Conditions: Tumors With Aberrations in ALK or ROS1
Keywords: hematological malignancy solid tumor malignancy mutation translocation rearrangement amplification ALK ROS1 NSCLC B-cell lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 47
Healthy volunteers: no

Brief summary:
The purpose of this signal seeking study was to determine whether treatment with ceritinib demonstrated sufficient efficacy in select pathway-activated solid tumors and/or hematologic malignancies to warrant further study.

Detailed description:
This was an open label study to determine the efficacy and safety of treatment with ceritinib in patients with a diagnosis of solid tumors or hematological malignancies that had been pre-identified (prior to study consent) to have ALK or ROS1 positive mutations, translocations, rearrangements or amplifications and whose disease had progressed on or after standard treatment. The study consisted of a treatment phase where all patients received ceritinib capsules for a total dose of 750 mg daily for up to 8 cycles of 28 days. Disease assessments for clinical benefit were performed every 8 weeks until disease progression or end of treatment. Following discontinuation of treatment for any reason, patients were followed for safety for 30 days. Survival information was collected every 3 months until 2 years after the last patient had enrolled into the study. Study was amended to allow for discontinuation of survival period if primary endpoint was not met.

Study was terminated due to low enrollment.

Arms:
arm 1: Ceritinib was dosed on a flat scale of 750 mg (e.g., 5 x 150 mg capsules) orally, once daily, on a continuous dosing cycle. A complete treatment cycle was defined as 28 days with no breaks between dosing cycles.

Interventions: intervention 1: Ceritinib
Intervention descriptions: intervention 1: Ceritinib was dosed on a flat scale of 750 mg (e.g., 5 x 150 mg capsules) orally,once daily, on a continuous dosing cycle. A complete treatment cycle was defined as 28 days. There were no breaks between dosing cycles.

Protocol document:
Prot_001.pdf: 
Clinical Development 
Ceritinib (LDK378) 
Protocol CLDK378AUS23 / NCT02186821 
Modular phase II study to link targeted therapy to patients 
with pathway activated tumors: 
Module 7 – Ceritinib (LDK378) for patients whose tumors 
have aberrations in ALK or ROS1 
Authors 
 
Document type 
Amended Protocol Version (Clean) 
EUDRACT number 
Not applicable 
Version number 
02 
Development phase 
II 
Document status 
Final 
Release date 
06-Jan-2016
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of figures ...................................................................................................................... 6 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 12 
Amendment 2 .................................................................................................................... 13 
Amendment 1 .................................................................................................................... 15 
Protocol summary .............................................................................................................. 19 
1 
Background ........................................................................................................................ 23 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 23 
1.1.1 
Ceritinib target pathway ........................................................................ 23 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 23 
1.2.1 
Overview of ceritinib ............................................................................ 23 
1.2.2 
Discovery of ROS1 rearrangement and its impact in NSCLC .............. 24 
1.2.3 
Non-clinical experience ........................................................................ 25 
1.2.4 
Clinical experience ................................................................................ 27 
1.3 
Risk and Benefits ................................................................................................... 31 
2 
Rationale ............................................................................................................................ 31 
2.1 
Study rationale and purpose ................................................................................... 31 
2.2 
Rationale for the study design ............................................................................... 32 
2.3 
Rationale for dose and regimen selection .............................................................. 32 
3 
Objectives and endpoints ................................................................................................... 32 
4 
Study design ...................................................................................................................... 34 
4.1 
Description of study design ................................................................................... 34 
4.1.1 
Treatment phase .................................................................................... 35 
4.1.2 
Follow-up phase .................................................................................... 35 
4.2 
Definition of end of the study ................................................................................ 35 
4.3 
Early study termination .......................................................................................... 36 
5 
Population .......................................................................................................................... 36 
5.1 
Patient population .................................................................................................. 36 
5.2 
Inclusion criteria .................................................................................................... 37 
5.3 
Exclusion criteria ................................................................................................... 38 
6 
Treatment ........................................................................................................................... 42 
6.1 
Study treatment ...................................................................................................... 42 
6.1.1 
Dosing regimen ..................................................................................... 42 


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6.1.2 
Guidelines for continuation of treatment .............................................. 43 
6.1.3 
Treatment duration ................................................................................ 43 
6.2 
Dose escalation guidelines ..................................................................................... 43 
6.3 
Dose modifications ................................................................................................ 43 
6.3.1 
Dose modification and dose delay ........................................................ 43 
6.3.2 
Permitted study treatment adjustments for ceritinib ............................. 44 
6.3.3 
Criteria for interruption and re-initiation of ceritinib treatment............ 45 
6.3.4 
Follow-up for toxicities ......................................................................... 49 
6.3.5 
Anticipated risks and safety concerns of the study drug ....................... 53 
6.4 
Concomitant medications ...................................................................................... 53 
6.4.1 
Permitted concomitant therapy ............................................................. 54 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ........... 55 
6.4.3 
Prohibited concomitant therapy ............................................................ 56 
6.5 
Patient numbering, treatment assignment and enrollment ..................................... 58 
6.5.1 
Patient numbering ................................................................................. 58 
6.5.2 
Treatment assignment and randomization ............................................ 58 
6.5.3 
Treatment blinding ................................................................................ 58 
6.6 
Study drug preparation and dispensation ............................................................... 58 
6.6.1 
Study drug packaging and labeling ....................................................... 58 
6.6.2 
Drug supply and storage ........................................................................ 59 
6.6.3 
Study drug compliance and accountability ........................................... 59 
6.6.4 
Disposal and destruction ....................................................................... 59 
7 
Visit schedule and assessments ......................................................................................... 60 
7.1 
Study flow and visit schedule ................................................................................ 60 
7.1.1 
Screening ............................................................................................... 67 
7.1.2 
Treatment period ................................................................................... 69 
7.1.3 
End of treatment visit, including premature withdrawal and study 
discontinuation visit .............................................................................. 69 
7.1.4 
Follow up period ................................................................................... 71 
7.1.5 
End of post-treatment follow-up (Study phase completion) ................. 71 
7.2 
Assessment types ................................................................................................... 71 
7.2.1 
Efficacy assessments ............................................................................. 71 
7.2.2 
Safety and tolerability assessments ....................................................... 79 
7.2.3 
Pharmacokinetics .................................................................................. 82 
 
 82 
7.2.5 
Other assessments ................................................................................. 84 


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8 
Safety monitoring and reporting ........................................................................................ 84 
8.1 
Adverse events ....................................................................................................... 84 
8.1.1 
Definitions and reporting ...................................................................... 84 
8.1.2 
Laboratory test abnormalities ................................................................ 86 
8.2 
Adverse events of special interest .......................................................................... 86 
8.3 
Serious adverse events ........................................................................................... 86 
8.3.1 
Definitions ............................................................................................. 86 
8.3.2 
Reporting ............................................................................................... 87 
8.4 
Emergency unblinding of treatment assignment ................................................... 88 
8.5 
Pregnancies ............................................................................................................ 88 
8.6 
Warnings and precautions ...................................................................................... 88 
8.7 
Data Monitoring Committee .................................................................................. 88 
8.8 
Steering Committee ............................................................................................... 88 
9 
Data collection and management ....................................................................................... 89 
9.1 
Data confidentiality ............................................................................................... 89 
9.2 
Site monitoring ...................................................................................................... 89 
9.3 
Data collection ....................................................................................................... 90 
9.4 
Database management and quality control ............................................................ 90 
10 Statistical methods and data analysis ................................................................................ 91 
10.1 
Analysis sets .......................................................................................................... 91 
10.1.1 
Full Analysis Set ................................................................................... 91 
10.1.2 
Safety Set .............................................................................................. 91 
10.2 
Patient demographics/other baseline characteristics ............................................. 91 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 91 
10.3.1 
Study medication ................................................................................... 91 
10.3.2 
Concomitant therapies ........................................................................... 91 
10.4 
Primary objective ................................................................................................... 92 
10.4.1 
Variable ................................................................................................. 92 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 92 
10.4.3 
Evaluation of trial success and futility .................................................. 93 
10.4.4 
Handling of missing values/censoring/discontinuations ....................... 94 
10.4.5 
Supportive analyses ............................................................................... 94 
10.5 
Secondary objectives ............................................................................................. 94 
10.5.1 
Key secondary objective(s) ................................................................... 94 
10.5.2 
Other secondary efficacy objectives ..................................................... 94 
10.5.3 
Safety objectives ................................................................................... 95 


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10.7 
Interim analysis ...................................................................................................... 97 
10.8 
Sample size calculation .......................................................................................... 97 
11 Ethical considerations and administrative procedures ...................................................... 97 
11.1 
Regulatory and ethical compliance ........................................................................ 97 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 98 
11.3 
Informed consent procedures ................................................................................. 98 
11.4 
Discontinuation of the study .................................................................................. 98 
11.5 
Publication of study protocol and results............................................................... 98 
11.6 
Study documentation, record keeping and retention of documents ....................... 99 
11.7 
Confidentiality of study documents and patient records ....................................... 99 
11.8 
Audits and inspections ......................................................................................... 100 
11.9 
Financial disclosures ............................................................................................ 100 
12 Protocol adherence .......................................................................................................... 100 
12.1 
Amendments to the protocol ................................................................................ 100 
13 References (available upon request) ................................................................................ 101 
14 Appendices ...................................................................................................................... 103 
14.1 
Appendix A: Criteria for therapeutic response/outcome assessment of solid 
tumors and/or lymph nodes (based on RECIST 1.1) ........................................... 103 
14.1.1 
Measurability of tumor lesions at baseline.......................................... 103 
14.1.2 
Specification by methods of measurement ......................................... 104 
14.1.3 
Evaluation of best overall response..................................................... 106 
14.1.4 
References (available upon request) ................................................... 108 
14.2 
Appendix B: Criteria for therapeutic response/outcome assessment in 
lymphoma studies (based on Cheson response criteria) ...................................... 109 
14.2.1 
Definitions and criteria for normalization ........................................... 109 
14.2.2 
Measurability of Tumor Lesions at Baseline ...................................... 109 
14.2.3 
Specification by methods of measurement ......................................... 110 
14.2.4 
Evaluation of Radiological Response ................................................. 112 
14.2.5 
References (available upon request) ................................................... 117 
14.3 
Appendix C: Ann Arbor staging classification .................................................... 118 
14.4 
Appendix D: Rai Staging Systema ....................................................................... 118 
14.5 
Appendix E: Criteria for Response assessment in Acute Myeloid Leukemia 
(based on IWG and Cheson) ................................................................................ 118 
14.6 
Appendix F: Criteria for Response assessment in Acute Lymphoblastic 
Leukemia (based on NCCN Guidelines Version 1.2013) ................................... 119 


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14.7 
Appendix G: Criteria for Response assessment in Chronic Myelogenous 
Leukemia (based on NCCN Guidelines Version 4. 2013) .................................. 120 
14.8 
Appendix H: Criteria for Response assessment in Chronic Lymphocytic 
Leukemia (based on modified IWG guidelines) .................................................. 121 
14.9 
Appendix I: Criteria for Response assessment in Myelofibrosis (based on 
modified IWG-MRT guidelines and European LeukemiaNet (ELN) 
consensus report)1 ................................................................................................ 122 
14.10 Appendix J: Criteria for Response assessment in polycythemia vera (based on 
modified IWG-MRT guidelines and European LeukemiaNet (ELN) 
consensus report)1 ................................................................................................ 124 
14.11 Appendix K: Criteria for Response assessment in Essential thrombocythemia 
(based on modified IWG-MRT guidelines and European LeukemiaNet (ELN) 
consensus report)1 ................................................................................................ 125 
14.12 Appendix L: Criteria for Response assessment in Myelodysplasia (based on 
modified IWG guidelines)1 .................................................................................. 126 
14.13 Appendix M: Eastern Cooperative Oncology Group Performance Status .......... 127 
14.14 Appendix N: International Myeloma Working Group (IMWG) uniform 
response criteria for multiple myeloma ............................................................... 127 
14.15 Appendix O: Myeloproliferative Neoplasm (MPN) Symptom Assessment 
Form Total Symptom Score (MPN-SAF TSS) .................................................... 128 
14.16 Appendix P: List of prohibited concomitant medications and concomitant 
medications requiring caution for ceritinib.......................................................... 129 
14.17 Appendix Q: Bayesian Adaptive Design ............................................................. 131 
14.17.1 
Introduction ......................................................................................... 131 
14.17.2 
Statistical Modeling ............................................................................ 133 
14.17.3 
Evaluation of Trial Success and Futility ............................................. 134 
14.17.4 
Simulation ........................................................................................... 135 
 
List of figures 
Figure 4-1 
Study Start-up Design ........................................................................... 34 
 
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) ..... 27 
Table 1-2 
Summary of best overall response based on investigator assessment 
in NSCLC patients in the 750 mg dose group, by prior ALK 


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inhibitor status (Full Analysis Set NSCLC 750 mg) (Cut-off date: 
31-Oct-2013) ......................................................................................... 29 
Table 3-1 
Objectives and related endpoints .......................................................... 33 
Table 6-1 
Dose and treatment schedule ................................................................. 42 
Table 6-2 
Ceritinib dose modifications ................................................................. 44 
Table 6-3 
Ceritinib related toxicity management guidelines ................................. 45 
Table 6-4 
Follow-up evaluations for selected toxicities ........................................ 53 
Table 6-5 
Packaging and labeling ......................................................................... 59 
Table 7-1 
Visit evaluation schedule ...................................................................... 61 
 
 83 
 
 84 
Table 14-1 
Evaluation of target lesions ................................................................. 105 
Table 14-2 
Evaluation of non-target lesions.......................................................... 105 
Table 14-3 
Time point response: patients with target (+/- non-target) disease ..... 106 
Table 14-4 
Time point response: patients with non-target disease only ............... 107 
Table 14-5 
Best overall response when confirmation of CR and PR required...... 107 
Table 14-6 
Response Definition for Lymphoma ................................................... 112 
Table 14-7 
Radiological status based on SPD calculation for all index lesions.... 113 
Table 14-8 
Radiological response criteria for index extranodal lesions in case 
of CR in index nodal lesions ............................................................... 113 
Table 14-9 
Radiological response for index lesions .............................................. 114 
Table 14-10 
Response criteria for non-index lesions (nodal, splenic and/or 
hepatic nodules and other extranodal lesions) .................................... 115 
Table 14-11 
Overall radiological response at each assessment ............................... 115 
Table 14-12 
Exploratory AML response categories according to IWG .................. 119 
Table 14-13 
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** ......... 129 
Table 14-14 
List of medications to be used with caution ........................................ 130 
Table 14-15 
List of prohibited enzyme-inducing anti-epileptic drugs .................... 131 
Table 14-16 
List of prohibited QT prolonging drugs .............................................. 131 
Table 14-17 
Assumed control CBR values used in the simulations........................ 135 
Table 14-18 
Probability of group success ............................................................... 136 
 


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List of abbreviations 
ADME 
Absorption Distribution Metabolism and Excretion 
AE 
Adverse Event 
AKT 
Protein Kinase B 
ALCL 
Anaplastic Large Cell Lymphoma 
ALL 
Acute lymphoblastic leukemia 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AML 
Acute myelogenous leukemia 
ANC 
Absolute Neutrophil Count  
AP 
Alkaline Phosphatase 
APL 
Acute promyelcytic leukemia 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC0-24h 
Area Under the Curve 0-24 h 
BID 
bis in diem/twice a day 
BLRM 
Bayesian Logistic Regression Model 
BP 
Blood pressure 
BRAF/B-Raf 
v-raf murine sarcoma viral oncogene homolog B1 
BSC 
Best supportive care 
BUN 
Blood Urea Nitrogen  
Ca 
Calcium 
CA-125 
Cancer Antigen-125 
CABG 
Coronary artery bypass graft 
CBC  
Complete blood count 
CBR 
Clinical benefit rate 
 
 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence Interval 
CL 
Clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
CLL 
Chronic lymphocytic leukemia 
Cmax 
Maximum Concentration 
CML 
Chronic Myeloid Leukemia 
CNS 
Central Nervous System  
CPK 
Creatine phosphokinase 
CR 
Complete Response 
CRC 
Colorectal Cancer 
CrCl 
Creatinine clearance 
CRO 
Contract Research Organization 
CSF 
Clinical service form 
CSR 
Clinical study report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 


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CVA 
Cerebrovascular accident 
CYP 
Cytochrome P 
DILI 
Drug Induced Liver Injury 
DLs 
dose levels 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration of Response 
DS&E 
Drug Safety & Epidemiology 
DVT 
Deep vein thrombosis 
e.g. 
for example 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
EGF 
Epidermal growth factor 
EGFR 
Epidermal growth factor receptor  
ET 
Essential thrombocythemia 
EOT 
End of Treatment 
ERK/MAPK 
Extracellular signal-regulated kinase/Mitogen-Activated Protein Kinase 
EU 
European Union 
FDA 
Food and Drug Administration 
FAS 
Full Analysis Set 
FDG-PET 
Fluorodeoxyglucose-Positron Emission Tomography 
FFPE 
Formalin fixed paraffin embedded 
FSH 
Follicle-stimulating hormone  
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor  
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 
hERG 
human Ether-à-go-go Related Gene 
HFSR 
Hand and Foot Skin Reaction 
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 


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ILD 
Interstitial Lung Disease 
IMWG 
International Myeloma Working Group 
IN 
Investigator notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device  
IUS 
intrauterine system 
IWG 
International working group 
KA 
Keratoacanthoma 
KRAS 
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LVEF 
Left Ventricular Ejection Fraction 
MAA 
Marketing Authorization Application 
mCRC 
Metastatic Colorectal Cancer 
MDS 
MedDRA 
Myelodysplasia 
Medical Dictionary for Regulatory Activities 
MF 
MEK 
Myelofribrosis 
Mitogen-activated ERK Kinase 
mg 
milligram 
MI 
Myocardial infarction 
MM 
Multiple Myeloma 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
mTOR 
Mammalian target of rapamycin 
MUGA 
Multiple Gated acquisition scan 
N 
Sample size 
NA 
Not applicable 
Na 
Sodium 
NCCN 
National Comprehensive Cancer Network 
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  
Ph 
Philadelphia chromosome 
PHI 
Protected health information 
PK 
Pharmacokinetics 
PLT 
Platelets 
PR 
Partial Response 


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PRBC 
Packed Red Blood Cells 
PSA 
Prostate-specific antigen 
PT 
Prothrombin time 
PTEN 
Phosphatase and tensin homolog 
PV 
Polycythemia vera 
QD 
quaque die/once a day 
QTc 
QT corrected 
QTcF 
Q-T interval in the ECG (corrected according to the formula of Fridericia) 
R Value 
ALT/ALP in x ULN 
RAF 
v-raf murine sarcoma viral oncogene 
RAP 
Reporting Analysis Plan 
RAS 
RAS oncogene (rat sarcoma viral oncogene homologue) 
RBC 
Red Blood Cells 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
Recommended phase two dose 
RTK 
Receptor tyrosine kinase 
RU 
Resource utilization 
SAE 
Serious Adverse Event 
SBP 
Systolic blood pressure 
SC 
Steering Committee 
SCC 
Squamous cell carcinoma 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase/AST 
SGPT 
Serum glutamic pyruvic transaminase/ALT 
SPEP 
Serum protein electrophoresis 
SUSAR 
Suspected unexpected serious adverse reaction 
TBIL 
Total bilirubin 
TdP 
Torsade de Pointes 
TIA 
Transient ischemic attack 
Tmax 
The time at which the maximum observed concentration (Cmax) occurs 
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 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days. For this protocol, a complete treatment cycle is 
defined as 28 days of once daily continuous treatment with ceritinib. The first 
dose of ceritinib defines Day 1 of the treatment cycle and the last day of a 
complete treatment cycle is Day 28, unless extended due to adverse events. 
Baseline 
Pre-dose Cycle 1 day 1 
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”. Ceritinib is the investigational drug in this study 
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. Ceritinib is the investigational treatment. 
Patient Number (Patient No.) 
A unique identifying number assigned to each patient who enrolls in the study 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at this 
time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for progression 
and/or survival 
Screening 
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) 
Stage related to study timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, completion of treatment, etc. 
Stage in cancer 
The extent of cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has 
spread from the original site to other parts of the body. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later 
Study treatment 
Ceritinib 
Study treatment discontinuation 
Point/time when patient permanently stops taking ceritinib, for any reason 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points 


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Amendment 2 
Amendment rationale 
This amendment provides follow-up evaluations for hepatic toxicities and work-up guidelines 
for potential Drug Induced Liver Injury (DILI) cases in order to optimize the patient safety. 
Other changes were implemented in this amendment: 
• Exclusion criteria for contraception use is being updated to reflect the current guidance. 
• Additional exclusion criteria to exclude patients with a history of carcinomatous 
meningitis. 
• Addition of dose modification guidance for QTcF text was updated to provide clarification 
on monitoring procedures. 
• Other general modifications to study language to maintain consistency with standard core 
protocol language for ceritinib clinical studies. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in track changes using strike through 
red font for deletions and red underlined for insertions. 
The following changes were implemented throughout the protocol: 
List of study authors was updated. 
List of abbreviations was updated to include the terms DILI (Drug Induced Liver Injury), 
TBIL (Total bilirubin), and R Value (ALT/ALP in x ULN). 
Section 1.2.1 “Overview of ceritinib” revised to include updated approval information for 
Zykadia. 
Section 5.3 “Exclusion criteria” includes an additional exclusion criteria for patients with a 
history of carcinomatous meningitis. 
Section 5.3 “Exclusion criteria” includes revised pregnancy language 
Old language: Combination of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or other forms of 
hormonal contraception that have comparable efficacy (failure rate <1%), for example 
hormone vaginal ring or transdermal hormone contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/vaginal suppository 
New language: 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. 


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Section 6.3.3 “Criteria for interruption and re-initiation of ceritinib treatment has been revised 
to include new language for continuation of treatment for patients ongoing at the time of data 
cutoff for the CSR. 
Table 6-3 “Ceritinib related toxicity management guidelines” includes revised language for 
electrocardiogram QT corrected (QTc) interval prolonged. 
Section 6.3.4.2 “Guidelines for follow-up of laboratory liver abnormalities” has been revised 
to include guidelines for DILI cases. 
Additional minor editorial corrections have been made throughout the protocol. 
IRB/IEC Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 


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Amendment 1 
Amendment rationale 
The main purpose of this protocol amendment is to incorporate updates based on currently 
available safety data. Pancreatic enzyme elevations (lipase and/or amylase) occur in patients 
treated with ceritinib. Clinical data suggest that a small proportion (<1%) of patients treated 
with ceritinib can develop clinical pancreatitis, and the causal role of ceritinib in these cases 
cannot be excluded. Due to this finding, the protocol has been amended to include additional 
dose modification and follow up monitoring language for patients who may experience this 
safety finding.  
 
 
 
 
 
 
 
 
Appendix Q “Bayesian Adaptive Design” was revised. In a single arm trial without a control 
arm, the quality of the inferences depend strongly on historical data used to create a credible 
estimate of the baseline control rate. For this and other trials within Novartis’s Modular phase 
II program, this required an estimate of the patient population that would be enrolled. A 
control estimate was initially formed for each group based on that population estimate. As 
enrollment progressed, a different patient population was enrolled in terms of previous line of 
therapy exposure (heavily pretreated). In order to produce the best inferences for future 
development decisions, it is important to change the assumed baseline control rates to match 
the population enrolled in the program, rather than relying on the pre-trial assumptions. 
Previously this section was tailored to the CLDK378AUS23 trial. The revised appendix will 
be used for all trials within Novartis’s Modular phase II program. The purpose of this section 
is to show how Bayesian adaptive design will be used for the analysis of the primary efficacy 
endpoint. Each trial will be analyzed according to the tumor cohorts that will be formed 
during the course of the study. 
Additional changes include the possible discontinuation of survival follow-up if the primary 
endpoint of the study is not met, a revised definition for “End of Study” to clarify when data 
will be reported, and language modifications to maintain consistency with standard core 
protocol language for ceritinib clinical studies. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in track changes using strike through 
red font for deletions and red underlined for insertions. 
The following changes were implemented throughout the protocol: 


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List of study authors was updated. 
 
 
 
 
Protocol Summary “Purpose and rationale”, “Study design” and “Inclusion criteria”, Section 
2.2 “Rationale for the study design”, Section 4.1 “Description of study design”, Section 5.1 
“Patient population”, and Section 5.2 “Inclusion criteria” removed the word “select”. 
Protocol summary “Study Design” and “Efficacy assessments”, Section 4.1.2 “Follow-up 
phase”, Section 7.1.4.3 “Survival Follow-up”, Section 10.5.2 “Other secondary efficacy 
objectives” was changed to clarify that survival follow up may be discontinued if the primary 
endpoint of the study is not met. 
Protocol Summary “Study design” and Section 7.1.1 “Screening” have been revised to clarify 
that laboratory results from genomic profiling must be ‘unambiguous’ or ‘unequivocal’. 
Results that state ‘ambiguous’ or ‘equivocal’ imply low probability that genetic deregulation 
is truly present and an important driver of patient’s tumor. 
Section 2.1 “Study rationale and purpose”, Table 7-1, 
 
 
 
Changes to the inclusion/exclusion criteria (Protocol summary and Sections 5.2 and 5.3): 
• Additional inclusion criteria for alkaline phosphatase (≤ 5.0 x ULN) and fasting plasma 
glucose (≤ 175 mg/dL (≤ 9.8 mmol/L). 
• Clarified that calcium should be corrected for serum albumin, not phosphorus.  
• Revised inclusion criteria for platelets, hemoglobin, serum creatinine, AST/ALT, and 
serum bilirubin. 
• Additional exclusion criteria for patients with a history of carcinomatous meningitis. 
• Revised exclusion criteria for patients with pancreatitis, cardiac function, severe acute or 
chronic medical conditions, radiotherapy, and major surgery. 
Section 1.2.1 “Overview of ceritinib” was revised to include information about marketing 
authorization applications for Zykadia. 
Section 1.2.3 “Non-clinical experience” includes new preclinical data. 
Section 1.2.4 “Clinical experience” and Table 1-1 includes new information regarding the 
incidence of grade 3-4 AEs. 
Section 1.2.4 “Clinical experience” includes removal of ECG data. 
Section 1.2.4.1.1 “Clinical efficacy” now includes data for PFS based on investigator 
assessment, and data on ceritinib activity in patients with brain metastases. Additionally, 
Tables 1-3, 1-4, and 1-5 were removed. 


