
QTc interval prolongation 
Concomitant use of ceritinib and any medication included in Appendix 14-1, Table 14-4 titled 
“List of prohibited QT prolonging drugs” (i.e., drugs that are generally accepted by the 
Qtdrugs.org Advisory Board of the Arizona CERT to have a known risk of causing Torsades 
de Pointes) is not permitted. 
 
6.4 
Patient numbering, treatment assignment or randomization 
6.4.1 
Patient numbering 
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first screened and is retained as the primary identifier for the patient throughout 
his/her entire participation in the trial. The Patient No. consists of the Center Number (Center 
No.) (as assigned by Novartis to the investigative site) with a sequential patient number 
suffixed to it, so that each Patient is numbered uniquely across the entire database. Upon 
signing the informed consent form, the patient is assigned to the next sequential Patient No. 
available at the site. 
 
6.4.2 
Treatment assignment 
The Investigator or his/her delegate will contact the IRT and confirm that the patient fulfills 
all the inclusion and exclusion criteria. The IRT will assign a number to the patient, which 
will be used to link the patient to the treatment and will specify unique medication numbers 
for the first packages of study treatment to be dispensed to the patient. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 74
5 Protocol No. 
 
 
 
 
 
IRT must be notified within 2 days in case that the patient did not start treatment. 
 
6.4.3 
Treatment blinding 
Not applicable. 
 
6.5 
Study drug preparation and dispensation 
6.5.1 
Study drug packaging and labeling 
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label. Responsible site personnel will identify the study treatment package(s) 
to dispense to the patient by using the IRT and obtaining the medication number(s). Site 
personnel will add the patient number on the label. Immediately before dispensing the 
package to the patient, site personnel will detach the outer part of the label from the packaging 
and affix it to the source document (Drug Label Form) for that patient’s unique patient 
number. 
Study treatment labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug and the medication number 
but no information about the patient. 
 
Table 6-5 
Packaging and labeling 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
Ceritinib 
150 mg capsules in HDPE bottles 
Labeled as LDK378 (daily) 
6.5.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the drug labels and in the [Investigator’s Brochure]. 
 
Table 6-6 
Supply and storage of study treatments 
 
Study treatments 
Supply 
Storage 
Ceritinib 
Centrally supplied by Novartis 
Refer to study treatment label 
 
6.5.3 
Study drug compliance and accountability 
 
6.5.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 75
5 Protocol No. 
 
 
 
 
 
6.5.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
 
6.5.3.3 
Handling of other study treatment 
Not applicable. 
 
6.5.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate 
 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. 
All data obtained from these assessments must be supported in the patient’s source 
documentation. No eCRF will be used as a source document. The table indicates which 
assessments produce data to be entered into the database (D) or remain in the source 
documents (S) only. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 76
6 Protocol No. 
 
 
 
 
 
Table 7-1 
Visit evaluation schedule 
 
Category 
Protocol 
Section 
Screening 
Day-28 
to -1 
Treatment Phase 
Safety 
Follow- 
up 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
Cycles 
CxD1 
(±3 day) 
End of 
study 
Treatment 
(EoT) 
Visit Name 
Screening 
C1D1 
C1D15 
(±1 day) 
C2D1 
(±3 day) 
C2D15 
(±3 day) 
C3D1 
(±3 day) 
CxD1 
(±3 day) 
Obtain Informed Consent 
D 
7.2.1. 
X 
Tumor sample (archival or 
fresh) for ALK testing for 
patients (obtained prior to first 
dose) 
D 
7.3.4. 
X 
Documentation of local ALK 
testing results ( ALK 
amplification, ALK mutation, 
ALK translocation, and/ or 
ALK protein overexpression) 
S/D 
X 
Demography 
D 
7.2.1.2. 
X 
Inclusion/exclusion criteria 
S/D 
5.2 & 5.3. 
X 
Eligibility checklist 
S 
X 
End of phase disposition 
D 
X 
X 
Tumor type identification 
( ALK+ solid or hematological 
tumor type) 
D 
4.1. 
X 
Relevant medical history/ 
current medical conditions 
D 
7.2.1.2. 
X 
History of smoking 
D 
7.2.1.2. 
X 
Diagnosis and Extent of 
cancer 
D 
7.2.1.2. 
X 
Prior anti-neoplastic therapy 
D 
7.2.1.2. 
X 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 77
6 Protocol No. 
 
 
 
 
Category 
Protocol 
Section 
Screening 
Day-28 
to -1 
Treatment Phase 
Safety 
Follow- 
up 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
Cycles 
CxD1 
(±3 day) 
End of 
study 
Treatment 
(EoT) 
Visit Name 
Screening 
C1D1 
C1D15 
(±1 day) 
C2D1 
(±3 day) 
C2D15 
(±3 day) 
C3D1 
(±3 day) 
CxD1 
(±3 day) 
Prior and concomitant 
medications 
D 
7.2.1.2. 
X 
Continuous 
Surgical and medical 
procedures 
D 
7.2.1.2. 
X 
Continuous 
Physical examination 
S 
7.3.2.1. 
X 
X 
X 
X 
X 
X 
WHO performance status 
D 
7.3.2.4. 
X 
X 
X 
X 
X 
X 
Vital signs 
D 
7.3.2.2. 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
D 
7.3.2.3. 
X 
Weight 
D 
7.3.2.3. 
X 
X 
X 
X 
X 
X 
ECG 
D 
7.3.2.6. 
X 
X 
X 
X 
X 
X 
X 
Ceritinib administration 
D 
6.1.2. 
Daily 
Hematology 
D 
7.3.2.5.1. 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
(including liver function tests, 
lipase and amylase) 
D 
7.3.2.5.2. 
X 
X 
X 
X 
X 
X 
X 
X 
Testosterone, LH, FSH, sex 
hormone binding globulin 
(SHBG) 
D 
7.3.2.5.3. 
X 
X 
X 
Coagulation 
D 
7.3.2.5.6. 
X 
X 
Urinalysis (dipstick) 
D 
7.3.2.5.3. 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 
D 
7.3.2.5.4. 
X 
X 
X 
X 
X 
X 
Adverse events 
D 
8.1.1. 
X 
X 
Continuous 
X 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 78
6 Protocol No. 
 
 
 
 
Category 
Protocol 
Section 
Screening 
Day-28 
to -1 
Treatment Phase 
Safety 
Follow- 
up 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
Cycles 
CxD1 
(±3 day) 
End of 
study 
Treatment 
(EoT) 
Visit Name 
Screening 
C1D1 
C1D15 
(±1 day) 
C2D1 
(±3 day) 
C2D15 
(±3 day) 
C3D1 
(±3 day) 
CxD1 
(±3 day) 
TUMOR EVALUATION 
Physical examination for 
measurement of superficial 
disease (only if present) 
S 
7.3.1. 
X 
Every 8 weeks after first dose of study drug (Day 1 of every odd 
cycle) 
X 
Examination for enlarged 
spleen or liver for lymphoma 
S 
7.3.1. 
X 
To confirm CR 
X 
Radiological tumor 
assessment/ response 
assessment (MRI/CT/PET-CT 
Scans) (± 7 days) 
D 
7.3.1. 
X 
Every 8 weeks (±7 days) from C1D1 to C6D1. 
Every 12 weeks (±7 days) after C6D1 
X (if not 
performed 
within 8 
weeks since 
the last 
assessment) 
Bone Marrow bilateral 
aspirate or Biopsy (±7 days) 
for lymphoma (if applicable at 
screening) 
D 
7.3.1. 
X 
To confirm CR 
X (if positive 
at screening) 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 790 
Protocol No. CLDK378A2407 
 
 
 
 
 
 
7.2 
Molecular pre-screening 
Not Applicable 
 
7.2.1 
Screening 
Written informed consent must be obtained before any study specific assessments are 
performed, including screening. All screening evaluations (see Table 7-1) must be performed 
as closely as possible to the beginning of treatment (within 28 days of the start of ceritinib) to 
confirm patient’s eligibility. 
Patients must be diagnosed with one of the per protocol selected ALK+ malignancy that has a 
dysregulation of ALK (such as a mutation, translocation, amplification or overexpression) 
(see Section 4.1 Table 4-2). The results of this testing must be known prior to signing the ICF 
and before formal screening begins. Patient must have archival tissue available for submission 
to allow for future confirmatory ALK testing. If the tissue is not available or not of sufficient 
quantity, the patient must be willing to undergo a fresh tumor biopsy to allow for this analysis. 
The tumor sample (archival or fresh) submitted will not be used to determine study eligibility. 
Rescreening may be allowed up to 2 times; laboratory parameters and ECGs may be retested 
within the 28-day screening period for an individual patient if such parameters meet an 
exclusion criterion when initially tested. If the repeated result meets the criterion, that result 
may be used to determine eligibility. If the repeated laboratory parameters and ECG results do 
not meet the criterion, the patient will be considered a screening failure. 
Patients will undergo baseline radiological assessments as detailed in Section 7.3 and Table 7- 
2. 
 
7.2.1.1 
Information to be collected on screening failures 
A patient who signs the informed consent but fails to satisfy all eligibility criteria for any 
reason will be considered a screen failure. The reason for not satisfying eligibility criteria and 
not being enrolled in the study will be entered on the Screening Phase Disposition Page. The 
demographic information, informed consent, and Inclusion/Exclusion eCRF pages must also 
be completed for Screen Failure patients. No other data will be entered into the clinical 
database for patients who are screen failures, unless the patient experienced a Serious Adverse 
Event during the Screening Phase (see Section 8 for SAE reporting details). If the patient fails 
to be enrolled, the IRT must be notified within 2 days of the screen fail that the patient was 
not enrolled. 
The following eCRFs must be completed for screening failure patients: 
• Screening Phase Disposition page 
• Informed consent 
• Demography 
• Adverse Events (only if an SAE occurs. Refer to Section 8.1.1.) 
• Inclusion/Exclusion Criteria 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 800 
Protocol No. CLDK378A2407 
 
 
 
 
 
7.2.1.2 
Patient demographics and other baseline characteristics 
 
Data to be collected on patient characteristics at screening include: 
• Demography (including: date of birth, age, gender, childbearing potential, race and 
ethnicity or as allowed by local regulations) 
• Relevant medical history 
• Smoking history 
• Tumor diagnosis and extent of disease, including: 
• Date of diagnosis and tumor stage at diagnosis 
• Site of active disease 
• Characteristics of disease 
• Prior antineoplastic therapies (medications, radiation, surgeries) 
• Prior and Concomitant Medications, surgical and medical procedures 
Note: All other medications taken within 28 days before the first dose of study treatment is 
administered must be recorded on the Prior and Concomitant medication eCRF page and 
updated on a continual basis if there is new change to the medication. 
 
7.2.2 
Treatment period 
Following completion of screening procedures and verifying patient eligibility, the patient 
will be enrolled via the IRT. Study treatment will begin on Cycle 1, Day 1 with the first 
administration of ceritinib. Cycle 1, Day 1 must occur within 28 days of screening date. 
 
7.2.2.1 
General guidelines 
Patients will be assessed as per visit schedule in Table 7-1. 
Visit windows of ± 1 days for Cycle 1 and ± 3 days for Cycle 2 and beyond from the 
scheduled study assessments will apply in all cycles. The only exception is imaging 
assessments, which have a ± 7 day window at all scheduled time points. If a given visit is out 
of window, the next visit should be performed with reference to the day of first dose in order 
to get the patient back on schedule. 
Patients will begin treatment on Day 1. Patients will self-administer study treatment at home 
daily. 
Note: If treatment with ceritinib is withheld at any time during the study, all study visits, 
safety and efficacy assessments should continue according to the appropriate number of 
calendar days from Cycle 1 Day 1 as per the schedule of assessments. 
 
 
 
 
 
 
 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 810 
Protocol No. CLDK378A2407 
 
 
 
 
 
7.2.3 
End of treatment (EOT) visit including study treatment discontinuation 
and premature withdrawal 
 
7.2.3.1 
Study treatment discontinuation 
Patients may voluntarily withdraw from study treatment at any time. In this situation, the 
patient should be encouraged to consent to be followed for tumor assessments until the 
development of Progressive Disease as assessed by the investigator. 
Patients must permanently stop the study treatment if one of the following occurs: 
• Pregnancy 
• Study Terminated by Sponsor 
• Patient/guardian decision 
• Physician decision 
• Lost to follow-up 
• Death 
Patients may permanently stop the study treatment for one of the following reasons: 
• Progression of disease (for example radiological as assessed by investigators for solid 
tumors) 
• AEs 
• Non-compliance with study treatment 
• Technical Problems 
• Protocol deviation 
Patients who become pregnant during the trial must be withdrawn (Section 8.4). Patients who 
become pregnant must cease all tumor assessments regardless of whether or not they 
developed Progressive Disease. 
Patients who discontinue ceritinib during the treatment phase should be scheduled for a visit 
within 7 days or as soon as possible after the last dose of study treatment, at which time all of 
the assessments listed for the EOT visit will be performed. If a patient withdraws from 
treatment at a study visit, EOT assessments do not need to be repeated. An End of Treatment 
Phase Disposition eCRF page should be completed, specifying the date of the subject’s last 
participation in the treatment study phase and reason for stopping study treatment. 
Patients who have RECIST, RANO or Cheson defined Progressive Disease, but who, in the 
opinion of the investigator, have evidence of continued clinical benefit from ceritinib may 
continue to receive this drug. These patients will continue assessments as detailed in Table 7- 
1 treatment phase except for the tumor assessments. In such cases, patients must complete the 
EOT visit only after permanent discontinuation of ceritinib. 
If patients refuse to return for these visits or are unable to do so, every effort should be made 
to contact them. Patients who discontinue study treatment should be considered withdrawn 
from the study after the final visit assessments are performed or when it is clear that the 
patient will not return for these assessments. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 820 
Protocol No. CLDK378A2407 
 
 
 
 
 
7.2.3.1.1 Additional guidance for premature withdrawal 
If a patient will have no further study data collected because he/she withdraws from the study 
completely, the investigator must determine the primary reason for a patient’s premature 
withdrawal from the study and record this information on the EOT Disposition eCRF as 
applicable. The investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 
Patients may voluntarily withdraw from the study or be discontinued from the study at the 
discretion of the investigator at any time. The Investigator must contact the IRT to register the 
subject’s discontinuation. 
 
7.2.3.2 
Replacement policy 
Patients lost to follow-up or withdrawing consent from the study without observed response 
rate will be censored for the primary analysis and will not be replaced. 
 
7.2.4 
Follow up period 
 
7.2.4.1 
Safety follow-up 
All patients will be followed for AEs and SAEs for at least 30 days following the last dose of 
study treatment at the end of treatment phase. At the end of this period, the investigator should 
assess and discuss with the patient any AE observed/concomitant medication taken since 
discontinuation of study treatment. 
Patients whose treatment is permanently discontinued due to an AE (clinical or based on 
abnormal laboratory value) must be followed until resolution or stabilization of the event, 
whichever comes first. In case of an abnormal laboratory value, blood tests should be repeated 
until resolution or stabilization. 
 
7.2.4.2 
Lost to follow-up 
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, 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. 
 
7.3 
Assessment types 
7.3.1 
Efficacy assessments 
Tumor response will be assessed by the investigator according to the Novartis guideline 
version 3.1 based on RECIST 1.1 (Eisenhauer et al 2009) for solid tumors; The Revised 
Assessment in  Neuro-Oncology  (RANO)  and  RECIST  1.1  criteria  for  Glioblastoma 
(Wen et al 2010) and Response Criteria for Malignant Lymphoma (Cheson et al 2007). 
Patients should have at least one documented measurable lesion at study entry as per RECIST 
1.1.; RANO and Cheson criteria. The imaging assessment collection plan is presented in 
Table 7-2. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 830 
Protocol No. CLDK378A2407 
 
 
 
 
 
At screening (within 28 days of the start of ceritinib), patients will undergo CT with i.v. 
contrast or MRI or PET-CT (lymphoma patients). 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. If there is 
clinical evidence of disease in the bone marrow at screening, bone marrow aspirate biopsies 
must be performed (for ALCL patients only). 
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 
 
Table 7-2 
Imaging assessment collection plan 
 
Procedure 
Screening/Baseline 
During Treatment/ EOT 
CT or MRI or PET-CT of Chest, 
Pelvis and Abdomen 
Mandated 
For GBM patients: If 
there is clinical 
evidence of disease 
Mandated, every 8 weeks (± 7 days) 
from C1D1 to C6D1. For subsequent 
sycles, every 12 weeks (± 7 days) 
after C6D1. 
For the EOT, only to be performed if 
the last assessment was more than 
8 weeks. 
Brain CT or MRI 
Mandated 
If clinically indicated or positive at 
baseline, follow same schedule as 
CT/MRI of chest and abdomen 
Whole body bone scan 
Only if clinically 
indicated 
If clinically indicated 
• 
CT scan or MRI of other 
metastatic sites (e.g., neck etc.) 
• 
Localized bone CT scan, MRI or 
x-ray (for any lesions identified 
on the whole body bone scan 
that are not visible on the 
chest/abdomen (and pelvis if 
applicable) CT scan or MRI) 
Only if clinically 
indicated 
If clinically indicated or positive at 
baseline, follow same schedule as 
CT/MRI of chest and abdomen 
 
7.3.1.1 
Baseline imaging assessment 
Imaging assessments will be performed at screening/baseline Day -28 to Day -1 prior to Cycle 
1 Day 1. Any imaging assessments already completed during the regular work-up of the 
patient within 28 days prior to start of treatment, including before signing the main study ICF, 
can be considered as the baseline images for this study. 
The following assessments are required at screening/baseline: 
• CT scan or MRI or PET-CT (lymphoma patients) of chest, pelvis and abdomen. For GBM 
patients only if there is clinical evidence of disease. 
• CT scan or MRI of brain 
The following assessments are required at screening if clinically indicated: 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 840 
Protocol No. CLDK378A2407 
 
 
 
 
 
• Additional CT scan or MRI of other metastatic sites (e.g., neck,etc.) 
• Localized bone CT scan, MRI or x-ray (for any lesions identified on whole body bone 
scan not visible on chest/abdomen (and pelvis if applicable) CT scan or MRI) 
• Whole body bone scan 
If a patient is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts, however if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen 
and pelvis (as applicable) should be performed. 
Brain, MRI or CT scan should be completed in order to assess CNS disease. Contrast 
enhanced brain MRI is preferred, however, if MRI contrast is contraindicated, then brain MRI 
without contrast or brain CT with/without contrast is acceptable. 
A whole body bone scan should be performed per institutional standard of care if clinically 
indicated to detect any skeletal metastases present [e.g., Tc-99 bone scan, whole body bone 
MRI, FDGPETor sodium fluoride positron emission tomography (NaF PET)]. Localized CT, 
MRI or Xrays should be acquired for all skeletal lesions identified on the screening bone scan, 
which are not visible on the chest, abdomen and pelvis CT/MRI. 
If clinically indicated, CT or MRI of other areas (neck,etc) of disease as appropriate should be 
performed. 
 
Required conditions for baseline tumor assessment: 
• Patients must have measurable disease as per RECIST 1.1, RANO and Cheson. 
Measurable (“target”) lesions include lytic or mixed (lytic + blastic) bone lesions with an 
identifiable soft tissue component that meets the measurability criteria per RECIST 1.1. 
• Patients with only non-measurable lesions are not eligible. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
Any potentially measurable lesion that has been previously treated with radiotherapy should 
be considered as a non-measurable (“non-target”) lesion. However, if a lesion previously 
treated with radiotherapy has clearly progressed since the radiotherapy, it can be considered as 
a measurable lesion. 
All measurable lesions up to a maximum of 5 nodal and/or non-nodal lesions in total (and a 
maximum of 2 lesions per organ), representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline. 
 
7.3.1.2 
Subsequent imaging for response assessment 
Tumor evaluations as described in Table 7-2 should be performed using the same imaging 
modality used at baseline, irrespective of study treatment interruption or actual dosing (see 
Table 7-1). Tumor assessment for response determination will be made every 8 weeks starting 
from C1D1 (+/- 7 days window) until C6D1. For subsequent cycles, every 12 weeks (+/- 7 
days window) ater C6D1. Scheduled assessments should be respected regardless of whether 
treatment with ceritinib is temporarily withheld. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 850 
Protocol No. CLDK378A2407 
 
 
 
 
 
Clinical suspicion of disease progression at any time requires a physical examination and 
radiological confirmation to be performed promptly rather than waiting for the next scheduled 
radiological assessment. 
Each lesion that is measured at baseline must be measured by the same method (either same 
radiological method or by photography, including a metric ruler) and when possible, the same 
local radiologist/physician throughout the study so that the comparison is consistent. If an off 
schedule imaging assessment is performed because progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule. 
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of oral and IV contrast media. 
If an off-schedule scan is performed for response confirmation purposes, subsequent imaging 
assessments should be performed in accordance with the original imaging schedule. 
 
7.3.2 
Safety and tolerability assessments 
Safety will be monitored by assessing (list the assessments) as well as collecting of the 
adverse events at every visit. For details on AE collection and reporting, refer to Section 8. 
 
7.3.2.1 
Physical examination 
Physical examinations will include an examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, and a basic nervous system evaluation. Information about the physical 
examination must be present in the source documentation at the study center. For the 
assessment schedule refer to Table 7-1. 
Significant findings that were present prior to the signing of informed consent must be 
included in the Medical History page on the patient’s eCRF. Significant new findings that 
begin or worsen after informed consent must be recorded on the Adverse Event page of the 
patient’s eCRF. 
 
7.3.2.2 
Vital signs 
Vital signs include body temperature, blood pressure, respiratory rate and pulse 
measurements. Blood pressure (systolic and diastolic) and pulse should be measured after the 
patient has been sitting for five minutes. 
For the assessment schedule refer to Table 7-1. 
 
7.3.2.3 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured. Height will be measured at screening only. For 
the assessment schedule for weight refer to Table 7-1. 
 
7.3.2.4 
Performance status 
Performance status may be performed within 3 days prior to the start of a cycle. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 860 
Protocol No. CLDK378A2407 
 
 
 
 
 
WHO performance status will be assessed as per the assessment schedule (refer to Table 7-1) 
in adult patients 18 years and older. 
Assessment of WHO performance status (Table 7-3) will be performed within the time 
windows described of the scheduled assessment, even if study treatment is being held. More 
frequent examinations may be performed at the investigator’s discretion, if medically 
indicated. 
 
Table 7-3 
WHO performance status scale 
 
Score 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g. light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
7.3.2.5 
Laboratory evaluations 
Central laboratories will be used for the analysis of scheduled biochemistry and ALK 
confirmatory testing (as detailed in Table 7-1). Hematology tests will be performed locally. 
Dipstick urinalysis will be performed locally. Laboratory values obtained during the 
Screening phase will be used to assess patient’s eligibility. The time windows granted for 
laboratory evaluations are identical to the corresponding visit time windows for each visit 
(refer to Section 7.1). 
Details on the collection, shipment of samples and reporting of results by the central 
laboratory are provided to investigators in a separate [Laboratory Manual]. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 870 
Protocol No. CLDK378A2407 
 
 
 
 
 
Table 7-4 
Clinical laboratory parameters collection plan 
 
Test Category 
Test Name 
Hematology 
Hemoglobin, Platelets, Red blood cells (RBC), White blood cells (WBC) with 
Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils in percentage or 
absolute) 
Chemistry 
Albumin, ALT, AST, calcium (at screening calcium corrected for albumin will be 
tested in addition to calcium), creatinine, creatinine clearance, total bilirubin, 
direct bilirubin (only if total bilirubin is ≥ grade 2), blood urea nitrogen (BUN) or 
urea, magnesium, potassium, sodium, fasting glucose, phosphate (inorganic 
phosphorus), alkaline phosphatase, amylase, lipase, GGT 
Urinalysis 
Macroscopic Panel (Dipstick) (Color, bilirubin, Blood, Glucose, Ketones, 
Leukocyte esterase, nitrite, pH, protein, specific gravity, urobilinogen) 
Microscopic panel (RBC, WBC, casts, crystals, bacteria, epithelial cells) 
Coagulation 
International normalized ratio [INR] 
Pregnancy 
At screening visit, serum pregnancy test 
At subsequent cycles, urinary pregnancy test. 
If local requirements dictate otherwise, local regulations should be followed 
Hormones (males 
only) 
Testosterone (total and free), LH, FSH, sex hormone binding globulin (SHBG) 
 
7.3.2.5.1 Hematology 
Hematology assessments of the parameters listed in Table 7-4 will be tested as per the 
schedule of assessments (Table 7-1). 
 
7.3.2.5.2 Clinical chemistry 
Blood chemistry assessments of the parameters listed in Table 7-4 will be tested as per the 
schedule of assessments (Table 7-1). 
 