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Section 1.2.4.1.2 “Clinical pharmacokinetics” was revised to expand upon the low-fat and 
high-fat meals, and to include the results of a food effect assessment. 
Section 1.3 “Risk and Benefits” was added to include an evaluation of the anticipated benefits 
and risks of ceritinib to comply with EU clinical trial regulations. 
Section 4.2 “Definition of end of the study” was revised to include information regarding the 
analysis of study data and the CSR. 
Section 6.3 “Dose modifications” includes a new section entitled: General guidelines for dose 
modifications for toxicities other than those listed in Table 6-3. Also included are revisions to 
the “Permitted study treatment adjustments for ceritinib” and “Criteria for interruption and re-
initiation of ceritinib treatment” sections. 
Table 6-3 was revised to include a Pancreatic section, updates to the Renal section (serum 
creatinine), a change to the Metabolic section (persistent hyperglycemia), and changes to the 
Cardiac section (Electrocardiogram QT corrected interval prolonged). 
Section 6.3.4 “Follow-up for toxicities” includes a new sentence (An unscheduled visit should 
be performed in all cases below where toxicity monitoring is recommended more frequently 
than defined by the schedule of assessments). Additionally, modifications were made to the 
guidelines for the follow-up of laboratory hematologic abnormalities, laboratory liver 
abnormalities, and laboratory renal abnormalities sections. 
Section 6.3.4.8 “Guidelines for the follow-up of laboratory pancreatic abnormalities” has been 
added. 
Table 6-4 includes revisions to the time points for monitoring toxicities, and includes a new 
section for pancreatic investigations. 
Section 6.4 “Concomitant medications” includes revisions to the language for medications 
that need to be recorded on the eCRF. 
Section 6.4.1.1 “Bisphosphonates” has been revised to include a statement about drug-drug 
interaction. 
Section 6.4.2.1 “Corticosteroids” has been modified. 
Section 6.4.2.2 “Drugs that are metabolized by CYP450 enzymes” was revised to clarify that 
strong “inhibitors or” inducers of CYP3A4/5 is prohibited.    
Section 6.4.2.4 “Palliative radiotherapy and surgery” includes the removal of “BIRC 
confirmed” for progressive disease. 
Section 6.4.3.1 “Other investigational and anti-neoplastic therapies” now includes “targeted 
therapy”. 
Section 6.4.3.2 “Warfarin and coumadin derivatives” was updated to clarify that “therapeutic 
doses of “ warfarin sodium or any other coumadin-derived anticoagulants are not permitted. 
Section 7.1.1 “Screening” includes a new statement about when archival or fresh tumor 
samples may not be required for patients. 


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Section 7.2.1.1 “Solid Tumors” and Section 10.4 “Primary objective” were updated to clarify 
that if the assessment of CR or PR evaluated 4 weeks after the initial observation differ, then 
the best overall response will be determined as outlined in Appendix B.  
Section 7.2.1.2.4 “Bone marrow assessment” includes the addition of a bone marrow aspirate. 
 
 
 
 
 
Section 8.2 “Adverse events of special interest” includes new AEs.  
Section 10.4.3 “Evaluation of trial success and futility” was revised to include an additional 
CBR evaluation after database lock for the primary CSR. 
Section 10.5 1 “Key secondary objective(s)” was revised to include assessment of Complete 
Response.  
Section 10.5.2 “Other secondary efficacy objectives” was revised. 
 
Section 10.7 “Interim analysis” has been revised. 
Section 10.8 “Sample size calculation has been revised.  
Appendix A: Criteria for therapeutic response/outcome assessment of solid tumors and/or 
lymph nodes” has been revised. 
Appendix Q “Bayesian Adaptive Design” has been revised. 
Additional minor editorial corrections have been made throughout the protocol. 
IRB/IEC Approval 
• A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
• The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into 
account the changes described in this amended protocol. 


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Protocol summary 
Protocol number 
CLDK378AUS23 
Title 
Modular phase II study to link targeted therapy to patients with pathway activated 
tumors: Module - 7 Ceritinib (LDK378) for patients whose tumors have aberrations in 
ALK or ROS1  
Brief title 
Ceritinib (LDK378) for patients whose tumors have aberrations in ALK or ROS1  
Sponsor and Clinical 
Phase 
Novartis 
Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this signal seeking study is to determine whether treatment with ceritinib 
demonstrates sufficient efficacy in pathway-activated solid tumors and/or hematologic 
malignancies to warrant further study. 
Primary Objective(s) 
and Key Secondary 
Objective 
Primary objectives: 
To assess clinical benefit 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. For hematologic tumors, other 
appropriate hematological response criteria will apply and are included in the 
appendices 
 
Key Secondary objective: 
To assess Overall Response (OR) of Partial Response (PR) or greater based on local 
investigator assessment 
 
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, other appropriate 
hematological response criteria will apply and are included in the appendices. 
Secondary 
Objectives 
To assess: 
Progression-Free Survival (PFS) based on local investigator assessment per RECIST 
1.1 or other appropriate hematological response criteria 
 
Overall Survival (OS) 
 
Duration of Response (DOR) based on local investigator assessment per RECIST 1.1 
or other appropriate hematological response criteria 
 
Safety and tolerability 
Study design 
This is a phase II, open label study to determine the efficacy and safety of treatment 
with ceritinib in patients with a diagnosis of  solid tumors or hematological malignancies 
that have been pre-identified (prior to study consent) to have ALK or ROS1 positive 
mutations, translocations, rearrangements or amplifications and whose disease has 
progressed on or after standard treatment. 
 
Genomic profiling is becoming more accessible to patients and their physicians. As 
such, more patients have been identified with potentially-actionable genomic alterations 
or pathway-activations but do not have access to targeted drug treatment. This is a 
signal seeking study to match patients with tumors containing ALK or ROS1 positive 


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mutations, translocations, rearrangements or amplifications to treatment with the ALK 
kinase inhibitor ceritinib. Pre-identification of ALK or ROS1 positive mutation, 
translocation, rearrangement or amplification status will be performed locally at a CLIA 
certified laboratory prior to participation on the trial. Laboratory results must be 
‘unambiguous’ or ‘unequivocal’. Results that state ‘ambiguous’ or ‘equivocal’ imply low 
probability that genetic deregulation is truly present and an important driver of patient’s 
tumor. 
 
Once the patient has been identified, treating physicians who are qualified investigators 
may contact Novartis to consider enrollment in this study. For the purpose of this study, 
genomic profiling is not considered part of screening. Informed consent must be signed 
before any screening activities take place. Once eligibility (screening criteria met) has 
been confirmed by Novartis, the patient will initiate therapy with ceritinib single-agent. 
The patient may not receive any additional anti-cancer therapy during treatment with 
ceritinib. 
 
Patients will continue to receive study treatment until disease progression (assessed by 
investigator per RECIST 1.1 or appropriate hematologic response criteria), 
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. 
 
Disease assessment (per RECIST 1.1 or appropriate hematological response criteria) 
will be performed every 8 weeks (±4 days) after first dose of study drug (Day 1 of every 
odd cycle), until disease progression or end of treatment, whichever occurs first. The 
frequency of disease assessment may be reduced to every 12 weeks for patients who 
have at least 4 post-baseline disease assessments and are clinically stable (except MM 
and AML patients). Scans will be assessed locally by the investigator. 
 
After discontinuation of treatment, patients, regardless of reason for treatment 
discontinuation, will be followed for safety for 30 days after the last dose. 
 
Survival information will be collected every 3 months until 2 years after the last patient 
has enrolled in the study regardless of treatment discontinuation reason (except if 
consent is withdrawn). If the study primary efficacy endpoint is not met, Novartis may 
decide not to conduct survival follow up for the study. 
Population 
The study population consists of approximately 70-90 adult patients with a diagnosis of 
a solid tumor or hematological malignancy that have been pre-identified as having ALK 
or ROS1 positive mutations, translocations, rearrangements or amplifications. Patients 
must have received at least one prior treatment for their recurrent, metastatic and/or 
locally advanced disease and have no remaining standard therapy options anticipated 
to result in a durable response. Patients must have progressive and measurable 
disease (per RECIST 1.1 or appropriate hematological response criteria) and be in 
need of treatment.  
 
This is a signal seeking study, attempting to identify additional patient populations who 
may benefit from treatment with single agent ceritinib. Tumors currently being studied 
under some key Novartis-sponsored trials will be excluded. This includes ALK+ non-
small cell lung cancer (NSCLC). Patients with ROS1 rearranged NSCLC may be 
included. Additional tumor types may be excluded during the course of the study at the 
discretion of Novartis. 
 
Patients must not have symptomatic cardiac disease or impairment of GI function.  
 
 
 
 
 


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Enrollment is meant to encompass solid tumors and hematologic malignancies as 
having ALK or ROS1 positive mutations, translocations, rearrangements or 
amplifications that may be inhibited by ceritinib who otherwise meet all the inclusion 
and none of the exclusion criteria. Though common for phase I studies, tissue-agnostic 
enrollment is unusual for phase II studies, which typically limit enrollment to one or a 
few well-defined tumor types. We expect that the study will enroll patients whose 
tumors have already been pre-identified to harbor ALK or ROS1 positive mutations, 
translocations, rearrangements or amplifications such as B-cell lymphoma, breast 
cancer, colorectal cancer, melanoma, Anaplastic Large Cell Lymphoma (ALCL) and 
ovarian cancer (enrollment will not be strictly limited to those particular cancers). 
Patients with ROS1 rearranged NSCLC may also be included. The total number of 
patients to be enrolled per tumor type will be based on an adaptive design. The 
adaptive design will be patient-sparing and allow the early closure of non-responding 
arms or arms where early success can be declared. 
Inclusion criteria 
Patient has a confirmed diagnosis of a solid tumor (except with a primary diagnosis of 
ALK+ NSCLC) or hematologic malignancy and is in need of treatment because of 
progression or relapse 
 
Patient’s tumor has been evaluated and pre-identified as having an ALK or ROS1 
positive mutation, translocation, rearrangement or amplification. The qualifying 
alteration must be assessed and reported by a CLIA-certified laboratory 
 
Patient must have received at least one prior treatment for recurrent, metastatic and /or 
locally advanced disease and for whom no standard therapy options are anticipated to 
result in a durable remission 
 
Patient must have progressive and measurable disease per RECIST 1.1. or other 
appropriate hematological response criteria 
 
Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 
 
See Section 5.2 for complete Inclusion criteria 
Exclusion criteria 
Patient has received prior treatment with ceritinib 
 
Patient has received chemotherapy or other anticancer therapy ≤ 4 weeks (6 weeks for 
nitrosourea, antibodies or mitomycin-C) prior to starting study drug 
 
Patients with a history of pancreatitis or increased amylase or lipase due to pancreatic 
disease  
 
Patients with  clinically significant uncontrolled heart disease and/or recent cardiac 
event (within 6 months) 
 
Patient has history of interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis (i.e., affecting activities of daily living or 
requiring therapeutic intervention) 
 
Patients with another primary malignancy within 3 years prior to starting study 
treatment, with the exception of adequately treated basal cell carcinoma, squamous cell 
carcinoma or other non-melanomatous skin cancer, or in-situ carcinoma of the uterine 
cervix 
 
See Section 5.3 for complete Exclusion criteria 
Investigational and 
reference therapy 
Ceritinib administered orally once daily at a dose of 750mg (5 capsules of 150 mg 
ceritinib (LDK378)). A complete treatment cycle is defined as 28 days. 


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Efficacy assessments 
All screening evaluations must be performed as closely as possible to the beginning of 
treatment and never more than 28 days prior to starting study drug dose of ceritinib to 
confirm patient’s eligibility. 
 
During treatment phase, disease assessments must be performed at screening and 
every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd cycle), until 
disease progression or end of treatment, whichever occurs first. The frequency of 
disease assessment may be reduced to every 12 weeks for patients who have at least 
4 post-baseline disease assessments and are clinically stable (except MM and AML 
patients). 
 
Patients will continue to receive study treatment until disease progression (assessed by 
investigator per RECIST 1.1 or appropriate hematologic response criteria), 
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). 
 
 Survival information will be collected every 3 months until 2 years after the last patient 
has enrolled in the study regardless of treatment discontinuation reason (except if 
consent is withdrawn). If the study primary efficacy endpoint is not met, Novartis may 
decide not to conduct survival follow up for the study. 
Safety assessments 
Adverse events 
 
Physical examination including vital signs and weight 
 
Performance status evaluation 
 
Cardiac monitoring (cardiac enzymes, ECGs, and assessment of LVEF) 
 
Laboratory evaluations (hematology, biochemistries, pregnancy tests and urinalysis) 
Data analysis 
The Full Analysis Set (FAS) will include all patients who have received at least one 
dose of study drug. FAS will be the primary population for the analysis of efficacy 
endpoints. 
Key words 
Solid tumor malignancy, hematologic malignancy, mutation, translocations, signature, 
ALK, ceritinib, ROS1, NSCLC, B-cell lymphoma, breast cancer, colorectal cancer, 
melanoma, ALCL, and ovarian cancer 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
1.1.1 
Ceritinib target pathway 
ALK is a receptor tyrosine kinase of the insulin receptor superfamily that plays a role in 
neural development and function. ALK gene rearrangements result in aberrant ALK 
activation, and ALK fusion proteins possess potent oncogenic activity in both in vitro and in 
vivo models. This activity can be effectively blocked by small-molecule inhibitors that target 
ALK. 
For further details on clinical and non-clinical experience, refer to the [LDK378 Investigator’s 
Brochure]. 
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 (isopropyl-
sulfonyl)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 ongoing Phase I clinical trial in patients (with 
and without previous crizotinib therapy) led to the approval of ceritinib by the Food and Drug 
Administration (FDA) under the trade name ZYKADIA™ on 29-Apr-2014 for the following 
indication: 
‘ZYKADIA™ is indicated for the treatment of patients with ALK-positive metastatic NSCLC 
who have progressed on or are intolerant to crizotinib. This indication is approved under 
accelerated approval based on tumor response rate and duration of response. An improvement 
in survival or disease-related symptoms has not been established. Continued approval for this 
indication may be contingent upon verification and description of clinical benefit in 
confirmatory trials.’ 
Furthermore, the European Commission approved ZYKADIA on 06-May-2015 for the 
following indications: 
• ZYKADIA is indicated for the treatment of adult patients with anaplastic lymphoma 
kinase (ALK) positive advanced non-small cell lung cancer (NSCLC) previously treated 
with crizotinib. 
Submissions to other health authorities worldwide have been completed in some countries and 
are underway in others.  


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Ceritinib has demonstrated potent antitumor activity in patients with advanced, ALK-
rearranged NSCLC (Shaw et al 2014). As reported in Shaw, et al 2014 a total of 130 patients 
were treated: 59 patients in the dose-escalation phase and 71 in the expansion phase. Eligible 
patients had a locally advanced or metastatic cancer harboring genetic alterations in ALK. 122 
(94%) patients had NSCLC, among the eight patients with advanced cancers other than 
NSCLC, two had a response to ceritinib: one patient with anaplastic large-cell lymphoma, and 
one with inflammatory myofibroblastic tumor. 
1.2.2 
Discovery of ROS1 rearrangement and its impact in NSCLC 
ROS1 is a receptor tyrosine kinase of the insulin receptor family with constitutive kinase 
activity. ROS1 rearrangement was initially found in glioblastoma and was shown to have 
oncogenic potential by Charest et al., using transgenic mouse model. Rikova et al. and Li et 
al. also reported ROS1 rearrangement in NSCLC and currently at least 13 known ROS1 
fusion variants involving 8 fusion partners were identified in ROS1 positive NSCLC. ROS1 
rearrangement is found in 1-2% of NSCLC and defines a unique molecular subset of NSCLC. 
ROS1 rearrangement in NSCLC is characterized by younger age of onset and history of never 
or light smokers with adenocarcinoma histology. Bergethon et al. screened 1073 NSCLC 
tumors and identified 18 (1.7%) patients with ROS1 rearrangement by break-apart FISH 
assay. The median age of the 18 ROS1-rearranged NSCLC patients was 49.8 years (range: 32-
79 years), 78% were never-smokers and all of them presented with adenocarcinoma. ROS1 
rearrangement is known to be mutually exclusive with other oncogenic mutations such as 
epidermal growth factor receptor (EGFR) mutation, KRAS mutation or ALK rearrangement. 
Preclinical studies have shown that cell lines and tumors harboring ROS1 fusion are sensitive 
to crizotinib, a dual ALK/MET inhibitor. Furthermore, cells harboring ROS1 fusions did not 
respond to treatment with EGFR-targeted kinase inhibitors. In accordance with preclinical 
data, preliminary results of a phase I clinical trial of crizotinib in the ROS1-rearranged 
NSCLC showed remarkable efficacy of crizotinib with an overall response rate of 57% at 8 
weeks of treatment. Altogether, these results define ROS1-rearranged NSCLC as a distinct 
druggable entity and highlight the importance of identification of ROS1-rearranged patients 
who will benefit from ROS1-targeted therapy. 
Rationale for the use of ceritinib in ROS1-driven NSCLC 
Ceritinib is an orally highly selective and potent ALK kinase inhibitor. Ceritinib is a potent 
inhibitor of tumor growth in rodent models of both anaplastic large cell lymphoma (ALCL) 
and NSCLC. Preclinical studies showed that ceritinib also has nanomolar-range IC50 values 
in cell lines engineered to express ROS1 rearrangement. ALK and ROS1 kinase domain share 
approximately 49% amino acid sequence homology, and several ALK inhibitors have been 
shown to inhibit ROS1. A recent finding with an in silico method showed that high number of 
conserved residues in the ALK and ROS1 kinase domains interacted with an ALK inhibitor, 
TAE684. 
The ongoing phase I study of ceritinib has demonstrated preliminary evidence of antitumor 
activity in ALK positive NSCLC. Section 1.2.4.1.1 details the efficacy of ceritinib from this 
study. This available data provides rationale for the clinical activity of ceritinib and is 
expected to bring benefit to ROS1-rearranged population in a similar aspect. 


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1.2.3 
Non-clinical experience 
1.2.3.1 
Non-clinical 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 the 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. 
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. 
1.2.3.2 
Non-clinical pharmacokinetics 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 in 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 brain-to-blood exposure (AUCinf) ratio of approximately 15%, it was higher 
than the 3% background associated with brain vasculature at all monitored time points. This 
indicates that drug-related radioactivity crossed the blood-brain barrier. Unchanged 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 


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(>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 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. 
1.2.3.3 
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-weeks studies in rat and monkeys, respectively), and 
included increases in liver transaminases in a few animals at high doses, and mixed cell 
inflammation, erosion and cytoplasmic vacuolation of the bile duct epithelium. The pancreas 
was a target organ in the rat, but not the monkey, with acinar cell atrophy and mixed cell 
inflammation noted at middle and high doses. Target organ effects showed partial to complete 
recovery during the 4-week non-dosing period. No effects in the rat central nervous system or 
on the respiratory system were observed at single, high doses (100 mg/kg). 
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. However, a preliminary analysis from an in vivo 
ultraviolet local lymph node assay (UV LLNA) demonstrated no phototoxic potential with 
ceritinib. 
Preclinical studies including an in vitro 3T3 NRU assay (refer to [Investigators Brochure]), 
indicated a low risk of phototoxicity with the use of ceritinib. In addition, a preliminary 


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analysis from an in vivo ultraviolet local lymph node assay (UV LLNA) demonstrated no 
phototoxic potential with ceritinib.  
1.2.4 
 Clinical experience 
1.2.4.1 
Clinical safety and tolerability 
Ceritinib is associated with a manageable safety profile (Table 1-1). For the 255 patients 
treated at the recommended dose of 750 mg in the ongoing study [CLDK378X2101], the 
median duration of exposure as of the 31-Oct-2013 cut-off date was 26.9 weeks (range 0.4 to 
82.3 weeks). The most common adverse events regardless of study drug relationship 
(incidence ≥25%) were diarrhea, nausea, vomiting, alanine aminotransferase (ALT) increased, 
fatigue, abdominal pain, decreased appetite, aspartate aminotransferase (AST) increased, and 
constipation.  
The incidence of grade 3-4 AEs, regardless of study drug relationship was <10% for all AEs 
except ALT increased (26.7%) (Table 1-1). The incidence of grade 3-4 AEs, regardless of 
study drug relationship was <5% for all AEs except AST increased (8.2%), diarrhea (5.9%), 
hyperglycemia (5.5%), lipase increased (5.1%), and blood alkaline phosphatase (ALP) 
increased (5.1%). 
Table 1-1 
All grades (at least 10%) and associated grade 3-4 adverse events, 
regardless of study drug relationship, by preferred term in patients 
treated in the 750 mg dose group (Data cut-off date: 31-Oct-2013) 
Preferred term 
Ceritinib 
750 mg 
N=255 
All Grades 
Grade 3/4 
n (%) 
n (%) 
Total 
255 (100.0) 
184 (72.2) 
Diarrhea 
219 (85.9) 
15 (5.9) 
Nausea 
205 (80.4) 
11 (4.3) 
Vomiting 
153 (60.0) 
10 (3.9) 
Alanine Aminotransferase Increased 
110 (43.1) 
68 (26.7) 
Fatigue 
102 (40.0) 
10 (3.9) 
Abdominal Pain 
91 (35.7) 
3 (1.2) 
Decreased Appetite 
87 (34.1) 
2 (0.8) 
Aspartate Aminotransferase Increased 
78 (30.6) 
21 (8.2) 
Constipation 
73 (28.6) 
0  
Cough 
62 (24.3) 
0  
Abdominal Pain Upper 
58 (22.7) 
2 (0.8) 
Dyspnea 
47 (18.4) 
8 (3.1) 
Asthenia 
45 (17.6) 
2 (0.8) 
Blood Alkaline Phosphatase Increased 
45 (17.6) 
13 (5.1) 
Back Pain 
43 (16.9) 
1 (0.4) 
Headache 
41 (16.1) 
3 (1.2) 
Weight Decreased 
39 (15.3) 
4 (1.6) 
Blood Creatinine Increased 
39 (15.3) 
0  


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Preferred term 
Ceritinib 
750 mg 
N=255 
All Grades 
Grade 3/4 
n (%) 
n (%) 
Pyrexia 
38 (14.9) 
0  
Rash 
32 (12.5) 
0  
Insomnia 
31 (12.2) 
0  
Dyspepsia 
26 (10.2) 
1 (0.4) 
Hypokalemia 
26 (10.2) 
11 (4.3) 
Dizziness 
26 (10.2) 
0  
Dose reductions due to adverse events (AEs) occurred in 584% 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 
5% of patients, consisting of: pneumonia (4 patients), respiratory failure, ILD/pneumonitis, 
pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary 
tuberculosis, cardiac tamponade, and sepsis (1 patient each). Adverse events of special 
interest to be monitored for ceritinib have also been identified and include hepatotoxicity, 
interstitial lung disease/pneumonitis, QT interval prolongation, bradycardia, hyperglycemia, 
gastrointestinal toxicity (nausea, vomiting and diarrhea) and pancreatitis (including lipase and 
amylase elevations). For additional details, refer to the [Investigator’s Brochure]. 
1.2.4.1.1 Clinical efficacy 
As of 31-Oct-2013, data from the ongoing 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 at the end of the study. 
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 


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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 the 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 metastasis 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]. 
Table 1-2 
Summary of best overall response based on investigator assessment 
in NSCLC patients in the 750 mg dose group, by prior ALK inhibitor 
status (Full Analysis Set NSCLC 750 mg) (Cut-off date: 31-Oct-2013) 
 
NSCLC with prior 
ALK inhibitor 
NSCLC ALK 
inhibitor naïve 
All NSCLC 
 
N=163 
N=83 
N=246 
 
n (%) 
n (%) 
n (%) 
Best overall response 
 
Complete response (CR) 
2 (1.2) 
1 (1.2) 
3 (1.2) 
 
Partial response (PR) 
87 (53.4) 
54 (65.1) 
141 (57.3) 
 
Stable disease (SD) 
32 (19.6) 
19 (22.9) 
51 (20.7) 
 
Progressive disease (PD) 
16 (9.8) 
0 
16 (6.5) 
 
Unknown 
26 (16.0) 
9 (10.8) 
35 (14.2) 
Overall response rate (ORR) (CR or 
PR), n (%) 
89 (54.6) 
55 (66.3) 
144 (58.5) 
 
95% CI 
(46.6-62.4) 
(55.1-76.3) 
(52.1-64.8) 
This table presents data for all patients with ALK-positive NSCLC in the 750 mg treatment dose group, FAS-
NSCLC 750 mg group 
Best overall response is based on investigator’s assessment of disease status using RECIST 1.0 criteria 
CR and PR are confirmed by repeat assessments performed not less than 4 weeks after the criteria for response 
are first met. 
Exact binomial 95% Confidence Interval 
1.2.4.1.2 Clinical pharmacokinetics 
In adult patients with tumors characterized by genetic abnormalities in ALK 
study [CLDK378X2101] 
and 
in 
healthy 
volunteers 
study [CLDK378A2101], 
study [CLDK378A2104] and study [CLDK378A2106], single-dose pharmacokinetics 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 AUClast 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 


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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. 
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 [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 gastrointestinal 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 [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 


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and 1.5 grams of fat) was also explored in an ongoing 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 
CLDK378A2101, suggesting that even a very low-fat meal could lead to a clinically 
meaningful ceritinib exposure increase. 
1.3 
Risk and Benefits 
An evaluation of the anticipated benefits and risks has been included in the protocol to 
comply with EU clinical trial regulations. 
Based on the experience from the ongoing single-agent ceritinib studies, the efficacy and 
safety profile of ceritinib was considered to be acceptable for continued clinical development. 
Data from these studies indicate that ceritinib provides a high rate of durable responses in 
patients with ALK-rearranged NSCLC, both in patients who have been previously treated 
with crizotinib and in those who are crizotinib-naïve. There may be unforeseen risks with 
ceritinib which could be serious. 
2 
Rationale 
2.1 
Study rationale and purpose 
Genomic profiling is becoming more accessible to patients and their physicians. As such, 
more patients have been identified with potentially actionable genomic alterations or 
pathway-activations but do not have access to targeted drug treatment. This is a signal seeking 
study to match patients with ALK or ROS1 positive mutations, translocations, rearrangements 
or amplifications to treatment with the ALK kinase inhibitor ceritinib. Pre-identification of 
ALK or ROS1 positive mutation, translocation, rearrangement or amplification status will be 
performed locally at a CLIA certified laboratory prior to participation on the trial. 
The purpose of this signal seeking study is to determine whether treatment with ceritinib 
demonstrates sufficient efficacy in select pathway-activated solid tumors and/or hematologic 
malignancies to warrant further study. Patients with ALK+ NSCLC will be excluded from this 
exploratory study because this indication is currently being studied under key Novartis-
sponsored ceritinib trials. Patients with ROS1 rearranged NSCLC may be included. 
Additional tumor types may be excluded during the course of the study at the discretion of 
Novartis. 
Details of the study design are provided in Section 4. 
Additionally, increased understanding of the genomic changes in tumors allows the selection 
of patients more likely to benefit from treatment. In most cases patients who respond well 
initially to treatment soon develop resistance to the new treatments; also, many patients have 
disease that does not respond. The biological complexity of cancers and lack of knowledge of 
the mechanisms responsible for resistance in patients pose challenges, therefore a successful 
development of treatments that provide sustained disease control or cure requires improving 
the understanding of the mechanisms responsible for drug resistance. Therefore, in patients 


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with a best response of SD or better, an optional tumor sample at the time of disease 
progression could be obtained for genomic analysis. 
 
 
2.2 
Rationale for the study design 
This is a phase II, open label study to determine the efficacy and safety of treatment with 
ceritinib in patients with a diagnosis of solid tumors or hematological malignancies that have 
been pre-identified (prior to study consent) to have ALK or ROS1 positive mutations, 
translocations, rearrangements or amplifications and whose disease has progressed on or after 
standard treatment. 
2.3 
Rationale for dose and regimen selection 
The recommended ceritinib phase II dose is 750 mg/day which corresponds to the single agent 
recommended phase two dose (RP2D). The selection of the starting dose follows the ICH S9 
guidelines for choosing a starting a dose for a first-in-human trial conducted in patients with 
cancer, and is shown in Table 6-2. It will be dosed on a flat scale and not adjusted by weight 
or body surface area. 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary: 
● To assess clinical benefit 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. For 
hematologic tumors other appropriate hematological response 
criteria will apply and are included in the appendices. 
 
● Clinical benefit rate (e.g. defined as CR or PR or SD ≥ 16 weeks for 
solid tumors). For hematologic tumors, other appropriate hematological 
response criteria will apply and are included in the appendices. 
Refer to Section 10.4 
Key secondary: 
● To assess Overall Response (OR) of Partial Response (PR) or 
greater based on local investigator assessment. 
● 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 other appropriate hematological response 
criteria will apply and are included in the appendices. 
 
● Overall response rate (PR or greater) 
Refer to Section 10.5.1 
Other secondary: 
● To assess Progression-Free Survival (PFS) based on local 
investigator assessment per RECIST 1.1 or other appropriate 
hematological response criteria 
● To assess Overall Survival (OS) 
● To assess Duration of Response (DOR) based on local 
investigator assessment per RECIST 1.1 or other appropriate 
hematological response criteria 
● To assess safety and tolerability 
 
● Time from the date of first dose to the date of first documented 
disease progression or relapse or death due to any cause 
 
● Time from the date of first dose to the date of death due to any cause 
● Time from the first documented response to the date first documented 
disease progression or relapse or death due to any cause 
 
● Incidence of AEs, SAEs, changes from baseline in vital signs, 
laboratory test results(hematology, biochemistry), ECG, and cardiac 
imaging will be assessed by the Common Terminology Criteria for 
Adverse Events (CTCAE), v4.03 
 
Refer to Section 10.5.2 
 
 
Refer to Section 10.5.2 
Refer to Section 10.5.2 
 
 
Refer to Section 10.5.3 


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4 
Study design 
4.1 
Description of study design 
This is a phase II, open label study to determine the efficacy and safety of treatment with 
ceritinib in patients with a diagnosis of solid tumors or hematological malignancies that have 
been pre-identified (prior to study consent) to have ALK or ROS1 positive mutations, 
translocations, rearrangements or amplifications and whose disease has progressed on or after 
standard treatment. 
This study is intended for patients who have already had genomic profiling of their tumors in 
a CLIA certified laboratory and have already been pre-identified to have a tumor with an 
ALK or ROS1 positive mutation, translocation, rearrangement or amplification. Eligibility is 
based on ALK or ROS1 positive mutation, translocation, rearrangement or amplification 
status as assessed in the local, CLIA certified laboratory. The results of this testing must be 
known prior to signing the ICF and before formal screening begins. Once the patient has been 
identified, treating physicians who are qualified investigators may contact Novartis to 
consider enrollment in this study. For the purpose of this study, genomic profiling is not 
considered part of screening. Informed consent must be signed before any screening activities 
take place. Once eligibility (screening criteria met) has been confirmed by Novartis, the 
patient will initiate therapy with ceritinib single-agent. The patient may not receive any 
additional anti-cancer therapy during treatment with ceritinib. 
A schematic representation of the study start-up design is shown in Figure 4-1. 
Figure 4-1 
Study Start-up Design 
 


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4.1.1 
Treatment phase 
Patients will continue to receive study treatment until disease progression (assessed by 
investigator per RECIST 1.1 or appropriate hematologic response criteria), 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. 
Disease assessments (per RECIST 1.1 or appropriate hematological response criteria) will be 
performed every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd cycle), 
until disease progression or end of treatment, whichever occurs first. The frequency of disease 
assessment may be reduced to every 12 weeks for patients who have at least four post-
baseline disease assessments and are clinically stable (except MM and AML patients). Scans 
will be assessed locally by the investigator. 
4.1.2 
Follow-up phase 
After discontinuation of treatment, patients, regardless of reason for treatment 
discontinuation, will be followed for safety for 30 days after the last dose. 
Survival information will be collected every 3 months until 2 years after the last patient has 
enrolled in the study regardless of treatment discontinuation reason (except if consent is 
withdrawn). If the study primary efficacy endpoint is not met, Novartis may decide not to 
conduct survival follow up for the study. For details on required assessments, please refer to 
Table 7-1. 
For patients with a best response of SD or better who discontinue study treatment due to 
disease progression, an optional tumor sample should be obtained for genomic analysis. This 
tumor sample must be obtained within 28 days of stopping  the study treatment  and no more 
than 14 days after starting another treatment for their cancer (at a time most convenient for the 
patient); exceptions may be made after discussion with the sponsor. 
 
 
4.2 
Definition of end of the study 
 End of study is defined as the time when the last patient completes survival follow-up, has 
expired, is lost to follow up or withdraws consent, or when the study is terminated early.  
The analysis of study data will be based on all patients’ data up to the time when all patients 
have had the opportunity to complete at least 4 cycles (or 16 weeks) of treatment or 
discontinued the study. This will be the cut-off point for the primary clinical study report 
(CSR). Additional data for patients continuing to receive study treatment past the data cutoff 
date for the primary CSR will be reported once all patients have discontinued treatment or 
been lost to follow-up. It will be reported in an addendum to the CSR, as appropriate. 
At the time of CSR data cut-off, if patients are ongoing after 16 weeks on treatment and 
benefitting, they will continue to receive treatment in the current study until enrollment into a 
separate protocol. 


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4.3 
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 
The study population will consist of 70-90 adult patients with a diagnosis of a solid tumor or 
hematological malignancy that has been pre-identified as having ALK or ROS1 positive 
mutations, translocations, rearrangements or amplifications. Patients must have received at 
least one prior treatment for their recurrent, metastatic and/or locally advanced disease and 
have no remaining standard therapy options anticipated to result in a durable response. 
Patients must have progressive and measurable disease (per RECIST 1.1 or other appropriate 
hematological response assessment criteria) and be in need of treatment. This is a signal 
seeking study, attempting to identify additional patient populations who may benefit from 
treatment with single agent ceritinib. Tumors currently being studied under some key 
Novartis-sponsored trials will be excluded. This includes ALK+ NSCLC. Patients with ROS1 
rearranged NSCLC may be included. Additional tumor types may be excluded during the 
course of the study at the discretion of Novartis. 
Patients must not have symptomatic cardiac disease, or impairment of gastrointestinal (GI) 
function. 
 
 
 
 
Enrollment is meant to encompass solid tumors and hematologic malignancies as having ALK 
or ROS1 positive mutations, translocations, rearrangements or amplifications that may be 
inhibited by ceritinib who otherwise meet the all of the inclusion and none of the exclusion 
criteria. Though common for phase I studies, tissue-agnostic enrollment is unusual for phase 
II studies, which typically limit enrollment to one or a few well-defined tumors types. We 
expect that the study will enroll patients whose tumors have already been pre-identified to 
harbor ALK or ROS1 positive mutations, translocations, rearrangements or amplifications 
such as B-cell lymphoma, breast cancer, colorectal cancer, melanoma, ALCL and ovarian 
cancer (enrollment will not be strictly limited to those particular cancers). Patients with ROS1 
rearranged NSCLC may also be included. The total number of patients to be enrolled per 
tumor type will be based on an adaptive design. The adaptive design will be patient-sparing 
and allow the early closure of non-responding arms or arms where early success can be 
declared. 


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5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Patient has provided a signed study Informed Consent Form prior to any screening 
procedure 
2. Patient is ≥ 18 years of age on the day of consenting to the study 
3. Patient has a confirmed diagnosis of a solid tumor (except ALK+ NSCLC) or 
hematological malignancy and is in need of treatment because of radiologic progression or 
relapse. Patients with ROS1 rearranged NSCLC may be included. Additional tumor types 
may be excluded during the course of the study at the discretion of Novartis. 
4. Patient is in need of treatment because of progression or relapse defined as: 
• radiological progression for solid tumor and lymphoma 
• for hematologic malignancies, measureable progression or relapse by appropriate 
criteria (see appendices) 
5. Patient must have been pre-identified as having a tumor with an ALK or ROS1 positive 
mutation, translocation, rearrangement or amplification. The qualifying alteration must be 
assessed and reported by a CLIA-certified laboratory. ALK positivity as assessed by IHC 
or FISH are allowed. 
 
 
 
. The sample must be submitted prior to first study dose unless agreed upon 
between Novartis and the investigator. See Section 7.2.4.2.1. 
6. Patient must have received at least one prior treatment for recurrent, metastatic and/or 
locally advanced disease and for whom no standard therapy options are anticipated to 
result in a durable remission 
7. Diffuse large B cell lymphoma only: Patient has received or is ineligible for autologous 
or allogeneic stem cell transplant. This does not apply to patients with Mantle cell 
lymphoma or follicular lymphoma 
8. Patients must have measurable disease as per appropriate guidelines: 
a. Solid Tumors: by RECIST 1.1 (Appendix A) 
b. Lymphoma: Patient has at least one measurable nodal lesion (≥2 cm) according to 
Cheson criteria (Cheson 2007). In case where the patient has no measurable nodal 
lesions ≥ 2 cm in the long axis at screening, then the patient must have at least one 
measurable extra-nodal lesion (Appendix B) 
c. Symptomatic Multiple Myeloma: by International Myeloma Working Group 
(IMWG) 
• Serum M-component of ≥1 gm/dL 
• Urine M-component of ≥200 mg/24 h 
• Patients with plasmacytoma must have a definite increase in the size; a definite 
increase is defined as a 50% (and at least 1 cm) increase as measured serially by 
the sum of the products of the cross-diameters of the measurable lesion 
d. Leukemia only: Relapsed/refractory leukemia for which no standard therapy options 
are anticipated to result in a durable remission: 


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• Acute myelogenous leukemia (AML) by World Health Organization (WHO) 
classification or acute lymphoblastic leukemia (ALL) relapsed or refractory to 
standard chemotherapy; unsuitable for standard chemotherapy or unwilling to 
undergo standard chemotherapy. Philadelphia chromosome (Ph) positive ALL 
eligible if failed prior tyrosine-kinase inhibitor therapy. 
• Age > 60 years with AML not candidates for or have refused standard 
chemotherapy, excluding patients with acute promyelocytic leukemia (APL) or 
with favorable cytogenetic abnormalities [inv16, t(8;21)] 
• For patients with Chronic Myeloid Leukemia (CML) only accelerated and blast 
phase CML will be allowed 
9. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 
(Appendix M) 
10. Patient has a life expectancy of at least 16 weeks 
11. Patients must have adequate bone marrow as described below: 
a. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L (not applicable for leukemia patients) 
b. Platelets (PLT) ≥ 75 x 109/L (no platelet transfusion within past 14 days) (not 
applicable for leukemia patients) 
c. Hemoglobin (Hgb) ≥ 8 g/dl (not applicable for leukemia patients) 
12. Patient must meet the following laboratory values at the screening visit: 
• International Normalized Ratio (INR) ≤ 1.5 
• Serum amylase ≤2 x ULN 
• Serum lipase ≤ ULN 
• Alkaline phosphatase (ALP) ≤ 5.0 x ULN 
• Fasting plasma glucose ≤ 175 mg/dL (≤ 9.8 mmol/L) 
13. All patients must have adequate organ function defined as described below: 
a. Potassium, calcium (corrected for serum albumin), phosphorus and magnesium within 
normal limits (WNL). Supplementation is allowed to meet eligibility requirements 
b.  Serum creatinine < 1.5 mg/dl and/or calculated creatinine clearance (using Cockcroft-
Gault formula) ≥ 30 mL/min 
c. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3.0 x 
upper limit of normal range (ULN) or ≤ 5 x ULN if liver metastases are present 
d. Total serum bilirubin within normal range or ≤ 1.5 x ULN except for patients with 
Gilbert’s syndrome who may only be included if total bilirubin ≤ 3 x ULN or direct 
bilirubin ≤ 1.5 x ULN 
14. For Leukemia patients, peripheral blast counts < 50,000 blasts/mm3 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patients who have received prior treatment with ceritinib 
2. Patients with a known hypersensitivity to ceritinib or to its excipients (microcrystalline 
cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate) 


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3. Patients with history of carcinomatous meningitis 
4. Patients 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 
5. Patients with diarrhea CTCAE ≥ grade 2 
6. Patients with neuropathy CTCAE ≥ grade 2 
7. Patients with a history of pancreatitis or history of increased amylase or lipase that was due 
to pancreatic disease 
8. Patients with external biliary drains 
9. Patients with a history of pulmonary embolism (PE), or untreated deep venous thrombosis 
(DVT) ≤ 6 months prior to starting study drug 
Note: Patients with recent DVT who have been treated with therapeutic anti-coagulant 
agents for at least 6 weeks are eligible. 
10. Patient has history of interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis (i.e., affecting activities of daily living or 
requiring therapeutic intervention) 
11.  Clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 
months), such as: 
• Unstable angina within 6 months prior to screening 
• Myocardial infarction within 6 months prior to screening 
• History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥100 mm Hg, with or without anti-
hypertensive medication. Initiation or adjustment of antihypertensive medication (s) is 
allowed prior to screening 
• Ventricular arrhythmias 
• Supraventricular and nodal arrhythmias not controlled with medication. 
• Other cardiac arrhythmia not controlled with medication 
• Corrected QT (QTcF) >470 ms using Fridericia’s correction on the screening ECG 
12.  Patient has other severe, acute, or chronic medical conditions including uncontrolled 
diabetes mellitus or psychiatric conditions or laboratory abnormalities that, in the opinion 
of the investigator, may increase the risk associated with study participation or may 
interfere with the interpretation of study results 
13. Patients with clinical evidence of active CNS leukemia 
14. Patients who have received Allogeneic stem cell transplant and/or have active graft-versus-
host disease (GVHD) 
15. Patient has received Autologous stem cell transplant within last 4 weeks 
16. Impairment of GI function or GI disease that may significantly alter the absorption of 
ceritinib (e.g. severe ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, or small bowel resection) 


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17. Any other condition that would, in the investigator’s judgment, contraindicate patient’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures, e.g. infection/inflammation, intestinal obstruction, social/psychological 
complications 
18. Patients who have been treated with any hematopoietic colony-stimulating growth factors 
(e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or 
darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued. 
Restriction is not applicable for patients with leukemia 
19. Patient has received chemotherapy or anticancer therapy ≤ 4 weeks (6 weeks for 
nitrosourea, monoclonal antibodies or mitomycin-C) prior to starting study drug or who 
have not recovered to ≤ grade 2 from side effects of such therapy (except for alopecia and 
neuropathy). Patients with leukemia may receive therapy with hydroxyurea and/or steroids 
for the purpose of cytoreduction but must discontinue use prior to first dose of study drug. 
20. Patients who have received the last administration of an anticancer targeted small molecule 
therapy (e.g. sunitinib, pazopanib, everolimus) ≤ 2 weeks prior to starting study drug, or 
who have not recovered from the side effects of such therapy 
21. Patients not able to discontinue their current anti-cancer therapy prior to first dose of study 
drug 
22.  Patient who has received thoracic radiotherapy to lung fields ≤4 weeks prior to starting the 
study treatment or patients who have not recovered from radiotherapy-related toxicities. 
For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs) 
radiotherapy ≤2 weeks prior to starting the study treatment or has not recovered from 
radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤2 weeks prior to 
starting study treatment is allowed. 
23. Patients who have undergone major surgery (e.g., intra-thoracic, intra-abdominal, intra-
pelvic) ≤ 4weeks prior to starting study treatment or who have not recovered from side 
effects of such surgery. Video-assisted thoracic surgery (VATS) and mediastinoscopy will 
not be counted as major surgery and patients can receive study treatment  ≥ 1 week after 
these procedures 
24. Patients with another primary malignancy within 3 years prior to starting study treatment, 
with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma or 
other non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix.  
25. Patients receiving treatment with medications that meet one of the following criteria and 
that cannot be discontinued at least 1 week prior to the start of treatment with ceritinib and 
for the duration of the study: 
a. Strong inhibitors or strong inducers of CYP3A4/5 (Appendix P). 
b. Medications with a low therapeutic index that are primarily metabolized by 
CYP3A4/5 and/or CYP2C9 (Appendix P). 
c. Medication with a known risk of prolonging the QT interval or inducing Torsades de 
Pointes (Appendix P) 
26. Patients who are currently receiving treatment with warfarin sodium (Coumadin®) or any 
other coumarin-derivative anticoagulants 
27. Patients receiving unstable or increasing doses of corticosteroids. If patients are on 
corticosteroids for endocrine deficiencies or tumor-associated symptoms (non-CNS), dose 


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must have been stabilized (or decreasing) for at least 5 days before first dose of study 
treatment 
28. Patients receiving treatment with any enzyme-inducing anticonvulsant (Appendix P) 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. 
29. Cirrhosis of the liver or known hepatitis B or C infection that is either acute or is 
considered chronic because the virus did not become undetectable: 
a. Hepatitis C Virus (HCV) infection: acute or chronic infection as depicted by a positive 
HCV RNA testing (note: in a patient with known anti-HCV but with a negative test for 
HCV RNA, re-testing for HCV RNA 4-6 months later is requested to confirm the 
resolution of HCV infection) 
b. Hepatitis B Virus (HBV) infection: acute infection (HBsAg+ with or without HBeAg+ 
or detectable serum HBV DNA), HBV carriers as evidence by ongoing presence of 
HBsAg and detectable serum HBV DNA levels 
30. Patients who have received investigational agents within ≤ 5t1/2 of the agent (or ≤ 4 weeks 
when half-life is unknown) prior to starting study drug 
31. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not 
mandatory) 
32. Patient has a history of non-compliance to medical regimen 
33. Pregnant or nursing (lactating) women,  confirmed by a positive hCG laboratory test 
34. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
(defined below). Highly effective contraception must be used by both sexes (female 
patients and their male partners) during dosing and for 3 months after the last dose of study 
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 study treatment. 
Reliable double-barrier contraception method should be used and maintained throughout 
the study and for 3 months after study treatment discontinuation. 


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Women of child-bearing potential (sexually mature) who have not undergone a 
hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive 
months (i.e., who has had menses any time in the preceding 12 consecutive months), must 
have a negative serum pregnancy test ≤ 14 days prior to starting study drug. 
Post-menopausal women are allowed to participate in this study. Women are considered 
post-menopausal and not of child bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum 
FSH levels > 40 mIU/mL or have had surgical bilateral oophorectomy (with or without 
hysterectomy) at least six weeks prior to entry in the study. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment, then she will be considered not of child bearing potential. 
35. Fertile males not willing to use contraception. Fertile males must use condom with 
spermicide. Highly effective contraception, as defined above, must be used by both sexes 
(male patients and their female partners) during study treatment and for 3 months after the 
last dose of study medication and should not father a child in this period. A condom is 
required to be used also by vasectomized men in order to prevent delivery of the drug via 
seminal fluid. 
6 
Treatment 
6.1 
Study treatment 
The investigational or study drug to be used in the course of this trial is ceritinib. 
Novartis Drug Supply Management or its designee will provide ceritinib as 150 mg hard 
gelatin capsules as individual patient supply, packaged in bottles or blisters. Ceritinib will be 
dosed on a flat scale and not be adjusted to body weight or body surface area. 
6.1.1 
Dosing regimen 
Ceritinib will be dosed on a flat scale of 750 mg (e.g., 5 x 150 mg capsules) once daily on a 
continuous dosing cycle. A complete treatment cycle is defined as 28 days. There will be no 
breaks between dosing cycles (refer to Table 6-1). 
The patient must continue to meet all eligibility criteria on C1D1, as they did during the 
screening period. Refer to Section 7.1 for more details. 
Table 6-1 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or 
Regimen 
ceritinib 
Capsule for oral use 
750 mg/day (5 x 150 mg capsule) 
Daily 
Different formulations and strengths of ceritinib can be used once these are approved 
6.1.1.1 
Ceritinib administration 
The following general guidelines should be followed for administration. 