7.3.2.5.3 Urinalysis 
Dipstick measurements will be performed as per Table 7-4 and according to the schedule of 
assessments. Any significant findings on dipstick will be followed up with microscopic 
evaluation as per Table 7-4. 
 
7.3.2.5.4 Pregnancy and assessments of fertility 
During screening, a serum pregnancy test will be completed (Day -28 to Day -1). On cycle 1 
Day 1 prior to dosing and at subsequent cycles and at EOT, urinary pregnancy test (dipstick) 
will be performed. The time windows granted for pregnancy testing are identical to the 
corresponding visit time windows for each visit. Refer to Table 7-1. If local requirements 
dictate otherwise, local regulations should be followed. 
When non-child bearing potential status is determined during the study, further pregnancy 
testing will not be continued. Women are considered post-menopausal if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms), and otherwise not of child bearing potential if 
they have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 880 
Protocol No. CLDK378A2407 
 
 
 
 
 
ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential (such testing is not covered as part of the study 
assessments). If local requirements dictate otherwise, local regulations should be followed. 
The time windows granted for pregnancy testing are identical to the corresponding visit time 
windows for each visit. Refer to Table 7-1. 
If a positive pregnancy test is performed in between study visits, the patients must 
immediately notify the investigator. 
 
7.3.2.5.5 Hormones 
Testosterone (total and free), LH, FSH and SHBG will be tested in male patients only and as 
per the schedule of assessments (Table 7-1). 
 
7.3.2.5.6 Coagulation 
International normalized ratio (INR) 
 
7.3.2.6 
Cardiac assessments 
 
7.3.2.6.1 Electrocardiogram (ECG) and blood pressure 
Standard 12-lead ECG assessment will be performed locally on all patients as per the 
schedule of assessments (Table 7-1). At screening, (as means of triplicate ECGs) ECGs will 
be assessed at C1, C2 and C3. For subsequent cycles, may be performed at the discretion of 
the investigator. 
An ECG may be repeated at the discretion of the investigator at any time during the study and 
as clinically indicated. 
Interpretation of the tracing must be made by a qualified physician. Each ECG tracing should 
be labeled with the study number, patient initials (where regulations permit), patient number, 
ECG actual date, measured variables (QT), derived variables (QTcF, and HR) and kept in the 
source documents at the study site. Clinically significant abnormalities present when the 
patient signed informed consent should be reported on the Medical History eCRF page. 
Clinically significant findings must be discussed with Novartis prior to enrolling the patient in 
the study. New or worsened clinically significant findings occurring after informed consent 
must be recorded on the Adverse Events eCRF page. 
 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 890 
Protocol No. CLDK378A2407 
 
 
 
 
 
 
 
 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 900 
Protocol No. CLDK378A2407 
 
 
 
 
 
 
 
7.3.5 
Resource utilization 
Not Applicable. 
 
7.3.6 
Patient reported outcomes 
Not Applicable. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 910 
Protocol No. CLDK378A2407 
 
 
 
 
 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s eCRF. Adverse event monitoring should 
be continued for at least 30 days following the last dose of study treatment. Adverse events 
(including laboratory abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a  separate 
Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected though a Death eCRF. 
Abnormal laboratory values or test results occurring after signing the ICF constitute adverse 
events only if they induce clinical signs and symptoms, or require therapy, (e.g., any 
hematologic abnormality that requires transfusion of hematological stem cell support) or 
changes in medication(s) are considered clinical significant and should be recorded on the 
Adverse Event eCRF under signs, symptoms or diagnosis associated with them. In addition, 
isolated abnormal laboratory values that are considered clinical significant (e.g. cause study 
discontinuation or constitute in and of itself a Serious Adverse Event) should be recorded on 
the Adverse Events eCRF. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1-4) 
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 920 
Protocol No. CLDK378A2407 
 
 
 
 
 
4. Action taken with respect to study or investigational treatment (none, dose adjusted 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy 
concomitant medication/non-drug therapy) 
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event 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 the study treatment, the interventions 
required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST 1.1 criteria for solid tumors, RANO and RECIST 1.1 
criteria for GBM or as per Cheson's guidelines for hematological malignancies), should not be 
reported as a serious adverse event. 
Whenever possible, a diagnosis should be reported instead of underlying signs and symptoms. 
 
8.1.2 
Laboratory test abnormalities 
 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such. 
 
8.1.3 
Adverse events of special interest 
Adverse events of special interest to be monitored for ceritinib have also been identified and 
include: hepatotoxicity, interstitial lung disease/pneumonitis, QT interval prolongation, 
bradycardia, hyperglycemia gastrointestinal toxicity (nausea, vomiting and diarrhea) and 
pancreatitis (including lipase and amylase elevations). 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 930 
Protocol No. CLDK378A2407 
 
 
 
 
 
Details regarding these adverse events are provided in the [Investigator’s Brochure] for 
ceritinib. Potential emergent new AEs will be monitored during the course of the study. 
 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 940 
Protocol No. CLDK378A2407 
 
 
 
 
 
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. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
If the SAE is not previously documented in the [Investigator’s Brochure] or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries 
 
8.3 
Emergency unblinding of treatment assignment 
Not applicable. This is an open-label study. 
 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis immediately (within 24 hours) of learning of its occurrence. 
Patients who become pregnant during the trial must be withdrawn. The pregnancy will be 
followed up from the estimated date of delivery plus 3 months to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis DS&E. Pregnancy follow-up should be recorded on the 
same form and should include an assessment of the possible relationship to the investigational 
treatment of any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment. A pregnancy outcome informed consent will be provided by Novartis. Consent to 
report information regarding these pregnancy outcomes should be obtained from the mother. 
Women of childbearing potential should be advised to use highly effective contraception 
methods while they are receiving study treatment and up to 3 months after treatment has been 
stopped. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 950 
Protocol No. CLDK378A2407 
 
 
 
 
 
If a pregnancy occurs while on study treatment, the newborn will be followed for at least 3 
months. 
 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
 
8.6 
Data Monitoring Committee 
Not applicable. 
 
8.7 
Steering Committee 
Not applicable. 
 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 960 
Protocol No. CLDK378A2407 
 
 
 
 
 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results. 
 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan. 
 
9.3 
Data collection 
Electronic Data Capture (EDC) is used for this study. The designated investigator staff will 
enter the data required by the protocol into the electronic Case Report Forms (eCRFs). The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies in 
the eCRFs and, allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator (PI) is responsible for assuring that the data entered into eCRFs is 
complete, accurate, and that entry and updates are performed in a timely manner. 
Blood samples for biochemistry, ALK confirmatory testing 
 will be collected 
by sites and sent to a central laboratory for processing. 
Blood samples for hematology tests will be processed and analyzed locally. 
Radiological and ECG data will be acquired by the sites and interpreted locally. 
In addition, data entered into IRT for screening, discontinuation, and patient identifiers (i.e. 
date of birth, gender, and patient ID) will be transferred electronically to Novartis as described 
in the Data Transfer Specification for designated IRT vendor. 
 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 970 
Protocol No. CLDK378A2407 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staffs are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). Data that will be processed centrally includes: 
• IRT data including information regarding screening, subsequent drug assignments and 
discontinuation 
• Centrally analyzed laboratory data including chemistry, 
 
 
Data about all study treatments dispensed to the patient will be tracked using IRT. The system 
will be supplied by the vendor(s), who will also manage the database. The data will be sent 
electrically to Novartis personnel. 
At the conclusion of the study, the occurrence of any protocol deviations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and the data available for data analysis. 
Authorization is required prior to making any database changes to locked data, by joint 
written agreement between Global Head of Biostatistics and Data Management and the Global 
Head of Clinical Development 
After database lock, the investigator will receive a CD-ROM or paper copies of the patient 
data for archiving at the investigative site. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 980 
Protocol No. CLDK378A2407 
 
 
 
 
 
10 
Statistical methods and data analysis 
10.1 
Analysis sets 
A patient is considered to be enrolled into the study if he/or she has signed informed consent. 
Only a patient who has signed informed consent will be included in the analysis data sets. 
 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients who receive at least one dose of Ceritinib. 
Unless otherwise specified the FAS will be the default analysis set used for all efficacy 
analyses, including the primary efficacy analysis. 
 
10.1.2 
Safety Set 
The Safety Set includes all patients who received at least one dose of study medication. 
 
10.1.3 
Per-Protocol Set 
Not applicable. 
 
10.1.4 
Dose-determining analysis set 
Not applicable. 
 
 
10.1.6 
Other analysis sets 
Not applicable. 
 
10.1.6.1 Efficacy/evaluable set 
Not applicable. 
 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for all patients by arm for the FAS. Categorical data will be presented as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 990 
Protocol No. CLDK378A2407 
 
 
 
 
 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
The actual dose and duration in days of ceritinib as well as the dose intensity (computed as the 
ratio of total dose received and actual duration) and the relative dose intensity (computed as 
the ratio of dose intensity and planned dose intensity received/planned duration), will be listed 
and summarized for all patients by arm. 
Dose reductions and dose interruptions delays (including the reasons for these) will be listed 
and summarized by arm. 
The safety set will be used. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized for all patients by arm. 
 
10.4 
Primary objective 
The primary objective is to assess the Disease Control Rate associated with ceritinib treatment 
based on local investigator assessment. 
 
10.4.1 
Variable 
The variable used to evaluate the primary objective is Disease Control Rate associated with 
ceritinib treatment based on local investigator assessment. For patients with solid tumors the 
assessment criteria will be RECIST 1.1 and will include responses of CR or PR or SD ≥ 16 
weeks after the first dose the study drug. For GBM, RANO and RECIST 1.1 response criteria 
will apply. For hematologic tumors, Cheson response criteria will apply. 
 
10.4.2 
Statistical hypothesis, model, and method of analysis 
This study will contain 5 arms with ALK+ patients, an adaptive design will be used to assess 
activity of treatment in terms of response (DCR) rate within each arm and across each arm. 
The rules for how the trial adapts are pre-specified and are not based on ongoing data. 
The design of the trial adapts to the data that are accumulated in the trial in such a way as to 
accommodate two possibilities: 
a. DCR to ceritinib is specific to ALK+ inhibition and independent of the tumor site (similar 
DCR irrespective of tumor type); 
b. the various tumor types have distinct DCR to ceritinib. 
The pre-specified analysis is adaptive in the sense that when response depends on ALK+ 
inhibition and not on arm (scenario A), then it borrows from across the various arms and 
provide more precise estimate of DCR rates for those arms with similar response rates. In the 
other possibility (the various arms have distinct anti-tumor activity to ceritinib (Scenario B), 
the design allows little/no borrowing across tumor types. In this case the trial will be similar  
to traditional stratified analysis. 
A hierarchical model (HM) will be used to analyze the binary data to facilitate the borrowing 
as specified above. Response rates (πj) will be inferred for arm j (= 1,…,5). For each arm j, 
the number of responders follows a binomial distribution; 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1000 
Protocol No. CLDK378A2407 
 
 
 
 
 
rj ~ Bin( nj, π j ) 
We further let the parameters log ( πj/ (1 − πj) ) (logistic transformation) be either 
exchangeable with some of the arms, or non-exchangeable with any of them. Based on the 
number of strata in this trial, we allow for two exchangeability distributions, which, for 
example, accounts for the case where some arm show no efficacy and some are promising. 
Thus, for each arm j three possibilities arise, with respective probabilities pj = ( pj1, pj2, pj3 ),  
as follows: 
1. With probability pj1 the parameter θj follows a normal distribution with exchangeability 
parameters µ1 and τ1: 
θj ~ N(µ1,τ12) 
2. With probability pj2, θj follows a normal distribution with exchangeability parameters µ1 < 
µ2 and τ2: 
θj ~ N(µ2,τ22) 
3. With remaining probability pj3 = 1−pj1−pj2, θj follows a weakly-informative prior 
distribution 
θj ~ N(mw,vw) 
For the detailed specifications of mw, vw, the a-priori weights pj (j=1,…,J), and the prior 
distributions for µ1, τ1, µ2, and τ2, see (Appendix 5). At any given time of the trial, including 
at the end, posterior probabilities of the various parameters will be estimated using Markov 
chain Monte Carlo methods. 
For a specific disease group, a Proof of Concept about treatment with ceritinib will be 
declared if both of the following conditions are met: 
a. Observed DCR ≥ “Disease Control Rate” threshold (column for C2 in Table 10-1) 
b. Posterior probability of “not being clinically meaningful” (column for C1 in Table 10-1) is 
less than 20% 
 
10.4.3 
Handling of missing values/censoring/discontinuations 
Confirmed partial or complete responses of stable disease reported prior to any additional 
anticancer therapy will be considered as responses in the calculation of the DCR irrespective 
of the number of missed assessments before response. 
For solid tumor, patients with a best overall response of ‘Unknown’ or ‘Not Assessed’ per 
RECIST v1.1 will be considered as non-responders and will be included in the denominator in 
estimating the DCR. For GMB or hematologic tumor, patients with unknown or missing 
response, or who are treated in the study but provide no information on response at the end of 
treatment will be treated as non-responders and will be included in the denominator when 
calculating DCR. 
 
10.4.4 
Supportive analyses 
Not applicable. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1010 
Protocol No. CLDK378A2407 
 
 
 
 
 
10.5 
Secondary objectives 
All secondary efficacy assessments (DOR, ORR, PFS, TTR) will be analyzed as per 
investigator assessment. Confirmation of response is required for all response endpoints, as 
per appropriate critetia (RECIST 1.1 for solid tumor, RANO and RECIST 1.1 for GMB, and 
Cheson for hematologic tumor) 
All secondary analyses will be performed based on the FAS for each arm, unless otherwise 
specified. 
No adjustment for multiple testing will be made. 
10.5.1 
Secondary objective(s) 
Overall Response Rate 
Overall Response Rate (ORR) is based on local investigator assessment per RECIST 1.1, 
RANO or Cheson criteria. For patients with solid tumors, the assessment criteria will be 
RECIST 1.1 and will include responses of CR and/or PR. For hematologic tumors, Cheson 
criteria will apply for evaluation of response and for GBM, RANO and RECIST 1.1 criteria 
will be used for response. ORR is defined as the proportion of patients with best overall 
response of CR, PR. For ORR, estimate and its 95% CI provided. 
 
Duration of Response 
Duration of Response (DOR) will be based on local investigator assessment per RECIST 1.1 
for solid tumor, RANO and RECIST 1.1 for GBM, or Cheson criteria for hematologic tumors. 
Among patients with a confirmed response (PR or CR), DOR is defined as the time from first 
documented response (PR or CR) to the date of first documented disease progression or death 
due to any cause. If a patient has not had an event, DOR is censored at the date of last 
adequate tumor assessment. DOR will be listed by patient and may be described using 
Kaplan-Meier curves and relevant statistics if appropriate. 
 
Time to response 
Time to response (TTR) is defined as the time from the date of the first dose of LDK378 to 
first documented response (CR or PR, which must be confirmed subsequently) per appropriate 
critetia (RECIST 1.1 for solid tumor, RANO and RECIST 1.1 for GMB, and Cheson for 
hematologic tumor). TTR will be described using Kaplan-Meier methods and appropriate 
summary statistics. The TTR analysis will be conducted with censoring rules as described in 
the Appendix 2. 
 
Progression-free survival 
Progression-free survival (PFS) is defined as the time from the date of first dose of Ceritinib 
to the date of first documented disease progression per appropriate critetia (RECIST 1.1 for 
solid tumor, RANO and RECIST 1.1 for GMB, and Cheson for hematologic tumor) or death 
due to any cause. 
A patient who has not progressed or died at the date of the analysis or when he/she receives 
any further anticancer therapy in the absence of disease progression will be censored at the 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1020 
Protocol No. CLDK378A2407 
 
 
 
 
 
time of the last adequate tumor evaluation before the earlier of the cut-off date or the 
anticancer therapy date. By default, if disease progression or death is documented after one 
single missing tumor evaluation, the actual event date of disease progression/death will be 
used for the PFS event date. If disease progression or death is documented after two or more 
missing tumor evaluations, the PFS time of these patients will be censored at the date of the 
last adequate tumor evaluation without PD. 
If the study primary objective is not met (did not met Proof of Concept criteria) for a given 
arm, Novartis may decide not to conduct some of the above secondary efficacy analyses in 
that arn but instead may choose to provide those endpoints in listings only. 
 
10.5.2 
Other secondary efficacy objectives 
Not applicable 
 
10.5.3 
Safety objectives 
 
10.5.3.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
arm and for all patients within the arm. 
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. post-treatment period: starting at day 31 after last dose of study medication. 
 
10.5.3.2 Adverse events (AEs) 
Summary tables for AEs will include only AEs that started or worsened during the on- 
treatment period. However, all safety data (including those from the pre- and post-treatment 
periods) will be listed and those collected during the pretreatment and post-treatment period 
will be flagged. 
The incidence of AEs will be summarized by system organ class and/or preferred term, 
maximum severity (based on Common Terminology Criteria for Adverse Events [CTCAE] 
grades version 4.03), and relation to study drug. 
Clinically notable adverse events (CNAEs) will be considered. Such categories consist of one 
or more well-defined safety events which are similar in nature and for which there is a 
specific clinical interest in connection with the study treatment. 
CNAEs SEC will be defined at the project level and may be regularly updated based on 
emergent data. For each specified CNAE SEC, number and percentage of patients with at 
least one event in each CNAE category will be reported 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1030 
Protocol No. CLDK378A2407 
 
 
 
 
 
10.5.3.3 Laboratory abnormalities 
For laboratory tests covered by the CTCAE version 4.03, the study’s biostatistical and 
reporting team will grade laboratory data accordingly. For laboratory tests covered by 
CTCAE, a Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
Further details will be specified in the statistical analysis plan (SAP). Grade 5 will not be 
used. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
A listing of laboratory values will be provided by laboratory test, patient, and study day. A 
separate listing will display notable laboratory abnormalities (i.e., newly occurring CTCAE 
grade 3 or 4 laboratory abnormalities). 
The following summaries will be generated separately for hematology and biochemistry 
laboratory tests: 
• shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
• for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) 
• listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges. 
A separate listing will display notable laboratory abnormalities (i.e. newly occurring CTCAE 
grade 3 or 4 laboratory toxicities). 
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the SAP. 
 
10.5.3.4 Other safety data 
Data from other tests (including ECGs and vital signs) will be summarized and listed, notable 
values will be flagged, and any other information collected will be listed as appropriate. 
Definitions of notably abnormal results will be provided in theSAP. 
 
10.5.3.5 Supportive analyses for secondary objectives 
Not applicable. 
 
10.5.3.6 Tolerability 
Tolerability will be summarized in terms of dose reductions or drug interruption or 
discontinuation due to an AE. 
 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1040 
Protocol No. CLDK378A2407 
 
 
 
 
 
Data handling principles 
 
10.5.5 
Biomarkers 
Not applicable 
 
10.5.5.1 Outline of the data analysis 
Not applicable 
 
10.5.5.2 Data handling principles 
Not applicable 
 
10.5.5.3 Data analysis principles 
Not applicable. 
 
10.5.5.3.1 
Analysis sets 
Not applicable. 
 
10.5.5.3.2 
Basic tables, figures and listings 
Not applicable. 
 
10.5.5.3.3 
Advanced analysis methods 
Not applicable. 
 
10.5.6 
Resource utilization 
Not applicable. 
 
10.5.7 
Patient-reported outcomes 
Not applicable. 
 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1050 
Protocol No. CLDK378A2407 
 
 
 
 
 
 
10.7 
Interim analysis 
Subjects will be continuously accrued and the data will be analyzed using a Bayesian 
hierarchical model mentioned in Section 10.4.2. Interim analysis for an arm will be performed 
when a predefined number of patients (5 for IMT or T2 and 10 for all other tumor type) are 
enrolled and have completed 16 weeks of follow-up after the first dose of study drug and have 
their responses confirmed by a subsequent assessment at least 4 weeks later. At each of these 
analyses, the current (posterior) probability that the response rate for each of the tumor types 
is greater than “clinically meaningful threshold (column for C2 in Table 10-1)” will be 
determined. 
These probabilities will be used to adapt the design. All available data will be used for 
analysis at the interim. However, a decision will be made only for arm with minimum number 
of pre-specified patients (a minimum of 5 patients in IMT arm or a minimum of 10 patients 
for any of the other arm). For a specific arm, a decision will be made based on the calculated 
probability as given below: 
1. Accrual to an arm (having at least predefined number of subjects) will cease for futility if 
it is very unlikely (posterior probability <20%) that the response rate for the arm is 
“clinically meaningful” (≥column for C2 in Table 10-1) 
2. Otherwise, recruitment will be extended for 10 more patients in that arm (including IMT). 
Accrual to an arm will cease when its maximum planned sample size is reached (15 for 
IMT or T2 and 20 for each of other arms). The results within an arm will be regarded as 
positive if the accrual for the arm reaches maximum and the conditions for positive 
conclusion [Section 10.4.2] are satisfied. 
Depending on enrollment and follow-up, there may be multiple interim analyses. 
 
Table 10-1 
Type of tumors of interest with definition of being clinically 
meaningful 
 
Disease 
Code 
Arm 
#Patients† 
at Interim 
Not Clinically 
meaningful (C1) 
Clinically 
meaningful (C2) 
T1 
Anaplastic large cell 
lymphoma (ALCL) 
10 
≤40% 
≥50% 
T2 
Inflammatory myofibroblastic 
tumor (IMT) 
5 
≤20% 
≥30% 
T3 
Glioblastoma 
10 
≤10% 
≥20% 
T4 
Inflammatory breast cancer 
10 
≤10% 
≥20% 
T5 
Any other ALK+ tumor 
10 
≤10% 
≥20% 
† Extend recruitment for 10 more patients in each arm according to IA outcome [p(clinically 
meaningful)>20%]. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1060 
Protocol No. CLDK378A2407 
 
 
 
 
 
Note that if there are at least 5 patients of the same arm in “Any other ALK+ tumor, T5)” arm, 
then a separate arm will be opened for that specific tumor type leading to a total of 6 different 
arms. However, interim analysis for decision making will not be performed until there are 10 
patients in each of the arm: “new tumor type” and modified “Any other ALK+ tumor”. 
 
10.8 
Sample size calculation 
The design of this study is adaptive in nature; hence, the final sample size is not fixed. A 
minimum of 10 and a maximum of 20 subjects in each arm T1, T3, T4 and T5 will receive 
treatment. For arm T2, the minimum and maximum sample size will be 5 and 15 respectively. 
Thus, the total sample size across all tumor types will be between 45 and 95. Assuming a 10% 
drop out rate, approximately 106 patients are planned to be enrolled in this study. 
Subjects will be continuously accrued, and, the accumulated data will be analyzed at interim 
as described in Section 10.7. Based upon the results of any of these analyses, enrollment into 
one or more arms may be terminated. 
The operating characteristics for this Bayesian Design are evaluated using simulation and are 
presented below. Simulation-based probability estimates (relative frequencies) of futility at 
interim, positive results at final analysis and average sample size for each arm in three 
scenarios are provided. 
1. Scenario 1 (not clinically meaningful for all arms): The true rates of response for T1, T2, 
T3, T4, and T5 are 40%, 20%, 10%, 10%, and 10%; respectively; 
2. Scenario 2 (clinically meaningful for all arms): The true rates of response for T1, T2, T3, 
T4, and T5 are 60%, 40%, 30%, 30%, and 30%; respectively; 
3. Scenario 3 (clinically meaningful for T1 and T4 but not for others): The true rates of 
response for T1, T2, T3, T4, and T5 are 60%, 20%, 10%, 10% and 30%; respectively; 
In all three cases it is assumed that accrual rates are in proportion 2:1:2:2:2 for the 5 arms (T1, 
T2, T3, T4, and T5). The type I error (false positive rate) of the adaptive design can be viewed 
as the probability estimate of a positive conclusion at final analysis in Scenario 1 (Table 10- 
2). The power of the adaptive design is defined as the probability estimate of positive 
conclusion at final analysis in Scenario 2 (Table 10-3). 
The simulation results for Scenario 1, when the effect of Ceritinib is not-clinically meaningful 
(true response rates equal 40% and 20 % and 10% for T1 and T2 and for other 3 arms 
respectively), show that the probability of stopping at interim for futility varies from 41.7% to 
59.9% for different arm. Probability of concluding positive trial at final analysis (i.e., crossed 
interim and maximum sample size reached) are 11.5%, 13.8%, 12.5%, 11.0%, and 11.0% for 
T1, T2, T3, T4, and T5 respectively. The overall sample size is approximately 67. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1070 
Protocol No. CLDK378A2407 
 
 
 
 
 
Table 10-2 
Simulation results Scenario 1 (ceritinib inactive for all arms) 
 
Probability of 
Probability for 
 
 
 
 
 
 
 
 
 
 
The simulation-based results for Scenario 2 (Table 10-3), when the truth is that the effect of 
Ceritinib is clinically meaningful in all arms, illustrate that approximately 69% to 87% of the 
simulated trial outcomes are positive at final analysis (passes futility interim and reaches the 
maximum enrollment) for different arm. In addition, the average overall sample size is 91 
subjects. 
 