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• Patients should take ceritinib once daily at approximately the same time each day, in the 
morning, afternoon, or evening. 
• ECG monitoring: Patients should take ceritinib in the morning to accommodate clinic 
visits when ECG evaluations are conducted. 
• Patients should take ceritinib on an empty stomach (i.e., fast from food and drink, except 
water) at least 1 hour before or 2 hours after a light meal. 
• Each dose of 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 should be instructed not to make up missed doses or partial doses (i.e., when the 
entire dose is not taken as instructed). A missed or partial dose will be defined as a case when 
the full dose is not taken within 8 hours after the approximate time of the usual daily dosing. 
That day’s dose (or partial remaining dose) should be omitted, and the patient should continue 
treatment with the next scheduled dose on the following day. 
• All dosages prescribed and dispensed to the patient, and all dose changes during the study, 
must be recorded on the Dosage Administration Record eCRF. Patients must be advised to 
bring their unused ceritinib capsules/tablets to the investigative site at each visit. 
6.1.2 
Guidelines for continuation of treatment 
Patients will be treated until disease progression (as assessed by investigator per RECIST 1.1 
or appropriate hematologic response criteria) or 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). Guidance for 
continuation of study treatment in case of toxicity (e.g. dose delay and/or modification) is 
provided in Section 6.3. 
6.1.3 
Treatment duration 
Patients may continue treatment with the study drug until the patient experiences unacceptable 
toxicity that precludes further treatment, disease progression as assessed by the investigator 
(per RECIST 1.1 or appropriate hematological response assessment criteria), death and/or 
treatment is discontinued due to any other reason. The reason EOT will be recorded in the 
corresponding eCRF. 
6.2 
Dose escalation guidelines 
Not applicable. 
6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule despite maximal 
medical support (e.g. loperamide, ondasetron), dose adjustments are permitted in order to 


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allow the patient to continue the study treatment. Any changes in ceritinib administration must 
be recorded on the Dosage Administration Record eCRF. 
Ceritinib dose modification guidelines are described in Section 6.3.2. Any planned variance 
from these guidelines in the view of the patient safety must be previously discussed with the 
sponsor unless there is an urgent need for action. 
All dose modifications, interruptions or discontinuations must be based on the worst 
preceding toxicity as graded by the NCI Clinical Toxicity Criteria for adverse events (NCI-
CTCAE version 4.03). Once a dose has been reduced during a treatment cycle, re-escalation 
will not be permitted during any subsequent cycle. 
General guidelines for dose modifications for toxicities other than those listed 
in Table 6-3: 
For grade 1 and tolerable grade 2 treatment-related toxicities, patients are encouraged to 
continue at the current dose of study treatment. For intolerable grade 2 treatment-related 
toxicities, dosing should be interrupted until resolution to grade 1 or lower followed by dose 
reduction to the next dose level.  
For grade 3 or grade 4 treatment-related toxicity that is not considered by the investigator to 
be life-threatening, patients should interrupt study treatment until resolution to grade 1 or 
lower; then study treatment may continue following a dose reduction to the next dose level, if, 
in the opinion of the Investigator, the patient continues to experience clinical benefit. For any 
grade 3 or 4 treatment-related toxicity that is considered by the investigator to be life-
threatening, permanently discontinue study treatment.  
6.3.2 
Permitted study treatment adjustments for ceritinib 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose reductions 
or interruptions are permitted to manage drug-related toxicities. 
• When dose reduction is necessary, the dose of ceritinib may be reduced to 600 mg, QD. 
• If an additional dose reduction is required, ceritinib may be reduced to 450 mg, QD. 
• If an additional dose reduction is required, ceritinib may be reduced to 300 mg, QD. 
• Once the ceritinib dose is reduced it cannot be re-escalated. 
• All dose reductions should be based on the worst preceding toxicity. 
• Patients are allowed only 3 dose reductions (to 600 mg and 450 mg, and 300 mg) as 
specified in (Table 6-2). 
Table 6-2 
Ceritinib dose modifications 
Ceritinib Dose Level 
Ceritinib Dose* 
Starting dose level (0) 
750 mg po QD 
Dose level – 1 
600 mg po QD 
Dose level – 2 
450 mg po QD 
Dose level – 3 
300 mg po 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 


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6.3.3 
Criteria for interruption and re-initiation of ceritinib treatment 
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 21 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 6.3.4. 
All patients will be followed for safety until 30 days after the last dose of ceritinib. Patients 
ongoing at the time of data cutoff for the CSR for this study may continue to receive treatment 
in the current study until: 
• All patients have died or discontinued from the study 
• Another clinical study becomes available that can continue to provide ceritinib in this 
patient population and all patients ongoing are eligible to be transferred to that clinical 
study  
• At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative setting to patients who in the opinion of the 
Investigator are still deriving clinical benefit.  
The final analysis will occur at the end of the study. All available data from all patients up to 
this cut-off date will be analyzed and summarized in a final CSR. 
Table 6-3 
Ceritinib related toxicity management guidelines 
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 
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 


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Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for ceritinib 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75 x 109/L) 
Grade 2 (PLT <75 and ≥50 x 109/L) 
Maintain dose level 
Grade 3 (PLT <50 and ≥25 x 109/L) 
Omit dose until resolved to ≤ Grade 2, then: 
If resolved in ≤7 days, then maintain dose level 
If resolved in >7 days, then  1 dose level 
Grade 4 (PLT <25 x 109/L) 
Omit dose until resolved to ≤ Grade 2, then  1 dose level 
HEPATIC 
Alkaline phosphatase and/or Gamma-glutamyl transpeptidase (GGT) 
Isolated elevations of any grade 
Maintain dose level 
Total Bilirubin** 
(for patients with Gilbert Syndrome these dose modifications apply to changes in direct [conjugated] bilirubin only) 
Grade 1 (> ULN and ≤1.5 x ULN) 
Maintain dose level with liver function test (LFTs)*** 
monitored as per protocol 
Grade 2 (>1.5 and ≤3.0 x ULN) with 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 6.3.4.2 for additional follow-up) 
PANCREATIC 
Amylase and/or lipase elevations (in the absence of clinical symptoms) 
Grade 1 (> ULN and ≤1.5 x ULN) 
Maintain dose level 
Grade 2 (>1.5 - 2.0 x ULN) 
Maintain dose level 
Grade ≥3 (> 2.0 x  ULN)  
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Note: Withhold ceritinib for acute onset of new or progressive unexplained abdominal symptoms, such as severe 
pain or vomiting; perform diagnostic procedures (e.g., abdominal CT scan or ultrasound) to exclude pancreatic 
pathology.     
RENAL 
Serum creatinine 
Grade 1 (>1 and ≤1.5 x baseline; > ULN and  
≤1.5 x ULN) 
Maintain dose level 
Grade 2 (>1.5 and ≤3.0 x baseline; >1.5 and ≤3.0 
x ULN) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤7 days, then maintain dose level 
If resolved in >7 days, then  1 dose level 
Grade 3 (>3.0 x baseline; >3.0 and ≤6.0 x ULN) 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Grade 4 (>6.0 x ULN) 
Permanently discontinue patient from ceritinib 


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Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for ceritinib 
Grade 1 (> ULN and <1.5 x ULN) 
Maintain dose level 
Grade 2 (≥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 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 
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, then consider resuming ceritinib at current dose level after the 
pneumonia  resolves. 


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Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for ceritinib 
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 
Grade 3 (QTc ≥501 ms on at least two separate 
ECGs) 
Omit dose until QTc is less than 481 ms, then ↓ 1 dose level  
 
- Assess the quality of the ECG recording and the QT value 
and repeat if needed 
 
Repeat ECG in 24 hours, or less, as clinically indicated; 
continue monitoring as clinically indicated until QTc < 481 ms 
In addition:-Determine the serum electrolyte levels (in 
particular hypokalemia, hypomagnesemia). If abnormal, 
correct abnormalities before resuming study drug treatment 
- Review concomitant medication use for drugs with the 
potential to increase the risk of drug exposure related to QT 
prolongation 
- Consider collecting a time-matched PK sample and record 
time and date of last study drug intake 
 
After resumption of dosing: 
-Repeat ECGs 7 days after dose resumption for all patients 
who had therapy interrupted due to QTc ≥ 501 ms. 
Grade 4 (QTc ≥501 or >60 ms change from 
baseline and Torsades de pointes or polymorphic 
ventricular tachycardia or signs/symptoms of 
serious arrhythmia) 
Permanently discontinue patient from 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. 
* Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All dose modifications should be 
based on the worst preceding toxicity. 
** If Grade 3 or 4 hyperbilirubinemia is due to the indirect (non-conjugated) component only, and hemolysis as the 
etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and haptoglobin 
determination), then ↓ 1 dose level and continue treatment at the discretion of the Investigator. 
***LFTs include albumin, ALT, AST, total bilirubin, alkaline phosphatase and GGT 
**** Dose modifications apply to patients who experience diarrhea despite appropriate antidiarrheal medication. 
This medication should be started at the first sign of abdominal cramping, loose stools or overt diarrhea (see 
Section 6.3.4.5) 
***** Dose modifications apply to patients who experience nausea and/or vomiting despite appropriate antiemetic 
medication. This medication should be started at the first sign of nausea and/or vomiting (see Section 6.3.4.6) 


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6.3.4 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. 
Appropriate clinical experts should be consulted as deemed necessary. Further guidelines and 
recommendations for the management of specific study drug induced toxicities are provided 
in sub-sections below. 
An unscheduled visit should be performed in all cases below where toxicity monitoring is 
recommended more frequently than defined by the schedule of assessments. 
6.3.4.1 
Guidelines for the follow-up of laboratory hematologic abnormalities 
In case of any occurrence of febrile neutropenia, neutropenia ≥ grade 3, or thrombocytopenia 
≥ grade 3, laboratory tests must be performed weekly (or more frequently if clinically 
indicated) until the event resolves to ≤ grade 2. Subsequent monitoring must be performed 
every 4 weeks. See Table 6-4. 
Hematopoietic growth factors (e.g., erythropoietins, G-CSF, and GM-CSF) are not to be 
administered prophylactically. Use of these drugs should be reserved to patients with severe 
neutropenia and anemia as per the labeling of these agents. 
6.3.4.2 
Guidelines for the follow-up of laboratory liver abnormalities 
In patients with any clinically relevant laboratory liver abnormality, as defined below, hepatic 
toxicity monitoring must include ALL of the following liver function tests (LFTs): albumin, 
ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline phosphatase 
and GGT. Note: for patients with Gilbert Syndrome, total and direct bilirubin must be 
monitored, but intensified monitoring applies to changes in direct bilirubin only. 
In case of any occurrence of ALT/AST/total bilirubin increase to grade 2 the LFTs must be 
monitored weekly (or more frequently if clinically indicated) until the event resolves to ≤ 
grade 1. Thereafter monitoring must be continued every other week (or more frequently if 
clinically indicated) for two additional cycles (e.g., 8 weeks). If there is no recurrence of  
grade 2 ALT/AST/total bilirubin elevations during this period, subsequent monitoring must be 
performed every 4 weeks. For patient with liver metastasis and grade 2 AST/ALT at baseline, 
increased monitoring is required for grade 3/4 AST/ALT; follow guidelines for grade 3 or 4 
AST/ALT. 
In case of any occurrence of ALT/AST/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 4 additional cycles (e.g., 16 weeks). If there is no 
recurrence of ≥ grade 2 ALT/AST/total bilirubin elevations during this period, subsequent 
monitoring must be performed every 4 weeks. 


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Patients who discontinue ceritinib 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). 
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential DILI, and should be considered as clinically important events.  
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below: 
• For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN  
• For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation > 2.0 x ULN with R value (ALT/ALP in x ULN) < 2 in patients without 
bone metastasis, or elevation of ALP liver fraction in patients with bone metastasis. 
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to 
cholestatic or hepatocellular liver injury). 
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from 
the awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.  
• Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 
•  A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.  
• Further testing for acute hepatitis A, B, C or E infection and liver imaging (eg, biliary 
tract) may be warranted.  
• Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study.  
• Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.  
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.3.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented. 


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Refer to Table 6-4. 
6.3.4.3 
Guidelines for the follow-up of laboratory renal abnormalities 
In case of any occurrence of serum creatinine results of grade 2, tests must be performed 
weekly (or more frequently if clinically indicated) until the event resolves to ≤ grade 1. 
Subsequent monitoring must be performed every 4 weeks. 
In case of any occurrence of serum creatinine ≥ grade 3, tests must be performed twice weekly 
(or more frequently if clinically indicated) until the event resolves to ≤ grade 1. Subsequent 
monitoring must be performed every 4 weeks. See Table 6-4. 
6.3.4.4 
Guidelines for monitoring pneumonitis (interstitial lung disease) 
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 in Table 6-3. 
6.3.4.5 
Management of study treatment-induced diarrhea 
Diarrhea is among the most frequently reported AEs following treatment with ceritinib, and 
patients must therefore be closely monitored for the appearance of this AE. The investigator 
should also 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 practices and the investigator’s 
best judgment and may follow “the recommended guidelines for the treatment of cancer 
treatment-induced diarrhea” (Benson et al 2004). For example: 
• For uncomplicated diarrhea (grade 1 or 2 without complicating signs or symptoms), 
loperamide given at a standard dose (e.g., initial administration of 4 mg orally, then 2 mg 
every 2-4 hours, maximum of 16 mg/day), along with oral hydration, and dietetic 
measures should be considered. Note: complicating signs or symptoms include: moderate 
to severe cramping, decreased performance status, fever, neutropenia, frank bleeding or 
dehydration. 
• For complicated diarrhea (all grade 3 or 4, grade 1-2 with complicating signs or 
symptoms), management should involve IV fluids, and consider treatment with octreotide 
(at starting dose of 100 to 150 μg sub-cutaneous tid or 25 to 50 μg IV) and antibiotics 
(e.g., fluoroquinolone) should be given. 
Dose adaptation of ceritinib in case of treatment-related diarrhea must follow the guidelines 
presented in Table 6-3. 


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6.3.4.6 
Guidelines for the treatment of study treatment -induced nausea and 
vomiting 
Nausea and vomiting are among the most frequently reported AEs following treatment with 
ceritinib, and patients must therefore be closely monitored for the appearance of these AEs. 
The investigator should also consider/investigate potential concomitant medication-, food-, or 
comorbidity-driven causes of nausea and/or vomiting and remedy these causes if possible 
(e.g., discontinuation of concomitant medication, dietary modification, treatment of 
comorbidity). 
Individualized supportive and anti-emetic treatment should be initiated, as appropriate, at the 
first signs and/or symptoms of these AEs. In patients with vomiting, the patient should be 
monitored for signs of dehydration and instructed to take preventive measures against 
dehydration. 
Concomitant medication for the treatment of nausea and/or vomiting should follow local 
practices and the investigator’s best judgment. For moderately emetogenic drugs, such as 
ceritinib, International Guidelines for anti-emetic treatment recommend early treatment with 
5-HT3-receptor antagonists (5-HT3RAs). Section 6.4.1.2 provides additional details on anti-
emetic use. Dose adaptation of ceritinib in case of treatment related nausea and/or vomiting 
must follow the guidelines presented above in Table 6-3. 
6.3.4.7 
Guidelines for treatment of hypophosphatemia 
In the phase I study [CLDK378X2101], as of 31-Oct-2013, there were 9 cases of grade 3 
hypophosphatemia in all dose groups, one of which was a DLT that contributed to the MTD 
determination – this patient was able to continue ceritinib at the same dose. One patient in the 
750 mg group had a grade 3 hypophosphatemia that resolved after dose adjustment or 
interruption; in the remaining 8 cases, patients were able to continue therapy without dose 
modification. Hypophosphatemia was a commonly reported AE (6.3%), regardless of 
relationship to 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 with 
ceritinib. 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. 
6.3.4.8 
Guidelines for the follow-up of laboratory pancreatic abnormalities 
In case of any occurrence of lipase or amylase increase to grade 3 or 4, both lipase and 
amylase must be monitored weekly (or more frequently if clinically indicated) until the event 
resolves to ≤ grade 1 (or to baseline).  
After resumption of dosing, monitoring must be continued weekly (or more frequently if 
clinically indicated) for one additional cycle. 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 6-4. 


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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 descried in Table 6-3. 
Table 6-4 
Follow-up evaluations for selected toxicities 
Toxicity 
Follow-up evaluation* 
Investigations 
(hematologic) 
Febrile neutropenia, neutropenia or thrombocytopenia ≥ CTCAE Grade 3 
Test weekly (or more frequent) until ≤ Grade 2 
Subsequent monitoring must be performed every cycle (4 weeks) 
Investigations 
(hepatic) 
Total bilirubin/AST/ALT Grade 2: (patients with liver metastasis and grade 2 AST/ALT 
at baseline, increased monitoring required for grade 3 ALT/AST. Follow guidelines for 
grade 3 or 4 AST/ALT 
Test weekly (or more frequently) until ≤ Grade 1 
Thereafter, continue to test every 2 weeks (or more frequently) for 2 cycles (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 
Investigations (renal) 
Serum creatinine Grade 2: 
Test weekly (or more frequent) until Grade 1 
Thereafter, test every cycle (4 weeks) 
Serum creatinine ≥ Grade 3: 
Test twice weekly (or more frequent) until ≤ Grade 1 
Thereafter, test every cycle (4 weeks) 
Investigations 
(pancreatic) 
Amylase/lipase ≥ Grade 3: 
Test weekly (or more frequently) until ≤ Grade 1. After resumption of dosing, continue to 
test weekly for one additional cycle (4 weeks). If no reoccurrence of ≥ Grade 2 event, 
continue monitoring every cycle (4 weeks). 
*Note: this table refers to the evaluation schedule only. Refer to Table 6-3 for dose modifications required for 
applicable toxicities 
6.3.5 
Anticipated risks and safety concerns of the study drug 
Appropriate eligibility criteria and specific dose modification and stopping rules are included 
in this protocol. Recommended guidelines for prophylactic or supportive treatment for 
expected toxicities, including management of study-drug induced AEs, e.g., diarrhea are 
provided in Section 6.3.2. Refer to preclinical toxicity and or clinical data found in the 
[Investigator’s Brochure]. 
6.4 
Concomitant medications 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient is permitted (see Section 6.4.1 and Section 6.4.2), except as specifically prohibited 
(see Section 6.4.3). 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of study treatment. All medications including herbal/natural medications 


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(excluding study treatment and prior antineoplastic treatments and blood transfusions), 
surgeries and procedures (including physical therapy) administered within 30 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 6.4.3.6), food and 
or vitamin supplements. Patients taking chronic medications should be maintained on the 
same dose and schedule throughout the study period, if medically feasible. 
6.4.1 
Permitted concomitant therapy 
In addition to receiving the study treatment, all patients should receive best supportive care 
(BSC), as per standard local practice for the treatment of pre-existing medical conditions or 
adverse events that may arise during the study. BSC is defined as drug or non-drug therapies, 
nutritional support, physical therapy, or any other treatment alternative that the investigator 
believes to be in the patient’s best interest, but excluding other antineoplastic treatments. 
Pain medication to allow the patient to be as comfortable as possible, nutritional support or 
appetite stimulants (e.g., megestrol), and oxygen therapy and blood products or transfusions 
will be allowed unless otherwise prohibited in Section 6.4.3. 
6.4.1.1 
Bisphosphonates 
The use of bisphosphonates regardless of indication is allowed provided patients have been on 
stable doses optimally for at least 4 weeks prior to the start of treatment. Patients requiring 
initiation of bisphosphonate treatment during the course of the study should be evaluated for 
progressive disease and the result of the evaluation should be clearly documented in the 
patients’ source documentation. 
No drug-drug interaction is expected between 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. 
6.4.1.2 
Antiemetics 
Use of antiemetics is allowed. Prophylactic antiemetics should be started only once the patient 
experiences nausea or vomiting and at the discretion of the investigator. It is recommended 
that patients use drugs that do not cause QT prolongation. Note that some anti-emetics have a 
known risk for Torsade de Pointes (TdP) (Appendix P). 
6.4.1.3 
Oral antidiabetics 
Patients who develop diabetes mellitus during the study should be treated according to the 
ADA (American Diabetes Association) guidance. It is recommended to start treatment with 
glimepiride, glibenclamide or metformin. Patients receiving oral antidiabetics which are 
predominantly metabolized by CYP2C9 and CYP2C8, including but not limited to, 


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repaglinide, rosiglitazone, glipizide and tolbutamide, must be carefully monitored for 
hypoglycemia. 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
6.4.2.1 
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. If increasing 
doses of corticosteroids are required, ceritinib must be held and the corticosteroid dose 
must have been stabilized (or decreasing) for at least 5 days before ceritinib is resumed. 
6.4.2.2 
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 BYP2A6 and CYP2E1 is largely mitigated by the 
low potential for drugs metabolized by these enzymes to be co-administered with ceritinib. 
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 (Table 14-14 of Appendix P). Duration of concomitant 
treatment should be kept as short as possible, 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 (Section 6.4.3.4). 
Concomitant treatment of ceritinib with medications known to be metabolized by CYP2C9 
and CYP3A4 is allowed with caution, except for drugs which have narrow therapeutic 
index/sensitive substrates for these CYP isoforms (Section 6.4.2.2 and Table 14-14 of 
Appendix P). 
6.4.2.3 
Non-enzyme inducing anti-epileptic drugs 
Non-enzyme inducing anti-epileptic medication (Non-EIAED) is allowed. 


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6.4.2.4 
Palliative radiotherapy and surgery 
Local radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be carried 
out if required. If palliative radiotherapy is initiated after start of ceritinib 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 surgery. Ceritinib may be resumed ≥ 3 days after completing radiotherapy or minor 
surgery, and ≥ 2 weeks after major surgery. 
6.4.2.5 
Gastric protection agents 
The use of gastric protection agents including antacids, H2-antagonists, and proton pump 
inhibitors (PPIs; Table 14-14 of Appendix P) is allowed. However, PPIs should be used with 
caution due to the theoretical effects of long-acting pH elevating agents (i.e., prolonged acid 
suppression) on reducing 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). 
6.4.3 
Prohibited concomitant therapy 
6.4.3.1 
Other investigational and anti-neoplastic therapies 
Concurrent use of other investigational drugs is not permitted. 
Anticancer therapy (chemotherapy, targeted therapy, biologic or radiation therapy (that 
includes > 30% of the bone marrow reserve and surgery) other than the study treatments must 
not be given to patients while the patient is on the study medication. If such agents are 
required for a patient then the patient must be discontinued from the study. 
6.4.3.2 
Warfarin and coumadin derivatives 
Therapeutic doses of warfarin sodium or any other coumadin-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. Anticoagulants not derived from 
warfarin are allowed (eg, dabigatran, rivaroxaban, apixaban). 
6.4.3.3 
Enzyme inducing anti-epileptic drug (EIAED) 
Use of EIAEDs is not permitted. Refer to Table 14-15 of Appendix P 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 ceritinib treatment. 


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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. 
6.4.3.4 
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 study. Refer to Table 14-13 of Appendix P for a list of 
these medications. Please note that this list may not be comprehensive. 
6.4.3.5 
Medications that are CYP2C9 and CYP3A4/5 substrates with narrow 
therapeutic index 
Ceritinib is a potent inhibitor of drugs metabolized by the CYP2C9 and CYP3A4/5 in vitro. 
Because of the potential risk for drug-drug interactions, using concomitant medications 
known to be metabolized by these enzymes and that have a narrow therapeutic index is not 
permitted concomitantly with ceritinib. Refer to Table 14-13 of Appendix P and Table 14-14 
of Appendix P for a list of these medications. Please note that this list may not be 
comprehensive. 
6.4.3.6 
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 ceritinib 
treatment. 
6.4.3.7 
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. 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). 
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 PK/PD analysis suggested concentration-dependent QTc interval 
prolongation. 


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Concomitant administration of ceritinib with drugs known to have a high risk of increasing 
the QTc interval and drugs known to increase the QTc interval that are also primarily 
metabolized by CYP3A4/5 should be avoided. Concomitant use of ceritinib and any 
medication included in Table 14-16 of Appendix P titled “List of prohibited QT prolonging 
drugs” (i.e., drugs that are generally accepted by the Qtdrugs.org Advisory Board of the 
Arizona CERT to have a known risk of causing Torsades de Pointes) is not permitted. 
6.5 
Patient numbering, treatment assignment and enrollment 
6.5.1 
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. 
6.5.2 
Treatment assignment and randomization 
Not applicable. 
6.5.3 
Treatment blinding 
This is an open-label study. 
6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF. 
Patients will be provided with an adequate supply of study drug for self-administration at 
home, including instructions for administration, until at least their next scheduled study visit. 
Patients will receive ceritinib on an outpatient basis. The investigator shall provide the patient 
with instructions for ceritinib administration according to the protocol. 
6.6.1 
Study drug packaging and labeling 
Ceritinib will be supplied as 150 mg capsules (refer to Table 6-5). 
Medication labels will comply with US legal requirements and are printed in the local 
language. The label contains ceritinib identifying information (e.g., formulation, batch 
number, and expiration date), the patient number (to be entered by the investigator or 
designee) and storage conditions. 


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Table 6-5 
Packaging and labeling 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
ceritinib (LDK378) 
Capsules or tablets (150 mg) in 
bottles or blisters 
Labeled as LDK378 
Dosing frequency: once-a-day, 28 days 
6.6.2 
Drug supply and storage 
Each site will be supplied by Novartis with oral ceritinib. Study drug must be received by a 
designated person 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, ceritinib should be stored according to the instructions specified on the drug 
labels and in the [Investigator’s Brochure]. These instructions should also be made clear to the 
patient for storage and self-administration of ceritinib at home. 
Site staff will be responsible for managing adequate re-supplies for ceritinib. 
6.6.3 
Study drug compliance and accountability 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver must be captured in the source 
document at each patient visit. 
6.6.3.2 
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 Novartis or designee. 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Study drug destruction at the investigational site will only be 
permitted if authorized by Novartis in a prior agreement and if permitted by local regulations. 


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7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. The table indicates which assessments produce data to be entered into the 
database (D) or remain in source documents only (S) (“Category” column). Every effort must 
be made to follow the schedule of assessments within the ±4 days. 


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Table 7-1 
Visit evaluation schedule 
Visit Number 
Category 
Reference to 
assessment 
Screening phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent cycles 
EOT 
Safety follow 
up 
Survival FU 
1 
2 
3 
4 
5 
6 
777 
501 
701 
Cycle days1 
 
 
-28 to -1 
1 
15 
1 
15 
1 
 
EOT + 30 
(±4) days 
EOT + 
every 3 
months2 
ALL PATIENTS 
INFORMED CONSENT 
Informed consent 
D 
7.1.1 
X 
 
 
 
 
 
 
 
 
PATIENT HISTORY 
Demography 
D 
7.1.1.3 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
S 
5.2 & 5.3 
X 
 
 
 
 
 
 
 
 
Eligibility checklist 
S 
7.1.1.1 
X 
 
 
 
 
 
 
 
 
End of phase disposition 
D 
7.1.3.1 
 
 
 
 
 
 
X 
 
 
Relevant medical history/ 
current medical conditions 
D 
7.1.1.3 
X 
 
 
 
 
 
 
 
 
Diagnosis and Extent of cancer 
D 
7.1.1.3 
X 
 
 
 
 
 
 
 
 
Prior anti-neoplastic therapy 
D 
7.1.1.3 
X 
 
 
 
 
 
 
 
PHYSICAL EXAMINATION 
Physical examination 
S 
7.2.2.1 
X 
X4 
 
X 
 
X 
X 
 
 
Vital signs 
D 
7.2.2.2 
X 
X4 
 
X 
 
X 
X 
 
 


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Visit Number 
Category 
Reference to 
assessment 
Screening phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent cycles 
EOT 
Safety follow 
up 
Survival FU 
1 
2 
3 
4 
5 
6 
777 
501 
701 
Cycle days1 
 
 
-28 to -1 
1 
15 
1 
15 
1 
 
EOT + 30 
(±4) days 
EOT + 
every 3 
months2 
Height 
D 
7.2.2.3 
X 
 
 
 
 
 
 
 
Weight 
D 
7.2.2.3 
X 
X4 
 
X 
 
X 
X 
 
 
ECOG performance status 
D 
7.2.2.4 
X 
X4 
 
X 
 
X 
X 
 
 
IMAGING AND OTHER ASSESSMENTS 
Cardiac imaging (MUGA/ECHO) 
D 
7.2.2.7.2 
X 
If clinically indicated 
 
 
 
ECG 
D 
7.2.2.7.1 
X 
X4 
 
X 
 
X 
X 
 
 
LABORATORY ASSESSMENTS 
Hematology 
D 
7.2.2.5.1 
X 
X4 
X 
X 
X 
X 
X 
 
 
Biochemistry  
(including liver function tests) 
D 
7.2.2.5.2 
X 
X4 
X 
X 
X 
X 
X 
 
 
Thyroid Function 
D 
7.2.2.5.3 
X 
X4 
 
 
 
Every 3 cycles 
starting from C3D1 or 
if clinically indicated 
X 
 
 
Cardiac enzymes 
D 
7.2.2.7.3 
X 
If clinically indicated 
 
 
Coagulation 
D 
7.2.2.5.4 
X 
X4 
If clinically indicated 
 
 
 
Urinalysis 
D 
7.2.2.5.5 
X 
X4 
 
X 
 
X 
X 
 
 
Pregnancy test6 
D 
7.2.2.5.6 
X 
X4 
 
X 
 
X 
X 
 
 
SAFETY 
Prior and concomitant 
medications 
D 
6.4 
X 
Continuous 
X 
 
Surgical and medical 
procedures 
D 
6.4 
X 
Continuous 
X 
 


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Visit Number 
Category 
Reference to 
assessment 
Screening phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent cycles 
EOT 
Safety follow 
up 
Survival FU 
1 
2 
3 
4 
5 
6 
777 
501 
701 
Cycle days1 
 
 
-28 to -1 
1 
15 
1 
15 
1 
 
EOT + 30 
(±4) days 
EOT + 
every 3 
months2 
Adverse events 
D 
8.1 
X 
Continuous 
X 
 
DRUG ADMINISTRATION AND OTHERS 
ceritinib administration 
D 
6.1.1 
 
Daily 
 
 
 
Survival 
D 
7.1.4.3 
 
 
 
 
 
 
 
 
X 
ADDITIONAL EFFICACY ASSESSMENTS 
SOLID TUMOR 
Physical examination for 
measurement of superficial 
disease (only if present) 9 
D 
7.2.1.1.1 
X 
Every 8 weeks (±4 days) after first dose of 
study drug (Day 1 of every odd cycle) 
X 
 
 
Radiological tumor assessment/ 
response assessment (MRI/CT 
Scans 3, 5, 7, 8) 
D 
7.2.1.1.4 
X 
Every 8 weeks (±4 days) after first dose of 
study drug (Day 1 of every odd cycle)  
X 
 
 
Cancer Antigen-125 
(for ovarian cancer only) 
D 
7.2.1.1.2 
X 
Every 8 weeks (±4 days) after first dose of 
study drug (Day 1 of every odd cycle)  
X 
 
 
Prostate-specific antigen (PSA) 
(for prostate cancer only) 
D 
7.2.1.1.3 
X 
Every 8 weeks (±4 days) after first dose of 
study drug (Day 1 of every odd cycle)  
X 
 
 
LYMPHOMA 
Examination for enlarged spleen 
or liver 
D 
7.2.1.2.1 
X 
To confirm response of CR 
X 
 
 
Physical examination for 
measurement of superficial 
disease and B symptoms 9 
D 
7.2.1.2.2 
X 
Day 1 of every cycle (±4 days) after first 
dose of study drug 
X 
 
 


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Visit Number 
Category 
Reference to 
assessment 
Screening phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent cycles 
EOT 
Safety follow 
up 
Survival FU 
1 
2 
3 
4 
5 
6 
777 
501 
701 
Cycle days1 
 
 
-28 to -1 
1 
15 
1 
15 
1 
 
EOT + 30 
(±4) days 
EOT + 
every 3 
months2 
Radiological tumor assessment/ 
response assessment (MRI/CT 
Scans 3, 5, 7, 8) 
D 
7.2.1.2.3 
X 
Every 8 weeks (±4 days) after first dose of 
study drug (Day 1 of every odd cycle)  
X 
 
 
Bone Marrow Biopsy or aspirate 
D 
7.2.1.2.4 
 
To confirm response of CR10 
 
 
 
Serum protein electrophoresis 
(SPEP) 
D 
7.2.1.2.5 
X 
Every 8 weeks (±4 days) after first dose of 
study drug (Day 1 of every odd cycle) only if 
abnormal M-protein detected at baseline 
X 
 
 
PET Scan 
D 
7.2.1.2.6 
 
To confirm response of CR (can be part of 
CT/PET) 
 
 
 
SYMPTOMATIC MULTIPLE MYELOMA 
Skeletal Survey 
D 
7.2.1.3.1. 
X 
If clinically indicated 
 
 
 
Urine protein electrophoresis 
(UPEP)7 
D 
7.2.1.3.2. 
X 
Every 8 weeks (±4 days) after first dose of 
study drug (Day 1 of every odd cycle)  
X 
 
 
Free light chain7 
D 
7.2.1.3.3. 
X 
Every 8 weeks (±4 days) after first dose of 
study drug (Day 1 of every odd cycle)  
X 
 
 
Serum protein electrophoresis 
(SPEP)7 
D 
7.2.1.3.4. 
X 
Every 8 weeks (±4 days) after first dose of 
study drug (Day 1 of every odd cycle) 
X 
 
 
MRI/CT Scans (For 
plasmacytoma Only) 
D 
7.2.1.3.5. 
X 
Every 8 weeks (±4 days) after first dose of study drug 
(Day 1 of every odd cycle)  
 
 
Bone Marrow Biopsy or aspirate 
D 
7.2.1.3.6. 
X 
To confirm response of CR 
 
 
 
Chronic Lymphocytic Leukemia (CLL) 
Examination for enlarged spleen 
or liver 
D 
7.2.1.2.1 
X 
To confirm response of CR 
 
 


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Visit Number 
Category 
Reference to 
assessment 
Screening phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent cycles 
EOT 
Safety follow 
up 
Survival FU 
1 
2 
3 
4 
5 
6 
777 
501 
701 
Cycle days1 
 
 
-28 to -1 
1 
15 
1 
15 
1 
 
EOT + 30 
(±4) days 
EOT + 
every 3 
months2 
Physical examination for 
measurement of superficial 
disease and B symptoms 9 
D 
7.2.1.2.2 
X 
Day 1 of every cycle (±4 days) after first 
dose of study drug 
X 
 
 
Radiological tumor assessment/ 
response assessment (MRI/CT 
Scans 3, 5, 7, 8) 
D 
7.2.1.2.3 
X 
Every 8 weeks (±4 days) after first dose of 
study drug (Day 1 of every odd cycle)  
X 
 
 
Bone Marrow Biopsy or aspirate 
D 
7.2.1.2.4 
 
To confirm response of CR  
 
 
 
Peripheral Blood for CBC 
differential and blast count 
D 
7.2.1.4.1 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical examination for 
assessment of Extramedullary 
disease or Organomegaly (if 
present) 
D 
7.2.1.4.3 
X 
X 
X 
X 
X 
X 
X 
 
 
LEUKEMIA, MDS, MF, PV and ET 
Peripheral Blood for CBC 
differential and blast count 
D 
7.2.1.4.1 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical examination for 
assessment of Extramedullary 
disease or Organomegaly (if 
present) 
D 
7.2.1.4.3 
X 
X 
X 
X 
X 
X 
X 
 
 
Bone Marrow Biopsy or aspirate 
D 
7.2.1.4.2 
X 
To confirm response of CR or if clinically 
indicated 
 
 
 
Assessments of chromosomal 
abnormalities/Karyotype 
S 
7.2.1.4.4 
X11 
 
 
 
 
 
 
 
 


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Visit Number 
Category 
Reference to 
assessment 
Screening phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent cycles 
EOT 
Safety follow 
up 
Survival FU 
1 
2 
3 
4 
5 
6 
777 
501 
701 
Cycle days1 
 
 
-28 to -1 
1 
15 
1 
15 
1 
 
EOT + 30 
(±4) days 
EOT + 
every 3 
months2 
Evaluation of transfusion 
dependency 
D 
7.2.1.4.5 
X 
X 
X 
X 
X 
X 
X 
 
 
1 A complete cycle is defined as 28 days. 
2 Additional survival assessments may be performed outside the 3 months follow-up schedules if a survival update is required for an interim assessment to meet safety or 
regulatory needs. 
3 Tumor assessments at EOT are required for patients who discontinue study treatment before the first scheduled post-screening tumor assessment and for patients 
whose previous tumor assessment did not demonstrate PD and was done at least 8 weeks (± 4 days) prior to end of treatment visit. 
4 These assessments should be performed only if the screening assessment occurred > 4 days from Cycle 1 Day 1. The patient must continue to meet all eligibility criteria 
on C1D1, as they did during the screening period prior to first dose. 
5 Tumor assessments include CT/MRI of the chest abdomen and pelvis at all timepoints. Tumor assessments are described in Section 7.2.1 
6 Women of childbearing potential must undergo a serum pregnancy test at screening and EOT. Women of child-bearing potential will undergo a monthly urine pregnancy 
tests during the study. 
7 For patients who have a response of PR or greater, a confirmation assessment must be performed at least 4 weeks after the initial observation. 
8 The frequency of disease assessment may be reduced to every 12 weeks for patients who have at least 4 post baseline disease assessments and are clinically stable. 
9 Skin lesions should be documented using a digital camera (color photography) in clear focus showing the ruler or calipers and the corresponding measurement in such a 
way that the size of the lesion(s) can be determined from the photograph 
10 Only to confirm complete responses in patients with bone marrow tumor involvement prior to study treatment 
11 Information on the patient’s chromosomal abnormalities/karyotyping based on documented history prior to study entry must be present in his/her source documents. 
Additional testing to confirm these response categories will not be required and should be done at the discretion of the attending physician 
 
 
 
 
 


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7.1.1 
Screening 
For the purpose of this study, genomic profiling is not considered part of screening. This 
study is intended for patients who have already had genomic profiling of their tumors in a 
CLIA certified laboratory 
 
 Eligibility is based on 
 study as assessed in the 
local, CLIA certified laboratory. The results of this testing must be known prior to signing the 
ICF and before formal screening begins. Laboratory results must be ‘unambiguous’ or 
‘unequivocal’. Results that state ‘ambiguous’ or ‘equivocal’ imply low probability that 
genetic deregulation is truly present and an important driver of patient’s tumor. Written 
informed consent must be obtained before any study specific assessments are performed, 
including screening. All screening evaluations must be performed as closely as possible to the 
beginning of treatment and never more than 28 days prior to starting study drug dose of 
ceritinib to confirm patient’s eligibility. 
Upon signing the Informed Consent Form (ICF), a patient will be assigned a 7-digit patient 
number. 
 
 
 
 
 
An archival or fresh tumor sample may not be required if the patient has had their genomic 
profiling performed at the same laboratory that will be used for confirmatory analysis, and the 
patient consents to allow Novartis to use that data as their baseline molecular analysis results. 
 
 
 
ALK positivity as assessed by IHC or FISH are 
allowed. 
Patients who fail to start on treatment may be re-screened. 
Disease assessments (per RECIST 1.1 or appropriate hematologic response criteria) must be 
performed within 28 days prior to enrollment and will be assessed locally by the investigator. 
When information from procedures (for example imaging assessments) that may have been 
previously performed as part of the patient’s routine disease care (prior to enrolling in the 
trial) is allowed to be used to satisfy inclusion criteria, if it was performed <28 days before the 
start of study treatment. 
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted for screening results out of the defined range. If the repeated 
laboratory result meets the criteria, that result may be used to determine eligibility. If the 
repeated laboratory result does not meet the criteria, the patient will be considered a screening 
failure. 


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For details of assessments, refer to Table 7-1 and Section 7.2. 
7.1.1.1 
Eligibility screening 
Subject’s mutational status will be confirmed by Novartis or designee prior to the subject 
receiving the first dose of study drug. 
7.1.1.2 
Information to be collected on screening failures 
Patients who sign the ICF, but are not enrolled for any reason will be considered a screen 
failure. A patient who is enrolled but does not start treatment is not considered a screen 
failure. 
For screen failure patients, the reason for not proceeding with enrollment will be entered on 
the Screening Log eCRF. No waivers will be granted. 
The following eCRFs must be completed for screening failure patients: 
• Screening Log eCRF page (including reason for not being started on treatment) 
• Informed Consent 
• Demography 
• Serious Adverse Event after signing the ICF - see Section 8 for SAE reporting details. 
7.1.1.3 
Patient demographics and other baseline characteristics 
Patient information to be collected at screening will include: 
• 
 
• Demographic data (age, gender, race) 
• Diagnosis and Extent of Cancer 
• Relevant Medical History (e.g., important medical, surgical, and allergic conditions from 
the patient’s medical history, which could have an impact on the patient’s 
evaluation)/Current Medical Conditions (e.g., all relevant current medical conditions 
which are present before the first dose of study drug is administered). 
• Cancer-related conditions and symptoms which are recorded on the Medical History 
eCRF should include the grade 
• Prior Anti-neoplastic Medications 
• Prior Anti-neoplastic Radiotherapy 
• Prior Anti-neoplastic Surgery 
• All other medications and non-drug therapies (including physical therapy, oxygen and 
blood transfusions) administered to the patient within 28 days prior to the first dose of 
study drug) must be reported on the appropriate eCRFs 
• Furthermore the following assessments will be performed to assess the eligibility of the 
patient: 
• Physical Examination (See Section 7.2.2.1) 
• Vital signs (See Section 7.2.2.2) 
• Height, weight (See Section 7.2.2.3) 


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• ECOG performance status (See Section 7.2.2.4) 
• Laboratory evaluations (e.g., hematology, coagulation, biochemistry, urinalysis, liver 
function monitoring) (See Section 7.2.2.5) 
• 
 
• Serum pregnancy (See Section 7.2.2.5.6) 
• Cardiac assessment (See Section 7.2.2.7) 
• Disease evaluations (See Section 7.2.1) 
• Radiological assessments (e.g., CT scan) if clinically indicated (See Section 7.2.1) 
7.1.2 
Treatment period 
Patients will be treated with ceritinib (750 mg, orally, once-a-day,) until disease progression, 
unacceptable toxicity, death or discontinuation from the study treatment due to any other 
reason. 
For details of safety and efficacy assessments, refer to Table 7-1 and Section 7.2. 
• Visits and associated assessments that occur ± 4 days from the scheduled date (except for 
cycle 1 Day1 where no visit window is allowed) will not constitute protocol deviations. 
• The cycle length is 28 days. Day 1 of subsequent cycles will be calculated from cycle 1, 
day 1. 
• Disease Assessments (per RECIST or appropriate hematological response criteria) must 
be performed every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd 
cycle), until disease progression or end of treatment, whichever occurs first. The 
frequency of disease assessment may be reduced to every 12 weeks for patients who have 
at least 4 post-baseline disease assessments and are clinically stable (except AML 
patients). 
• Laboratory assessments performed as part of the screening evaluations and within 4 days 
of the first dose of study treatment, are not required to be repeated on the first dosing day. 
• 
 
  
7.1.3 
End of treatment visit, including premature withdrawal and study 
discontinuation visit 
7.1.3.1 
End of treatment (EOT) visit 
Patients who completely discontinue study treatment should be scheduled for an End of 
Treatment (EOT) visit within 7 days following the date study treatment is permanently 
discontinued, at which time all of the assessments listed for the EOT visit will be performed. 
For details of assessments, refer to Table 7-1. If the decision to withdraw the patient occurs at 
a regularly scheduled visit, that visit may become the EOT visit rather than having the patient 
return for an additional visit. 
An End of Treatment Phase Disposition eCRF page should be completed, giving the date and 
reason for stopping the study treatment. If a study withdrawal occurs, or if the patient fails to 


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return for visits, the investigator must determine the primary reason for a patient’s premature 
withdrawal from the study and record this information on the End of Treatment Phase 
Disposition eCRF page. 
End of treatment/Premature withdrawal visit is not considered as the end of the study. 
For patients with a best response of SD or better who discontinued study treatment due to 
disease progression, an optional tumor sample should be obtained for genomic analysis.  
 
 
 
 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following 
the last dose of study treatment. 
7.1.3.2 
Criteria for premature patient withdrawal (EOT phase completion) 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator or by the sponsor at any time. 
Premature patient withdrawal refers to the point/time when the patient exits from the study 
treatment prior to the planned completion of all study treatment administration and/or 
assessments; at this time, all study drug treatment is discontinued and no further assessments 
are planned, unless the patient will be followed for progression and/or survival. 
Patients may be withdrawn from the study treatment if any of the following occur: 
• Adverse Event 
• Lost to follow-up 
• Non-compliance with study treatment 
• Physician decision 
• Pregnancy 
• Progressive Disease 
• Protocol deviation 
• Study terminated by sponsor 
• Subject/guardian decision 
• Death 
• In addition to the general withdrawal criteria, the following study specific criteria will 
also require study treatment discontinuation: 
• Adjustments to study treatment that result in discontinuation. Please refer to Section 
6.3 
• Use of prohibited medication. Please refer to Section 6.4.3 


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7.1.4 
Follow up period 
7.1.4.1 
Safety follow up 
All patients who discontinue study treatment, including those who refuse to return for a final 
visit, will be contacted for safety evaluations (i.e., assessment of AEs and/or SAEs, 
concomitant medications) for 30 days after the last dose of study treatment. Patients whose 
treatment is interrupted or permanently discontinued due to an adverse event, including 
abnormal laboratory value, must be followed at least once a week for 4 weeks and 
subsequently at 4-weeks intervals until resolution or stabilization of the event, whichever 
comes first. 
If patients refuse to return for safety evaluation visits or are unable to do so, every effort 
should be made to contact them by telephone to determine their status. Attempts to contact the 
patient should be documented in the source documents (e.g., dates of telephone calls, 
registered letters, etc.). 
7.1.4.2 
Efficacy follow-up 
Not applicable. 
7.1.4.3 
Survival follow-up 
Survival information will be collected every 3 months until 2 years after the last patient has 
enrolled in the study regardless of treatment discontinuation reason (except if consent is 
withdrawn). If the study primary efficacy endpoint is not met, Novartis may decide not to 
conduct survival follow-up for the study. Additional survival assessments may be performed 
outside the 3 months follow-up schedules if a survival update is required for an interim 
assessment to meet safety or regulatory needs. 
Survival information can be obtained via phone, and information will be documented in the 
source documents and relevant eCRFs. 
7.1.4.4 
Lost to follow-up 
Patients lost to follow up should be recorded as such in the eCRFs. 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. 
7.1.5 
End of post-treatment follow-up (Study phase completion) 
Not applicable. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
The primary efficacy endpoint is clinical benefit rate as defined in Section 10.4. The key 
secondary efficacy endpoint is overall response rate of PR or greater as defined in Section 
10.5. Other secondary endpoints are time from the date of first dose to the date of first 


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documented disease progression or relapse or death due to any cause, time from the date of 
first dose to the date of death due to any cause, time from the first documented response to the 
date first documented disease progression or relapse or death due to any cause, AE rate, and 
other safety measurements as defined in Section 10. The local investigator’s assessment will 
be used for the analysis and for treatment decision making. 
Clinical suspicion of disease progression at any time will require assessment and confirmation 
to be performed promptly, rather than waiting for the next scheduled tumor assessment. In 
case of an unscheduled or delayed tumor assessment for any reason, subsequent disease 
assessments must be performed according to the originally planned schedule from baseline. 
7.2.1.1 
Solid Tumors 
Response will be evaluated, using modified Response Evaluation Criteria in Solid Tumors, 
based on RECIST 1.1. For complete details, refer to Appendix A. 
Clinical evaluation and tumor assessments will be performed as is indicated in Table 7-1, 
based on physical examination and radiological evaluation. For solid tumors, an assessment of 
CR or PR using RECIST 1.1 must be confirmed at least 4 weeks after initial observation. If 
the two assessments differ, the best overall response will be determined as outlined in Table 
14-5 of Appendix B. 
Any lesion that has been previously treated with radiotherapy should be considered as a non-
target lesion. However, if a lesion previously treated with radiotherapy has clearly progressed 
since the radiotherapy, it can be considered as a target lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
Definitions for measurable and non-measurable lesions, and criteria for response, should be 
based on RECIST 1.1 (Appendix A). 
7.2.1.1.1 Physical examination for superficial disease 
Clinical assessment of any existing superficial lesions (skin nodules and palpable lymph 
nodes) at screening and at each subsequent tumor assessment must be performed on the same 
schedule as radiological tumor assessments (see Section 7.2.1.1.4). 
Skin lesions should be documented using a digital camera (color photography) in clear focus 
showing the ruler or calipers and the corresponding measurement in such a way that the size 
of the lesion(s) can be determined from the photograph. Skin photographs should be 
continued at subsequent tumor assessments for any lesions that were photographed at 
screening. 
7.2.1.1.2 Cancer Antigen-125 (CA-125) 
Cancer Antigen-125 (CA-125) will be used in the assessment of ovarian cancer at screening. 
Subsequent tumor assessments must be performed on the same schedule as radiological tumor 
assessments (see Section 7.2.1.1.4). 


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7.2.1.1.3 Prostate Specific Antigen (PSA) 
Prostate Specific Antigen (PSA) will be used in the assessment of prostate cancer at 
screening. Subsequent tumor assessments must be performed on the same schedule as 
radiological tumor assessments (see Section 7.2.1.1.4). 
7.2.1.1.4 Radiological tumor assessment 
At screening and at each subsequent tumor assessment, all patients must have a CT scan with 
contrast of the Chest/Abdomen and Pelvis. If a patient is known to have a contraindication to 
CT contrast media or develops a contraindication during the trial, a non-contrast CT of the 
chest (MRI is not recommended due to respiratory artifacts) plus a contrast-enhanced MRI (if 
possible) of abdomen and pelvis should be performed. 
The same type of CT scan used at screening must be used for all subsequent assessments. 
MRI with contrast will be allowed only in those cases when CT scan cannot be performed and 
will be used at baseline and all subsequent assessments in these patients. No modality change 
would be allowed during the study when assessing overall tumor status. For subsequent scans 
in the same patient, the radiologist must account for all lesions that were present at screening 
and must use the same technique as used at screening. If possible, a single radiologist should 
perform all tumor response evaluations for an individual patient. Only in exceptional cases 
when during the study a patient develops intolerance to the CT scan contrast medium, a CT 
scan without contrast will be acceptable to avoid modality change. At screening, tumor 
assessments should preferably be performed ≤ 4 days prior to the first dose of ceritinib, 
however tumor assessments ≤ 28 days prior to first dose of study drug will be acceptable. 
Tumor assessments will be performed at screening and every 8 weeks (±4 days) after first 
dose of study drug (Day 1 of every odd cycle). The frequency of disease assessment may be 
reduced to every 12 weeks for patients who have at least 4 post-baseline disease assessments 
and are clinically stable. 
7.2.1.2 
Lymphoma 
Response will be evaluated, using modified criteria for malignant lymphoma Cheson 
(Appendix B) and Ann Arbor Staging Classification (Appendix C). 
Clinical evaluation and tumor assessments will be performed periodically, as is indicated in 
Table 7-1, based on evaluation of spleen and liver, physical examination for superficial 
disease and B symptoms, radiological evaluation, Serum Protein electrophoresis (SPEP), core 
bone marrow biopsy (only to confirm complete responses in patients with bone marrow tumor 
involvement prior to study treatment), and positron emission tomography (PET) (only to 
confirm complete responses in patients where PET was used for study entrance). 
7.2.1.2.1 Enlarged spleen and liver 
The presence of enlarged spleen or liver before start of treatment on the basis of CT scan (or 
MRI scan) should be recorded on the corresponding eCRF at baseline, and reassessed if the 
patient has a radiological CR. 