Table 10-3 Simulation results Scenario 2 (ceritinib active for all arms) 
 
Probability of a 
Probability for 
 
 
 
 
 
 
 
 
 
 
In order to illustrate the design behavior one addition scenario (Scenario 3) is explored. In 
Scenario 3 the effect of Ceritinib is clinically meaningful for arms T1, T5 and not-clinically 
meaningful for all other arms (Table 10-4). Table 10-4 shows reasonable operating 
characteristics (futility at interim and positive results at final analysis) under Scenario 3. The 
average overall sample size under this scenario is 78. 
 
Table 10-4 Simulation results Scenario 3 (certinib active for T1 and T5 arms) 
 
Probability of 
Probability for 
Arm 
True CBR 
stopping at IA 
positive 
(%) 
for futility (%)
conclusion in 
Average 
Sample Size 
final analysis (%) 
T1 
40.0 
59.3 
11.5 
14.1 
T2 
20.0 
41.7 
13.8 
10.8 
T3 
10.0 
59.9 
12.5 
14.0 
T4 
10.0 
58.8 
11.0 
14.1 
T5 
10.0 
59.7 
11.0 
14.0 
Overall 
67.0 
Arm 
True CBR 
stopping at IA 
positive 
(%) 
for futility (%)
conclusion in 
Average 
Sample Size 
final analysis (%) 
T1 
60.0 
14.2 
69.3 
18.6 
T2 
40.0 
8.6 
77.8 
14.1 
T3 
30.0 
5.0 
86.8 
19.5 
T4 
30.0 
4.6 
86.4 
19.5 
T5 
30.0 
4.9 
86.0 
19.5 
Overall 
91.2 
Arm 
True CBR 
stopping at IA 
positive 
(%) 
for futility (%)
conclusion in 
Average 
Sample Size 
final analysis (%) 
T1 
60.0 
15.1 
71.3 
18.5 
T2 
20.0 
35.0 
14.9 
11.7 
T3 
10.0 
52.2 
10.8 
14.8 
T4 
10.0 
52.7 
11.6 
14.7 
T5 
30.0 
13.4 
81.0 
18.7 
Overall 
78.4 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1080 
Protocol No. CLDK378A2407 
 
 
 
 
 
10.9 
Power for analysis of key secondary variables 
Not applicable. 
 
11 
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. 
 
11.1 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
 
11.2 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
 
11.3 
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. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1090 
Protocol No. CLDK378A2407 
 
 
 
 
 
11.4 
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. 
 
11.5 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study  
safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratories, and medico-technical 
departments involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported in the CRFs and all other required reports. Data 
reported on the CRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the CRF 
must be recorded. Any missing data must be explained. Any change or correction to a paper 
CRF should be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. For electronic CRFs an audit trail will be maintained by the system. The 
investigator should retain records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1100 
Protocol No. CLDK378A2407 
 
 
 
 
 
11.6 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 
 
11.7 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
 
11.8 
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. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1110 
Protocol No. CLDK378A2407 
 
 
 
 
 
 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1120 
Protocol No. CLDK378A2407 
 
 
 
 
 
 
13 
References (available upon request) 
Anderson WF, Chu KC, Shine Chang (2003) Inflammatory Breast Carcinoma and 
Noninflammatory Locally Advanced Breast Carcinoma: Distinct Clinicopathologic Entities J 
Clin Oncol 21:2254-2259. © 2003. 
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. 
Butrynski JE, D’Adamo DR, Hornick JL, et al (2010) Crizotinib in ALK-Rearranged 
Inflammatory Myofibroblastic Tumor N Engl J Med 2010;363:1727-33. 
Camidge DR, Bang YJ, Kwak EL, et al (2012) Activity and safety of crizotinib in patients 
with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet 
Oncol 2012; 13: 1011–19. 
CBTRUS : Central Brain Tumor Registry of the United States. 
Cessna MH1, Zhou H, Sanger WG, et al (2002) Expression of ALK1 and p80 in inflammatory 
myofibroblastic tumor and its mesenchymal mimics: a study of 135 cases Mod Pathol. 2002 
Sep;15(9):931-8. 
Chen X, Soma L, Fromm J (2014) Targeted therapy for Hodgkin lymphoma and systemic 
anaplastic large cell lymphoma: focus on brentuximab vedotin. OncoTargets and Therapy 
214:7 45-56. 
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. 
Chugh R, Wathen K, Maki RG, et al (2009) Phase II multicenter trial of imatinib in 10 
histologic subtypes of sarcoma using a Bayesian hierarchical statistical model. Journal of 
Clinical Oncology, 27(19):3148-53. 
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. 
Cohen MH, Shen YL, Keegan P, et al (2009) FDA drug approval summary: bevacizumab 
(Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist. 2009 
Nov;14(11):1131-8. 
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. 
Giuriato S, Faumont N, Bousquet E, et al (2007) Development of a conditional 
bioluminescent transplant model for TPM3-ALK-induced tumorigenesis as a tool to validate 
ALK-dependent cancer targeted therapy Cancer Biology & Therapy 6:8, e1-e6, 2007. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1130 
Protocol No. CLDK378A2407 
 
 
 
 
 
Grande E, Bolos MV, Arriola E (2011) Targeting Oncogenic ALK: A Promising Strategy for 
Cancer Treatment. Mol Cancer Ther 211;1:569-579. 
Griffin CA, Hawkins AL, Dvorak C, et al (1999) Recurrent Involvement of 2p23 in 
Inflammatory Myofibroblastic Tumors. Cancer Research; 59: 2776-80. 
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. 
Jazii FR, Najafi Z, Malekzadeh R, et al (2006) Identification of squamous cell carcinoma 
associated proteins by proteomics and loss of beta tropomyosin expression in esophageal 
cancer World J Gastroenterol 2006 November 28; 12(44): 7104-7112. 
Key TJ, Verkasalo PK (2001) Banks Epidemiology of breast cancer. The Lancet Oncology, 
Volume 2, Issue 3, March 2001, Pages 133–140. 
Krishnamurthy S, Woodward W, Yang W, et al (2013) Status of the anaplastic lymphoma 
kinase (ALK) gene in inflammatory breast carcinoma. SpringerPlus 2013, 2:409. 
Kwak EL, Bang YJ, Camidge DR, et al (2010) Anaplastic Lymphoma Kinase Inhibition in 
Non–Small-Cell Lung Cancer. N Engl J Med 2010;363:1693-703. 
Ladanyi M (2000) Aberrant ALK Tyrosine Kinase Signaling American Journal of Pathology, 
Vol. 157, No. 2, August 2000. 
Lawrence B, Perez-Atayde A, Hibbard MK, et al (2000) TPM3-ALK and TPM4-ALK 
Oncogenes in inflammatory Myofibroblastic Tumors. Am J Pathol. Aug 2000; 157(2): 377- 
384. 
Le Delay MC (2008) European Intergroup for Childhood Non-Hodgkin Lymphoma: 
Prognostic factors in childhood anaplastic large cell lymphoma: results of a large European 
intergroup study Blood 208;111(3):156-1566. 
Lin E, Li L, Guan Y, et al (2009) Exon Array Profiling Detects EML4-ALK Fusion in Breast, 
Colorectal, and Non–Small Cell Lung Cancers. Mol Cancer Res 2009;7(9). September 2009. 
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. 
Merkel O, Hamacher F, Sifft E, et al (2011) European Research Initiative on Anaplastic Large 
Cell Lymphoma: molecular targets and immunological tools. Mol Cancer 
Ther.2011;10(7):1127-1136 REPLACE with. 
Mossé PY, Lim MS, Voss SD, et al (2013) Safety and activity of crizotinib for paediatric 
patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s 
Oncology Group phase 1 consortium study Lancet Oncol 2013; 14: 472–80. 
Mosse YP, Laudenslager M, Long L, et al (2008) Identification of ALK as a major familial 
neuroblastoma predisposition gene. Nature; 455 (7261): 930-5. 
Mrugala M (2013) Advances and Challenges in the Treatment of Glioblastoma: A clinician’s 
Perspective. Discovery Medicine April 2013. 
Murugan AK, Xing M (2011) Anaplastic Thyroid Cancers Harbor Novel Oncogenic 
Mutations of the ALK Gene. Cancer Res. 2011 July 1; 71(13): 4403–4411. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1140 
Protocol No. CLDK378A2407 
 
 
 
 
 
Palmer RH, Vernersson E, Grabbe C, et al (2009) Anaplastic lymphoma kinase: signaling in 
development and disease. Biochem J; 420: 345-361. 
Powers C, Aigner A, Stoica GE, et al (2002) Pleiotrophin signaling through anaplastic 
lymphoma kinase is rate limiting for glioblastoma growth. J Biol Chem, 2002 
Apr19;277(16):14153-8. 
Santosh K (2011) Understanding Glioblastoma Tumor Biology: The Potential to Improve 
Current Diagnosis and Treatments Semin Oncol 38:S2-S10, 2011. 
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, Kim DW, Mehra R, et al (2014) Ceritinib in ALK-Rearranged Non–Small-Cell 
Lung Cancer. N Engl J Med 2014; 370:1189-1197. 
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. 
Sukov RW, Hodge JC, Lohse CM, et al (2012) ALK alterations in adult renal cell carcinoma: 
frequency, clinicopathologic features and outcome in a large series of consecutively treated 
patients Modern Pathology (2012) 25, 1516–1525. 
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. 
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. 
Thall PF, Wathen KJ, Bekele NB, et al (2003) “Hierarchical Bayesian approaches to phase II 
trials in diseases with multiple subtypes”; Statistics in Medicine; 22: 763–780. 
Tuma SR (2012) ALK Gene Amplified in Most Inflammatory Breast Cancers. JNCI Journal 
of the National Cancer Institute Advance Access, January 3. 
Wong ET, Hess KR, Gleason MJ, et al (1999) Outcomes and Prognostic Factors in Recurrent 
Glioma Patients Enrolled Onto Phase II Clinical Trials J Clin Oncol 17:2572-2578 1999. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1150 
Protocol No. CLDK378A2407 
 
 
 
 
 
 
14 
Appendices 
14.1 
Appendix 1: List of prohibited concomitant medications and 
concomitant medications requiring caution for ceritinib for 
LDK378 
Table 14-1 Prohibited medications that are strong inducers or inhibitors of 
CYP3A, or CYP3A substrates with narrow therapeutic index, or 
sensitive CYP2C9 substrates with narrow therapeutic index** 
CYP2C9 substrates with narrow therapeutic index 
 
warfarin 
phenytoin 
 
CYP3A4/5 substrates with narrow therapeutic index 
astemizole* 
diergotamine 
pimozide 
alfentanil 
cisapride* 
ergotamine 
quinidine* 
terfenadine* 
cyclosporine 
fentanyl 
tacrolimus 
sirolimus 
Strong CYP3A4/5 inhibitors 
Macrolide antibiotics: 
Antivirals: 
Antifungals: 
Others: 
clarithromycin 
indinavir 
itraconazole 
conivaptan 
telithromycin 
lopinavir 
ketoconazole 
elvitegravir 
troleandomycin 
nelfinavir 
posaconazole 
mibefradil 
ritonavir 
voriconazole 
nefazodone 
saquinavir 
tipranavir 
Strong CYP3A/5 inducers 
avasimibe 
carbamazepine 
phenobarbital 
phenytoin 
rifabutin 
rifampin 
St. John’s wort 
* Compounds known to increase QTc interval that are also primarily metabolized by CYP3A4/5. 
For an updated list of CYP2C9 substrates, CYP3A substrates, inhibitors and inducers, please 
reference the Novartis Oncology Clinical Pharmacology internal memo: drug-drug interactions (DDI) 
database, Oct 2010, which is compiled primarily from the FDA’s “Guidance for Industry, Drug 
Interaction Studies”, the Indiana University School of Medicine’s Drug Interactions Database, and the 
University of Washington’s Drug Interaction Database. 
**Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co- 
administered with a known potent inhibitor. 
Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that 
increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious 
safety concerns (e.g., Torsades de Pointes). 
 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1160 
Protocol No. CLDK378A2407 
 
 
 
 
 
Table 14-2 
List of medications to be used with caution 
 
CYP2C9 substrates 
losartan 
irbesartan 
diclofenac 
ibuprofen 
piroxicam 
tolbutamide 
glipizide 
acenocoumarol 
celecoxib 
sulfamethoxazole 
tolbutamide 
torsemide 
CYP3A4/5 substrates 
dronedarone 
capravirine 
aripiprazole 
casopitant 
alprazolam 
ritonavir 
haloperidol 
quinine 
diazepam 
telaprevir 
imatinib 
tamoxifen 
amlodipine 
atorvastatin 
nilotinib 
tolvaptan 
diltiazem 
everolimus 
methadone 
trazodone 
nifedipine 
erythromycin 
boceprevir 
vincristine 
nisoldipine 
brecanavir 
verapamil 
nitrendipine 
Moderate CYP3A4/5 inhibitors 
ciprofloxacin 
darunavir 
grapefruit juice 
dronedarone 
erythromycin 
fosamprenavir 
aprepitant 
tofisopam 
amprenavir 
diltiazem 
casopitant 
atazanavir 
verapamil 
cimetidine 
Moderate CYP3A4/5 inducers 
bosentan 
efavirenz 
etravirine 
modafinil 
nafcillin 
ritonavir 
talviraline 
tipranavir 
Proton pump inhibitors 
esomeprazole 
lansoprazole 
omeprazole 
pantoprazole 
rabeprazole 
The list of CYP2C9 and 3A4/5 substrates, 3A4/5 inhibitors and inducers is from the Novartis Oncology 
Clinical Pharmacology internal memo: drug-drug interactions (DDI) database, Oct 2010, which is 
compiled primarily from the Indiana University School of Medicine’s “Clinically Relevant” Table 
(http://medicine.iupui.edu/flockhart/table.htm), the University of Washington’s Drug Interaction 
Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction Studies”. 
 
Table 14-3 
List of prohibited enzyme-inducing anti-epileptic drugs 
Prohibited enzyme-inducing anti-epileptic drugs 
carbamazepine 
ethotoin 
felbamate 
fosphenytoin 
phenobarbital 
phenytoin 
primidone 
topiramate 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1170 
Protocol No. CLDK378A2407 
 
 
 
 
 
Table 14-4 
List of prohibited QT prolonging drugs 
Prohibited medications causing QTc prolongation 
Antiarrhythmic: 
Anticancer: 
Antibiotic: 
Antianginal: 
amiodarone 
arsenic trioxide 
azithromycin 
bepridil 
disopyramide 
vavdetanib 
clarithromycin* 
Antipsychotic: 
dofetilide 
Antihistamine: 
erythromycin* 
chlorpromazine 
flecainide 
astemizole* 
moxifloxacin 
haloperidol* 
ibutilide 
terfenadine* 
sparfloxacin 
mesoridazine 
procainamide 
Antimalarial: 
Antinausea: 
pimozide 
quinidine* 
chloroquine 
domperidone 
thioridazine 
sotalol 
halofantrine 
droperidol 
Opiate agonist: 
Antilipemic: 
Anti-infective: 
GI stimulant: 
levomethadyl 
probucol 
pentamidine 
cisapride* 
methadone 
Antidepressant: 
citalopram 
Please note: *CYP3A substrate 
Source: Arizona Center for Education and Research on Therapeutics (CERT), Drugs that prolong the 
QT interval and/or induce Torsades de Pointes, http://.azcert.org/medical-pros/drug-lists/drug-lists.cfm 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1180 
Protocol No. CLDK378A2407 
 
 
 
 
 
 
14.2 
Appendix 2: Harmonization of efficacy analysis of solid tumor 
studies (RECIST 1.1) 
Tumor assessments will be based on Response Evaluation Criteria in Solid Tumors (RECIST 
1.1) guidelines (Eisenhauer 2009). 
 
14.2.1 
Measurability of tumor lesions at baseline 
All tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
 
14.2.1.1 Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
• 10mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 20mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be >15mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). 
 
14.2.1.2 Non-measurable 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph 
nodes with >10 to <15mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: Leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
 
14.2.1.2.1 
Bone lesions 
• B, PET and plain films are not adequate to measure bone lesions; they may be used to 
determine the presence or absence of a lesion. 
• Lytic or lytic-blastic lesions with identifiable soft tissue component that can be measured 
by CT or MRI and meets size requirement can be considered measurable. Blastic bone 
lesions are non-measurable. 
 
14.2.1.2.2 
Cystic lesions 
• Cystic lesions that meet the criteria for simple cysts are not measurable. 
• Cystic lesions that are thought to be cystic metastatic disease can be considered 
measurable disease, however if non-cystic lesions are present in the same patient these are 
preferable to include as target lesions. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1190 
Protocol No. CLDK378A2407 
 
 
 
 
 
14.2.1.2.3 
Lesions previously treated 
• Lesions within radiotherapy ports or who have been subject to other loco-regional 
treatment are usually not considered to be measurable and will be allowed on this study 
only with approval of the sponsor. 
 
14.2.2 
Specification by methods of measurement 
 
14.2.2.1 Measurement of lesions 
All measurements should be taken and recorded in metric notation. The same method of 
assessment and the same technique should be used to characterize each identified and reported 
lesion at baseline and during follow-up. 
 
14.2.2.1.1 
Target lesions 
All lesions up to a maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions. If the largest lesion 
does not lend itself to reproducible measurement, the next largest lesion which can be 
measured reproducibly should be selected. 
Pathological lymph nodes which are measurable may be identified as target lesions if they 
have a short axis of >15mm by CT scan. Only the short axis of these nodes will contribute to 
the baseline sum. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained. The smaller of these measures is the short axis. All other pathological 
nodes (those with short axis >10mm but <15 mm) should be considered non-target lesions. 
Nodes that have a short axis <10mm are considered non-pathological and should not be 
recorded or followed. 
 
14.2.2.1.2 
Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. It is possible to record multiple non-target lesions involving the 
same organ as a single item on the case record form (e.g. “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). Measurements of these lesions are not required, but  
the presence or absence of each should be noted throughout follow-up. 
 
14.2.2.2 Response criteria 
 
14.2.2.2.1 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine overall tumor response 
for target lesions as shown below in Table 14-5. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1200 
Protocol No. CLDK378A2407 
 
 
 
 
 
Table 14-5 
Evaluation of target lesions 
 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 
mm.1 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameter of all measured target 
lesions, taking as reference the smallest sum of diameter of all target 
lesions recorded at or after baseline. In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm (Note: the appearance of one or more new lesions is also 
considered progression) 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study 
Notes on the assessment of Lymph nodes: Lymph nodes identified as target lesions should 
always have the actual short axis measurement recorded (measured in the same anatomical 
plane as the baseline examination), even if the nodes regress to below 10mm on study. This 
means that when lymph nodes are included as target lesions, the ‘sum’ of lesions may not be 
zero even if complete response criteria are met, since a normal lymph node is defined as 
having a short axis of <10mm. In order to qualify for CR, each node must achieve a short axis 
<10mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be included 
in the sum of target lesions. 
 
14.2.2.2.2 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for 
the group of non-target lesions as shown below in Table 14-6. While some non-target lesions 
may actually be measurable, they need not be measured and instead should be assessed only 
qualitatively at the time points specified in the protocol. 
 
Table 14-6 
Evaluation of non-target lesions 
 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10mm 
short axis) 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered 
progression). 
 
14.2.2.2.3 
New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded appropriately in the eCRF. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1210 
Protocol No. CLDK378A2407 
 
 
 
 
 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion. 
• 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. 
• 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. 
a. Negative FDG-PET at baseline, with a positive1 FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and 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 scans 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 
FDG-PET 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. 
 
14.2.2.2.4 
Tumor markers 
Tumors markers alone will not be used to assess overall response. If elevated at baseline, they 
must normalize for a patient to be considered as having a CR. For the purpose of this protocol, 
Cancer Antigen-125 (CA-125) will be used in the assessment of ovarian and Prostate Specific 
Antigen (PSA) will be used in the assessment of prostate. 
 
14.2.3 
Evaluation of best overall 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 indicated below in 
Table 14-7 and Table 14-8. 
The best overall response is the best response recorded from the start of treatment until 
disease progression/recurrence. The best overall response for CR and PR will be determined 
at 8 weeks as indicated below in Table 14-9. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1220 
Protocol No. CLDK378A2407 
 
 
 
 
 
Table 14-7 
Point response: patients with target (+/- non-target) disease 
 
Target lesions 
Non-target lesions 
New lesions 
Overall lesion response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR PR 
Not evaluated 
Non-PD or not all evaluated 
No 
No 
PR 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
PD 
Non-PD Any 
No 
Yes or No 
NE 
PD 
Any 
Any 
PD Any 
Yes or No 
Yes 
PD 
PD 
 
Table 14-8 
Time point response: patients with non-target disease only 
Non-target lesions 
New lesions 
Overall lesion response 
 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Not all evaluated 
No 
Non-CR/non-PRa 
NE 
Unequivocal PD 
Yes or No 
PR 
Any 
Yes 
SD 
 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly 
used as endpoint for assessment of efficacy in some trials so to assign this category when no lesions 
can be measured is not advised. 
 
 
Table 14-9 
Best overall response when confirmation of CR and PR required 
 
Overall lesion response at 
first time point 
Overall lesion response at 
subsequent time point 
Best overall lesion response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SDb 
CR 
PD 
SDb 
CR 
NE 
SDc 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SDb 
PR 
NE 
SDc 
NE 
NE 
NE 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even 
disease meeting PR criteria relative to baseline, makes the disease PD at that point (since disease 
must have reappeared after CR). Best response would depend on whether minimum duration for SD 
was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions 
were likely still present and in fact the patient had PR, not CR at the first time point. Under these 
circumstances, the original CR should be changed to PR and the best response is PR. 
b  Provided minimum criteria for SD duration met, otherwise, PD 
c  Provided minimum criteria for SD duration met, otherwise, NE 
 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1230 
Protocol No. CLDK378A2407 
 
 
 
 
 
14.2.4 
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. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1240 
Protocol No. CLDK378A2407 
 
 
 
 
 
14.3 
Appendix 3: Response assessment in neuro-oncology (RANO) 
criteria for high-grade gliomas 
Antitumor response will be primarily evaluated by the Response Assessment in Neuro- 
Oncology (RANO) working group (Wen et al 2010) criteria in this study. The RANO Criteria 
updates its established predecessor, the modified Macdonald Criteria (Macdonald et al 1990), 
by adding assessment of non-enhancing lesions. 
Patients will undergo Contrast MRI assessments for response evaluation starting at Week 8 
and every 8 weeks thereafter to evaluate brain lesions, as outlined in the Visit schedule Table 
7-1 and Table 7-2. 
The following components will be taken into account when assessing a patient’s overall 
response at an individual evaluation. 
• Tumor evaluation eCRF page for measureable enhancing lesions (T1-Gd+) 
• Tumor evaluation eCRF page for non-measurable enhancing lesions (T1-Gd+) 
• Tumor evaluation eCRF page for non-enhancing lesions (T2/FLAIR) 
• Tumor evaluation eCRF page for new lesion 
• Concomitant medication eCRF page for steroid usage 
• Clinical status eCRF page for KPS and other clinical evaluation finding 
• Overall response eCRF page for response category (CR/PR/PD/SD/NA) 
14.3.1 
Antitumor effect - definitions 
Evaluable for toxicity 
All participants who receive at least one dose of study treatment will be evaluable for toxicity 
from the time of their first treatment. 
 
Evaluable for objective response 
Only those participants who have measurable disease present at baseline (cycle 1, day 1 scan) 
and have received at least one dose of therapy will be considered evaluable for response. 
These participants will have their response classified according to the definitions  stated 
below. (Note: Participants who exhibit objective disease progression or die prior to the end of 
cycle 1 will also be considered evaluable.) 
 
Measurable disease 
Bidimensionally, contrast-enhancing, measurable lesions with clearly defined margins by CT 
or MRI scan, with a minimal diameter of 10mm, and visible on 2 axial slices which are at 
least 5 mm apart with 0 mm skip. Measurement of tumor around a cyst or surgical cavity, if 
necessary, requires a minimum thickness of 3 mm. If there are multiple measurable lesions, 
the investigator must choose a minimum of two and a maximum of five of the largest lesions 
to be followed before a participant is entered on study. The remaining lesions will be 
considered non-measureable for the purpose of objective response determination. Unless 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1250 
Protocol No. CLDK378A2407 
 
 
 
 
 
progression is observed, objective response can only be determined when all measurable and 
non-measurable lesions are assessed. 
 