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A maximum four of the largest dominant measurable nodules representing all involved 
anatomic locations should be selected as splenic and hepatic index lesions to be measured. 
All other splenic or hepatic nodules (both measurable and non-measurable) are considered as 
non-index lesions. 
7.2.1.2.2 Physical examination for superficial disease and B symptoms 
Tumor assessment by physical examination and evaluation of disease related B symptoms 
(unexplained fever of ≥ 38°C; unexplained, recurrent drenching night sweats; or unexplained 
loss of >10% body weight within the previous 6 months) will be performed at screening and 
day 1 of every cycle (±4 days) after first dose of study drug. Refer to Appendix B for 
specifications and measurement. 
Skin lesions should be documented using a digital camera (color photography) in clear focus 
showing the ruler or calipers and the corresponding measurement in such a way that the size 
of the lesion(s) can be determined from the photograph. Skin photographs should be 
continued at subsequent tumor assessments for any lesions that were photographed at 
screening. 
7.2.1.2.3 Radiological tumor assessment 
Tumor assessments will be performed at screening, and every 8 weeks (±4 days) after first 
dose of study drug (Day 1 of every odd cycle), until disease progression or end of treatment, 
whichever occurs first. The frequency of disease assessment may be reduced to every 12 
weeks for patients who have at least 4 post-baseline disease assessments and are clinically 
stable. 
At screening and at each subsequent tumor assessment, all patients must have a CT scan with 
contrast of the Chest/Abdomen and Pelvis. If a patient is known to have a contraindication to 
CT contrast media or develops a contraindication during the trial, a non-contrast CT of the 
chest (MRI is not recommended due to respiratory artifacts) plus a contrast-enhanced MRI (if 
possible) of abdomen and pelvis should be performed. 
MRI with contrast will be allowed only in those cases when CT scan cannot be performed and 
will be used at baseline and all subsequent assessments in these patients. No modality change 
would be allowed during the study. when assessing overall tumor status. For subsequent scans 
in the same patient, the radiologist must account for all lesions that were present at screening 
and must use the same technique as used at screening. If possible, a single radiologist should 
perform all tumor response evaluations for an individual patient. Only in exceptional cases 
when during the study a patient develops intolerance to the CT scan contrast medium, a CT 
scan without contrast will be acceptable to avoid modality change. At screening, tumor 
assessments should preferably be performed ≤ 4 days prior to the first dose of ceritinib, 
however tumor assessments ≤ 28 days prior to first dose of study drug will be acceptable. 
All patients should have at least one site of measurable nodal disease > 2.0 cm in the longest 
transverse diameter and clearly measurable in at least two perpendicular dimensions, as 
determined by CT scan (MRI is allowed only if CT scan cannot be performed). Complete 
guidance for selecting index lesions is provided in Appendix A. Index lesions will be 
measured and recorded at baseline and during the course of the study. They should be selected 


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on the basis of their size and suitability for accurate repeat measurements. Skin lesions, if the 
area is ≥ 2 cm in at least one diameter, must be histologically confirmed for lymphoma 
involvement (the site must document the histological confirmation (yes or no) to the 
corresponding eCRF) and photographed (color photography using digital camera). 
A sum of the product of diameters (SPD) for lesions measured prior to study treatment will be 
calculated and reported at cycle 1 day 1. 
Conventional CT and MRI should be performed with contiguous cuts of 7.5 mm or less in 
slice thickness. Spiral CT should be performed using a 5 mm or less contiguous 
reconstruction algorithm (this specification applies to tumors of the chest, abdomen and 
pelvis). 
If a very small lesion cannot be reliably measured because of its size, it is recommended to 
enter the minimum lesion size (i.e., 5 mm for spiral CT). In other cases where the lesion 
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. 
Any measurable extranodal lesions (organs other than lymph nodes) that resolves from 
baseline (disappear completely) must be assigned a size of 0 mm when documenting on the 
corresponding eCRFs. An extranodal lesion must be ≥ 1 cm x 1 cm to be considered 
measurable. Refer to Appendix A for complete reporting guidelines. 
7.2.1.2.4 Bone marrow assessment 
Information on the patient’s bone marrow involvement based on documented history prior to 
study entry must be present in his/her source documents. Prior tumor bone marrow 
involvement should be entered on the corresponding eCRF. 
Core bone marrow biopsy or aspirate will not be performed at screening but is required to 
confirm complete responses (at the first occurrence of radiological and clinical evidence of 
CR) in patients with bone marrow tumor involvement prior to study treatment who achieve 
Complete Response based on clinical and radiological evidence. The biopsy sample on which 
this determination is made must be adequate (with a goal of > 20 mm unilateral core). Bone 
marrow biopsy or aspirate should be obtained no later than at the next visit immediately 
following clinical and radiological evidence of CR (i.e. < 28 days ± 7 days from the date of 
the radiological assessment, on which the CR is based on). 
7.2.1.2.5 Serum Protein electrophoresis (SPEP) 
Serum protein electrophoresis (SPEP) will be performed by the local laboratory at screening 
and on the same schedule as radiological tumor assessments (see Section 7.2.1.2.3) only if 
abnormal M-protein is detected at screening. 
7.2.1.2.6 Positron emission tomography (PET) 
The use of Positron emission tomography (PET) is not standard in Novartis Oncology 
Lymphoma studies. PET evaluations that have been done as standard of care prior to 
enrollment will be recorded in the eCRF. Repeat PET will be required only for patients who 


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have responses of CR for the purpose of this study and should be done within +/- 7 days of the 
CT or MRI to confirm CR. Refer to Appendix B for lesion measurements. 
7.2.1.3 
Symptomatic multiple myeloma 
Response will be evaluated using the International Myeloma Working Group (IMWG) 
Uniform Response Criteria for Multiple Myeloma. For complete details, refer to Appendix N. 
Clinical evaluation and disease assessments will be performed periodically, as is indicated in 
Table 7-1, based on a skeletal survey Urine protein electrophoresis (UPEP), Free light chain, 
Serum Protein electrophoresis (SPEP), bone marrow biopsy, and MRI/CT Scans (For 
plasmacytoma only). 
7.2.1.3.1 Skeletal survey 
Skeletal survey will be performed at screening and if clinically indicated as outlined in Table 
7-1. 
7.2.1.3.2 Urine protein electrophoresis (UPEP) 
Urine protein electrophoresis (UPEP) will be performed by the local laboratory at screening, 
every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd cycle) and EOT. 
7.2.1.3.3 Free Light Chain 
Free Light Chain will be performed by the local laboratory at screening and on the same 
schedule as UPEP assessments (see Section 7.2.1.3.2). 
7.2.1.3.4 Serum protein electrophoresis (SPEP) 
Serum protein electrophoresis (SPEP) will be performed by the local laboratory at screening 
and on the same schedule as UPEP assessments (see Section 7.2.1.3.2). 
7.2.1.3.5 MRI/CT scans (for plasmacytoma only) 
For patients with plasmacytoma, a MRI/CT scan will be performed by the local laboratory at 
screening and on the same schedule as UPEP assessments (see Section 7.2.1.3.2). 
7.2.1.3.6 Bone marrow assessment 
Information on the patient bone marrow involvement prior to study entry must be present in 
his/her source documents. Prior tumor bone marrow involvement should be entered on the 
corresponding eCRF. 
Core bone marrow biopsy is required to confirm Complete Responses (at the first occurrence 
of radiological and clinical evidence of CR) in patients with bone marrow tumor involvement 
prior to study treatment who achieve Complete Response based on clinical and radiological 
evidence. The biopsy sample on which this determination is made must be adequate (with a 
goal of > 20 mm unilateral core). Bone marrow biopsy should be obtained no later than at the 
next visit immediately following clinical and radiological evidence of CR (i.e. < 28 days ± 7 
days from the date of the radiological assessment, on which the CR is based on). 


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7.2.1.4 
Leukemia 
Response for AML will be evaluated using the revised recommendations of the International 
Working Group (IWG) as noted in Cheson 2003 (Appendix E). Response for ALL will be 
evaluated using guidelines adapted from NCCN Guidelines Version 2.2012 (Appendix F). 
CML will be evaluated using guidelines adapted from NCCN Guidelines Version 3. 2013 
(Appendix G). The response for CLL will be evaluated using the revised recommendation of 
the IWG as noted in Hallek 2008 (Appendix H). The response for myelodysplasia (MDS) will 
be evaluated using the revised recommendation of the IWG as noted in Cheson 2005 
(Appendix L). The response for polycythemia vera (PV) and essential thrombocythemia (ET) 
will be evaluated using the recommendation of IWG-MRT as noted in Barosi 2013  
(Appendix J and Appendix K respectively). The response for myelofibrosis (MF) will be 
evaluated using IWG-MRT as noted in Tefferi 2013 (Appendix I). 
Clinical evaluation and disease assessments for AML, ALL, CML, MDS, PV, ET, and MF 
will be performed periodically, as is indicated in Table 7-1, based on peripheral blood and 
bone marrow assessment as well as the presence or absence of extramedullary disease, and 
organomegaly, and evaluation of transfusion dependency. 
Clinical evaluations and disease assessments for CLL will be performed periodically as is 
indicated in Table 7-1, based on the lymphoma schedule for evaluation of physical 
examination for superficial disease and B symptoms, radiological evaluation, core bone 
marrow biopsy (only to confirm complete responses in patients with bone marrow tumor 
involvement prior to study treatment) and Rai staging criteria (Appendix D). Peripheral blood, 
and the presence or absence of extramedullary disease and organomegaly will also be 
performed on the same schedule as other leukemia evaluations as indicated below. 
To assess response, the time interval between bone marrow and blood assessments may not 
exceed 5 days. If the time interval is more than 5 days, response status cannot be assessed at 
that time point. Regular bone marrow assessments are not required after achieving a CR 
unless indicated by blood counts or clinical assessments or specified in the protocol. 
The response assessment date is defined as the last of all dates of measurements which are 
required to qualify for a response category within the period listed above. This rule applies 
also in case of multiple measurements of the same variable. In case of relapse, the first of all 
measurement dates associated with a disease assessment will be used as assessment date. The 
assessment date will be used for the derivation of the time-to-event endpoints. 
7.2.1.4.1 Peripheral blood evaluation for CBC 
Peripheral blood evaluations will be performed by the local laboratory at screening, Day 1 and 
Day 15 of Cycles 1 and 2, at Day 1 of each subsequent cycle, and at EOT. 
Peripheral blood evaluation for CBC will be taken from the same sample and include 
evaluation of blast, neutrophil, and platelet cell count. 
7.2.1.4.2 Bone Marrow assessment 
Bone marrow will be assessed for blast cell count at screening, to confirm response of CR or 
if clinically indicated. 


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Percent blast cell count will be determined by cytological examination. This assessment can 
be performed in terms of bone marrow aspirate and/or biopsy. Results from these tests are 
considered to be interchangeable to assess blasts counts. In case both aspirate and biopsy were 
done, both tests will be considered for response assessment: 
• In case of only one assessment with non-missing values: Data of the non-missing test 
result will be used. 
• In case of both assessments with differing, non-missing data: For blast counts, the highest 
value will be considered. For Auer rods, the positive finding will be considered, if 
applicable 
7.2.1.4.3 Physical examination for Extramedullary disease and/or organomegaly 
Extramedullary involvement (CNS and/or soft tissue) is to be assessed at each visit for 
response assessment. Presence with specification of location or absence of extramedullary 
disease is to be captured in the eCRF. Extramedullary disease is to be assessed via clinical 
examination or relevant imaging techniques as clinically appropriate. 
In case of extramedullary disease at baseline or (re-)appearance during the study, the lesions 
need be confirmed cytologically if technically and/or clinically feasible. A clinical assessment 
will be made in case a cytological confirmation is not possible. 
The presence of organomegaly (hepatomegaly and/or splenomegaly) is to be assessed at 
baseline at visits as part of the response assessment. The modality used: scan or palpation is to 
be noted. 
7.2.1.4.4 Assessments of chromosomal abnormalities 
Information on the patient’s chromosomal abnormalities/karyotyping based on documented 
history prior to study entry must be present in his/her source documents. Additional testing to 
confirm these response categories will not be required and should be done at the discretion of 
the attending physician. 
7.2.1.4.5 Evaluation of transfusion dependency 
Transfusion dependency will be assessed at screening as well as during the course of the trial 
for all patients. Transfusion of blood products will be recorded in a separate module of the 
eCRF. The type and reason for transfusion, start and end date as well as the number of units 
will be captured at each visit with hematologic assessment. 
A period of one week without any transfusion has been taken as a convention to define the 
status of transfusion independence to assess response. Any sample of peripheral blood which 
was taken within seven days after a transfusion will be considered as transfusion dependent. 
For the definition of transfusion dependency, it does not matter which type of blood product 
was transfused. Moreover, the rules and time windows defined below apply not only to blood 
transfusions but also to erythropoietin, thrombopoietic agents and/or myeloid growth factors. 


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7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing physical examination, vital signs, weight, performance 
status evaluation, ECG, cardiac imaging, laboratory evaluations as well as collecting all 
serious and non-serious Adverse Events (AE). For details on AE collection and reporting, 
please refer to Section 8.1. 
Clinically significant findings that were present prior to the signing of informed consent must 
be included in the Relevant Medical History/Current Medical Conditions page on the patient’s 
eCRF. Significant new findings that begin or worsen after informed consent and meet the 
definition of an AE must be recorded on the Adverse Event page of the patient’s eCRF. 
7.2.2.1 
Physical examination 
A complete physical examination will be performed at screening at Day 1 of each cycle and at 
the EOT visit. Visit windows of ± 4 days are allowed (except at cycle 1 Day 1). As specified 
in Table 7-1, a screening physical examination performed within 4 days of first dosing does 
not need to be repeated at Cycle 1 Day 1. 
The physical examination comprises a total body examination that should include: general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, 
back, lymph nodes, extremities, vascular and neurological review. If indicated, rectal, external 
genitalia, breast and pelvis exams will be performed. Information about the physical 
examination must be present in the source documentation at the study site. 
7.2.2.2 
Vital signs 
Vital signs (body temperature, pulse rate, blood pressure) will be monitored at screening, 
EOT, and before administration of ceritinib at Day 1 of each cycle. Screening vital sign 
assessments performed within 4 days of first dosing do not need to be repeated at Cycle 1 Day 
1. Vital signs will be measured according to normal medical practice. 
7.2.2.3 
Height and weight 
Height and body weight will be measured. Weight will be measured at the screening visit, at 
Day 1 of each cycle, and at EOT. Screening weight assessment performed within 4 days of 
first dosing does not need to be repeated at Cycle 1 Day 1. Height will be collected at 
screening only. 
7.2.2.4 
Eastern Cooperative Oncology Group (ECOG) Performance status 
The performance status will be assessed according to the ECOG performance status scale 
(Oken 1982). ECOG performance status will be assessed at screening, at Day 1 of each cycle 
and at the EOT visit (Appendix M). ECOG performance assessment performed within 4 days 
of first dosing does not need to be repeated at Cycle 1 Day 1. 
7.2.2.5 
Laboratory evaluations 
Clinical laboratory analyses (hematology, biochemistry, coagulation, lipase, urinalysis, 
pregnancy test) are to be performed by the local laboratory according to the Visit Schedule 
outlined in Table 7-1. Visit windows of ± 4 days are allowed (except at cycle 1 Day 1). As 


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specified in Table 7-1, screening laboratory assessments performed within 4 days of first 
dosing do not need to be repeated at Cycle 1 Day 1. 
Novartis must be provided with a copy of the local laboratory’s certification (if applicable), 
and a tabulation of the normal ranges and units of each parameter collected in the eCRF. Any 
changes regarding normal ranges and units for laboratory values assessed during the study 
must be reported via an updated tabulation indicating the date of revalidation. Additionally, if 
at any time a patient has laboratory parameters obtained from a different (outside) laboratory, 
Novartis must be provided with a copy of the certification and a tabulation of the normal 
ranges and units for this laboratory as well. The investigator is responsible for reviewing all 
laboratory reports for patients in the study and evaluating any abnormalities for clinical 
significance. 
More frequent laboratory examinations may be performed at the investigator’s discretion if 
clinically indicated. 
At any time during the study, abnormal laboratory parameters which are clinically relevant 
and require an action to be taken with study treatment (e.g., require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the 
Adverse Events eCRF page. Laboratory data will be summarized using the Common 
Terminology Criteria for Adverse events (CTCAE) version 4.0.3. Additional analyses are left 
to the discretion of the investigator. 
7.2.2.5.1 Hematology 
Hematology tests are to be performed by the local laboratory at screening, Day 1 and Day 15 
of Cycles 1 and 2, at Day 1 of each subsequent cycle and at EOT according to the Visit 
Schedule outlined in Table 7-1. The hematology panel includes hemoglobin, hematocrit, 
platelet count, total red blood cells (RBC), total white blood cells (WBC) count, and a WBC 
differential including neutrophils, lymphocytes, monocytes, eosinophils and basophils. 
7.2.2.5.2 Biochemistry 
Biochemistry tests are to be performed by the local laboratory at screening, Day 1 and Day 15 
of Cycles 1 and 2, at Day 1 of each subsequent cycle and at EOT according to the Visit 
Schedule outlined in Table 7-1. The full biochemistry panel includes creatine phosphokinase 
(CPK) (if total CPK is elevated ≥ CTCAE Grade 2, then weekly measure isoenzymes in 
blood, and myoglobin in blood and urine until resolved to ≤ CTCAE Grade 1), urea or blood 
urea nitrogen (BUN), creatinine, uric acid, sodium, magnesium, potassium, glucose, calcium, 
LDH, total protein, albumin, bicarbonate, phosphorus amylase, lipase, total cholesterol, high 
density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides. Additionally 
liver function test including AST/SGOT, ALT/SGPT, GGT, alkaline phosphatase, total, direct 
and indirect bilirubin will be measured. 
7.2.2.5.3 Thyroid function 
Thyroid function tests parameters include: thyroid stimulating hormone (TSH), free T3, and 
free T4. 


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Thyroid function should be assessed at screening, Day 1 of Cycle 1, Day 1 of Cycle 3, every 3 
cycles from C3D1 during the treatment phase (or if clinically indicated), and at EOT. 
7.2.2.5.4 Coagulation 
International normalized ratio (INR) and pro-thrombin time (PT), activated partial 
thromboplastin time and fibrinogen will be measured at screening, Day 1 of Cycle 1, and 
during the treatment phase if clinically indicated. 
7.2.2.5.5 Urinalysis 
Urinalysis includes dipstick analysis of pH, bilirubin, ketones, leukocytes, protein, glucose, 
blood, and specific gravity, and will be performed at screening, Day 1 of each cycle and at 
EOT. 
If clinically indicated based on macroscopic urinalysis results, a microscopic evaluation 
examination will be performed and will include Red Blood Cells, White Blood Cells, Casts, 
Crystals, Bacteria, and Epithelial cells. 
If screening urinalysis results are ≥ +1 for protein on dipstick reading, then total urinary 
protein must be ≤ 500 mg and measured creatinine clearance must be ≥ 50 mL/min/1.73m2 in 
order for the patient to be eligible to participate in the study. 
7.2.2.5.6 Pregnancy and assessments of fertility 
Women of childbearing potential must undergo a serum pregnancy test at screening to 
confirm eligibility in the trial (≤ 4 days before first dose of study drug), and at EOT. Women 
of child-bearing potential must additionally undergo a monthly urine pregnancy test during 
the treatment phase. 
In case of pregnancy, the patient must permanently stop study treatment immediately, 
withdraw from the trial, and the pregnancy must be reported on the Clinical Trial Pregnancy 
Form. 
7.2.2.6 
Radiological examinations (for safety) 
Not applicable. 
7.2.2.7 
Cardiac assessments 
7.2.2.7.1 Electrocardiogram (ECG) 
A standard 12-lead ECG will be performed at screening, Day 1 of Cycles 1 and 2, at Day 1 of 
every other cycle and at EOT according to the Visit Schedule outlined in Table 7-1. 
The interpretation of the tracing must be made by a qualified physician and documented in the 
ECG section of the eCRF. Each ECG tracing should be labeled with the study number, patient 
initials (if permitted by local regulations), Patient Number, date, and kept in the source 
documents at the study site. Only clinically significant abnormalities should be reported in the 
Adverse Events eCRF. Clinically significant abnormalities present when the patient signed 
informed consent should be reported on the Medical History eCRF page. Clinically significant 


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findings must be discussed with the Novartis Medical Monitor 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. 
7.2.2.7.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram 
MUGA (multiple gated acquisitions) scan or echocardiogram (ECHO) will be used to assess 
LVEF at screening and during the treatment phase as clinically indicated to assess signs or 
symptoms of cardiotoxicity. In case of clinically significant abnormalities, they should be 
reported on the Adverse Events eCRF. 
In case a patient develops left ventricular systolic dysfunction while on study treatment dose 
adjustment guidelines described in Section 6.3 must be followed. 
7.2.2.7.3 Cardiac enzymes 
Cardiac enzymes (Cardiac troponin-I or troponin-T) will be measured at screening and during 
the treatment phase if clinically indicated, especially in case of LVEF decrease. 
7.2.3 
Pharmacokinetics 
Not Applicable. 


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7.2.5 
Other assessments 
No additional tests will be performed on patients entered into this study. 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event (AE) is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained. 
For patients who sign the ICF, all AEs will be captured in the AE eCRF from time of 
signature through 30 days after permanent study treatment discontinuation. For patients who 
fail the screening, only SAEs will be captured in the AE eCRF page. 


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Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History eCRF. Adverse event monitoring should be continued for at 
least 30 days following the last dose of study treatment. Adverse events (including lab 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1-4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected though a Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine: 
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) 
or 
Its relationship to the study treatment (Reasonable possibility that AE is related: No, 
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable) 
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 taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.3 
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. 


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Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (as per RECIST 1.1 criteria for solid tumors or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a serious adverse event or adverse 
event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities will be assessed according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. 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 eCRF. Whenever possible, a diagnosis, rather than a 
symptom should be provided (e.g. anemia instead of low hemoglobin). Laboratory 
abnormalities that meet the criteria for Adverse Events should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found. When an abnormal 
laboratory or test result corresponds to a sign/symptom of an already reported adverse event, 
it is not necessary to separately record the lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAEv4.03 does not 
automatically indicate an 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 and is still, by definition, an adverse event. 
8.2 
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). 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. 
8.3 
Serious adverse events 
8.3.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 


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• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• 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 
• Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• 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 
8.3.2 
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. 
SAE collection starts at time of ICF signature whether the patients is a screen failure or not. 
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 (either initial or follow up information) is collected and recorded 
on the Serious Adverse Event Report Form on a paper SAE Form. The investigator must 
assess and record the relationship of each SAE to each specific study treatment (if there is 
more than one study treatment), and complete the SAE Report Form in English. 
The SAEs recorded on the paper SAE form should be faxed to 
 within 24 hours 
of awareness of the SAE to the local Novartis Drug Safety and Epidemiology Department 
(DS&E). 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. 
Note that any follow up information provided should describe whether the event has resolved 
or continues, if and how it was treated, and whether the patient continued or withdrew from 
study participation. 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. 


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The follow up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the patient continued or withdrew from study participation. 
Refer to Section 7.1.1.2 for additional details regarding the reporting of SAEs which occur 
during the screening period. 
8.4 
Emergency unblinding of treatment assignment 
Not applicable. 
8.5 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up 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 department. Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to 
the Novartis study 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 in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
8.6 
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’s 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. 
8.7 
Data Monitoring Committee 
Not applicable. 
8.8 
Steering Committee 
Not applicable. 


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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 at least vital status (i.e. that the subject is alive) 
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. 
9.2 
Site monitoring 
Before study initiation, Novartis personnel (or designated CRO) will review the protocol and 
eCRFs with the investigators and their staff. During the study, the Investigator or designee 
will enter all required patient data into the eCRF within 72 hours (3 days) of the patient visit. 
The field monitor will visit the site regularly to check the completeness of patient records, the 
accuracy of entries on the eCRFs, the adherence to the protocol to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria 
and documentation of SAEs. Additional checks of the consistency of the source data with the 
eCRFs are performed according to the study-specific monitoring plan. 


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9.3 
Data collection 
This study will use Electronic Data Capture (EDC) and the designated investigator staff will 
enter the data required by the protocol into the eCRF. The eCRFs have been built using fully 
validated secure web-enabled software that conforms to 21 CFR Part 11 requirements, 
Investigator site staff will not be given access to the EDC system until they have been trained. 
Automatic validation programs check for data discrepancies in the eCRFs and, allow 
modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
Mutational analysis data will be generated by CLIA certified local labs. We anticipate that the 
data available in the report will vary from lab to lab.
 
 
 
If a tumor sample is obtained at the time of disease progression (optional), data about the 
sample will be collected in the eCRF. 
Laboratory assessments for hematology, biochemistry, coagulation, urinalysis, MUGA and 
ECGs will be collected locally and entered directly onto the eCRFs. 
9.4 
Database management and quality control 
This study will be using eCRFs and the designated CRO will review the data entered by 
investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing 
values and sent to the investigational site via the EDC system. Designated investigator site 
staff are required to respond promptly to queries and to make any necessary changes to the 
data. 
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA current version) 
terminology. 
Data from the screening molecular analysis will be collected locally and entered directly onto 
the eCRF. 
 
At the conclusion of the study, the occurrence of any protocol deviations will be determined. 
After this action has been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and the data made available for data analysis. 
Authorization is required prior to making any database changes to locked data, by joint 
written agreement between the US Oncology Medical Affairs Franchise Head and the US 
Oncology Medical Affairs Franchise Vice President. 
After database lock, the investigator will receive a CD-ROM or paper copies of the patient 
data for archiving at the investigational site. 