Non-measurable evaluable disease 
Unidimensionally measurable lesions, masses with margins not clearly defined, lesions with 
maximal diameter < 10mm. 
14.3.2 
Response/progression categories 
Complete response (CR) 
All of the following criteria must be met: 
a. Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this scan 
will be considered only stable disease. 
b. No new lesions. 
c. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline. 
d. Participants must be on no steroids or on physiologic replacement doses only. 
e. Stable or improved non-enhancing (T2/FLAIR) lesions 
f. Stable or improved clinically, for clinical signs and symptoms present at baseline and 
recorded to be disease related 
Participants with non-measurable disease cannot have a complete response. The best 
response possible is stable disease. 
 
Partial response (PR) 
All of the following criteria must be met: 
a. Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. 
In the absence of a confirming scan 4 weeks later, this scan will be considered only stable 
disease. 
b. No progression of non-measurable disease. 
c. No new lesions. 
d. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline. 
e. The steroid dose at the time of the scan evaluation should be no greater than the dose at 
time of baseline scan. 
f. Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. 
g. Stable or improved, for clinical signs and symptoms present at baseline and recorded to be 
disease related clinically. 
Participants with non-measurable disease cannot have a partial response. The best 
response possible is stable disease. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1260 
Protocol No. CLDK378A2407 
 
 
 
 
 
Progressive disease (PD) 
The following criterion must be met: 
a. 25% increase in sum of the products of perpendicular diameters of enhancing lesions (over 
best response or baseline if no decrease) on stable or increasing doses of corticosteroids 
and/or one or more of the of the following: 
b. Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of 
corticosteroids steroids compared to baseline scan or best response following initiation of 
therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, 
infection, seizures, post-operative changes, or other treatment effects). 
c. Any new lesion 
d. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection, etc.). The definition of clinical deterioration is left to the discretion of the 
investigator but it is recommended that a decline in the Karnofsky Performance Score 
(KPS) from 100 or 90 to 70 or less, a decline in KPS of at least 20 from 80 or less, or a 
decline in KPS from any baseline to 50 or less, for at least 7 days, be considered 
neurologic deterioration, unless attributable to co-morbid events or changes in 
corticosteroid dose. 
e. Failure to return for evaluation due to death or deteriorating condition. 
f. Clear progression of non-measurable disease 
 
Stable disease (SD) 
All of the following criteria must be met: 
a. Does not qualify for CR, PR, or progression. 
b. All measurable and non-measurable sites must be assessed using the same techniques as 
baseline. 
c. Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. In the event that the corticosteroid dose has been increased, the 
last scan considered to show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose. 
d. Stable clinically. 
 
Unknown response status 
Progressive disease has not been documented and one or more measurable or non-measurable 
lesions have not been assessed. 
These RANO Response Criteria are also summarized in Table 14-10: 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1270 
Protocol No. CLDK378A2407 
 
 
 
 
 
Table 14-10 
Summary of the RANO response criteria 
 
CR 
PR 
SD 
PD# 
T1-Gd + 
None 
≥50% decrease 
<50% decrease but 
<25% increase 
≥25% increase* 
T2/FLAIR 
Stable or decrease 
Stable or decrease 
Stable or decrease 
Increase* 
New Lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or decrease 
Stable or decrease 
NA** 
Clinical Status 
Stable or improve 
Stable or improve 
Stable or improve 
Deterioration* 
Requirement for 
Response 
All 
All 
All 
Any* 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease 
*: Progression when this criterion is met **: Increase in corticosteroids alone will not be taken into 
account in determining progression in the absence of persistent clinical deterioration 
 
14.3.3 
Methods for evaluation of measurable disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or 
digital measurement tool. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 14 days before the beginning of the 
treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
 
14.3.4 
Evaluation of best response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). If a response recorded at one scheduled MRI does not 
persist at the next regular scheduled MRI, the response will still be recorded based on the 
prior scan, but will be designated as a non-sustained response. If the response is sustained, i.e. 
still present on the subsequent MRI, it will be recorded as a sustained response, lasting until 
the time of tumor progression. Participants without measurable disease may only achieve SD 
or PD as their best “response.” 
 
14.3.5 
Other effect measures 
 
14.3.5.1 Neurological exam 
Although not used for determining response, it is useful to evaluate changes in the 
neurological exam compared to the previous exam. The following scale may be used: 
 
+2 
Definitely better 
+1 
Possibly better 
0 
Unchanged 
-1 
Possibly worse 
-2 
Definitely worse 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1280 
Protocol No. CLDK378A2407 
 
 
 
 
 
14.3.5.2 Performance status 
Participants will be graded according to KPS score 
 
14.3.5.3 Overall survival time 
From date of first dose (date of first post-surgery treatment for participants in Dose Level 1) 
to date of death due to any cause. 
 
14.3.5.4 Progression-free survival time: 
From date of first dose (date of first post-surgery treatment for participants in Dose Level 1) 
to date of progression or death. Participants who stop treatment for causes other than 
progression may be censored if other therapy is initiated or if regular assessments for 
assessing progression are no longer available. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1290 
Protocol No. CLDK378A2407 
 
 
 
 
 
 
14.4 
Appendix 4: Guidelines for efficacy evaluation in lymphoma 
studies (based on Cheson response criteria). International 
Working Group guidelines for hematological malignancies 
Disease assessments will be based on the International Working Group response criteria 
(Cheson 1999), and the International Harmonization Project revised response  criteria  
(Cheson et al 2007b). Further clarification on  these  criteria  has  been  published  by  
(Cheson 2007a). 
 
14.4.1 
Definitions and criteria for normalization 
 
14.4.1.1 Definitions 
 
14.4.1.1.1 
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. 
 
14.4.2 
Measurability of tumor lesions at baseline 
All tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
 
14.4.2.1 Measurable nodal and extranodal lesions 
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. 
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 Screening, then the patient must have at least one measurable extranodal lesion. 
 
14.4.2.2 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. 
• 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. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1300 
Protocol No. CLDK378A2407 
 
 
 
 
 
• 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. 
14.4.2.3 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. 
 
14.4.3 
Specification by methods of measurement 
 
14.4.3.1 Measurement of lesions 
All radiological measurements should be taken in two perpendicular dimensions and recorded 
in metric notation, using a ruler or calipers. 
 
14.4.3.1.1 
PET 
Visual assessment currently is considered adequate for determining whether a PET scan is 
positive, and use of the standardized uptake value is not necessary.1 In brief, a positive scan is 
defined as focal or diffuse FDG uptake above background in a location incompatible with 
normal anatomy or physiology, without a specific standardized uptake value cutoff.1 Other 
causes of false-positive scans should be ruled out. Exceptions include mild and diffusely 
increased FDG uptake at the site of moderate- or large-sized masses with an intensity that is 
lower than or equal to the mediastinal blood pool, hepatic or splenic nodules 1.5 cm with FDG 
uptake lower than the surrounding liver/spleen. 
 
14.4.3.1.2 
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 Screening and during follow-up. 
Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed using a 
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 Screening 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 (e.g. from CT to MRI, 
or vice-versa), or a change in any other imaging modality. A change in methodology will 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1310 
Protocol No. CLDK378A2407 
 
 
 
 
 
result by default in an “Unknown” overall radiological response assessment. However, 
another overall radiological response than the Novartis calculated “Unknown” response may 
be accepted from the investigator 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 eCRFs. If, during the 
course of the study, either of the perpendicular diameters of a lesion cannot 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. 
 
14.4.3.1.3 
Bone marrow assessment 
Documentation of status of bone marrow involvement by lymphoma based on prior bone 
marrow biopsy or aspirate findings is required at Screening for all patients. 
If no such documentation is available then a bone marrow biopsy or aspirate should be 
performed at Screening. 
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 
confirm the findings. 
 
14.4.3.1.4 
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 eCRF) and photographed including a ruler 
(color photography using digital camera). Tumor assessment will be performed and results 
will be recorded on the corresponding eCRF at Screening and at Day 1 of every cycle (±4 
days) after first dose of study drug. 
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 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1320 
Protocol No. CLDK378A2407 
 
 
 
 
 
• Unexplained loss of > 10% body weight within the previous 6 months, as assessed and 
reported (present vs. absent) by the Investigator. 
 
14.4.4 
Evaluation of radiological response 
For the sake of simplicity, complete remission and complete response will both be referred to 
as complete response. 
Definitions of Response for Lymphoma patients are listed in Table 14-11. 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 14-13) identified at Screening, then a 
combined overall radiological response is determined (Table 14-16). 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1330 
Protocol No. CLDK378A2407 
 
 
 
 
 
Table 14-11 
Response definition for lymphoma 
Response 
Definition 
Nodal Masses 
Spleen. Liver 
Bone Marrow 
CR 
Disappearance 
of all evidence 
of disease 
 
 
 
 
PR 
Regression of 
measurable 
disease and no 
new sites 
 
 
 
 
 
 
 
SD 
Failure to attain 
CR/PR or PD 
a. FDG-avid or PET positive 
prior to therapy; mass of 
any size permitted if PET 
negative 
b. Variably FDG-avid or PET 
negative; regression to 
normal size on CT 
≥ 50% decrease in SPD of up 
to 6 largest dominant masses; 
no increase in size of other 
nodes 
a. FDG-avid or PET positive 
prior to therapy; one or 
more PET positive at 
previously involved site 
b. Variably FDG-avid or PET 
negative; regression on 
CT 
a. FDG-avid or PET positive 
prior to therapy; PET 
positive at prior sites of 
disease and no new sites 
on CT or PET 
b. Variably FDG-avid or PET 
negative; no change in 
size of previous lesions on 
CT 
Not palpable, 
nodules 
disappeared 
 
 
 
 
≥ 50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or spleen 
Infiltrate cleared 
on repeat biopsy; 
if indeterminate 
by morphology, 
immunohistochem 
is try should be 
negative 
Irrelevant if 
positive prior to 
therapy; cell type 
should be 
specified 
Relapsed 
disease or 
PD 
Any new lesion 
or increase by 
≥ 50% of 
previously 
involved sites 
from nadir 
Appearance of a new 
lesion(s) > 1.5 cm in any axis, 
≥50% increase in SPD of more 
than one node, or ≥ 50% 
increase in longest diameter of 
a previously identified node > 
1 cm in short axis 
Lesions PET positive if FDG- 
avid lymphoma or PET 
positive prior to therapy 
> 50% increase 
from nadir in 
the SPD of any 
previous 
lesions 
New or recurrent 
involvement 
 
 
14.4.4.1 Evaluation of index lesions (nodal and extranodal) 
 
14.4.4.1.1 
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 14.4.2.3). 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1340 
Protocol No. CLDK378A2407 
 
 
 
 
 
Table 14-12 
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 Screening 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 Screening. 
 
 
14.4.4.1.2 
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 14.4.2.3: 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 14-8). 
 
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 Screening in the SPD restricted to all 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 Screening. 
 
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. 
 
14.4.4.1.3 
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 and the status 
based on the SPD calculated on all index lesions (nodal and extranodal), as described in Table 
14-14. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1350 
Protocol No. CLDK378A2407 
 
 
 
 
 
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 Screening, then index lesions response is equal to the index 
extranodal lesions response. A similar rule applied if no index extranodal lesions are present at 
Screening, then index lesions response is equal to the index nodal lesions response. 
In case of 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 Screening, 
otherwise the radiological response for index lesions at that assessment will be “Unknown 
(UNK)”. 
 
14.4.4.1.4 
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 Screening. 
• 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): 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1360 
Protocol No. CLDK378A2407 
 
 
 
 
 
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 Screening, 
otherwise the radiological response for non-index lesions at that assessment will be 
“Unknown (UNK)”. 
 
14.4.4.2 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 
• any discrete extranodal (including splenic and/or hepatic nodules) lesions reliably 
appearing on CT scan or MRI after Screening. 
is always considered as Progressive Disease (PD) and has to be recorded as a new lesion in 
the appropriate module of the eCRF. 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 eCRF. 
 
14.4.4.2.1 
Overall radiological response 
Overall radiological response is calculated as shown in Table 14-16. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1370 
Protocol No. CLDK378A2407 
 
 
 
 
 
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 Screening, 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 Screening 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. 
 
14.4.4.2.2 
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). 
 
14.4.4.2.3 
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. 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. 
 
14.4.4.2.4 
Overall disease response 
If a patient has an overall radiological response of CR 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: 
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 Screening) and the liver and spleen are normal in size and there are no 
lymphoma related B-symptoms in addition to radiological CR. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1380 
Protocol No. CLDK378A2407 
 
 
 
 
 
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 eCRF. 
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. 
 
14.4.5 
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. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1390 
Protocol No. CLDK378A2407 
 
 
 
 
 
14.5 
Appendix 5: Details statistical methodology 
This section provides the details of model stated in Section 10.4.2. Prior specifications of 
model parameters are provided in details. Data analysis and decision making in real trial are 
illustrated using some hypothetical data scenarios. Further operating characteristics by 
simulation are provided in Section 10.8 as part of sample size justification. 
 
14.5.1 
Prior specification of model parameters 
Bayesian model requires prior specification of parameters. The detailed prior specification of 
µ1, µ2,τ1, τ2, mw, vw, and pj (j= 1,2,..,5) are described in this section. 
14.5.1.1 Prior specification of exchangeability distribution (µ1, µ2, τ1 and τ2) 
Prior for τ1 and τ2 are assumed to be half-normal distribution with scale 0.25, implying a prior 
95%-interval for τ1 and τ2 as (0.008, 0.560), which allows for small to substantial between 
strata heterogeneity (see Spiegelhalter et al 2004). 
µ1 and µ2 are given normal prior distributions. For first exchangeability distribution µ1, the 
mean of the prior distribution (mµ1) is set to logit(0.15) (or mµ1= log(1/3)) which corresponds 
to no treatment effect. For second exchangeability distribution µ2, the prior mean (mµ2) was 
set to logit(0.6) (or mµ1= log(3/2)). This corresponds to a substantial treatment effect. The 
variance parameter (Vµ1 and Vµ2) are derived using the following formula from law of total 
variance 
Vµi = V(θ) - E(τi2) and V(θ)=1/π + 1/(1- π) ; π= 0.15, 0.60 and i=1,2 
This yields Vµ1= 7.780 (≈2.7892) and Vµ2= 4.101 (≈2.0252). This allows a considerable 
uncertainty on prior belief of θ. 
14.5.1.2 Prior specification for stratified or “non-exchangeability” distributions 
(mw and vw) 
The strata-specific normal priors for the stratified or “non-exchangeable” case are defined by 
mw and vw were. The prior median for the response probability was set as 10% (no treatment 
effect) i.e., mw=logit(0.1) (or mw = log(1/9)) and the corresponding variance (vw) is set to 9 
(=32) to allow large variability in prior. 
14.5.1.3 Specification of mixture weights (pj) 
Finally, for each stratum j, the prior mixture weights pj were chosen as 
pj = (0.25, 0.25, 0.50), 
j=1,…,5. 
This means that each stratum has 25% prior probability to belong to the first exchangeability 
distribution (µ1 and τ1), 25% probability to belong to the second exchangeability distribution 
(µ2 and τ2), and 50% probability to be stratified or non-exchangeable with some (or all) of the 
other strata. 
The prior distributions are summarized in Table 14-17, which also shows the prior medians 
and 95%-intervals for the disease specific disease control rare (DCR) πj. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1400 
Protocol No. CLDK378A2407 
 
 
 
 
 
Table 14-17 
Specifications for model parameters, and prior median (95%-interval) 
for disease specific DCR 
Parameter 
Prior distribution 
 
µ1 
N(-1.735, 2.7892) 
 
µ2 
N(0.405, 2.0252) 
 
τ1 
Half Normal(scale=0.25) 
 
τ2 
Half Normal(scale=0.25) 
 
mj, vj 
N(-2.197, 32) 
 
pj = (pj1,pj2,pj3), j=1,…,5 
(0.25, 0.25, 0.5) 
 
Prior disease specific DCR 
median (2.5%, 97.5%) 
 
πj, j=1,…,5 
0.218 (0.001, 0.981) 
 
14.5.2 
Hypothetic scenario testing 
It is important to know that the design should make reasonable decisions at interim and final 
analysis based on the observed responses in each tumor type. This section shows on-study 
decisions made under the model and prior for the specified DLT observations. The 
hypothetical data scenarios for interim and final analysis can be found in Table 14-2 and 
Table 14-3 respectively. For each scenario, the probability of being “clinically meaningful” 
and “not clinically meaningful” (Table 10-1) are calculated by tumor type and displayed in the 
tables. 
Table 14-18 shows 6 different scenarios for interim analyses. As stated in Section 10.7 at 
interim a tumor type is stopped if the probability of being “clinically meaningful” is less than 
20%. At interim if no arm or tumor type shows any activity (scenarios 1 and 2) the decision 
based on model based inference are reasonable. The posterior probabilities of “clinically 
meaningful” are less than 20% for all tumor type in both scenarios (Column 6 of Table 14- 
18). Similarly for scenarios 3 and 4 where all tumor types show some clinically meaningful 
activity the proposed decision rule suggests to “continue” all arms (posterior probability of 
“clinically meaningful” > 20%). The proposed design also shows reasonable decision for 
mixed scenarios (5 and 6). For example, under scenario 4, data for arms T3 and T5 show no 
clinically activity but the rest shows some activity. Based on the calculated probability of 
being clinically meaningful, the design allows correctly stopping (probability<0.20) for T3 
and T5 at the interim while continues for the other arms. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1410 
Protocol No. CLDK378A2407 
 
 
 
 
 
Table 14-18 
Hypothetical data scenarios and decision at interim 
 
Scenario 
Arm (Tumor 
Type) 
No of 
responder/ 
No. of 
patients 
Observed 
CBR 
Posterior 
probability of 
not clinically 
meaningful † 
Posterior 
probability 
being clinically 
meaningful † 
Decision‡ 
1 
T1 
3/10 
30% 
0.8595 
0.0468 
Stop 
T2 
1/5 
20% 
0.6005 
0.1900 
Stop 
T3 
1/10 
10% 
0.4498 
0.1878 
Stop 
T4 
1/10 
10% 
0.4685 
0.1808 
Stop 
T5 
1/10 
10% 
0.4615 
0.1755 
Stop 
2 
T1 
3/10 
30% 
0.8450 
0.0550 
Stop 
T2 
1/5 
20% 
0.6223 
0.1800 
Stop 
T3 
1/10 
10% 
0.4898 
0.1743 
Stop 
T4 
1/10 
10% 
0.4833 
0.1813 
Stop 
T5 
0/10 
0 
0.8620 
0.0265 
Stop 
3 
T1 
7/10 
70% 
0.0843 
0.7580 
Continue 
T2 
2/5 
40% 
0.1475 
0.6390 
Continue 
T3 
3/10 
30% 
0.0298 
0.7970 
Continue 
T4 
3/10 
30% 
0.0250 
0.7980 
Continue 
T5 
2/10 
20% 
0.1128 
0.6083 
Continue 
4 
T1 
8/10 
80% 
0.0198 
0.9273 
Continue 
T2 
2/5 
40% 
0.1515 
0.6040 
Continue 
T3 
3/10 
30% 
0.0253 
0.7965 
Continue 
T4 
3/10 
30% 
0.0303 
0.7925 
Continue 
T5 
2/10 
20% 
0.1135 
0.6063 
Continue 
5 
T1 
7/10 
70% 
0.0373 
0.8870 
Continue 
T2 
4/5 
40% 
0.0028 
0.9835 
Continue 
T3 
1/10 
10% 
0.4983 
0.1883 
Stop 
T4 
3/10 
30% 
0.0665 
0.6865 
Continue 
T5 
1/10 
10% 
0.5123 
0.1818 
Stop 
6 
T1 
7/10 
70% 
0.0290 
0.8778 
Continue 
T2 
4/5 
40% 
0.0028 
0.9870 
Continue 
T3 
1/10 
10% 
0.5538 
0.1775 
Stop 
T4 
4/10 
40% 
0.0090 
0.9138 
Continue 
T5 
0/10 
0 
0.9118 
0.0168 
Stop 
† Calculated using a Bayesian hierarchical model mentioned in Section 10.4.2. 
‡ A tumor type will be stopped if posterior probability being clinically meaningful is less than 20%. 
 
Similar to interim Table 14-19 shows 5 different hypothetic scenarios for final analyses in 
order to illustrate final decision making process in the proposed  design.  As  stated  in  
Section 10.4.2 at final a Proof of Concept (PoC) about treatment with ceritinib will be 
declared for an arm (tumor type) if both of the following conditions are met: 
a. Observed DCR ≥ “Disease Control Rate” threshold (Table 10-1) 
b. Posterior probability of “not being clinically meaningful” (Table 10-1) is less than 20% 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1420 
Protocol No. CLDK378A2407 
 
 
 
 
 
If no arm shows any significant activity (scenario 1) at final analysis the decision using model 
based inference are reasonable (declared fail to support PoC for all arms). The posterior 
probabilities of “not clinically meaningful” are less than 20% for all arms in this scenario 
(Column 5 of Table 14-19) but the observed CBR’s do not cross “clinically meaningful” 
threshold (as stated in Table 10-1). Similarly for scenario 2 where all arms show clinically 
meaningful activity the proposed decision rule (to declared success) leads to PoC for all arms 
(posterior probability of “not clinically meaningful” < 20% and observed CBR’s are more 
than “clinically meaningful” threshold). The proposed design also shows reasonable decision 
for mixed scenarios (3, 4, and 5). For example, under scenario 4, data for arms T1 and T3 
show no clinically activity but the rest of the arms show activity. Based on the posterior 
probability of being not clinically meaningful and observed CBR, the design correctly 
declared fail for T1 and T3 while success for the other arms. 


Novartis 
Amended Protocol Version 01 (Clean) 
Confidential 
Page 1430 
Protocol No. CLDK378A2407 
 
 
 
 
 
Table 14-19 
Hypothetical data scenarios and decision at final 
 
Scenario 
Arm 
(Tumor 
Type) 
No of 
responder/ 
No. of 
patients 
CBR at 
final 
Posterior 
probability of 
not clinically 
meaningful † 
Posterior 
probability being 
clinically 
meaningful † 
Decision‡ 
1 
T1 
8/20 
40% 
0.6133 
0.1283 
Fail 
T2 
3/15 
20% 
0.6155 
0.1330 
Fail 
T3 
2/20 
10% 
0.4678 
0.0958 
Fail 
T4 
2/20 
10% 
0.4588 
0.0968 
Fail 
T5 
2/20 
10% 
0.4670 
0.0980 
Fail 
2 
T1 
14/20 
70% 
0.0125 
0.9318 
Success 
T2 
6/15 
40% 
0.0550 
0.6570 
Success 
T3 
6/20 
30% 
0.0048 
0.8395 
Success 
T4 
4/20 
20% 
0.0500 
0.6040 
Success 
T5 
4/20 
20% 
0.0500 
0.6153 
Success 
3 
T1 
6/20 
30% 
0.9113 
0.0113 
Fail 
T2 
415 
40% 
0.3198 
0.2733 
Fail 
T3 
2/20 
10% 
0.4145 
0.1703 
Fail 
T4 
5/20 
25% 
0.0255 
0.6825 
Success 
T5 
1/20 
5% 
0.7243 
0.0490 
Fail 
4 
T1 
8/20 
40% 
0.5765 
0.1283 
Fail 
T2 
9/15 
60% 
0.0013 
0.9800 
Success 
T3 
1/20 
5% 
0.7740 
0.0403 
Fail 
T4 
6/20 
30% 
0.0040 
0.8988 
Success 
T5 
5/20 
25% 
0.0205 
0.7753 
Success 
5 
T1 
14/20 
70% 
0.0063 
0.9500 
Success 
T2 
9/15 
60% 
0.0003 
0.9810 
Success 
T3 
6/20 
30% 
0.0100 
0.7983 
Success 
T4 
4/20 
20% 
0.0950 
0.4938 
Success 
T5 
2/20 
10% 
0.4188 
0.1608 
Fail 
† Calculated using a Bayesian hierarchical model mentioned in Section 10.4.2. 
‡ A tumor type will be declared “Success” if posterior probability of being not clinically meaningful is 
less than 20% and observed CBR is at least clinically meaningful threshold. 
 