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10 
Statistical methods and data analysis 
All data except the primary efficacy variable clinical benefit rate will be analyzed by a 
designated CRO in collaboration with Novartis. Any data analysis carried out independently 
by the investigator should be submitted to Novartis before publication or presentation. The 
data from all centers that participate in this study will be combined in the final safety and 
efficacy analysis. 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) will include all patients who have received at least one dose of 
study drug. 
FAS will be used for the analysis of efficacy endpoints. 
10.1.2 
Safety Set 
The Safety Set will include all patients who received at least one dose of study treatment and 
had at least one post-baseline safety assessment. 
Please note: the statement that a patient had no adverse event (on the Adverse Event eCRF) 
constitutes a safety assessment. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data (including disease characteristics) will be listed and 
summarized by patients groups formed by the type of cancer at study entry using the FAS 
(See Appendix Q for predicted target cancer population). Additional groups may be added 
based on enrollment (See Appendix Q). Categorical data, such as gender, race, etc., will be 
presented by frequencies and percentages. Descriptive summary statistics (e.g., frequency, 
mean, median, range and standard deviation) will be used to present numeric data. 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
10.3.1 
Study medication 
Duration of study treatment exposure, cumulative dose and dose intensity will be summarized 
by the patient groups as above using the Safety Set. The number of patients with dose 
changes/interruptions will be presented along with reasons for the dose change/interruption. 
The safety set will be used for the tables and listings. 
10.3.2 
Concomitant therapies 
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drugs will be listed and summarized for the FAS by Anatomical Therapeutic Chemical 
Classification System (ATC) term, preferred term and treatment arm by means of frequency 
counts and percentages. These summaries will include medications starting on or after the 


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start of study treatment (defined as cycle 1 day 1) or medications starting prior to the start of 
study treatment and continuing after the start of study treatment. 
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed. The safety set will be used for all above 
mentioned concomitant medication tables and listings. 
10.4 
Primary objective 
The primary objective is to assess clinical benefit 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. For hematologic tumors other appropriate 
hematological response criteria will apply and are included in the appendices. 
For solid tumors, an assessment of CR or PR using RECIST 1.1 must be confirmed at least 4 
weeks after initial observation, If the two assessments differ, the best response will be 
determined by Table 14-5 of Appendix A. 
10.4.1 
Variable 
The primary efficacy variable is the clinical benefit rate (CBR) (e.g. defined as CR or PR or 
SD ≥ 16 weeks for solid tumors). 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The study will enroll patients from at least 6 histologic groups. In addition, another group 
simply referred to as “Other” may be identified and enrolled throughout the study. 
We let Yi be the response indicator for the ith subject, and let Rg be the assumed probability of 
response within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability 
of response for group g within the treatment group. We transform to the logit scale for 
modeling purposes. Let θg be the mean log odds treatment effect, i.e.: 
θg = log ቆ
πg
1 −πg
ቇ−log ቆ
Rg
1 −Rg
ቇ. 
Thus, θg is the group specific logistic regression coefficient for the treatment within group g. 
The primary analysis is a set of group specific tests that θg>0, meaning that the treatment is 
better than the assumed control rate within that group. Thus, we wish to test the set of 
hypotheses 
H0g : θg≤0 
H1g : θg>0 
We proceed in a Bayesian fashion, assigning a prior distribution (details in Appendix Q) and 
computing the posterior probability of H1g within each group g. If, at the final analysis, 
Pr(θg>0 | data) > 0.90 


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Then group g will be declared a success (thus, the final analysis produces a separate decision 
for each group). The trial also allows for early stopping of groups, described below. 
The statistical design borrows information across groups with a hierarchical model. The 
hierarchical model allows dynamic borrowing of information between groups such that more 
borrowing occurs when the groups are consistent and less borrowing occurs when the groups 
differ. In this way, the model is a compromise between the two alternate extremes of either a 
completely pooled analysis or a separate analysis in each group.  
The purpose of such an analysis (discussed in more detail in the Appendix Q) is to produce 
higher power or lower type I error in situations where we see some commonality (identical 
effects are not required) among the groups. Details of the hierarchical model is provided in 
Appendix Q. 
10.4.3 
Evaluation of trial success and futility 
The clinical benefit rate will be evaluated for futility and early success by comparing posterior 
quantities for the rate to pre-specified early stopping criteria. The evaluations are planned to 
occur after the first 30 patients are dosed for at least 16 weeks or discontinued, then every 13 
weeks thereafter until the enrollment closure of the study. An additional CBR evaluation will 
be performed after the database lock for the primary CSR. 
Early Futility 
If there is less than 10% probability that the response rate in a group exceeds the historical 
rate Rg, then the group will stop enrollment early for futility. Formally, enrollment will stop 
early for futility if: 
Pr(πg > Rg) < 0.10. 
A group is only eligible for early stopping once a minimum of 10 patients has been evaluated 
for response in that group. 
Early Success 
If there is at least 95% probability that the response rate in a group exceeds the historical rate, 
then the group will stop enrollment early for success. Formally, enrollment will stop early for 
success if: 
Pr(πg > Rg) > 0.95. 
A minimum of 15 subjects will need to be evaluated prior to declaring a group to be 
efficacious. 
Final Analysis 
The final analysis will occur when both accrual and follow-up are complete in all groups. If, 
at the completion of the trial, there is at least 90% probability that the response rate in a group 
exceeds the historical rate, then the group will be considered a success. Formally if: 
Pr(πg > Rg) > 0.90. 


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In addition, a group will be considered as “promising’ if: 
0.80< Pr(πg > Rg) < 0.90. 
10.4.4 
Handling of missing values/censoring/discontinuations 
A patient who has not progressed or died at the date of the analysis cut-off would have his/her 
PFS and OS censored at the time of the last adequate assessment before the cut-off date. Any 
disease assessment indicating response status other than “unknown” or “not done” is 
considered an adequate response assessment. 
10.4.5 
Supportive analyses 
Not applicable. 
10.5 
Secondary objectives 
10.5.1 
Key secondary objective(s) 
The key secondary objective of this study is to assess Overall Response (OR) of Partial 
Response (PR) or Complete Response (CR)  based on local investigator assessment. 
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 other appropriate hematological response 
criteria will apply and are included in the appendices. 
The overall response rate (PR plus CR) and its 95% exact confidence interval will be provided 
for each patient group. In the event where sample size in each patient group is small (<10), 
only ORR summary for the entire study cohort will be presented. 
10.5.2 
Other secondary efficacy objectives 
The secondary objectives of the study: 
• To assess progression free survival (PFS) based on local investigator assessment per 
RECIST 1.1 or other appropriate hematological response criteria 
• To assess overall survival 
• To assess duration of response (DOR) based on local investigator assessment per RECIST 
1.1 or other appropriate hematological response criteria 
• To assess safety and tolerability 
The secondary efficacy variable progression free survival (PFS) is defined as the time from 
the date of first dose to the date of first documented disease progression or relapse or death 
due to any cause. 
PFS will be summarized and graphed using the Kaplan-Meier product-limit method for the 
entire study cohort. For cohorts with at least 10 subjects, separate PFS analyses will be 
conducted for each cohort. Patients who drop-out without progression will be censored at the 
time of last adequate assessment. The estimates of the 25th, median, 75th percentiles of the 
PFS and their 95% confidence intervals will be provided, if applicable. 


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Overall survival (OS) is defined as the time from the date of first dose to the date of death due 
to any cause. If a patient is not known to have died, survival time will be censored at the date 
of the last contact. 
OS will be summarized and graphed using the product-limit method as above. 
The duration of response applies only to patients whose best response was PR or CR. 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 other appropriate hematological response 
criteria will apply and are included in the appendices. The duration of response is defined as 
the time from the first documented response to the date first documented disease progression 
or relapse or death due to any cause. The duration of response will be summarized 
descriptively for the entire study cohort. 
If the study primary efficacy endpoint is not met, Novartis may decide not to conduct some of 
the above secondary efficacy analyses but instead provide those endpoints in listings only. 
10.5.3 
Safety objectives 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
patient groups. 
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g., 
electrocardiogram, vital signs) will be considered as appropriate. All safety data will be listed. 
The safety summary tables will include only assessments collected no later than 30 days after 
study treatment discontinuation. Those collected later than 30 days after study treatment 
discontinuation will be flagged in listings. 
10.5.3.1 Analysis set and grouping for the analyses 
10.5.3.1.1 
Adverse events (AEs) 
All adverse events recorded during the study will be summarized. The incidence of treatment-
emergent adverse events (new or worsening from baseline) will be summarized by system 
organ class and/or preferred term, maximum severity (based on CTCAE v4.03), type of 
adverse event, relationship to the study treatment by treatment group. Deaths reportable as 
SAEs and non-fatal serious adverse events will be listed by patient and tabulated by type of 
adverse event and patient group. 
Adverse events will be summarized by presenting the number and percentage of patients by 
system organ class and/or preferred term, the maximum severity (based on CTCAE v4.03) 
and treatment arm. Adverse events related to study treatment will also be summarized. In 
addition, adverse events of related nature may be analyzed by categories regrouping the 
relevant preferred terms, as appropriate. 
10.5.3.1.2 
Laboratory abnormalities 
All laboratory values will be converted into SI units and the severity grade will be calculated 
using appropriate common terminology criteria (CTCAE v4.03). 


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A severity grade of 0 will be assigned when the value is within normal limits. For lab 
parameters for which severity grades are determined both through normal limits and absolute 
cut-offs, in the unlikely case when a local laboratory normal range overlaps into the higher 
(i.e. non-zero) CTCAE grade, the laboratory value will still be taken as within normal limits 
and assigned a CTCAE grade of zero. 
A listing of laboratory values will be provided by laboratory parameter, patient, and treatment 
arm. A separate listing will display notable laboratory abnormalities (i.e., newly occurring 
CTCAE grade 3 or 4 laboratory toxicities). Lab values collected later than 30 days after study 
treatment discontinuation will be flagged in the listings. 
The following by-group summaries will be generated separately for hematology, and 
biochemistry parameters: 
• shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
• for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value. 
• listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges. 
10.5.3.1.3 
Other safety data 
Summary statistics for data from other tests will be provided, notable values will be flagged, 
and any other information collected will be listed as appropriate. 
Descriptive summary statistics will be provided for : 
• Electrocardiograms: changes from baseline to last available ECG results 
• Cardiac imaging: number and percentage of patients with notable LVEF values 
• Vital signs: number and percentage of patients with at least one post-baseline vital sign 
abnormality 
• ECOG performance status: shift table comparing baseline to worst post baseline ECOG 
performance status. 
• All other safety related procedures as required 
• Listings with flagged notable values and any other information collected will be provided 
as appropriate. 


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10.7 
Interim analysis 
There is no plan for a formal interim analysis of safety or other secondary endpoints for this 
study. However, for publication or other purposes, interim data review of clean data will be 
performed as necessary. At these interim reviews, patient demographics/baseline 
characteristics, the primary and secondary endpoints as applicable, and all important safety 
endpoints will be summarized.  
No formal report will be issued for these interim data reviews. 
10.8 
Sample size calculation 
 The sample size was chosen by the usual criteria of obtaining adequate power for the 
alternative hypothesis of interest as shown in Table 14-18 of Appendix Q. This hypothesis 
corresponds to a generally effective treatment across groups and incorporates variation in 
treatment effects to reflect the realistic expectation that treatment effects may differ by group. 
In this setting, analytical power calculations are not possible, but the design was simulated to 
obtain the power of the study as shown in the appendix. The sample sizes shown (minimum of 
10 for futility stopping, minimum of 15 for early success and maximum of 30 as a group cap) 
achieve adequate power for the alternative hypothesis. The simulations included the expected 
variable accrual by simulating a Poisson process with expected accrual also shown in the 
appendix. 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice (GCP), 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. 


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11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Prior to study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs and 
regulatory authorities as required. 
11.3 
Informed consent procedures 
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 eCRFs. 
Novartis will provide investigators in a separate document with a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH and 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 approval. 
Women of child bearing potential and fertile males 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. Women of child bearing potential must agree to 
adhere to contraception requirement until at least 3 months after the final dose of study 
treatment. Fertile males must agree to adhere to contraception requirement until at least 3 
months after the final dose of study treatment. If there is any question that the patient will not 
reliably comply, they should not be entered in the study. 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.3. 
11.5 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 


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11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratories, and medico-technical 
departments involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study eCRF is the primary data collection instrument for 
the study. The investigator should ensure the accuracy, completeness, legibility, and 
timeliness of the data reported in the eCRFs and all other required reports. Data reported on 
the eCRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the eCRF must be 
recorded. Any missing data must be explained. An audit trail will be maintained by the 
system. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 


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11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who is 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 clinical study report (CSR). 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC/REB at the 
study site should be informed within 10 working days. 


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13 
References (available upon request) 
Barosi G, et al; (2013) Revised response criteria for polycythemia vera and essential 
thrombocythemia: an ELN and IWG-MRT consensus project. Blood 121: 4778-4781. 
Barosi G, Mesa RA, Thiele J, et al; (2008)International Working Group for Myelofibrosis 
Research and Treatment (IWG-MRT). Proposed criteria for the diagnosis of post-
polycythemia vera and postessential thrombocythemia myelofibrosis: a consensus statement 
from the International Working Group for Myelofibrosis Research and Treatment. 
Leukemia.;22(2):437-438. 
Benson AB 3rd, Ajani JA, Catalano RB, et al (2004) Recommended guidelines for the 
treatment of cancer treatment-induced diarrhea. J Clin Oncol ;22(14):2918-26. 
Bergethon K, Shaw AT, Ou SH, et al: ROS1 rearrangements define a unique molecular class 
of lung cancers. J Clin Oncol 30:863-70, 2012Charest A, Lane K, McMahon K, et al. Fusion 
of FIG to the receptor tyrosine kinase ROS in a Glioblastoma with an interstitial del 
(6)(q21q21). Genes Chromosomes Cancer 2003; 37: 58-71 
Cheson, et al. Clinical application and proposal for modification of the InternationalWorking 
Group (IWG) response criteria in myelodysplasia. blood-2005-10-4149. 
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, et al (2003). Revised Recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia, J Clin Oncol: pp 4642-4649. 
Cheson BD, Greenberg JM, Bennett JM, et al (2006) Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood; 108: 419-425. 
Cheson BD (2007a) The international harmonization project for response criteria in 
lymphoma clinical trials. Hematol Oncol Clin N Am 21:841-854. 
Cheson BD, Pfistner B, Juweid ME, et al (2007b) Revised response criteria for malignant 
lymphoma. J Clin Oncol 25:579-586. 
Cheson BD (2009) The case against heavy PETing. J Clin Oncol 27:1742-1743. 
Emanuel RM, Dueck AC, Geyer HL, et al (2012) Myeloproliferative neoplasm (MPN) 
symptom assessment form total symptom score: prospective international assessment of an 
abbreviated symptom burden scoring system among patients with MPNs [published correction 
appears in J Clin Oncol. 2012;30(36):4590]. J Clin Oncol. 2012;30(33):4098-4103. 
Li C, Fang R, Sun Y, et al. Spectrum of oncogenic driver mutations in lung adenocarcinomas 
from East Asian never smokers. PloS One 2011; 6: e15640 
Mehra R, Camidge DR, Sharma S, et al (2012) First-in-human phase I study of the ALK in 
advanced solid tumors (abstract). J Clin Oncol 30, 2012 (suppl; 3007A). 


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National Cancer Institute (NCI) (2009) Common terminology Criteria for Adverse Events 
(CTCAE) v4.03. 
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Acute 
Lymphoblastic Leukemia Version 1. 2013. 
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for 
Chronic Myelogenous Leukemia Version 3. 2014. 
Oken MM, Creech RH, Tormey DC, et al (1982) Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol 5; 649-655. 
Rikova K, Gluo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies 
oncogenic kinases in lung cancer. Cell 2007; 131: 1190-1203 
Shaw AT, Camidge DR, Felip E, et al (2012) Results of a first-in-human Phase I study of the 
ALK in advanced solid tumors. Ann Oncol 23 (Suppl 9, abstr 4400). 
Shaw AT, Kim DW, Mehra R, et al (2013) Ceritinib in ALK-rearranged Non Small Cell Lung 
Cancer. N Engl J Med; 370(13):1189-97. 
Swerdlow SH, Campo E, Harris NL, et al (2008), eds. WHO Classification of Tumours of 
Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2008. 
Tefferi et al. (2013) Revised response criteria for myelofibrosis: International Working (IWG-
MRT) and European LeukemiaNet (ELN) consensus report Group-Myeloproliferative 
Neoplasms Research and Treatment. Blood; 122: 1395-1398. 
LDK378 Investigator’s Brochure ed.6. 


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14 
Appendices 
14.1 
Appendix A: Criteria for therapeutic response/outcome 
assessment of solid tumors and/or lymph nodes (based on 
RECIST 1.1) 
Tumor assessments will be based on Response Evaluation Criteria in Solid Tumors (RECIST 
1.1) guidelines (Eisenhauer 2009). 
14.1.1 
Measurability of tumor lesions at baseline 
All tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
14.1.1.1 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). 
14.1.1.2 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. 
14.1.1.2.1 
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. 


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14.1.1.2.2 
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. 
14.1.1.2.3 
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. 
14.1.2 
Specification by methods of measurement 
14.1.2.1 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. 
14.1.2.1.1 
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. 
14.1.2.1.2 
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. 
14.1.2.2 Response criteria 
14.1.2.2.1 
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 14-1. 


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Table 14-1 
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. 
14.1.2.2.2 
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 14-2. 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 14-2 
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). 
14.1.2.2.3 
New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded appropriately in the eCRF. 
• 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 


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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. 
14.1.3 
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 14-3 and Table 14-4. 
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 14-5. 
Table 14-3 
Time 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 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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Table 14-4 
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 
Non-CR/non-PRa 
Not all evaluated 
No 
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 14-5 
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 
aIf 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. 
bProvided minimum criteria for SD duration met, otherwise, PD 
cProvided minimum criteria for SD duration met, otherwise, NE 


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14.1.4 
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 


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14.2 
Appendix B: Criteria for therapeutic response/outcome 
assessment in lymphoma studies (based on Cheson response 
criteria) 
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). 
14.2.1 
Definitions and criteria for normalization 
14.2.1.1 Definitions 
14.2.1.1.1 
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. 
14.2.2 
Measurability of Tumor Lesions at Baseline 
All tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
14.2.2.1 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. 
14.2.2.2 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. 


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• 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. 
14.2.2.3 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. 
14.2.3 
Specification by methods of measurement 
14.2.3.1 Measurement of lesions 
All radiological measurements should be taken in two perpendicular dimensions and recorded 
in metric notation, using a ruler or calipers. 
14.2.3.1.1 
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. 
14.2.3.1.2 
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 


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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. 
14.2.3.1.3 
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. 
14.2.3.1.4 
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 


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• Unexplained loss of > 10% body weight within the previous 6 months, as assessed and 
reported (present vs. absent) by the Investigator. 
14.2.4 
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 14-6. 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 14-9) and non-index lesions (Table 14-8) identified at Screening, then a 
combined overall radiological response is determined (Table 14-11). 
Table 14-6 
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, 
immunohistochemis
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 


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14.2.4.1 Evaluation of Index Lesions (nodal and extranodal) 
14.2.4.1.1 
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 14-7), except when there is a Complete 
Response for index nodal lesions (i.e. complete normalization of all index nodal lesions) (see 
Section 14.2.4.1.2). 
Table 14-7 
Radiological status based on SPD calculation for all index 
lesions 
Response Criteria1 
Evaluation of index lesions 
Complete Response (CR) 
See Table 14-9 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. 
14.2.4.1.2 
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 14.2.4.2: all index lesion ≤ 15 mm in long axis), the 
SPD for these index nodal lesions may not be equal to zero and therefore a calculation of a 
SPD for all index lesions may be misleading. Therefore, by default, a specific response for 
extranodal index lesions needs to be evaluated, based on the SPD calculation restricted to all 
index extranodal lesions only (see Table 14-8). 
Table 14-8 
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. 


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14.2.4.1.3 
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 
14-9. 
Table 14-9 
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)”. 
14.2.4.1.4 
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 14-10): 


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Table 14-10 
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)”. 
14.2.4.2 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. 
14.2.4.2.1 
Overall radiological response 
Overall radiological response is calculated as shown in Table 14-11. 
Table 14-11 
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 


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Index lesions 
Non-index lesions1 
New lesions 
Overall radiological response 
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. 
14.2.4.2.2 
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). 
14.2.4.2.3 
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. 
14.2.4.2.4 
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. 
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 


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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. 
14.2.5 
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. 


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14.3 
Appendix C: Ann Arbor staging classification 
 
Stage  Area of involvement 
I 
 
Single lymph node group 
II  
Multiple lymph node groups on the same side of the diaphragm 
III  
Multiple lymph node groups on both sides of the diaphragm 
IV  
Multiple extranodal sites or lymph nodes and extranodal disease 
X  
Bulk disease > 10 cm 
E  
Extranodal extension or single isolated site of extranodal disease 
Class A are patients who experience no B symptoms 
Class B are patients experience unexplained fever of ≥ 38°C; unexplained, recurrent drenching night sweats; or 
unexplained loss of >10% body weight within the previous 6 months 
1 Cotswolds modification of Ann Arbor staging system adapted from 2007 NCCI guidelines for non-Hodgkin’s 
lymphoma 
14.4 
Appendix D: Rai Staging Systema 
 
Stage  Area of involvement 
Risk Status 
0 Lymphocytosis, lymphocytes in blood >15 x 109/L and >40% lymphocytes in bone marrow 
I 
Stage 0 with enlarged node(s) 
II Stage 0-1 with splenomegaly, hepatomegaly, or both 
IIIb Stage 0-II with hemoglobin < 11.0 g/dL or hematocrit <33% 
IVb Stage 0-III with platelets <100 x 109/L 
Low 
Intermediate 
Intermediate 
High 
High 
a Research originally published in Blood. Rai KR et al. Clinical staging of chronic lymphocytic leukemia. Blood 
1975;46(2):219-234. (c) The American Society of Hematology 
b Immune-mediated cytopenias are not the basis for these stage definitions. 
14.5 
Appendix E: Criteria for Response assessment in Acute Myeloid 
Leukemia (based on IWG and Cheson) 
Disease assessments will be based on standardized response criteria as defined by the 
International Working Group (IWG) for AML (Cheson et al 2003). 
 
Response classification in AML at a given evaluation time (Cheson 2003) 
Response category 
Definition# 
Complete remission (CR) 
Bone marrow 
< 5% blasts 
no blasts with Auer rods 
 
Peripheral blood 
neutrophils ≥ 1.0 x 109/L 
platelets ≥ 100 x 109/L 
≤ 1% blasts 
No evidence of extramedullary disease (such as CNS or soft tissue involvement). 
Transfusion independent (see Section 7.2.1.4.5). 
 
In case all criteria for CR apply and the patient receives platelet and/or neutrophil 
transfusions, the patient will be assessed as CRi. 