SAP_001.pdf: 
Clinical Development 
LDK378/Ceritinib/Zykadia® 
LDK378A2407 / NCT02465528
A Phase II, Open Label, Multi-Center, Multi-Arm Study of 
Ceritinib in Patients with Advanced Solid Tumors and 
Hematological Malignancies Characterized by Genetic 
Abnormalities of Anaplastic Lymphoma Kinase (ALK) 
Statistical Analysis Plan (SAP) – Final analysis 
Author: 
Trial Statistician, 
 
 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
20-Sep-2018
Number of pages: 
63 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
For business use only 
Page 2 
SAP 
 
Study number 
 
 
Document History – Changes compared to previous final version of SAP 
The CLDK378A2407 is a non-pivotal/non-registration study. 
In July 2017, a first interim analysis (IA) for the Glioblastoma (GBM) cohort with the cut-off 
date of 07-Apr-2017 was performed.  The results of the IA, in which a total of 12 GBM patients 
were evaluated, showed that ceritinib was generally well tolerated, and no new safety signals 
were identified. Unfortunately the primary endpoint of antitumor activity as measured by 
Disease Control Rate (DCR) at 16 weeks based on local investigator assessment was not met. 
These results were presented to the LDK378 GPT in August 2017 and a decision was made to 
stop further enrollment in the GBM cohort as per protocol.  The GPT also recommended to plan 
out a study close-out strategy based on these results.   The study enrollment was halted in 
December 2017 based on the results of the IA and the significant challenges to identify eligible 
patients. 
The SAP for the final close-out analysis was based on the SAP approved in CREDI on 16-Mar-
2016. According to teams agreement, an abbreviated CSR will be written. Therefore, the 
analysis was simplified by reducing the number of analyses to those needed for an abbreviated 
CSR. 
Compared to the planned analyses in protocol amendment 1, following changed: 
• In Section 10.3, the protocol suggests to summarize concomitant medications and 
significant non-drug therapies. For the purpose of the abbreviated CSR, it was decided to 
only provide a listing. 
• Section 10.5.3.3 states that shift tables will be generated for laboratory tests where 
CTCAE grades are not defined, using the low/normal/high/(low and high). It was decided 
to only provide shift tables for laboratory tests where CTCAE grades are defined. All 
laboratory data will be listed, with values flagged to show the CTCAE grades and the 
classifications relative to the laboratory normal ranges. 


Novartis 
For business use only 
Page 3 
SAP 
 
Study number 
 
Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 6 
1.2 
Study objectives and endpoints ............................................................................... 9 
1.2.1 
Primary objective .................................................................................... 9 
1.2.2 
Secondary objectives ............................................................................... 9 
 
 9 
2 
Statistical methods ............................................................................................................. 12 
2.1 
Data analysis general information ......................................................................... 12 
2.1.1 
General definitions ................................................................................ 13 
2.2 
Analysis sets .......................................................................................................... 15 
Full Analysis Set ................................................................................................................ 15 
Safety Set ........................................................................................................................... 15 
 16 
Interim Analysis Set .......................................................................................................... 16 
Patient Classification: ........................................................................................................ 16 
2.2.1 
Subgroup of interest .............................................................................. 17 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 17 
2.3.1 
Patient disposition ................................................................................. 18 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 18 
2.4.1 
Study treatment / compliance ................................................................ 18 
2.4.2 
Prior, concomitant and post therapies ................................................... 20 
2.5 
Analysis of the primary objective .......................................................................... 20 
2.5.1 
Primary endpoint ................................................................................... 21 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 21 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 22 
2.5.4 
Supportive analyses ............................................................................... 22 
2.6 
Analysis of the key secondary objective ............................................................... 22 
2.6.1 
Efficacy ................................................................................................. 22 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 25 
2.8 
Safety analyses ....................................................................................................... 25 
2.8.1 
Adverse events (AEs) ............................................................................ 25 
2.8.2 
Deaths .................................................................................................... 26 
2.8.3 
Laboratory data ..................................................................................... 26 


Novartis 
For business use only 
Page 4 
SAP 
 
Study number 
 
2.8.4 
Other safety data ................................................................................... 28 
 
 29 
2.10 
Patient-reported outcomes ..................................................................................... 30 
 
 30 
2.12 
Other Exploratory analyses .................................................................................... 30 
2.13 
Interim analysis ...................................................................................................... 30 
3 
Sample size calculation ..................................................................................................... 31 
4 
Change to protocol specified analyses .............................................................................. 33 
5 
Appendix ........................................................................................................................... 33 
5.1 
Efficacy endpoints ................................................................................................. 33 
5.1.1 
Implementation of RECIST guidelines ................................................. 34 
5.1.2 
Response assessment in neuro-oncology (RANO) criteria for GBM ... 38 
5.1.3 
Guidelines for efficacy evaluation in lymphoma studies (based on 
Cheson response criteria). International Working Group guidelines 
for hematological malignancies ............................................................ 42 
5.2 
Imputation rules ..................................................................................................... 51 
5.2.1 
Study drug ............................................................................................. 51 
5.2.2 
AE date imputation ............................................................................... 52 
5.2.3 
Concomitant medication date imputation ............................................. 54 
5.2.4 
Incomplete date of initial diagnosis of cancer and  date of most 
recent recurrence ................................................................................... 54 
5.2.5 
Incomplete date for anti-neoplastic therapies ....................................... 54 
5.2.6 
Incomplete assessment dates for tumor assessment .............................. 55 
5.2.7 
Incomplete date for death ...................................................................... 55 
5.2.8 
Incomplete dates for disease progression on medication prior to the 
start of study drug.................................................................................. 55 
5.2.9 
Incomplete dates for last dose of study drug ......................................... 56 
5.3 
Safety evaluations .................................................................................................. 56 
5.3.1 
Multiple assessments within post-baseline visits .................................. 56 
5.3.2 
Baseline ................................................................................................. 57 
5.3.3 
Laboratory Parameters .......................................................................... 57 
5.4 
Details statistical methodology .............................................................................. 58 
5.4.1 
Prior specification of model parameters ............................................... 58 
5.4.2 
Hypothetic scenario testing ................................................................... 59 
5.4.3 
Kaplan-Meier estimates ........................................................................ 62 
5.4.4 
Confidence interval and p-value for response rate ................................ 62 
6 
Reference ........................................................................................................................... 62 


Novartis 
For business use only 
Page 5 
SAP 
 
Study number 
 
List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
bid 
bis in diem/twice a day 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
DCR 
Disease Control Rate 
DMC 
Data Monitoring Committee  
DLT 
Dose limiting toxicity 
DOR 
Duration of response 
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
ORR 
Objective response rate 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
 
 
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 
System Organ Class 
TFLs 
Tables, Figures, Listings 
TTR 
Time to response 
WHO 
World Health Organization 
 


Novartis 
For business use only 
Page 6 
SAP 
 
Study number 
 
1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of study LDK378A2407, a Phase II, Open Label, Multi-Center, Multi-Arm Study of 
Ceritinib in Patients with Advanced Solid Tumors and Hematological Malignancies 
Characterized by Genetic Abnormalities of Anaplastic Lymphoma Kinase (ALK). 
All decisions regarding final analysis, as defined in the SAP document, have been made prior 
to database lock of the study data. 
 
1.1 
Study design 
This is a phase II, open-label, multicenter, parallel multi-arm, POC clinical trial that will be 
assessing ceritinib as monotherapy in diverse populations of patients with various life 
threatening tumors other than NSCLC and hematological malignancies (see Table 1-1) 
characterized by ALK genetic alteration (and/or overexpression in some diseases).  
Table 1-1 Tumor types of interest 
Arm 
Tumor types 
T1 
Anaplastic Large Cell Lymphoma (ALCL) 
T2 
Inflammatory Myofibroblastic Tumor (IMT) 
T3 
Glioblastoma (GBM) 
T4 
Inflammatory Breast cancer (IBC) 
T5 
Any other ALK+ tumor 
Disease Control Rate (DCR) based on local investigator assessment is the primary objective of 
this study. For patients with solid tumors the assessment criteria will be RECIST 1.1. For GBM, 
RECIST 1.1 (for primary endpoint) and RANO 
 criteria will apply. 
For hematologic tumors, Cheson response criteria will apply. The DCR is defined as the 
proportion of ceritinib treated patients with complete response (CR), partial response (PR) or 
stable disease (SD) at 16 weeks from the start of the treatment. The DCR responses will need 
to be confirmed at least 4 weeks later by the same method. An adaptive design using a Bayesian 
Hierarchical model (BHM) is planned for the analysis of DCR.   
Interim analysis for each arm is planned for decision making (early stopping or continuation of 
recruitment) when a predefined number of patients (5 for IMT and 10 for all other arms) have 
completed 16 weeks of treatment with ceritinib and have their anti-tumor activity assessed and 
confirmed by a subsequent assessment at least 4 weeks later. An additional 10 patients may be 
enrolled for a given arm (including IMT) subsequent to the interim analysis  
if the probability of the pre-defined clinically meaningful response for the arm is at least 20%.  
The final analysis for a given arm is planned to be performed when a predefined number of 
patients (15 for IMT and 20 for all other arms) have completed efficacy evaluation with 
confirmation of response (see Figure 1-1).  


Novartis 
For business use only 
Page 7 
SAP 
 
Study number 
 
Due to adaptive nature of the proposed design the final sample size is not fixed. Approximately 
106 patients are planned to be enrolled in this study in order to get 95 patients for the final 
analysis assuming an estimated attrition rate of 10%. 
Given that the study was terminated based on the results of the first IA on GBM, the Bayesian 
hierarchical model will not be run for the final analysis.  


Novartis 
For business use only 
Page 8 
SAP 
 
Study number 
 
Figure 1-1 
Study design 
 
Note: the references in this figure refer to sources in the protocol 


Novartis 
For business use only 
Page 9 
SAP 
 
Study number 
 
1.2 
Study objectives and endpoints 
1.2.1 
Primary objective 
The primary objective is to assess the antitumor activity of ceritinib treatment as measured by 
Disease Control Rate (DCR) based on local investigator assessment. 
Antitumor activity in each arm will be evaluated after 16 weeks of ceritinib treatment and will 
include responses of CR or PR or SD. The primary end point DCR at 16 weeks since the start 
of the treatment is considered clinically meaningful duration of drug activity in the selected 
patient population. 
For patients with solid tumors the assessment criteria will be RECIST 1.1. For GBM, RECIST 
1.1 (for primary endpoint) and RANO 
 criteria will apply. For 
hematologic tumors, Cheson response criteria will apply. DCR will include complete response 
(CR), partial response (PR) or stable disease (SD) at 16 weeks since the start of the treatment. 
The responses (CR or PR) will need to be confirmed at least 4 weeks later by the same method. 
1.2.2 
Secondary objectives 
The key secondary objectives are to: 
• assess the antitumor activity of ceritinib as measured by objective response rate (ORR), 
duration of response (DOR), time to response (TTR) determined by investigators 
• assess the antitumor activity of ceritinib as measured by progression free survival (PFS) 
determined by investigators 
• assess safety and tolerability: 
Hematology, biochemistry, urinalysis, coagulation, pregnancy test and hormones (males 
only); ECG; Performance status; Physical examination, Vital signs; Adverse events 
CTCAE 4.03 will be used to assess events. 


Novartis 
For business use only 
Page 10 
SAP 
 
Study number 
 
Table 1-2 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 1.2.1 
To assess the antitumor activity of ceritinib as 
measured by DCR determined by investigators 
DCR, defined as the proportion of patients with best overall response of 
CR, PR, or SD ≥ 16 weeks of ceritinib treatment. Responses (CR or PR) 
observed at week 16 must be confirmed by a subsequent assessment at 
least 4 weeks later.  
 
Secondary 
 
Refer to Section 1.2.2 
1. To assess the antitumor activity of ceritinib 
as measured by ORR determined by 
investigators 
1. ORR, defined as the proportion of patients with a best overall 
response defined as CR or PR; (CR+PR) 
 
2. To assess the antitumor activity of ceritinib 
as measured by DOR,TTR and PFS 
determined by investigators 
2. The following endpoints will be evaluated by investigator assessment 
per RECIST 1.1 and Cheson criteria: 
a. DOR, defined as the time from date of first documented CR or 
PR to date of first documented disease progression or death due 
to any cause 
b. TTR, defined as the time from date of the first dose to date of 
first documented response (CR or PR) 
c. PFS, defined as time from date of the first dose to date of first 
documented disease progression (assessed by investigators per 
or date of death due to any cause 
For solid tumor and GBM, RECIST 1.1 criteria will apply. For 
hematologic tumors, Cheson response criteria will apply. 
 
3. To assess the safety profile of ceritinib 
3. ECG, Performance status, Vital signs, Physical examination; AEs 
(assessed by CTCAE 4.03), and laboratory (hematology, 
biochemistry, urinalysis, coagulation, pregnancy test and hormones 
(males only), 
 


Novartis 
For business use only 
Page 11 
SAP 
 
Study number 
 
Objective 
Endpoint 
Analysis 


 
 
 
 
 
2 
Statistical methods 
This section and its subsections will be be used to draft section 9.7 of the CSR after the analyses 
have been conducted.  
In what follows, study drug refers to LDK378. 
2.1 
Data analysis general information 
Data will be analyzed by Novartis Oncology Biostatistics and Statistical Programming 
personnel according to the data analysis plan in this SAP, which will be available in Appendix 
16.1.9 of the Clinical Study Report (CSR). Important information is given in the following 
sections and details are provided, as applicable, in Section 4 from which Appendix 16.1.9 of 
the CSR will be extracted. 
SAS® version 9.4 (or later version if available at time of database lock) will be used in all 
analyses. 
Data from all patients who signed informed consent in centers that participate in this study will 
be used in the analysis. Data collected after withdrawal of informed consent will not be reported. 
Due to expected small size of enrollment at individual centers, no center effect will be assessed. 
Each analysis will use all data in the database up to the analysis cutoff date, determined prior 
to database lock.  
Interim analysis for each arm will be performed for decision making (early stopping or 
continuation of recruitment) when a predefined number of patients (5 for IMT and 10 for all 
other arms) have completed 16 weeks of treatment with ceritinib and have their anti-tumor 
activity assessed. Responses observed at week 16 (CR or PR) must be confirmed by a 
subsequent assessment at least 4 weeks later. The reduced number of patients (5) in the IMT 
arm is based on the rare incidence of this tumor type. An additional 10 patients may be enrolled 
for a given arm (including IMT) subsequent to the interim analysis if the probability of the pre-
defined clinically meaningful response for the arm is at least 20%. 
For a specific arm, a decision will be made based on the calculated probability as given below: 
• If the posterior probability of being clinically meaningful (Table 2-1) is less than 20% 
then recruitment will be stopped in that arm 
• Otherwise, recruitment will be extended for at least 10 more patients in that arm 
All available data will be used for analysis at the interim. However, a decision will be made 
only for arms with a minimum number of pre-specified patients (a minimum of 5 patients in 
IMT arm or a minimum of 10 patients for any of the other arm). Depending on enrollment and 
follow-up, there may be multiple interim analyses. Details of the interim analysis is given in 
Section 2.13. 
The study will end approximately 38 weeks after the last patient started treatment with study 
medication or once at least 75% of patients have died or have been lost to follow-up or 
withdraws consent, or when the study is terminated early. The primary analysis for a given arm 
will occur once all patients in that arm, after initial accrual and the accrual following-up the 


Novartis 
For business use only 
Page 13 
SAP 
 
Study number 
 
interim analysis, complete at least 16 weeks of treatment with ceritinib unless discontinued 
earlier; have their efficacy evaluation completed at week 16 and the responses (CR or PR) are 
confirmed by subsequent visit by a subsequent assessment at least 4 weeks later. The final 
analysis of study data will be conducted at the end of the study.  
Section 2.2 provides further details regarding data to be included in the analyses. 
Table 2-1 
Type of tumors of interest with definition of being clinically 
meaningful 
Disease 
Code 
Arm 
#Patients† 
at Interim 
Not Clinically 
meaningful (C1) 
Clinically 
meaningful (C2) 
T1 
Anaplastic large cell 
lymphoma (ALCL) 
10 
≤40% 
≥50% 
T2 
Inflammatory 
myofibroblastic tumor (IMT) 
5 
≤20% 
≥30% 
T3 
Glioblastoma 
10 
≤10% 
≥20% 
T4 
Inflammatory breast cancer 
10 
≤10% 
≥20% 
T5 
Any other ALK+ tumor 
10 
≤10% 
≥20% 
† Extend recruitment for at least 10 more patients in each arm according to IA outcome [p(clinically 
meaningful)>20%]. 
General analysis conventions 
 
Pooling of center: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small size of centers, no center effect will be assessed.  
 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables  
by tumor type; a missing category will be included as applicable. Percentages will be  
calculated using the number of patients in the relevant population or subgroup as the  
denominator.  
 
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate  
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum) by  
tumor type.  
 
2.1.1 
General definitions  
Study drug and study treatment both refer to LDK378 and will be used interchangeably. 
Date of first/last administration of study drug 
The date of first administration of study drug is defined as the first date when a non-zero dose 
of study drug was administered and recorded on the Dosage Administration Record (DAR) 
eCRF. The date of first administration of study drug will also be referred to as start date of study 
drug. 


Novartis 
For business use only 
Page 14 
SAP 
 
Study number 
 
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 to as 
last date of study drug. 
Study day 
The study day for all assessments (e.g. tumor assessment, death, disease progression, tumor 
response, performance status, adverse event onset, laboratory abnormality occurrence, vital sign 
measurement, dose interruption) will be calculated using the start date of study drug as the 
origin. For assessments occurring after or on the start date of study drug, study day will be 
calculated as: 
Study Day =Event date - start date of study drug + 1.  
The first day of study drug is therefore study day 1. 
For any assessment or events such as baseline disease characteristics or medical history (e.g., 
time since diagnosis of disease) occurring prior to the start of the study drug, study day will be 
negative and will be calculated as: 
Study Day = Event date - start date of study drug. 
Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is  reported in 
years, duration in days will be divided by 365.25. 
Baseline 
For safety and efficacy evaluations, the last available assessment on or before the date of start 
of study treatment is defined as “baseline” assessment. If an assessment is planned to be 
performed prior to the first dose of study drug in the protocol and the assessment is performed 
on the same day as the first administration of study drug, it will be assumed that it was 
performed prior to study drug administration, if assessment time point is not collected or is 
missing. If assessment time points are collected, the observed time point will be used to 
determine pre-dose on study day 1 for baseline calculation. 
Patients who start treatment and discontinue from the study on the same day may have 2 
different sets of data collected on study day 1, one being reported to the cycle 1 day 1 visit, the 
other reported to the end of treatment (EOT) visit. Data reported at the EOT visit are not eligible 
for baseline selection. 
If patients have no value as defined above, the baseline result will be missing. 
On-treatment assessment/event and observation periods 
The overall observation period will be divided into three mutually exclusive segments:  
1. pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment 


Novartis 
For business use only 
Page 15 
SAP 
 
Study number 
 
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last actual administration of any study treatment (including start and stop date).  
For ongoing patients, on-treatment period is from date of first administration of study 
treatment to the data cut-off date (including start and cut-off date). 
3. post-treatment period: starting at day 31 after last dose of study drug 
The safety summaries (tables, figures) 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. Specifically, data from the post-treatment period with the 
exception of deaths will not be included unless requested from Health Authorities or external 
committees.   
For select items, shift tables or change from baseline summaries generated for laboratory, ECG, 
vital signs and change score generation may use data from pre-treatment period for baseline 
calculations.  
All summary tables for adverse events (AEs) will summarize only on-treatment events, with a  
start date during the on-treatment period, the so-called treatment-emergent AEs.   
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period are to be flagged. 
Windows for multiple assessments  
In order to summarize performance status/
/vital sign/other data collected over time 
(including unscheduled visits), the assessments will be time slotted. The following general rule 
will be applied in creating the assessment windows: If more than one assessment is done within 
the same time window, the assessment performed closest to the target date will be used. If 2 
assessments within a time window are equidistant from the target date, then the earlier of the 2  
assessments will be used.. If multiple assessments on the same date then the the average will be 
used.  Data from all assessments (scheduled and unscheduled), including multiple assessments, 
will be listed. 
2.2 
Analysis sets 
A patient is considered to be enrolled into the study if he/or she has signed informed consent. 
Only a patient who has signed informed consent will be included in the analysis data sets. 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients who receive at least one dose of Ceritinib. 
Unless otherwise specified the FAS will be the default analysis set used for all efficacy analyses, 
including the primary efficacy analysis. 
Safety Set 
The Safety Set includes all patients who received at least one dose of study medication. 


Novartis 
For business use only 
Page 16 
SAP 
 
Study number 
 
Interim Analysis Set 
The Interim Analysis Set comprises all patients who received ≥ 16 weeks of ceritinib treatment 
or discontinued early, and had their response confirmed by subsequent assessment at least 4 
weeks later. 
NOTE: The interim analysis set was not explicitely specified in the protocol. At the time of the 
first IA it was considered appropriate to perform the analysis of the primary endpoint based on 
the interim analysis set. 
Any blood samples with missing blood collection date or time, or missing associated study drug 
dosing date or time will be excluded from PAS. 
Patient Classification:  
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in Table 
2-2.  
Table 2-2 
Subject classification based on protocol deviations and non-PD 
criteria 
 
Analysis set 
Protocol deviations leading 
to exclusion 
Non 
protocol 
deviation 
leading to exclusion 
FAS  
No written inform consent 
Not applicable 
Safety set 
No written inform consent 
No dose of study medication  


Novartis 
For business use only 
Page 17 
SAP 
 
Study number 
 
 
  
 
 
Withdrawal of Informed Consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis data sets.  The date on which 
a patient withdraws full consent is recorded in the eCRF.  
 
 
2.2.1 
Subgroup of interest 
Not applicable. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
The FAS will be used for all patient demographic and baseline characteristic summaries and 
listings with the exception of screen failures. 
 
Basic demographic and background data 
 
All demographic and baseline disease characteristics data will be summarized and listed. 
Categorical data (e.g. gender, race, ethnicity, smoking history, WHO performance status, 
etc.) will be summarized by frequency count and percentages. Continuous data (e.g. age, 
weight, height, BMI, etc.) will be summarized by descriptive statistics (as defined in Section 
2.1). BMI (kg/m2) will be calculated as weight[kg] / (height[m]2) using weight at Baseline. 
 
Diagnosis and extent of cancer 
Descriptive statistics and frequency counts and percentages will be tabulated, as appropriate, 
for diagnosis and extent of cancer based on the data collected on the electronic Case Report 
Form (eCRF) including primary site of cancer, tumor histology/cytology, histological grade, 
time (in months) since initial diagnosis of primary site, stage at initial diagnosis, time (in 
months) from initial diagnosis to first recurrence/progression, time (in months) since most 
recent relapse/progression, current extent of disease (metastatic sites),  types of lesions (target 
and non-target lesions) at baseline, and disease burden at baseline for target lesion (based on 
the data collected on the RECIST eCRF page for solid tumor, on the RANO eCRF page for 
GBM, and on the Cheson response criteria eCRF page for hematologic tumors). 
Medical history 
 
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
will be listed. Medical history and current medical conditions are coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. 


Novartis 
For business use only 
Page 18 
SAP 
 
Study number 
 
 
Prior anti-cancer therapy 
 
Prior anti-neoplastic (anti-cancer) therapy will be listed in three separate categories: 1. 
medications, 2. radiotherapy, and 3. surgery. 
 
The number and percentage of patients who received any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery will be summarized. 
 
Prior anti-neoplastic medications will be summarized by chemotherapy (medication) setting 
and other therapy (medication) setting.  
Others 
All data collected at baseline will be listed. 
2.3.1 
Patient disposition 
The FAS will be used for the patient disposition summary tables and listings.  The following 
will be tabulated: 
• Number (%) of patients who are still on-treatment (based on the absence of the ‘End of 
Treatment Phase Completion’ page); 
• Number (%) of patients who discontinued  treatment (based on completion of the ‘End of 
Treatment Phase Completion’ page with date of discontinuation and reason of 
discontinuation/ ‘Subject Status’ entered); 
• Primary reasons for study treatment discontinuation (based on discontinuation reasons 
entered under ‘Subject Status’ in the ‘End of Treatment Phase Completion’ page); 
Protocol deviations 
 
 
All protocol deviations will be listed. 
Analysis sets 
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized  by 
tumor type. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The Safety Set will be used for all medication data summaries and listings unless 
otherwise specified. 
2.4.1 
Study treatment / compliance 
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized by tumor type. Duration of exposure will be categorized into time 
intervals; frequency counts and percentages will be presented for the number(%) of subjects in 
each interval. The number (%) of subjects who have dose changes, reductions or interruptions, 
and the reasons, will be summarized by tumor type.  


Novartis 
For business use only 
Page 19 
SAP 
 
Study number 
 
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.   
The safety set will be used for all summaries and listings of study treatment.  
Dose exposure and intensity 
Definitions of duration of exposure, cumulative dose, average daily dose, dose intensity (DI), 
relative dose intensity (RDI), as well as intermediate calculations, include: 
• Duration of exposure (days): 
last date of study drug − first date of study drug + 1 
(periods of interruption are not excluded)  
• Cumulative dose (mg): 
total dose of study drug taken by a patient in the study 
• Number of dosing days (days): 
duration of exposure − number of zero dose days 
• Average daily dose (mg/day): 
cumulative dose (mg) ∕ number of dosing days (days) 
• DI (mg/day): 
cumulative dose (mg) ∕ duration of exposure (days) 
• RDI (%): 
100 × [DI (mg/day) ∕ planned dose (750 mg)] 
Note: given the planned LDK378 dose of 750mg/day, the planned dose intensity can be 
calculated as: 
PDI (mg/day) = cumulative planned dose (mg)/Duration of exposure (days), 
where  
cumulative planned dose (mg) = Protocol planned dose of 750 (mg)* Duration of 
exposure. 
then, RDI (%) which is calculated as 100*DI/PDI can be simplified as shown above. 
Dose reductions, interruptions or permanent discontinuations 
The number of subjects who have dose reductions, permanent discontinuations or interruptions, 
and the reasons, will be summarized separately for each tumor type.  
‘Dose changed’, ‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the 
Dosage Administration CRF pages (DAR) will be used to determine the dose reductions, dose 
interruptions, and permanent discontinuations, respectively. 
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons. 
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose. 
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this block of entries, then it will be 
counted as one interruption.  
Reduction: A dose change where the prescribed dose level is lower than the previous prescribed 
dose level or where the actual dose administered/total daily dose is lower than the calculated 
dose amount based on the prescribed dose. Therefore any dose change to correct a dosing error 


Novartis 
For business use only 
Page 20 
SAP 
 
Study number 
 
will not be considered a dose reduction.  Number of reductions will be derived 
programmatically  based on the change and the  direction of the change. 
2.4.2 
Prior, concomitant and post therapies 
Prior anti-cancer therapy 
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 by tumor 
type. Prior anti-neoplastic medications will be summarized by therapy type (e.g. chemotherapy, 
hormonal therapy etc.), setting (e.g. adjuvant, metastatic, etc.) and tumor type (arm). Summaries 
will also include total number of regimens. The medication therapy type of any combination 
therapy will be classified based on the following order: chemotherapy, biologic therapy, 
targeted therapy, hormonal therapy. For example, a combination therapy of chemotherapy and 
hormonal therapy will be classified as ‘chemotherapy’. For radiotherapy, time since last 
radiotherapy, locations and setting of last therapy will be summarized. For prior surgery, time 
since last surgery and procedure will be summarized.  
Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery. Palliative antineoplastic radiotherapy administered during the treatment phase may also 
be summarized by tumor type. 
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD); anti-
neoplastic surgery will be coded using MedDRA. Details regarding MedDRA and WHO-DD 
version will be included in the footnote in the tables/listings.  
The above analyses will be performed using the FAS. 
Concomitant medications 
Concomitant therapies are defined as any medications (excluding study drug, prior 
antineoplastic treatments and blood transfusions), surgeries or procedures (including physical 
therapy) administered in the study and are recorded in the Prior and Concomitant Medications 
and the Surgical and Medical Procedures eCRF, respectively. 
 
Concomitant medications will be coded using the WHO Drug Reference Listing (WHO DRL) 
dictionary that employs the WHO Anatomical Therapeutic Chemical (WHO ATC) 
classification system. Surgeries or procedures will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology.  
 
 
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study drug or starting more than 30 days after the last date of study drug will be 
flagged in the listings. 
2.5 
Analysis of the primary objective 
The primary objective is to assess the antitumor activity of ceritinib as measured by DCR 
determined by investigators in patients with ALK-positive ALCL, IMT, GBM, IBC or any other 
tumor type that is ALK positive, except from NSCLC. Patients must have received at least one 
line of prior systemic treatment for recurrent, locally advanced and/or metastatic disease.   


Novartis 
For business use only 
Page 21 
SAP 
 
Study number 
 
2.5.1 
Primary endpoint 
The variable used to evaluate the primary objective is DCR associated with ceritinib treatment 
based on local investigator assessment. For patients with solid tumors or GMB the assessment 
criteria will be RECIST 1.1 and will include responses of CR or PR or SD ≥ 16 weeks after the 
first dose of the study drug. For hematologic tumors, Cheson response criteria will apply.  
Responses (CR or PR) should be confirmed by a subsequent assessment at least 4 weeks later.  
In general, the definition of SD is applicable to patients with measurable disease only.  If a 
patient without measurable disease is enrolled in the study, the non-CR/non-PD response for 
these patients will be considered equivalent to an SD response in endpoint determination.  
2.5.2 
Statistical hypothesis, model, and method of analysis 
This study will contain 5 arms with ALK+ patients, an adaptive design will be used to assess 
activity of treatment in terms of response (DCR) rate within each arm and across each arm. The 
rules for how the trial adapts are pre-specified and are not based on ongoing data. 
The design of the trial adapts to the data that are accumulated in the trial in such a way as to 
accommodate two possibilities: 
a. DCR to ceritinib is specific to ALK+ inhibition and independent of the tumor site (similar 
DCR irrespective of tumor type); 
b. the various tumor types have distinct DCR to ceritinib. 
The pre-specified analysis is adaptive in the sense that when response depends on ALK+ 
inhibition and not on arm (scenario A), then it borrows from across the various arms and provide 
more precise estimate of DCR rates for those arms with similar response rates. In the other 
possibility (the various arms have distinct anti-tumor activity to ceritinib (Scenario B), the 
design allows little/no borrowing across tumor types. In this case the trial will be similar to 
traditional stratified analysis. 
A hierarchical model (HM) will be used to analyze the binary data to facilitate the borrowing 
as specified above. Response rates (πj) will be inferred for arm j (= 1,…,5). For each arm j, the 
number of responders follows a binomial distribution; 
 
rj ~ Bin( nj, π j ) 
We further let the parameters log ( πj/ (1 − πj) ) (logistic transformation) be either exchangeable 
with some of the arms, or non-exchangeable with any of them. Based on the number of strata 
in this trial, we allow for two exchangeability distributions, which, for example, accounts for 
the case where some arm shows no efficacy and some are promising. 
Thus, for each arm j three possibilities arise, with respective probabilities pj = ( pj1, pj2, pj3 ), as 
follows: 
1. With probability pj1 the parameter θj follows a normal distribution with exchangeability 
parameters µ1 and τ1: 
 
θj ~ N(µ1,τ12) 
2. With probability pj2, θj follows a normal distribution with exchangeability parameters µ1 < 
µ2 and τ2: 


Novartis 
For business use only 
Page 22 
SAP 
 
Study number 
 
 
θj ~ N(µ2,τ22) 
3. With remaining probability pj3 = 1−pj1−pj2, θj follows a weakly-informative prior 
distribution 
 
θj ~ N(mw,vw) 
For the detailed specifications of mw, vw, the a-priori weights pj (j=1,…,J), and the prior 
distributions for µ1, τ1, µ2, and τ2, see (Appendix 5.4.1). At any given time of the trial, including 
at the end, posterior probabilities of the various parameters will be estimated using Markov 
chain Monte Carlo methods. 
For a specific disease group, a Proof of Concept about treatment with ceritinib will be declared 
if both of the following conditions are met: 
a. Observed DCR ≥ “Disease Control Rate” threshold (column for C2 in Table 2-1) 
b. Posterior probability of “not being clinically meaningful” (column for C1 in Table 2-1) is 
less than 20% 
2.5.3 
Handling of missing values/censoring/discontinuations 
Confirmed partial or complete responses or stable disease reported prior to any additional 
anticancer therapy will be considered as responses in the calculation of the DCR irrespective of 
the number of missed assessments before response. 
For solid tumor, patients with a best overall response of ‘Unknown’ or ‘Not Assessed’ per 
RECIST v1.1 will be considered as non-responders and will be included in the denominator in 
estimating the DCR. For GMB or hematologic tumor, patients with unknown or missing 
response, or who are treated in the study but provide no information on response at the end of 
treatment will be treated as non-responders and will be included in the denominator when 
calculating DCR. 
2.5.4 
Supportive analyses 
As a sensitivity analysis ORR and its 95% confidence interval will also be provided based on 
the exact binomial distribution (Clopper & Pearson, 1934). 
2.6 
Analysis of the key secondary objective 
2.6.1 
Efficacy 
All secondary efficacy assessments (DOR, ORR, PFS, TTR) will be analyzed as per investigator 
assessment. Confirmation of response is required for all response endpoints, as per appropriate 
criteria (RECIST 1.1 for solid tumor and GMB, and Cheson for hematologic tumor). 
All secondary analyses will be performed based on the FAS for each arm, unless otherwise 
specified. 
No adjustment for multiple testing will be made. 
The key secondary efficacy endpoints are: 
• ORR  
• DOR 


Novartis 
For business use only 
Page 23 
SAP 
 
Study number 
 
• TTR 
• PFS 
 
The definitions and details on the derivation of the secondary endpoints are given in Section 14 
(Appendix 2) of the LDK378A2407 protocol. Further details and rules needed for programmatic 
implementation of RECIST 1.1 guidelines and hematology criteria are provided in Section 5.1. 
Overall Response Rate 
Overall Response Rate (ORR) is based on local investigator assessment per RECIST 1.1 or 
Cheson criteria. For patients with solid tumors and GBM, the assessment criteria will be 
RECIST 1.1 and will include responses of CR and/or PR. For hematologic tumors, Cheson 
criteria will apply for evaluation of response. ORR is defined as the proportion of patients with 
best overall response of CR, PR. For ORR, estimate and its 95% CI will be provided. 
Best overall response 
The BOR will be assessed based on reported lesion responses at different evaluation time points. 
Both CR and PR must be confirmed by repeat assessments performed not less than 4 weeks 
after the criteria for response are first met. The next scheduled assessment may be used for 
purposes of confirmation of response.   
BOR for each patient is determined from the sequence of overall (lesion) responses according 
to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression  
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR)  
• SD = at least one SD assessment (or better) > 6 weeks after start of study drug (and not 
qualifying for CR or PR). 
• PD = progression ≤ 12 weeks after start of study drug (and not qualifying for CR, PR or 
SD). 
• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or progression within the first 12 weeks) 
Only tumor assessments performed before the start of any further anti-neoplastic therapies (i.e. 
any additional secondary anti-neoplastic therapy or anti-cancer surgery) will be considered in 
the assessment of BOR.  If a patient receives any further anti-neoplastic therapy while on study, 
any subsequent assessments will be excluded from the BOR determination.  Further anti-
neoplastic therapies will be identified via protocol deviations or from the data collected on 
‘Anti-neoplastic therapies since last date of study drug’ as appropriate. Clinical deterioration 
will not be considered as documented disease progression. Patients with BOR ‘unknown’ will 
be summarized by reason for having unknown status. The following reasons will be used: 
• No valid post-baseline assessment 
• All post-baseline assessments have overall response UNK 


Novartis 
For business use only 
Page 24 
SAP 
 
Study number 
 
• New anti-neoplastic therapy started before first post-baseline assessment 
• Stable disease (SD) too early (≤ 6 weeks after start date of study drug) 
• PD too late (> 12 weeks after start date of study drug) 
Special (and rare) cases where BOR is ‘unknown’ due to both early SD and late PD will be 
classified as ‘SD too early’. 
Duration of Response 
Duration of Response (DOR) will be based on local investigator assessment per RECIST 1.1 
for solid tumor, RANO and RECIST 1.1 for GBM, or Cheson criteria for hematologic tumors. 
Among patients with a confirmed response (PR or CR), DOR is defined as the time from first 
documented response (PR or CR) to the date of first documented disease progression or death 
due to any cause. If a patient has not had an event, DOR is censored at the date of last adequate 
tumor assessment. DOR will be listed by patient and may be described using Kaplan-Meier 
curves and relevant statistics if appropriate. 
Time to response 
Time to response (TTR) is defined as the time from the date of the first dose of LDK378 to first 
documented response (CR or PR, which must be confirmed subsequently) per appropriate 
critetia (RECIST 1.1 for solid tumor and GMB, and Cheson for hematologic tumor). TTR will 
be described using Kaplan-Meier methods and appropriate summary statistics. The TTR 
analysis will be conducted with censoring rules as described in the Appendix 5.1.1. 
Progression-free survival 
Progression-free survival (PFS) is defined as the time from the date of first dose of Ceritinib to 
the date of first documented disease progression per appropriate criteria (RECIST 1.1 for solid 
tumor and GMB, and Cheson for hematologic tumor) or death due to any cause. 
A patient who has not progressed or died at the date of the analysis or when he/she receives any 
further anticancer therapy in the absence of disease progression will be censored at the time of 
the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy 
date. By default, if disease progression or death is documented after one single missing tumor 
evaluation, the actual event date of disease progression/death will be used for the PFS event 
date. If disease progression or death is documented after two or more missing tumor evaluations, 
the PFS time of these patients will be censored at the date of the last adequate tumor evaluation 
without PD. 
If the study primary objective is not met (did not meet Proof of Concept criteria) for a given 
arm, Novartis may decide not to conduct some of the above secondary efficacy analyses in that 
arm but instead may choose to provide those endpoints in listings only. 
Waterfall plot to depict anti-tumor activity 
Waterfall graphs will be used to depict the anti-tumor activity. These plots will display the 
best percentage change from baseline in the sum of diameters of all target lesions for each 
patient with solid tumor (See Section 5.1.1 for details).   


Novartis 
For business use only 
Page 25 
SAP 
 
Study number 
 
2.7 
Analysis of secondary efficacy objective(s) 
Not applicable. 
2.8 
Safety analyses 
All safety analyses will be performed based on the Safety Set. All listings and tables will be 
presented by arm and for all patients within the arm. 
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. post-treatment period: starting at day 31 after last dose of study medication. 
2.8.1 
Adverse events (AEs) 
AE summaries will include all AEs occurring during on treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc.  AEs with start date outside of on-treatment period 
will be flagged in the listings.  
 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding (using the latest version available prior to clinical database lock) by 
maximum severity (based on Common Terminology Criteria for Adverse Events [CTCAE] 
grades version 4.03), and relation to study drug. A subject with multiple occurrences of an AE 
will be counted only once in the respective AE category. A subject with multiple CTCAE grades 
for the same preferred term will be summarized under the maximum CTCAE grade recorded 
for the event. 
 
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency.  
 
AEs will be coded using MedDRA using the latest version available locket the time of analysis 
and will be graded using Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03.  The CTCAE represents a comprehensive grading system for reporting the acute and late 
effects of cancer treatments. CTCAE grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 is not necessarily twice as bad as a grade 1). The 
CTCAE grade of 5 (death) is not used; rather, ‘fatal’ is collected as AE outcome and death 
information is also collected on a separate (e)CRF page.   


Novartis 
For business use only 
Page 26 
SAP 
 
Study number 
 
 
The following AE summaries will be produced by tumor type: 
• AEs regardless of study drug relationship 
• AEs suspected to be study drug related 
• 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 discontinuation of study drug 
• AEs requiring dose adjustment or study drug interruption 
• AEs requiring significant additional therapy 
• AEs excluding SAEs 
 
All AEs regardless of study drug relationship will be summarized by tumor type and all patients.  
2.8.1.1 
Adverse events of special interest / grouping of AEs 
NA for the abbreviated CSR for final analysis.  
2.8.2 
Deaths 
Summary for on-treatment will be produced by tumor type, system organ class and preferred 
term. All deaths will be listed, post treatment deaths will be flagged. 
2.8.3 
Laboratory data 
Data from all sources (central and local laboratories) will be combined. The summaries will 
include all laboratory assessments collected no later than 30 days after study drug 
discontinuation. All laboratory assessments will be listed and those collected later than 30 days 
after study drug discontinuation will be flagged in the listings.  
Laboratory data will be classified (by Novartis Oncology Statistical Programming) into CTC 
grades according to the NCI CTCAE v4.03.  For all reports, CTC grade is always obtained on 
the converted measurement in SI unit.  Grade 5 will not be used.The CTC grade 0 will be 
assigned as below in different scenarios:   
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 lab values with missing baseline grading, the 
grade will be derived using the criteria based only on the normal range as per CTCAE 


Novartis 
For business use only 
Page 27 
SAP 
 
Study number 
 
v4.03. A severity grade of 0 will be assigned when the post-baseline value is ≤ ULN (for  
hyper) or ≥ LLN (for hypo). 
Parameters for which a grading does not exist will be classified into low/normal/high group by 
means of laboratory normal ranges. 
The following summaries will be produced for the hematology and biochemistry laboratory 
data (by laboratory parameter): 
• Shift tables using CTC grades to compare baseline to the worst post-baseline value for 
laboratory parameters with CTC grades  
The following lab parameters will be summarized:  
• Hematology: absolute lymphocytes , absolute neutrophils ,  hemoglobin (anemia), WBC; 
platelet counts, absolute basophils, absolute eosinophils, absolute monocytes, RBC 
• Biochemistry: alkaline phosphatase (APT), SGPT (ALT), SGOT (AST), total bilirubin, 
amylase, lipase, potassium (hyper and hypo), sodium (hyper and hypo), creatinine, glucose 
(fasting) (hyper and hypo), phosphate; albumin, calcium (at screening only corrected for 
albumin), magnesium, creatinine clearance, total bilirubin, blood urea nitrogen (BUN) or 
urea, GGT. 
• For bi-directional parameters, both hyper and hypo summaries will be presented.  
• Hormones (males only): Testosterone, LH, FSH, sex hormone binding globulin (SHBG). 
The following laboratory parameters will be presented in listings and will not be summarized:  
• Urinalysis: Macroscopic Panel (Dipstick) (Color, bilirubin, Blood, Glucose, Ketones, 
Leukocyte esterase, nitrite, pH, protein, specific gravity, urobilinogen). 
• Microscopic panel (RBC, WBC, casts, crystals, bacteria, epithelial cells) 
• Coagulation: INR 
The following listings will be produced for the laboratory data for all laboratory parameters 
where CTC grades are defined: 
• Listing of patients with laboratory abnormalities of CTC grade 3 or 4 
• Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory reference ranges. 
Liver function tests (LFTs) of interest for LDK378 are total bilirubin (TBILI), ALT, AST and 
ALP.  In what follows, AT refers to ALT or AST values. LFTs will be summarized as follows: 
• Frequency counts and percentages of patients with worst post-baseline on-treatment 
values in the categories: 
o ALT > 3xULN, ALT > 5xULN, ALT > 8xULN, ALT > 10xULN, ALT > 20xULN 
o AST > 3xULN, AST > 5xULN, AST > 8xULN, AST > 10xULN, AST > 20xULN 
o AT > 3xULN, AT > 5xULN, AT > 8xULN, AT > 10xULN, AT > 20xULN 
o TBILI > 2xULN, TBILI > 3xULN 
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 


Novartis 
For business use only 
Page 28 
SAP 
 
Study number 
 
Concurrent measurements are those occurring on the same date. 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
ECG data will be analyzed 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 study drug 
discontinuation will be flagged in the listing.  
Selecting Primary QT Correction for Heart Rate 
The analysis of QT data is complicated by the fact that the QT interval is highly correlated with 
heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected value, 
denoted QTc, which is independent of heart rate. This QTc interval is intended to represent the 
QT interval at a standardized heart rate. Several correction formulas have been proposed in the 
literature. For this analysis we will use QTcF as described below.  
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as  
3 RR
QT
QTcF =
 , 
where where RR=60/HR  represents the RR interval of the ECG, in seconds.   
Data will be summarized using QTcF. 
ECG Summaries 
The following analyses will be performed for each applicable ECG parameters (QT, ventricular 
rate – denoted as HR in what follows, and QTcF) as noted. 
• Frequency counts and percentages of patients having notable ECG values according to the 
following categories:            
o QT parameter (QT, QTcF) 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 
The denominator to calculate percentages for each category is the number of patients at risk 
for a specific category. For new abnormality post baseline, the denominator is the number 
of patients with both a baseline and a post-baseline evaluation and baseline not meeting the 
criterion.  A newly occurring post-baseline ECG notable value is defined as a post-baseline 
value that meets the criterion post-baseline but did not meet the criterion at baseline.  
All ECG assessments will be listed by patient and ECG parameter. In the listings, clinically 
notable values will also be flagged. 
 


Novartis 
For business use only 
Page 29 
SAP 
 
Study number 
 
2.8.4.2 
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), and respiration rate (breaths per minute).  
Clinically notable elevated values are defined as: 
• Systolic BP: ≥ 160 mmHg and an increase ≥ 20 mmHg from baseline 
• Diastolic BP: ≥ 100 mmHg and an increase ≥ 15 mmHg from baseline. 
• Body temperature: ≥ 39.1°C 
• Weight: increase from baseline of ≥ 10% 
• Pulse rate: ≥ 120 bpm with increase from baseline of ≥15 bpm 
Clinically notable below normal values are defined as: 
• Systolic BP: ≤ 90 mmHg and a decrease ≥ 20 mmHg from baseline 
• Diastolic BP: ≤ 50 mmHg and a decrease ≥ 15 mmHg from baseline 
• Body temperature: ≤ 35°C 
• Weight: decrease from baseline of ≥ 10% 
• Pulse rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm  
All vital sign assessments will be listed by patient and vital sign parameter. 
In the listings, clinically notable values will also be flagged. 
2.8.4.3 
ECOG performance status (WHO) 
The ECOG performance assessment allows patients to be classified as to their functional 
impairment, the definition of scores in relation to their performance status is provided in Table 
2-3, ranging from 0 (most active) to 5 (dead): 
Table 2-3 
ECOG performance scale 
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than  50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
ECOG performance status at each time point will be listed. 


Novartis 
For business use only 
Page 30 
SAP 
 
Study number 
 
 
 
2.10 
Patient-reported outcomes 
Not applicable. 
2.12 
Other Exploratory analyses 
Not applicable 
2.13 
Interim analysis 
Subjects will be continuously accrued and the data will be analyzed using a Bayesian 
hierarchical model. Interim analysis for an arm will be performed when a predefined number 
of patients (5 for IMT or T2 and 10 for all other tumor types) are enrolled and have completed 
16 weeks of follow-up after the first dose of study drug and have their responses (CR or PR) 


Novartis 
For business use only 
Page 31 
SAP 
 
Study number 
 
confirmed by a subsequent assessment at least 4 weeks later. At each of these analyses, the 
current (posterior) probability that the response rate for each of the tumor types is greater than 
“clinically meaningful (column for C2 in Table 2-1)” response rate will be determined. 
These probabilities will be used to adapt the design as follows: 
1. Accrual to an arm that has at least predefined number of subjects will cease for futility if: 
it is very unlikely (probability <20%) that the response rate for the tumor is “clinically 
meaningful” (≥column for C2 in Table 2-1) 
2. Accrual to an arm will cease when its maximum planned sample size is reached. The 
results within an arm will be regarded as positive if the accrual for the arm reaches 
maximum and the conditions for positive conclusion are satisfied. 
Table 2-4 
Type of tumors of interest with definition of being clinically 
meaningful 
Disease 
Code 
Arm 
#Patients† 
at Interim 
Not Clinically 
meaningful (C1) 
Clinically 
meaningful (C2) 
T1 
Anaplastic large cell 
lymphoma (ALCL) 
10 
≤40% 
≥50% 
T2 
Inflammatory 
myofibroblastic tumor (IMT) 
5 
≤20% 
≥30% 
T3 
Glioblastoma 
10 
≤10% 
≥20% 
T4 
Inflammatory breast cancer 
10 
≤10% 
≥20% 
T5 
Any other ALK+ tumor 
10 
≤10% 
≥20% 
† Extend recruitment for at least 10 more patients in each arm according to IA outcome [p(clinically 
meaningful)>20%]. 
Note that if there are at least 5 patients of the same arm in “Any other ALK+ tumor, T5)” arm, 
then a separate arm will be opened for that specific tumor type leading to 5 different arms. 
However, interim analysis for decision making will not be performed until there are 10 patients 
in each of the arm: “new tumor type” and modified “Any other ALK+ tumor”. 
Since all patients will be treated with ceritinib in this open label study, it is not necessary to 
control access to interim results. Therefore, interim analysis will be performed by the study 
team to decide weather to terminate a given tumor type for futility. Note that recruitment will 
not be stopped while interim analysis is performed.  This SAP decrribes the plan for interim 
analysis and no additional SAP that will be developed for the interim analysis. 
3 
Sample size calculation 
The design of this study is adaptive in nature; hence, the final sample size is not fixed. A 
minimum of 10 and a maximum of 20 subjects in each arm T1, T3, T4 and T5 will receive 
treatment. For arm T2, the minimum and maximum sample size will be 5 and 15 respectively. 
Thus, the total sample size across all tumor types will be between 45 and 95. Assuming a 10% 
drop out rate, approximately 106 patients are planned to be enrolled in this study. 
Subjects will be continuously accrued, and, the accumulated data will be analyzed at interim as 
described in Section 2.13. Based upon the results of any of these analyses, enrollment into one 
or more arms may be terminated. 


Novartis 
For business use only 
Page 32 
SAP 
 
Study number 
 
The operating characteristics for this Bayesian Design are evaluated using simulation and are 
presented below. Simulation-based probability estimates (relative frequencies) of futility at 
interim, positive results at final analysis and average sample size for each arm in three scenarios 
are provided. 
1. Scenario 1 (not clinically meaningful for all arms): The true rates of response for T1, T2, 
T3, T4, and T5 are 40%, 20%, 10%, 10%, and 10%; respectively; 
2. Scenario 2 (clinically meaningful for all arms): The true rates of response for T1, T2, T3, 
T4, and T5 are 60%, 40%, 30%, 30%, and 30%; respectively; 
3. Scenario 3 (clinically meaningful for T1 and T5 but not for others): The true rates of 
response for T1, T2, T3, T4, and T5 are 60%, 20%, 10%, 10% and 30%; respectively; 
In all three cases it is assumed that accrual rates are in proportion 2:1:2:2:2 for the 5 arms (T1, 
T2, T3, T4, and T5). The type I error (false positive rate) of the adaptive design can be viewed 
as the probability estimate of a positive conclusion at final analysis in Scenario 1 (Table 3-1). 
The power of the adaptive design is defined as the probability estimate of positive conclusion 
at final analysis in Scenario 2 (Table 3-2). 
The simulation results for Scenario 1, when the effect of Ceritinib is not-clinically meaningful 
(true response rates equal 40% and 20% and 10% for T1 and T2 and for other 3 arms 
respectively), show that the probability of stopping at interim for futility varies from 41.7% to 
59.9% for different arm. Probability of concluding positive trial at final analysis (i.e., crossed 
interim and maximum sample size reached) are 11.5%, 13.8%, 12.5%, 11.0%, and 11.0% for 
T1, T2, T3, T4, and T5 respectively. The overall sample size is approximately 67. 
Table 3-1 
Simulation results Scenario 1 (ceritinib inactive for all arms) 
Arm 
True CBR 
(%) 
Probability of 
stopping at IA 
for futility (%) 
Probability for 
positive 
conclusion in 
final analysis (%) 
Average 
Sample Size 
T1 
40.0 
59.3 
11.5 
14.1 
T2 
20.0 
41.7 
13.8 
10.8 
T3 
10.0 
59.9 
12.5 
14.0 
T4 
10.0 
58.8 
11.0 
14.1 
T5 
10.0 
59.7 
11.0 
14.0 
Overall 
 
 
 
67.0 
The simulation-based results for Scenario 2 (Table 3-2), when the truth is that the effect of 
Ceritinib is clinically meaningful in all arms, illustrate that approximately 69% to 87% of the 
simulated trial outcomes are positive at final analysis (passes futility interim and reaches the 
maximum enrollment) for different arm. In addition, the average overall sample size is 91 
subjects. 


Novartis 
For business use only 
Page 33 
SAP 
 
Study number 
 
Table 3-2 
 
Simulation results Scenario 2 (ceritinib active for allarms) 
Arm 
True CBR 
(%) 
Probability of a 
stopping at IA 
for futility (%) 
Probability for 
positive 
conclusion in 
final analysis (%) 
Average 
Sample Size 
T1 
60.0 
14.2 
69.3 
18.6 
T2 
40.0 
8.6 
77.8 
14.1 
T3 
30.0 
5.0 
86.8 
19.5 
T4 
30.0 
4.6 
86.4 
19.5 
T5 
30.0 
4.9 
86.0 
19.5 
Overall 
 
 
 
91.2 
In order to illustrate the design behavior one additional scenario (Scenario 3) is explored. In 
Scenario 3 the effect of Ceritinib is clinically meaningful for arms T1, T5 and not-clinically 
meaningful for all other arms (Table 3-3). Table 3-3 shows reasonable operating characteristics 
(futility at interim and positive results at final analysis) under Scenario 3. The average overall 
sample size under this scenario is 78. 
Table 3-3 
 
Simulation results Scenario 3 (certinib active for T1 and T5 arms) 
Arm 
True CBR 
(%) 
Probability of 
stopping at IA 
for futility (%) 
Probability for 
positive 
conclusion in 
final analysis (%) 
Average 
Sample Size 
T1 
60.0 
15.1 
71.3 
18.5 
T2 
20.0 
35.0 
14.9 
11.7 
T3 
10.0 
52.2 
10.8 
14.8 
T4 
10.0 
52.7 
11.6 
14.7 
T5 
30.0 
13.4 
81.0 
18.7 
Overall 
 
 
 
78.4 
4 
Change to protocol specified analyses 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment for all patients by arm will not be summarized. For laboratory tests where 
CTCAE grades are not defined, shift tables using the low/normal/high/(low and high) will not 
be generated. Only listings will be provided. 
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 details on 
programming rules that will be followed to implement the analyses described in Section 2. 
5.1 
Efficacy endpoints  
For further details on efficacy endpoints, see Section 14 (Appendix II) of the protocol. For the 
evaluation of tumor-response related endpoints, response is assessed by investigator according 


Novartis 
For business use only 
Page 34 
SAP 
 
Study number 
 
to RECIST 1.1 criteria for solid tumors, RECIST 1.1 (for primary endpoint) criteria and RANO 
 for GBM or as per Cheson's guidelines for hematological 
malignancies). 
Response and progression evaluation will be performed according to the Novartis RECIST 1.1 
guidelines, included in Section 14 (Appendix II) of the LDK378A2407 protocol. 
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Section 2. 
5.1.1 
Implementation of RECIST guidelines 
Disease progression 
PD should only be assigned if it is confirmed by an objective assessment method as per RECIST 
1.1 (e.g. radiologic scan, histology for bronchoscopy, photos for skin lesions). If a new lesion 
is detected using an objective assessment method other than radiologic scan, it should be entered 
on the ‘New lesion’ RECIST eCRF with appropriate method (or method=‘Other’).  
In particular, discontinuation due to disease progression or death due to progressive disease, 
without supporting objective evidence (as defined above), will not be considered as PD in the 
determination of BOR, the derivation of any efficacy endpoint or efficacy analysis.  
Change in imaging modality 
Per RECIST 1.1, a change in methodology can be defined as either a change in contrast use 
(e.g. keeping the same technique, like CT, but switching from with to without contrast use or 
vice-versa, regardless of the justification for the change) or a change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK (unknown) overall lesion response assessment. However, a 
response assessment other than the Novartis calculated UNK response may be accepted from 
the investigator if a definitive response assessment can be justified based on the available 
information. Potential discrepancies between the modality used and overall lesion response 
reported by the investigator (e.g. change in modality but investigator assessment of response is 
different from UNK) will be queried during the data validation process. 
Determination of missing adequate tumor assessments 
For the computation of ORR, patients without any radiological assessment after the start date 
of study drug will be counted as failure. 
Partial or complete responses reported prior to any additional anticancer therapy will be 
considered for ORR computation irrespective of the number of missed assessments before 
response. In this section, the ‘missing adequate assessment’ is defined as assessment not done 
or assessment with overall lesion response equal to UNK.  For the sake of simplicity, the 
‘missing adequate assessment’ will also be referred as ‘missing assessment’. 
As detailed in Section 14 (Appendix II) of the LDK378A2407 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. 


Novartis 
For business use only 
Page 35 
SAP 
 
Study number 
 
An exact rule to determine whether there is none, one or two missing assessments is therefore 
needed. This rule will be based on the distance between the last adequate tumor assessment date 
and the event date. 
If the distance is larger than threshold D1 or D2 then the analysis will assume one or two missing 
assessments, respectively. The threshold D1 will be defined as the protocol specified interval 
between the tumor assessments plus the protocol allowed window around the assessments. 
Similarly, the threshold D2 is defined as two times the protocol specified interval between the 
tumor assessments plus the protocol allowed window around the assessments. In this study, the 
protocol defined schedule of tumor assessment is every 8 weeks and each assessment is 
expected to be performed at the scheduled time point plus or minus 1 week, i.e. the window is 
2 weeks, then any distance larger than D1 = 8+2 = 10 weeks means one missing assessment and 
any distance larger than D2 = (2*8) + 2 = 18 weeks means two missing assessments. 
The same definition of D2 will be used to determine the PFS censoring reason. If the distance 
between the last adequate tumor assessment date and one of the following dates is ≤ D2:  
1. Analysis cut-off date 
2. Start date of further anti-neoplastic therapy  
3. Visit date of study treatment discontinuation due to consent withdrawal 
4. Visit date of study treatment discontinuation due to loss to follow-up 
then the associated censoring reason will be  
1. Ongoing  
2. New cancer therapy  
3. Withdrew consent 
4. Loss to follow-up 
However, if this distance is larger than D2, then the censoring reason will be ‘Adequate 
assessment no longer available’. 
Non-measurable disease at baseline 
As specified in Section 14 (Appendix II) of the LDK378A2407 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. Therefore, a rule needs to 
be specified on how to handle these cases. 
As specified in Tables 14-7, 14.8, and 14.9 of Section 14 (Appendix II) of the LDK378A2407 
protocol, overall lesion response can be derived for patients without measurable disease at 
baseline as follows (Table 5-1). 


Novartis 
For business use only 
Page 36 
SAP 
 
Study number 
 
Table 5-1 
Overall lesion response at each assessment: patients with non-target 
disease only 
Non-target lesions 
New Lesions 
Overall lesion 
response 
CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination.  
Missing baseline tumor assessment 
As specified in Section 14 (Appendix II) of the protocol, since the timing of PD cannot be 
determined for patients with missing baseline tumor assessment, these patients are censored in 
the PFS analysis at the start date of treatment. This rule, however, only applies to the ‘PD 
component’ of the PFS 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. 
Construction of waterfall graphs 
The waterfall graphs will be used to depict the anti-tumor activity. These plots will display the 
best percentage change from baseline in the sum of the measured diameter of all target lesions 
for each patient.  The proportions of patients with various degrees of tumor shrinkage or growth 
can then represent a useful efficacy metric. 
However, caution needs to be paid to the assessments, where an occurrence of a new lesion or 
worsening in non-target lesions (resulting in PD as an overall lesion response at given 
assessment) contradicts the measurements obtained on target lesions.  These assessments will 
not be displayed as bars in the graph. If such a “contradicting” assessment represents the only 
post-baseline assessment for a patient, then the patient will be represented by a special symbol 
(e.g. *) in the waterfall graph. 
The assessments with unknown target response and also assessments with unknown overall 
response will be excluded. Patients without any valid assessments will be completely excluded 
from the graphs. 
The total number of patients displayed in the graph needs to be shown and this number will be 
used as a denominator when calculating the percentages of patients with tumor shrinkage and 
tumor growth.  Footnote will explain the reason for excluding some patients (due to absence of 
any valid assessment). 
All possible assessment scenarios are described in Table 5-2. 


Novartis 
For business use only 
Page 37 
SAP 
 
Study number 
 
Table 5-2 
 
Inclusion/exclusion of assessments used in waterfall graph 
Criteria for inclusion/exclusion 
Possible 
source 
of 
contradictions 
Target response 
Overall 
lesion 
response 
Include in waterfall 
Non-target 
response 
New lesion? 
CR/PR/SD 
PD 
Yes but as * only 
PD 
any 
CR/PR/SD 
PD 
Yes but as * only 
any 
Yes 
UNK 
UNK or PD 
No 
any 
any 
CR/PR/SD 
UNK 
No 
UNK 
No 
CR/PR/SD 
CR/PR/SD 
Yes as a bar 
SD/IR 
No 
PD 
PD 
Yes as a bar 
any 
any 
The following algorithm will be used to construct the graph: 
1. Select “valid” post-baseline assessments to be included, i.e. for each patient and each 
assessment repeat the following four steps: 
1.1. Check the target lesion response and overall lesion response at each assessment.  If at least 
one of them is UNK then exclude the whole assessment.  Otherwise, go to step 1.2. 
1.2. Check the overall lesion response.  If PD, then go to step 1.3. Otherwise, go to step 1.4 
1.3. Check target response.  If PD, then go to step 1.4.  Otherwise flag the assessment . 
1.4. Calculate the % change from baseline in target lesions.  
2. For each patient, go through all valid assessments identified in step 1 and find the 
assessment with best % change from baseline in target lesions.  The “best” means best for 
the patient, i.e. the largest shrinkage or if a patient only has assessments with tumor growth 
take the assessment where the growth is minimal. (Example 1: Patient 1 has the following % 
changes from baseline at assessments 1, 2, 3, 4 and 5, respectively: -10%; -25%; -13%; -4% 
and +6%. His/her best % change is then -25%. Example 2: Patient 2 has the following % 
changes from baseline at assessments 1, 2 and 3, respectively: +5%; +18% and +35%. 
His/her best % change is then +5%. 
3. Construct the waterfall graph displaying the best % change from baseline for each patient. 
Patients having only  flagged assessment(s) will be displayed separately.  
Investigator assessment will be used in the construction of waterfall plot. 
The recommended way of the display from left to right is: 
1. Bars under the horizontal axis representing tumor shrinkage 
2. Bars above the horizontal axis representing tumor growth 
3. “Zero” bars with  symbol representing patients with contradiction 


Novartis 
For business use only 
Page 38 
SAP 
 
Study number 
 
5.1.2 
Response assessment in neuro-oncology (RANO) criteria for GBM 
Antitumor response will be primarily evaluated by the Response Assessment in Neuro- 
Oncology (RANO) working group (Wen et al 2010) criteria in this study. The RANO Criteria 
updates its established predecessor, the modified Macdonald Criteria (Macdonald et al 1990), 
by adding assessment of non-enhancing lesions. 
Patients will undergo Contrast MRI assessments for response evaluation starting at Week 8 and 
every 8 weeks thereafter to evaluate brain lesions, as outlined in the Visit schedule [Table 7-1] 
and [Table 7-2] in the protocol. 
The following components will be taken into account when assessing a patient’s overall 
response at an individual evaluation. 
• Tumor evaluation eCRF page for measureable enhancing lesions (T1-Gd+) 
• Tumor evaluation eCRF page for non-measurable enhancing lesions (T1-Gd+) 
• Tumor evaluation eCRF page for non-enhancing lesions (T2/FLAIR) 
• Tumor evaluation eCRF page for new lesion 
• Concomitant medication eCRF page for steroid usage 
• Clinical status eCRF page for ECOG performance status (WHO)  and other clinical 
evaluation finding as per investigator 
• Overall response eCRF page for response category (CR/PR/PD/SD/NA) 
5.1.2.1 
Antitumor effect - definitions 
Evaluable for toxicity 
All participants who receive at least one dose of study treatment will be evaluable for toxicity 
from the time of their first treatment. 
Evaluable for objective response 
Only those participants who have measurable disease present at baseline (cycle 1, day 1 scan) 
and have received at least one dose of therapy will be considered evaluable for response. These 
participants will have their response classified according to the definitions stated below. (Note: 
Participants who exhibit objective disease progression or die prior to the end of cycle 1 will also 
be considered evaluable.) 
Measurable disease 
Bidimensionally, contrast-enhancing, measurable lesions with clearly defined margins by CT 
or MRI scan, with a minimal diameter of 10mm, and visible on 2 axial slices which are at least 
5 mm apart with 0 mm skip. Measurement of tumor around a cyst or surgical cavity, if 
necessary, requires a minimum thickness of 3 mm. If there are multiple measurable lesions, the 
investigator must choose a minimum of two and a maximum of five of the largest lesions to be 
followed before a participant is entered on study. The remaining lesions will be considered non-
measureable for the purpose of objective response determination. Unless progression is 
observed, objective response can only be determined when all measurable and non-measurable 
lesions are assessed. 


Novartis 
For business use only 
Page 39 
SAP 
 
Study number 
 
Non-measurable evaluable disease 
Unidimensionally measurable lesions, masses with margins not clearly defined, lesions with 
maximal diameter < 10mm. 
5.1.2.2 
Response/progression categories 
Complete response (CR) 
All of the following criteria must be met: 
a. Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this scan 
will be considered only stable disease. 
b. No new lesions. 
c. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline. 
d. Participants must be on no steroids or on physiologic replacement doses only. 
e. Stable or improved non-enhancing (T2/FLAIR) lesions 
f. Stable or improved clinically, for clinical signs and symptoms present at baseline and 
recorded to be disease related 
Participants with non-measurable disease cannot have a complete response. The best 
response possible is stable disease. 
Partial response (PR) 
All of the following criteria must be met: 
a. Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. 
In the absence of a confirming scan 4 weeks later, this scan will be considered only stable 
disease. 
b. No progression of non-measurable disease. 
c. No new lesions. 
d. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline. 
e. The steroid dose at the time of the scan evaluation should be no greater than the dose at 
time of baseline scan. 
f. Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. 
g. Stable or improved, for clinical signs and symptoms present at baseline and recorded to be 
disease related clinically. 
Participants with non-measurable disease cannot have a partial response. The best 
response possible is stable disease. 
Progressive disease (PD) 
The following criterion must be met: 


Novartis 
For business use only 
Page 40 
SAP 
 
Study number 
 
a. 25% increase in sum of the products of perpendicular diameters of enhancing lesions (over 
best response or baseline if no decrease) on stable or increasing doses of corticosteroids 
and/or one or more of the of the following: 
b. Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of 
corticosteroids steroids compared to baseline scan or best response following initiation of 
therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, 
infection, seizures, post-operative changes, or other treatment effects). 
c. Any new lesion 
d. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection, etc.). The definition of clinical deterioration is left to the discretion of the 
investigator but it is recommended that a decline in the ECOG performance score (WHO)  
from 0 or 1 to 2 or 2 to 3 would be considered neurologic deterioration, unless attributable 
to co-morbid events or changes in corticosteroid dose.  
e. Failure to return for evaluation due to death or deteriorating condition. 
f. Clear progression of non-measurable disease 
Stable disease (SD) 
All of the following criteria must be met: 
a. Does not qualify for CR, PR, or progression. 
b. All measurable and non-measurable sites must be assessed using the same techniques as 
baseline. 
c. Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. In the event that the corticosteroid dose has been increased, the 
last scan considered to show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose. 
d. Stable clinically. 
Unknown response status 
Progressive disease has not been documented and one or more measurable or non-measurable 
lesions have not been assessed. 
These RANO Response Criteria are also summarized in Table 5-3:  


Novartis 
For business use only 
Page 41 
SAP 
 
Study number 
 
Table 5-3 
Summary of the RANO response criteria 
 
CR 
PR 
SD 
PD# 
T1-Gd + 
None 
≥50% decrease 
<50% decrease but 
<25% increase 
≥25% increase* 
T2/FLAIR 
Stable or decrease 
Stable or decrease 
Stable or decrease 
Increase* 
New Lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or decrease 
Stable or decrease 
NA** 
Clinical Status 
Stable or improve 
Stable or improve 
Stable or improve 
Deterioration* 
Requirement for 
Response 
All 
All 
All 
Any* 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease 
*: Progression when this criterion is met **: Increase in corticosteroids alone will not be taken into 
account in determining progression in the absence of persistent clinical deterioration 
5.1.2.3 
Methods for evaluation of measurable disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or 
digital measurement tool. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 14 days before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
5.1.2.4 
Evaluation of best response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). If a response recorded at one scheduled MRI does not 
persist at the next regular scheduled MRI, the response will still be recorded based on the prior 
scan, but will be designated as a non-sustained response. If the response is sustained, i.e. still 
present on the subsequent MRI, it will be recorded as a sustained response, lasting until the time 
of tumor progression. Participants without measurable disease may only achieve SD or PD as 
their best “response.” 
5.1.2.5 
Neurological exam 
Although not used for determining response, it is useful to evaluate changes in the neurological 
exam compared to the previous exam. The following scale may be used: 
 
+2 
Definitely better 
+1 
Possibly better 
0 
Unchanged 
-1 
Possibly worse 
-2 
Definitely worse 
5.1.2.6 
Performance status 
Participants will be graded according to WHO performance status.  


Novartis 
For business use only 
Page 42 
SAP 
 
Study number 
 
5.1.2.7 
Overall survival time 
From date of first dose (date of first post-surgery treatment for participants in Dose Level 1) to 
date of death due to any cause. 
5.1.2.8 
Progression-free survival time: 
From date of first dose (date of first post-surgery treatment for participants in Dose Level 1) to 
date of progression or death. Participants who stop treatment for causes other than progression 
may be censored if other therapy is initiated or if regular assessments for assessing progression 
are no longer available. 
5.1.3 
Guidelines for efficacy evaluation in lymphoma studies (based on 
Cheson response criteria). International Working Group guidelines for 
hematological malignancies 
Disease assessments will be based on the International Working Group response criteria 
(Cheson 1999), and the International Harmonization Project revised response criteria 
(Cheson et al 2007b). Further clarification on these criteria has been published by 
(Cheson 2007a). 
5.1.3.1 
Definitions and criteria for normalization 
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. 
5.1.3.2 
Measurability of tumor lesions at baseline 
All tumor lesions/lymph nodes will be categorized as measurable or non-measurable as follows: 
5.1.3.2.1 Measurable nodal and extranodal lesions 
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. 
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 Screening, then the patient must have at least one measurable extranodal lesion. 
5.1.3.2.2 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. 


Novartis 
For business use only 
Page 43 
SAP 
 
Study number 
 
• 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. 
• 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. 
5.1.3.2.3 Criteria for normalization of lesions 
The normalization of lesions is defined as follows: 
• 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. 
5.1.3.3 
Specification by methods of measurement 
5.1.3.3.1 Measurement of lesions 
All radiological measurements should be taken in two perpendicular dimensions and recorded 
in metric notation, using a ruler or calipers. 
PET 
Visual assessment currently is considered adequate for determining whether a PET scan is 
positive, and use of the standardized uptake value is not necessary.1 In brief, a positive scan is 
defined as focal or diffuse FDG uptake above background in a location incompatible with 
normal anatomy or physiology, without a specific standardized uptake value cutoff.1 Other 
causes of false-positive scans should be ruled out. Exceptions include mild and diffusely 
increased FDG uptake at the site of moderate- or large-sized masses with an intensity that is 
lower than or equal to the mediastinal blood pool, hepatic or splenic nodules 1.5 cm with FDG 
uptake lower than the surrounding liver/spleen. 
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 Screening and during follow-up. 
Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed using a 
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 Screening 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. 


Novartis 
For business use only 
Page 44 
SAP 
 
Study number 
 
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 may be accepted from 
the investigator 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 eCRFs. If, during the 
course of the study, either of the perpendicular diameters of a lesion cannot 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. 
Bone marrow assessment 
Documentation of status of bone marrow involvement by lymphoma based on prior bone 
marrow biopsy or aspirate findings is required at Screening for all patients. 
If no such documentation is available then a bone marrow biopsy or aspirate should be 
performed at Screening. 
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 
confirm the findings. 
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 eCRF) and photographed including a ruler (color 
photography using digital camera). Tumor assessment will be performed and results will be 
recorded on the corresponding eCRF at Screening and at Day 1 of every cycle (±4 days) after 
first dose of study drug. 
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). 


Novartis 
For business use only 
Page 45 
SAP 
 
Study number 
 
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. 
5.1.3.4 
Evaluation of radiological response 
For the sake of simplicity, complete remission and complete response will both be referred to 
as complete response. 
Definitions of Response for Lymphoma patients are listed in Table 5-5. 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 5-
8) and non-index lesions (Table 5-7) identified at Screening, then a combined overall 
radiological response is determined (Table 5-10). 


Novartis 
For business use only 
Page 46 
SAP 
 
Study number 
 
Table 5-4 
Response definition for lymphoma 
Response 
Definition 
Nodal Masses 
Spleen. Liver 
Bone Marrow 
CR 
Disappearance 
of all evidence 
of disease 
a. FDG-avid or PET positive 
prior to therapy; mass of 
any size permitted if PET 
negative 
b. Variably FDG-avid or PET 
negative; regression to 
normal size on CT 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared 
on repeat biopsy; 
if indeterminate 
by morphology, 
immunohistochem
is try should be 
negative 
PR 
Regression of 
measurable 
disease and no 
new sites 
≥ 50% decrease in SPD of up 
to 6 largest dominant masses; 
no increase in size of other 
nodes 
a. FDG-avid or PET positive 
prior to therapy; one or 
more PET positive at 
previously involved site 
b. Variably FDG-avid or PET 
negative; regression on 
CT 
≥ 50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or spleen 
Irrelevant if 
positive prior to 
therapy; cell type 
should be 
specified 
SD 
Failure to attain 
CR/PR or PD 
a. FDG-avid or PET positive 
prior to therapy; PET 
positive at prior sites of 
disease and no new sites 
on CT or PET 
b. Variably FDG-avid or PET 
negative; no change in 
size of previous lesions on 
CT 
 
 
Relapsed 
disease or 
PD 
Any new lesion 
or increase by 
≥ 50% of 
previously 
involved sites 
from nadir 
Appearance of a new 
lesion(s) > 1.5 cm in any axis, 
≥50% increase in SPD of more 
than one node, or ≥ 50% 
increase in longest diameter of 
a previously identified node > 
1 cm in short axis 
Lesions PET positive if FDG-
avid lymphoma or PET 
positive prior to therapy 
> 50% increase 
from nadir in 
the SPD of any 
previous 
lesions 
New or recurrent 
involvement 
5.1.3.5 
Evaluation of index lesions (nodal and extranodal) 
5.1.3.5.1 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 5-6), except when there is a Complete Response for index 
nodal lesions (i.e. complete normalization of all index nodal lesions) (see Section 5.1.3.2.3). 


Novartis 
For business use only 
Page 47 
SAP 
 
Study number 
 
Table 5-5 
Radiological status based on SPD calculation for all index lesions 
Response Criteria1 
Evaluation of index lesions 
Complete Response (CR) 
See Table 5-8 below (not based on SPD calculation for all index 
lesions) 
Partial Response (PR) 
At least 50% decrease from Screening 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 Screening. 
5.1.3.5.2 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 5.1.3.2.3: 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 5-7). 
Table 5-6 
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 Screening in the SPD restricted to all 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 Screening. 
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. 
5.1.3.5.3 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 and the status based on 
the SPD calculated on all index lesions (nodal and extranodal), as described in Table 5-8. 


Novartis 
For business use only 
Page 48 
SAP 
 
Study number 
 
Table 5-7 
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 Screening, then index lesions response is equal to the index 
extranodal lesions response. A similar rule applied if no index extranodal lesions are present at 
Screening, then index lesions response is equal to the index nodal lesions response. 
In case of 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 Screening, 
otherwise the radiological response for index lesions at that assessment will be “Unknown 
(UNK)”. 
5.1.3.5.4 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 Screening. 
• 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 5-9): 


Novartis 
For business use only 
Page 49 
SAP 
 
Study number 
 
Table 5-8 
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 Screening, 
otherwise the radiological response for non-index lesions at that assessment will be “Unknown 
(UNK)”. 
5.1.3.6 
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 
• any discrete extranodal (including splenic and/or hepatic nodules) lesions reliably 
appearing on CT scan or MRI after Screening. 
is always considered as Progressive Disease (PD) and has to be recorded as a new lesion in the 
appropriate module of the eCRF. 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 eCRF. 
5.1.3.6.1 Overall radiological response 
Overall radiological response is calculated as shown in Table 5-10. 


Novartis 
For business use only 
Page 50 
SAP 
 
Study number 
 
Table 5-9 
Overall radiological response at each assessment 
Index lesions 
Non-index lesions1 
New lesions 
Overall radiological response 
CR 
CR 
CR 
SD 
No 
No 
CR 
PR 
PR 
SD 
CR or SD 
CR or SD 
No 
No 
PR 
SD 
PD 
Any 
Yes or No 
PD 
Any 
Any 
PD 
Any 
Yes or No 
Yes 
PD 
PD 
1 If no non-index lesions are present at Screening, 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 Screening 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. 
5.1.3.6.2 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). 
5.1.3.6.3 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. 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. 
5.1.3.6.4 Overall disease response 
If a patient has an overall radiological response of CR 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: 
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 Screening) and the liver and spleen are normal in size and there are no lymphoma 
related B-symptoms in addition to radiological CR. 


Novartis 
For business use only 
Page 51 
SAP 
 
Study number 
 
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 
eCRF. 
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. 
5.1.3.7 
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. 
 
5.2 
Imputation rules 
5.2.1 
Study drug 
For patients not known to have died prior to the cut-off date: 
• All events with start date before or on the cut-off date, and with end date missing or after 
the cut-off date will be reported as “continuing at the cut-off date”.  
• 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.  
For patients known to have died prior to or on the cut-off date: 
• All events with start date before or on the cut-off date, and with end date missing or after 
the cut-off date will have the end date imputed to the death date.  


Novartis 
For business use only 
Page 52 
SAP 
 
Study number 
 
• This approach applies, in particular, to AEs and concomitant medication reports. For these 
events, the imputed end date will not appear in the listings.  
If imputation of an end date is required for a specific analysis (e.g. for a dose administration 
record with missing end date or last date of study drug after the cut-off date), the end date will 
be imputed to the cut-off 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. 
5.2.2 
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 5-11 explains the abbreviations used. 
Table 5-10 
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 5-12 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). 


Novartis 
For business use only 
Page 53 
SAP 
 
Study number 
 
Table 5-11 
AE partial date imputation algorithm 
 
 
AEM MISSING 
 
AEM < TRTM 
AEM = TRTM 
AEM > TRTM 
AEY MISSING 
NC 
Uncertain 
NC 
Uncertain 
NC 
Uncertain 
NC 
Uncertain 
AEY < TRTY 
( D ) 
Before TRTSTD 
( C ) 
Before TRTSTD 
( C ) 
Before TRTSTD 
( C ) 
Before TRTSTD 
AEY = TRTY 
( B ) 
Uncertain 
( C ) 
Before TRTSTD 
( B ) 
Uncertain 
( A ) 
After TRTSTD 
AEY > TRTY 
( E ) 
After TRTSTD 
( A ) 
After TRTSTD 
( A ) 
After TRTSTD 
( A ) 
After TRTSTD 
The following Table 5-13 is the legend to the above table. 
Table 5-12 
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 5-14 gives a few examples. 
Table 5-13 
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 


Novartis 
For business use only 
Page 54 
SAP 
 
Study number 
 
Partial 
AE start date 
Treatment 
start date 
Relationship 
Imputation 
Calculation 
Imputed Date 
ddOCT2001 
20OCT2001 
Uncertain 
( B ) 
21OCT2001 
ddNOV2001 
20OCT2001 
After 
( A ) 
01NOV2001 
5.2.3 
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. 
5.2.4 
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.  
5.2.5 
Incomplete date for anti-neoplastic therapies 
5.2.5.1 
Prior therapies date imputation 
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. 
5.2.5.2 
Post therapies date imputation 
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.  


Novartis 
For business use only 
Page 55 
SAP 
 
Study number 
 
5.2.6 
Incomplete assessment dates for tumor assessment 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year. 
If one or more investigation dates are incomplete but other investigation dates are available, the 
incomplete date(s) are not considered for calculation of the assessment date and assessment date 
is calculated as the latest of all investigation dates (e.g. X-ray, CT-scan) if the overall lesion 
response at that assessment is CR/PR/SD/UNK. Otherwise, if overall lesion response is PD, the 
assessment date is calculated as the earliest date of all investigation dates at that evaluation 
number.  If all measurement dates have no day recorded, the 1st of the month is used.  
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between the previous and the following assessment. 
If both a previous and following assessments are not available, this assessment will not be used 
for any calculations.  
5.2.7 
Incomplete date for death  
All dates must be completed with day, month and year. 
If the day or month is missing, death will be imputed to the maximum of the full (non-imputed) 
last contact date (excluding the date of death) and the following: 
• Missing day: 
 
 15th day of the month and year of death 
• Missing day and month: July 1st  of the year of death 
5.2.8 
Incomplete dates for disease progression on medication prior to the 
start of study drug.  
If day of progression associated with the ‘Prior Antineoplastic Therapy – Medication’ page is 
missing then the imputed PD date is: 
= min (midpoint between the end date of the prior medication and the end of the month, 
start date of LDK), if end date of prior medication is in the same month as the PD date.  
=  min (15th of the month of the PD date, start date of LDK), if end date of prior medication 
is in a month prior to the PD date.  
= 15th of the month of the PD date, if end date of medication is in a month after the PD date.  
If both day and month of progression associated with the ‘Prior Antineoplastic Therapy – 
Medication’ page is missing then the imputed PD date is: 
= min (midpoint between the end date of the prior medication and the end of the year, start 
date of LDK) if end date of prior medication is in same year as the PD date 
= min (July 1 of the year of the PD date, start date of LDK), if end date of prior medication 
is in a year prior to the PD date.  
= July 1 of the year of the PD date, if end date of prior medication is in a year after the PD 
date.  


Novartis 
For business use only 
Page 56 
SAP 
 
Study number 
 
Completely missing PD dates will not be imputed. For the midpoint calculation, if odd days in 
between (e.g last dose of criztonib is 27 June 2012, and end of the month is 30 June 2012), then 
use the next day from the midpoint calculation (e.g midpoint is 29 June 2013).  
5.2.9 
Incomplete dates for last dose of study drug 
Scenario 1  
If the last date of study drug is after the cut-off date or is completely missing and there is no 
end of treatment eCRF page and no death date the patient should be considered to be on-going 
and use the cutoff date for the analysis as the last dosing date 
Scenario 2  
If the last date of study drug is completely or partially missing and there is EITHER an end of 
treatment eCRF page OR a death date available then imputed last dose date: 
 
= 31DECYYYY, if only Year is available and Year < Year of min (EOT visit date, death 
date)  
= Last day of the month, if both Year and Month are available and Year = Year of min (EOT 
visit date, death date) and Month < the month of min (EOT visit date, death date) 
    = min (EOT visit date, death date), for all other cases 
The imputed date will be compared with start date of study drug.  
If the imputed date < start date of study drug, then last date of study drug is set to start date 
of study drug; 
 
Otherwise, use the imputed date. 
 
5.3 
Safety evaluations 
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Section 2. 
5.3.1 
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  
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 


Novartis 
For business use only 
Page 57 
SAP 
 
Study number 
 
ULN for each patient) although the worst values for the different parameters may be coming 
from different laboratories.   
ECGs 
For all patients, 3 ECGs are targeted to be measured at the protocol-defined (nominal) time-
points. If a patient has more than one measurement at a nominal time point, the average of all 
available measurements associated with the nominal time point will be used for the analyses.   
5.3.2 
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 the pre-dose replicate measurements on the 
baseline day. Unscheduled assessments will not be included in the calculation of the average. 
Study day 1 scheduled pre-dose ECGs will be considered to have been obtained prior to study 
drug administration if dosing time or ECG time is missing. 
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement. 
For unscheduled assessments on study day 1,  
• if dosing time is non-missing, then the assessment is classified as post-baseline if ECG 
collection time is later than dosing time.  
• if dosing time is missing, the assessment is classified as post-baseline.  
5.3.3 
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.  
Hematology 
Hematologic tests include: Hemoglobin, platelets, white blood cells (WBC), red blood cells 
(RBC), differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils (% or 
absolute) 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available (this is mainly for neutrophils and lymphocytes, because CTC grading 
is based on the absolute counts).  
The method to convert the value is straightforward: for each 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) 


Novartis 
For business use only 
Page 58 
SAP 
 
Study number 
 
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. 
5.4 
Details statistical methodology 
This section provides the details of model stated in Section 2.13. Prior specifications of model 
parameters are provided in detail. Data analysis and decision making in real trial are illustrated 
using some hypothetical data scenarios. Further operating characteristics by simulation are 
provided in Section 3 as part of sample size justification. 
5.4.1 
Prior specification of model parameters 
Bayesian model requires prior specification of parameters. The detailed prior specification of 
µ1, µ2,τ1, τ2, mw, vw, and pj (j= 1,2,..,5) are described in this section. 
5.4.1.1 
Prior specification of exchangeability distribution (µ1, µ2, τ1 and τ2) 
Prior for τ1 and τ2 are assumed to be half-normal distribution with scale 0.25, implying a prior 
95%-interval for τ1 and τ2 as (0.008, 0.560), which allows for small to substantial between strata 
heterogeneity (see Neuenschwander Neuenschwander et al 2015). 
µ1 and µ2 are given normal prior distributions. For first exchangeability distribution µ1, the 
mean of the prior distribution (mµ1) is set to logit(0.15) (or mµ1= log(1/3)) which corresponds 
to no treatment effect. For second exchangeability distribution µ2, the prior mean (mµ2) was set 
to logit(0.6) (or mµ1= log(3/2)). This corresponds to a substantial treatment effect. The variance 
parameter (Vµ1 and Vµ2) are derived using the following formula from law of total variance 
 
Vµi = V(θ) - E(τi2) and V(θ)=1/π + 1/(1- π) ; π= 0.15, 0.60 and i=1,2 
This yields Vµ1= 7.780 (≈2.7892) and Vµ2= 4.101 (≈2.0252). This allows a considerable 
uncertainty on prior belief of θ. 


Novartis 
For business use only 
Page 59 
SAP 
 
Study number 
 
5.4.1.2 
Prior specification for stratified or “non-exchangeability” distributions 
(mw and vw) 
The strata-specific normal priors for the stratified or “non-exchangeable” case are defined by 
mw and vw were. The prior median for the response probability was set as 10% (no treatment 
effect) i.e., mw=logit(0.1) (or mw = log(1/9)) and the corresponding variance (vw) is set to 9 
(=32) to allow large variability in prior. 
5.4.1.3 
Specification of mixture weights (pj) 
Finally, for each stratum j, the prior mixture weights pj were chosen as 
 
pj = (0.25, 0.25, 0.50), 
j=1,…,5. 
This means that each stratum has 25% prior probability to belong to the first exchangeability 
distribution (µ1 and τ1), 25% probability to belong to the second exchangeability distribution 
(µ2 and τ2), and 50% probability to be stratified or non-exchangeable with some (or all) of the 
other strata. 
The prior distributions are summarized in Table 5-15, which also shows the prior medians and 
95%-intervals for the disease specific disease control rare (DCR) πj. 
Table 5-14 
Specifications for model parameters, and prior median (95%-interval) 
for disease specific DCR 
Parameter 
Prior distribution 
µ1 
N(-1.735, 2.7892) 
µ2 
N(0.405, 2.0252) 
τ1 
Half Normal(scale=0.25) 
τ2 
Half Normal(scale=0.25) 
mj, vj 
N(-2.197, 32) 
pj = (pj1,pj2,pj3), j=1,…,5 
(0.25, 0.25, 0.5) 
Prior disease specific DCR 
median (2.5%, 97.5%) 
πj, j=1,…,5 
0.218 (0.001, 0.981) 
5.4.2 
Hypothetic scenario testing 
It is important to know that the design should make reasonable decisions at interim and final 
analysis based on the observed responses in each tumor type. This section shows on-study 
decisions made under the model. The hypothetical data scenarios for interim and final analysis 
can be found in Table 5-16 and Table 5-17 respectively. For each scenario, the probability of 
being “clinically meaningful” and “not clinically meaningful” (Table 2-1) are calculated by 
tumor type and displayed in the tables. 
Table 5-16 shows 6 different scenarios for interim analyses. As stated in Section 2.13 at interim 
a tumor type is stopped if the probability of being “clinically meaningful” is less than 20%. At 
interim if no arm or tumor type shows any activity (scenarios 1 and 2) the decision based on 
model based inference are reasonable. The posterior probabilities of “clinically meaningful” are 
less than 20% for all tumor type in both scenarios (Column 6 of Table 5-16). Similarly for 
scenarios 3 and 4 where all tumor types show some clinically meaningful activity the proposed 


Novartis 
For business use only 
Page 60 
SAP 
 
Study number 
 
decision rule suggests to “continue” all arms (posterior probability of “clinically meaningful” > 
20%). The proposed design also shows reasonable decision for mixed scenarios (5 and 6). For 
example, under scenario 4, data for arms T3 and T5 show no clinically activity but the rest 
shows some activity. Based on the calculated probability of being clinically meaningful, the 
design allows correctly stopping (probability<0.20) for T3 and T5 at the interim while continues 
for the other arms. 
Table 5-15 
Hypothetical data scenarios and decision at interim 
Scenario 
Arm (Tumor 
Type) 
No of 
responder/ 
No. of 
patients 
Observed 
CBR 
Posterior 
probability of 
not clinically 
meaningful † 
Posterior 
probability 
being clinically 
meaningful † 
Decision‡ 
1 
T1 
3/10 
30% 
0.8595 
0.0468 
Stop 
 
T2 
1/5 
20% 
0.6005 
0.1900 
Stop 
 
T3 
1/10 
10% 
0.4498 
0.1878 
Stop 
 
T4 
1/10 
10% 
0.4685 
0.1808 
Stop 
 
T5 
1/10 
10% 
0.4615 
0.1755 
Stop 
2 
T1 
3/10 
30% 
0.8450 
0.0550 
Stop 
 
T2 
1/5 
20% 
0.6223 
0.1800 
Stop 
 
T3 
1/10 
10% 
0.4898 
0.1743 
Stop 
 
T4 
1/10 
10% 
0.4833 
0.1813 
Stop 
 
T5 
0/10 
0 
0.8620 
0.0265 
Stop 
3 
T1 
7/10 
70% 
0.0843 
0.7580 
Continue 
 
T2 
2/5 
40% 
0.1475 
0.6390 
Continue 
 
T3 
3/10 
30% 
0.0298 
0.7970 
Continue 
 
T4 
3/10 
30% 
0.0250 
0.7980 
Continue 
 
T5 
2/10 
20% 
0.1128 
0.6083 
Continue 
4 
T1 
8/10 
80% 
0.0198 
0.9273 
Continue 
 
T2 
2/5 
40% 
0.1515 
0.6040 
Continue 
 
T3 
3/10 
30% 
0.0253 
0.7965 
Continue 
 
T4 
3/10 
30% 
0.0303 
0.7925 
Continue 
 
T5 
2/10 
20% 
0.1135 
0.6063 
Continue 
5 
T1 
7/10 
70% 
0.0373 
0.8870 
Continue 
 
T2 
4/5 
40% 
0.0028 
0.9835 
Continue 
 
T3 
1/10 
10% 
0.4983 
0.1883 
Stop 
 
T4 
3/10 
30% 
0.0665 
0.6865 
Continue 
 
T5 
1/10 
10% 
0.5123 
0.1818 
Stop 
6 
T1 
7/10 
70% 
0.0290 
0.8778 
Continue 
 
T2 
4/5 
40% 
0.0028 
0.9870 
Continue 
 
T3 
1/10 
10% 
0.5538 
0.1775 
Stop 
 
T4 
4/10 
40% 
0.0090 
0.9138 
Continue 
 
T5 
0/10 
0 
0.9118 
0.0168 
Stop 
† Calculated using a Bayesian hierarchical model mentioned in Section 2.13. 
‡ A tumor type will be stopped if posterior probability being clinically meaningful is less than 20%. 


Novartis 
For business use only 
Page 61 
SAP 
 
Study number 
 
Similar to interim Table 5-17 shows 5 different hypothetic scenarios for final analyses in order 
to illustrate final decision making process in the proposed design. As stated in Section 2.1 at 
final a Proof of Concept (PoC) about treatment with ceritinib will be declared for an arm (tumor 
type) if both of the following conditions are met: 
a. Observed DCR ≥ “Disease Control Rate” threshold (Table 2-1) 
b. Posterior probability of “not being clinically meaningful” (Table 2-1) is less than 20% 
If no arm shows any significant activity (scenario 1) at final analysis the decision using model 
based inference are reasonable (declared fail to support PoC for all arms). The posterior 
probabilities of “not clinically meaningful” are less than 20% for all arms in this scenario 
(Column 5 of Table 5-17) but the observed CBR’s do not cross “clinically meaningful” 
threshold (as stated in Table 2-1). Similarly for scenario 2 where all arms show clinically 
meaningful activity the proposed decision rule (to declared success) leads to PoC for all arms 
(posterior probability of “not clinically meaningful” < 20% and observed CBR’s are more than 
“clinically meaningful” threshold). The proposed design also shows reasonable decision for 
mixed scenarios (3, 4, and 5). For example, under scenario 4, data for arms T1 and T3 show no 
clinically activity but the rest of the arms show activity. Based on the posterior probability of 
being not clinically meaningful and observed CBR, the design correctly declared fail for T1 and 
T3 while success for the other arms. 
Table 5-16 
Hypothetical data scenarios and decision at final 
Scenari
o 
Arm 
(Tumor 
Type) 
No of 
responder/ 
No. of 
patients 
CBR at 
final 
Posterior 
probability of 
not clinically 
meaningful † 
Posterior 
probability being 
clinically 
meaningful † 
Decision‡ 
1 
T1 
8/20 
40% 
0.6133 
0.1283 
Fail 
 
T2 
3/15 
20% 
0.6155 
0.1330 
Fail 
 
T3 
2/20 
10% 
0.4678 
0.0958 
Fail 
 
T4 
2/20 
10% 
0.4588 
0.0968 
Fail 
 
T5 
2/20 
10% 
0.4670 
0.0980 
Fail 
2 
T1 
14/20 
70% 
0.0125 
0.9318 
Success 
 
T2 
6/15 
40% 
0.0550 
0.6570 
Success 
 
T3 
6/20 
30% 
0.0048 
0.8395 
Success 
 
T4 
4/20 
20% 
0.0500 
0.6040 
Success 
 
T5 
4/20 
20% 
0.0500 
0.6153 
Success 
3 
T1 
6/20 
30% 
0.9113 
0.0113 
Fail 
 
T2 
415 
40% 
0.3198 
0.2733 
Fail 
 
T3 
2/20 
10% 
0.4145 
0.1703 
Fail 
 
T4 
5/20 
25% 
0.0255 
0.6825 
Success 
 
T5 
1/20 
5% 
0.7243 
0.0490 
Fail 
4 
T1 
8/20 
40% 
0.5765 
0.1283 
Fail 
 
T2 
9/15 
60% 
0.0013 
0.9800 
Success 
 
T3 
1/20 
5% 
0.7740 
0.0403 
Fail 
 
T4 
6/20 
30% 
0.0040 
0.8988 
Success 
 
T5 
5/20 
25% 
0.0205 
0.7753 
Success 


Novartis 
For business use only 
Page 62 
SAP 
 
Study number 
 
Scenari
o 
Arm 
(Tumor 
Type) 
No of 
responder/ 
No. of 
patients 
CBR at 
final 
Posterior 
probability of 
not clinically 
meaningful † 
Posterior 
probability being 
clinically 
meaningful † 
Decision‡ 
5 
T1 
14/20 
70% 
0.0063 
0.9500 
Success 
 
T2 
9/15 
60% 
0.0003 
0.9810 
Success 
 
T3 
6/20 
30% 
0.0100 
0.7983 
Success 
 
T4 
4/20 
20% 
0.0950 
0.4938 
Success 
 
T5 
2/20 
10% 
0.4188 
0.1608 
Fail 
† Calculated using a Bayesian hierarchical model mentioned in Section 2.13. 
‡ A tumor type will be declared “Success” if posterior probability of being not clinically meaningful is 
less than 20% and observed CBR is at least clinically meaningful threshold. 
5.4.3 
Kaplan-Meier estimates 
To analyze time to event variables (DOR, TTR 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.  The PROC LIFETEST statement will use the option 
CONFTYPE=LOGLOG. Median survival for each treatment group will be obtained along 
with 95% confidence intervals calculated from PROC LIFETEST output using the method of 
[Brookmeyer and Crowley 1982]. Kaplan-Meier estimates of the survival function with 95% 
confidence intervals at specific time points will be summarized. The standard error of the 
Kaplan-Meier estimate will be calculated using Greenwood’s formula [Collett 1994]. 
 
5.4.4 
Confidence interval and p-value for response rate 
This sections provides the programming details for the secondary objective to assess the 
antitumor activity of ceritinib as measured by ORR. For the statistical details of the primary 
objective, to assess the antitumor activity of ceritinib as measured by DCR, it is referred to 
Section 5.4  
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.  
 
6 
Reference 
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time, 
Biometrics 38, 29 - 41.    
Clopper CJ, Pearson ES (1934).  The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika; 26, 404-413. 


Novartis 
For business use only 
Page 63 
SAP 
 
Study number 
 
Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall. 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the 
EORTC Quality of Life Group (2001). The EORTC QLQ-C30 Scoring Manual (3rd Edition). 
Published by: European Organisation for Research and Treatment of Cancer, Brussels. 
FDA (2007). Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics, US Department of Health and Human Services. 
Hollen, P. J., Gralla, R. J., & Kris, M. G. (1995). Lung Cancer Symptom Scale (LCSS): 
Administration, Scoring, and Procedures Manual. 
Kalbfleisch JD, Prentice RL. (2002) The Statistical Analysis of Failure Time Data. Wiley 
Series in Probability and Statistics. 
Macdonald DR, Cascino TL, Schold SC et-al. (1990). Response criteria for phase II studies of 
supratentorial malignant glioma. J. Clin. Oncol. 1990;8 (7): 1277-80.  
Neuenschwander B, Wandel S, Roychoudhury S, and Bailey S (2015). Robust  
exchangeability designs for early phase clinical trials with multiple strata.  Pharmaceutical 
Statistics. Article first published online: 18 DEC 2015. DOI: 10.1002/pst.1730. 
Wen PY, Macdonald DR, Reardon DA et-al. (2010). Updated response assessment criteria for 
high-grade gliomas: response assessment in neuro-oncology working group. J. Clin. Oncol. 
2010;28 (11): 1963-72.