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Response classification in AML at a given evaluation time (Cheson 2003) 
Response category 
Definition# 
Complete remission with 
incomplete blood count 
recovery (CRi) 
Bone marrow 
< 5% blasts 
no blasts with Auer rods 
 
Peripheral blood 
neutrophils < 1.0 x 109/L and/or platelets < 100 x 109/L 
≤ 1% blasts 
No evidence of extramedullary disease (such as CNS or soft tissue involvement). 
Transfusion-independent (see Section 7.2.1.4.5). Exception: Platelet and neutrophil 
transfusions are allowed. 
Partial Remission (PR) 
Bone marrow 
50% or greater decrease (absolute range 5-25% blasts) 
< 5% of blasts contain Auer rods 
 
Peripheral blood 
neutrophils < 1.0 x 109/L and/or platelets < 100 x 109/L 
 
No evidence of extramedullary disease (such as CNS or soft tissue involvement). 
Treatment failure 
Treatment failure includes those patients for whom treatment has failed to achieve 
PR, CRi or CR throughout the treatment.  
Relapse from CR or CRi* 
Only in patients with a CR or CRi: 
Reappearance of blasts in peripheral blood (> 1%) OR 
≥ 5% blasts in bone marrow OR 
(Re-)appearance of extramedullary disease 
No response 
In case a patient does not achieve CR, CRi, PR or relapse for an individual 
response assessment. 
Unknown 
In case the response assessment was not done, the baseline assessment was not 
done, the assessment was incomplete or was not done within the respective time 
frame. 
# If not defined otherwise, all of the criteria apply. 
* Cheson et al (2003) does not specify relapse after PR but this may be considered in Phase I or II protocols. 
Table 14-12 
Exploratory AML response categories according to IWG 
Response category 
Definition 
Cytogenetic complete remission (CRc) 
All criteria for CR plus 
no cytogenetic abnormalities 
Molecular complete remission (CRm) 
All criteria for CRc plus 
no leukemic cells by RQ-PCR assay 
14.6 
Appendix F: Criteria for Response assessment in Acute 
Lymphoblastic Leukemia (based on NCCN Guidelines Version 
1.2013) 
Response classification in ALL for Blood and Bone Marrow at a given evaluation time 
Response category 
Definition# 
Complete remission (CR) 
No circulating blasts or extramedullary disease (such as 
lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass, 
CNS or soft tissue involvement) 
Trilineage hematopoiesis (TLH) and < 5% blasts 
neutrophils ≥ 1.0 x 109/L 
platelets ≥ 100 x 109/L 
No recurrence for 4 weeks 


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Response classification in ALL for Blood and Bone Marrow at a given evaluation time 
Response category 
Definition# 
Complete remission with incomplete 
blood count recovery (CRi) 
Peripheral blood 
Recovery of platelets but < 100 x 109/L or neutrophils is < 1.0 x 109/L. 
Progressive Disease (PD) 
Increase of at least 25% in the absolute number of circulating or bone 
marrow blasts or development of extramedullary disease. 
Treatment failure 
Treatment failure includes those patients for whom treatment has failed to 
achieve a CR at the end of treatment 
Relapse from CR or CRi* 
Only in patients with a CR or CRi: 
Reappearance of blasts in peripheral blood (> 1%) OR 
≥ 5% blasts in bone marrow OR 
(Re-)appearance of extramedullary disease 
No response 
In case a patient does not achieve CR, CRi, PR or relapse for an 
individual response assessment. 
Unknown 
In case the response assessment was not done, the baseline assessment 
was not done, the assessment was incomplete or was not done within the 
respective time frame. 
# If not defined otherwise, all of the criteria apply. 
14.7 
Appendix G: Criteria for Response assessment in Chronic 
Myelogenous Leukemia (based on NCCN Guidelines Version 4. 
2013) 
Response classification in CML for hematologic, cytogenetic, and molecular evaluation at a given 
evaluation time 
Response category 
Definition# 
Complete hematologic 
response (CR)1 
Complete normalization of peripheral blood counts with leukocyte count < 10 x 109/L 
platelets < 450 x 109/L 
No immature cells such as myelocytes, promyelocytes, or blasts in peripheral blood 
No signs and symptoms of disease with disappearance of splenomegaly 
Cytogenetic response2,3 
Complete 
No Ph-positive metaphases 
Partial 
1% - 35% Ph-positive metaphases 
Major 
0% - 35% Ph-positive metaphases (complete + partial) 
Minor 
> 35% Ph-positive metaphases 
Molecular response4,5 
Complete 
No detectable BCR-ABL mRNA by QPCR using an assay with a sensitivity of at least 
4.5 logs below standardized baseline. 
Major 
≥ 3 log reduction in international scale of BCR-ABL mRNA 
Treatment failure 
Treatment failure includes those patients for whom treatment has failed to achieve a 
complete hematologic response (CR) throughout treatment. 
No response 
In case a patient does not achieve CR, PR or relapse for an individual response 
assessment. 
Unknown 
In case the response assessment was not done, the baseline assessment was not 
done, the assessment was incomplete or was not done within the respective time 
frame 


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Response classification in CML for hematologic, cytogenetic, and molecular evaluation at a given 
evaluation time 
Response category 
Definition# 
# If not defined otherwise, all of the criteria apply. 
1 Federl S et al: Chronic myelogenous leukemia: Biology and therapy. Ann Intem Med 1999; 131:207-219. 
2 A minimum of 20 metaphases should be examined. 
3 O’Brien SG, et al: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase 
chronic myeloid leukemia. N Engl J Med 2003;348:994-1004. 
4 Hughes TP, et al: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly 
diagnoses chronic myeloid leukemia. N Engl J Med 2003;349:1423-1432 
5 Hughes T, et al: Monitoring CML patients responding to treatment with tyrosine kinase inhibitors; review and 
recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain 
mutations and for expressing results. Blood 2006;108:28-37 
14.8 
Appendix H: Criteria for Response assessment in Chronic 
Lymphocytic Leukemia (based on modified IWG guidelines) 
Disease assessments will be based on standardized response criteria as defined by the 
modified IWG guidelines for CLL. Response in CLL must meet the criteria in both Group A 
and Group B. Group A criteria defines tumor load. Group B criteria define the function of the 
hematopoietic system (or marrow). 
Response Definition for Chronic Lymphocytic Leukemia1 
Group A Response for Tumor Burden 
Response 
Nodal Masses 
Organomegaly 
Bone Marrow 
CR 
None > 1.5 cm 
No splenomegaly 
No hepatomegally 
Normocellular >30% Lymph. No B 
lymphoid nodules 
CRi 
None > 1.5 cm 
No splenomegaly 
No hepatomegally 
Hypocellular marrow 
PR 
Decrease ≥50% 
Spleen/Liver decrease ≥50 
50% reduction in marrow infiltrate, or 
B-lymphoid nodules 
Group B Response for hepatopoietic system2 
Response 
Platelet count 
Hemoglobin 
Neutrophils 
CR 
>100 x 109/L 
>11 g/dL 
>1.5 x 109/L 
CRi 
If meets criteria from Group A but does not meet criteria from Group B 
PR 
>100 x 109/or increase 
≥50% over baseline 
>11 g/dL or increase ≥50% 
over baseline 
>1.5 x 109/L or >50% improvement 
over baseline 
SD 
Failure to attain CR/CRi/PR or PD  
Relapsed 
disease or 
PD 
Appearance of any new lesions; at least one of the above criteria. Isolated progressive 
lymphocytosis in the setting of reduced lymph node size or organomegaly or improvement in 
hemoglobin/platelets will not be considered progressive disease 
Hallek M, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia updating the National 
Cancer Institute-Working Group 1996 Guidelines. Blood 2008; 111:5446-5456 
All values are without transfusion or hepatopoietic growth factors 


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14.9 
Appendix I: Criteria for Response assessment in Myelofibrosis 
(based on modified IWG-MRT guidelines and European 
LeukemiaNet (ELN) consensus report)1 
Response category 
Definition 
CR 
Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF† and 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥ 1 X 109/L and 
<UNL; 
Platelet count ≥100 X 109/L and <UNL; <2% immature myeloid cells‡ and 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH 
PR 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥1 X 109/L and 
<UNL; platelet count ≥100 X 109/L and <UNL; <2% immature myeloid cells‡ and 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH or 
Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF†, and 
peripheral blood: Hemoglobin ≥85 but <100 g/L and <UNL; neutrophil count ≥1 X 
109/L and <UNL; platelet count ≥50, but <100 X 109/L and <UNL; <2% immature 
myeloid cells‡ and 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH 
Clinical improvement (CI) 
The achievement of anemia, spleen or symptoms response without progressive 
disease or increase in severity of anemia, thrombocytopenia, or neutropenia§ 
Anemia response 
Transfusion-independent patients: a ≥20 g/L increase in hemoglobin level||  
Transfusion-dependent patients: becoming transfusion-independent^ 
Spleen response# 
A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not 
palpable** or 
A baseline splenomegaly that is palpable at >10 cm, below the LCM, decreases by 
≥50%** 
A baseline splenomegaly that is palpable at <5 cm, below the LCM, is not eligible for 
spleen response 
A spleen response requires confirmation by MRI or computed tomography showing 
≥35% spleen volume reduction 
Symptoms response 
A ≥50% reduction in the MPN-SAF TSS†† 
Progressive disease‡‡ 
Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM or 
A ≥100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-
10 cm or 
A 50% increase in palpable distance, below LCM, for baseline splenomegaly of >10 
cm or 
Leukemic transformation confirmed by a bone marrow blast count of ≥20% or 
A peripheral blood blast content of ≥20% associated with an absolute blast count of 
≥1 X 109/L that lasts for at least 2 weeks 
Stable disease 
Belonging to none of the above listed response categories 
Relapse 
No longer meeting criteria for at least CI after achieving CR, PR, or CI, or 
Loss of anemia response persisting for at least 1 month or 
Loss of spleen response persisting for at least 1 month 


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Response category 
Definition 
Recommendations for assessing treatment-induced cytogenetic and molecular changes 
Cytogenetic remission 
At least 10 metaphases must be analyzed for cytogenetic response evaluation and 
requires confirmation by repeat testing within 6 months window 
CR: eradication of a preexisting abnormality 
PR: ≥50% reduction in abnormal metaphases 
(partial response applies only to patients with at least ten abnormal metaphases at 
baseline) 
Molecular remission 
Molecular response evaluation must be analyzed in peripheral blood granulocytes 
and 
requires confirmation by repeat testing within 6 months window 
CR: Eradication of a pre-existing abnormality 
PR: ≥50% decrease in allele burden 
(partial response applies only to patients with at least 20% mutant allele burden at 
baseline) 
Cytogenetic/molecular 
relapse 
Re-emergence of a pre-existing cytogenetic or molecular abnormality that is 
confirmed by repeat testing 
1Tefferi et al. (2013) Revised response criteria for myelofibrosis: International Working (IWG-MRT) and European 
LeukemiaNet (ELN) consensus report Group-Myeloproliferative Neoplasms Research and Treatment. Blood; 
2013 122: 1395-1398 
EMH, extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology- or imaging study-
proven nonhepatosplenic EMH); LCM, left costal margin; UNL, upper normal limit. 
Grading of MF is according to the European classification 
Thiele et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 
2005;90:1128. 
It is underscored that the consensus definition of a CR bone marrow is to be used only in those patients in which 
all other criteria are met, including resolution of leukoerythroblastosis. It should also be noted that it was a 
particularly difficult task for the working group to reach a consensus regarding what represents a complete 
histologic remission. 
‡Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood 
cells. In splenectomized patients, <5% immature myeloid cells is allowed. 
§See above for definitions of anemia response, spleen response, and progressive disease. Increase in severity of 
anemia constitutes the occurrence of new transfusion dependency or a ≥20 g/L decrease in hemoglobin level from 
pretreatment baseline that lasts for at least 12 weeks. Increase in severity of thrombocytopenia or neutropenia is 
defined as a 2-grade decline, from pretreatment baseline, in platelet count or absolute neutrophil count, according 
to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. In addition, assignment to CI 
requires a minimum platelet count of ≥25 000 X 109/L and absolute neutrophil count of ≥0.5 X 109/L. 
||Applicable only to patients with baseline hemoglobin of<100 g/L. In patients not meeting the strict criteria for 
transfusion dependency at the time of study enrollment (see as follows), but have received transfusions within the 
previous month, the pre-transfusion hemoglobin level should be used as the baseline. 
^Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red 
blood cells (PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of <85 g/L, in the absence of 
bleeding or treatment-induced anemia. In addition, the most recent transfusion episode must have occurred in the 
28 days prior to study enrollment. Response in transfusion-dependent patients requires absence of any PRBC 
transfusions during any consecutive “rolling” 12-week 
interval during the treatment phase, capped by a hemoglobin level of ≥85 g/L. 
#In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy. 
**Spleen or liver responses must be confirmed by imaging studies where a ≥35% reduction in spleen volume, as 
assessed by MRI or CT, is required. Furthermore, a ≥35% volume reduction in the spleen or liver, by MRI or CT, 
constitutes a response regardless of what is reported with physical examination. 
††Symptoms are evaluated by the MPN-SAF TSS.1 The MPN-SAF TSS is assessed by the patients themselves 
and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal 
discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as 
bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). 
Symptoms response requires ≥50% reduction in the MPN-SAF TSS. 
‡‡Progressive disease assignment for splenomegaly requires confirmation my MRI or computed tomography 
showing a ≥25% increase in spleen volume from baseline. Baseline values for both physical examination and 
imaging studies refer to pretreatment baseline and not to post-treatment measurements. 


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Appendix J: Criteria for Response assessment in polycythemia 
vera (based on modified IWG-MRT guidelines and European 
LeukemiaNet (ELN) consensus report)1 
Response categories 
Required criteria 
Complete remission 
Durable resolution of disease-related signs including palpable hepatosplenomegaly, 
large symptoms improvement† AND 
Durable peripheral blood count remission, defined as Ht lower than 45% without 
phlebotomies; platelet count ≤400 X 109/L, WBC count <10 X 109/L, AND 
Without progressive disease, and absence of any hemorrhagic or thrombotic event, 
AND 
Bone marrow histological remission defined as the presence of age-adjusted 
normocellularity and disappearance of tri-linear hyperplasia, and absence of >grade 1 
reticulin fibrosis 
Partial remission 
Durable resolution of disease-related signs including palpable hepatosplenomegaly, 
large symptoms improvement† AND 
Durable peripheral blood count remission, defined as Ht lower than 45% without 
phlebotomies; platelet count ≤400 X 109/L, WBC count <10 X 109/L, AND 
Without progressive disease, and absence of any hemorrhagic or thrombotic event, 
AND 
Without bone marrow histological remission defined as persistence of tri-linear 
hyperplasia. 
No response 
Any response that does not satisfy partial remission 
Progressive disease 
Transformation into post-PV myelofibrosis, myelodysplastic syndrome or acute 
leukemia‡ 
Molecular response is not required for assignment as complete response or partial response. Molecular response 
evaluation requires analysis in peripheral blood granulocytes. Complete response is defined as eradication of a 
preexisting abnormality. Partial response applies only to patients with at least 20% mutant allele burden at 
baseline. Partial response is defined as ≥ 50% decrease in allele burden. 
WBC, white blood cell. 
†Large symptom improvement (≥10-point decrease) in MPN-SAF TSS.2 
‡For the diagnosis of post-PV myelofibrosis, see the IWG-MRT criteria3; for the diagnosis of myelodysplastic 
syndrome and acute leukemia, see WHO criteria. 
References (available upon request) 
1Barosi G, et al; Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and 
IWG-MRT consensus project. Blood 2013 121: 4778-4781 
2Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total 
symptom score: prospective international assessment of an abbreviated symptom burden scoring system among 
patients with MPNs [published correction appears in J Clin Oncol. 2012;30(36):4590]. J Clin Oncol. 
2012;30(33):4098-4103 
3Barosi G, Mesa RA, Thiele J, et al; International Working Group for Myelofibrosis Research and Treatment (IWG-
MRT). Proposed criteria for the diagnosis of post-polycythemia vera and postessential thrombocythemia 
myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and 
Treatment. Leukemia. 2008;22(2):437-438 


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Appendix K: Criteria for Response assessment in Essential 
thrombocythemia (based on modified IWG-MRT guidelines and 
European LeukemiaNet (ELN) consensus report)1 
Response category 
Definition 
Complete remission 
Durable resolution of disease-related signs including palpable hepatosplenomegaly, 
large symptoms improvement,† AND 
Durable peripheral blood count remission, defined as: platelet count ≤400 X 109/L, 
WBC count <10 X 109/L, absence of leukoerythroblastosis, AND 
Without signs of progressive disease, and absence of any hemorrhagic or 
thrombotic events, AND 
Bone marrow histological remission defined as disappearance of megakaryocyte 
hyperplasia and absence of >grade 1 reticulin fibrosis. 
Partial remission 
Durable resolution of disease-related signs including palpable hepatosplenomegaly, 
and large symptoms improvement, AND 
Durable peripheral blood count remission, defined as: platelet count ≤400 X 109/L, 
WBC count <10 X 109/L, absence of leukoerythroblastosis, AND 
Without signs of progressive disease, and absence of any hemorrhagic or 
thrombotic events, AND 
Without bone marrow histological remission, defined as the persistence of 
megakaryocyte hyperplasia. 
No response 
Any response that does not satisfy partial remission 
Progressive disease 
Transformation into PV, post-ET myelofibrosis, myelodysplastic syndrome or acute 
leukemia‡ 
Molecular response is not required for assignment as complete response or partial response. Molecular response 
evaluation requires analysis in peripheral blood granulocytes. Complete response is defined as eradication of a 
preexisting abnormality. Partial response applies only to patients with at least 20% mutant allele burden at 
baseline. Partial response is defined as ≥50% decrease in allele burden. 
WBC, white blood cell. 
†Large symptom improvement (≥10-point decrease) in MPN-SAF TSS.3 
‡For the diagnosis of PV see World Health Organization criteria (WHO)4; for the diagnosis of post-ET 
myelofibrosis, see the IWG-MRT criteria2; for the diagnosis of myelodysplastic syndrome and acute leukemia, see 
WHO criteria.4 
References (available upon request) 
1 Barosi G, et al; Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and 
IWG-MRT consensus project. Blood 2013 121: 4778-4781 
2 Barosi G, Mesa RA, Thiele J, et al; International Working Group for Myelofibrosis Research and Treatment 
(IWG-MRT). Proposed criteria for the diagnosis of post-polycythemia vera and postessential thrombocythemia 
myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and 
Treatment. Leukemia. 2008;22(2):437-438. 
3 Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total 
symptom score: prospective international assessment of an abbreviated symptom burden scoring system among 
patients with MPNs [published correction appears in J Clin Oncol. 2012;30(36):4590]. J Clin Oncol. 
2012;30(33):4098-4103. 
4 Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid 
Tissues. Lyon, France: IARC; 2008. 


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Appendix L: Criteria for Response assessment in 
Myelodysplasia (based on modified IWG guidelines)1 
Category 
Response Criteria 
Complete remission 
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines* 
Persistent dysplasia will be noted* 
Peripheral blood 
● Hgb ≥ 11 g/dL 
● Platelets ≥ 100 x 109/L 
● Neutrophils ≥ 1.0 x 109/L 
● Blasts 0% 
Partial remission 
All CR criteria if abnormal before treatment except: 
Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5% 
Cellularity and morphology not relevant 
Marrow CR 
Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment 
Peripheral blood: if HI responses, they will be noted in addition to marrow CR 
Stable disease 
Failure to achieve at least PR, but no evidence of progression for > 8 wks 
Failure 
Death during treatment or disease progression characterized by worsening of 
cytopenias, increase in percentage of bone marrow blasts, or progression to a more 
advanced MDS FAB subtype than pretreatment 
Relapse after CR or PR 
At least 1 of the following: 
● Return to pretreatment bone marrow blast percentage 
● Decrement of ≥ 50% from maximum remission/response levels in granulocytes or 
platelets 
● Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence 
Cytogenetic response 
Complete - Disappearance of the chromosomal abnormality without appearance of 
new ones 
Partial - At least 50% reduction of the chromosomal abnormality 
Disease progression 
For patients with: 
● Less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts 
● 5%-10% blasts: ≥ 50% increase to > 10% blasts 
● 10%-20% blasts: ≥ 50% increase to > 20% blasts 
● 20%-30% blasts: ≥ 50% increase to > 30% blasts 
Any of the following: 
● At least 50% decrement from maximum remission/response in granulocytes or 
platelets 
● Reduction in Hgb by > 2 g/dL 
● Transfusion dependence 
*Dysplastic changes should consider the normal range of dysplastic changes (modification). 
1Cheson, et al. Clinical application and proposal for modification of the InternationalWorking Group (IWG) 
response criteria in myelodysplasia. blood-2005-10-4149. 


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14.13 
Appendix M: Eastern Cooperative Oncology Group Performance 
Status 
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 
14.14 
Appendix N: International Myeloma Working Group (IMWG) 
uniform response criteria for multiple myeloma 
Response 
IMWG Criteria 
sCR 
CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow3 by 
immunohistochemistry or immunofluorescence4 
CR 
Negative immunofixation on the serum and urine and disappearance of any soft tissue 
plasmacytomas and < 5% plasma cells in bone marrow3 
VGPR 
Serum and urine M-component detectable by immunofixation but not on electrophoresis or ≥ 90% 
reduction in serum M-component plus urine M-component < 100 mg per 24 hr 
PR 
> 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >90% or to < 
200 mg/24 h 
If the serum and urine M-protein are unmeasurable,5 a > 50% decrease in the difference between 
involved and uninvolved FLC levels is required in place of the M-protein criteria 
If serum and urine M-protein are not measurable, and serum free light assay is also not 
measureable, > 50% reduction in plasma cells is required in place of M-protein, provided baseline 
bone marrow plasma cell percentage was > 30% 
In addition to the above listed criteria, if present at baseline, a > 50% reduction in the size of soft 
tissue plasmacytomas is also required 
SD 
Not meeting criteria for CR, VGPR, PR, or progressive disease 
PD5 
Increase of > 25% from lowest response value in any one or more of the following: 
Serum M-component and/or (the absolute increase must be > 0.5 g/dL)6 
Urine M-component and/or (the absolute increase must be > 200 mg/24 h) 
Only in patients without measurable serum and urine M-protein levels; the difference between 
involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL 
Bone marrow plasma cell percentage; the absolute percentage must be > 10%7 
Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the 
size of existing bone lesions or soft tissue plasmacytomas 
Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can 
be attributed solely to the plasma cell proliferative disorder 
Relapse 
Clinical relapse requires one or more of: 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB features).6 It is not 
used in calculation of time to progression or progression-free survival but is listed here as 
something that can be reported optionally or for use in clinical practice 
Development of new soft tissue plasmacytomas or bone lesions 
Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is 
defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the products of 
the cross-diameters of the measurable lesion 
Hypercalcemia (> 11.5 mg/dL) [2.65 mmol/L] 
Decrease in haemoglobin of > 2 g/dL [1.25 mmol/L] 
Rise in serum creatinine by 2 mg/dL or more [177 mmol/L or more] 


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Response 
IMWG Criteria 
1 BGM Durie et al. International uniform response criteria for multiple myeloma. Leukemia (2006) 1-7. 
2 Adapted from Durie BGM, et al. Leukemia 2006; 20: 1467-1473; and Kyle RA, Rajkumar SV. Leukemia 
2008;23:3-9 
Note: A clarification to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is 
by serum FLC levels: CR in such patients is defined as a normal FLC ratio of 0.26–1.65 in addition to CR criteria 
listed above. VGPR in such patients is defined as a >90% decrease in the difference between involved and 
uninvolved free light chain (FLC) levels. 
3 Confirmation with repeat bone marrow biopsy not needed. 
4 Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An 
abnormal ratio reflecting presence of an abnormal clone is kappa/lambda of > 4:1 or < 1:2. 
5 All relapse categories require two consecutive assessments made at any time before classification as relapse or 
disease progression and/or the institution of any new therapy. In the IMWG criteria, CR patients must also meet 
the criteria for progressive disease shown here to be classified as progressive disease for the purposes of 
calculating time to progression and progression-free survival. The definitions of relapse, clinical relapse and 
relapse from CR are not to be used in calculation of time to progression or progression-free survival. 
6 For progressive disease, serum M-component increases of >1 gm/dL are sufficient to define relapse if starting 
M-component is >5 g/dL. 
7 Relapse from CR has the 5% cut-off versus 10% for other categories of relapse. 
8 For purposes of calculating time to progression and progression-free survival, CR patients should also be 
evaluated using criteria listed above for progressive disease. 
14.15 
Appendix O: Myeloproliferative Neoplasm (MPN) Symptom 
Assessment Form Total Symptom Score (MPN-SAF TSS) 
 
Name: 
 
 
 
 
 
 
 
 
 Date: 
 
 
 
 
Fill out the form below to track the burden of your symptoms. 
For each symptom, please circle the number that best describes how severe that symptom is, 
on a scale of 0 to 10, with 0 being absent or as good as it can be and 10 being worst 
imaginable. Make sure you circle a number for every symptom. Be sure to share your 
answers with your haematologist or other healthcare professional. 
Symptom - 1 to 10, 0 if absent and 10 being worst imaginable 
Please rate your fatigue (weariness, tiredness) by circling the one number that best describes your WORST level of 
fatigue during the past 24 hours 
Fatigue 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT)  
 
 
 
 
 
 
 
   
          (WORST IMAGINABLE) 
Circle the one number that describes how much difficulty you have had with each of the following symptoms during 
the past week 
Filling up quickly when you eat (early satiety) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT)  
 
 
 
 
 
 
 
   
          (WORST IMAGINABLE) 
Abdominal discomfort 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT)  
 
 
 
 
 
 
 
   
          (WORST IMAGINABLE) 


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Inactivity 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT)  
 
 
 
 
 
 
 
   
          (WORST IMAGINABLE) 
Problems with concentration - compared to before my diagnosis 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT)  
 
 
 
 
 
 
 
   
          (WORST IMAGINABLE) 
Night sweats 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT)  
 
 
 
 
 
 
 
   
          (WORST IMAGINABLE) 
Itching (pruritus) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT)  
 
 
 
 
 
 
 
   
          (WORST IMAGINABLE) 
Bone pain (diffuse, not joint pain or arthritis) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT)  
 
 
 
 
 
 
 
   
          (WORST IMAGINABLE) 
Fever (> 37.8°C or 100°F) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT)  
 
 
 
 
 
 
 
   
          (WORST IMAGINABLE) 
Unintentional weight loss last 6 months 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT)  
 
 
 
 
 
 
 
   
          (WORST IMAGINABLE) 
To help you get a clear overall picture of how you are feeling, you can add up all your scores to 
calculate your Total Symptom Score. 
Total: 
 
1Adapted from Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom 
assessment form total symptom score: prospective international assessment of an abbreviated 
symptom burden scoring system among patients with MPNs [published correction appears in J Clin 
Oncol. 2012;30(36):4590]. J Clin Oncol. 2012;30(33):4098-4103 
14.16 
Appendix P: List of prohibited concomitant medications and 
concomitant medications requiring caution for ceritinib 
Table 14-13 
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* 
cisapride* 
cyclosporine 
diergotamine 
ergotamine 
fentanyl 
pimozide 
quinidine* 
tacrolimus 
alfentanil 
terfenadine* 
sirolimus 


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Strong CYP3A4/5 inhibitors 
Macrolide antibiotics: 
clarithromycin 
telithromycin 
troleandomycin 
Antivirals: 
indinavir 
lopinavir 
nelfinavir 
ritonavir 
saquinavir 
tipranavir 
Antifungals: 
itraconazole 
ketoconazole 
posaconazole 
voriconazole 
Others: 
conivaptan 
elvitegravir 
mibefradil 
nefazodone 
Strong CYP3A/5 inducers 
avasimibe 
carbamazepine 
phenobarbital 
phenytoin 
rifabutin 
rifampin 
St. John’s wort 
 
* Compounds with risk of QT prolongation 
For an updated list of CYP2C substrates, CYP3A substrates, inhibitors and inducers, please reference the 
Novartis Oncology Clinical Pharmacology internal memo: drug-drug interactions (DDI) database, Oct 2010, which 
is compiled primarily from the FDA’s “Guidance for Industry, Drug Interaction Studies”, the Indiana University 
School of Medicine’s Drug Interactions Database, and the University of Washington’s Drug Interaction Database. 
**Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with a 
known potent inhibitor. 
Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades 
de Pointes). 
Table 14-14 
List of medications to be used with caution 
CYP2C9 substrates 
losartan 
piroxicam 
celecoxib 
irbesartan 
tolbutamide 
sulfamethoxazole 
diclofenac 
glipizide 
tolbutamide 
ibuprofen 
acenocoumarol 
torsemide 
CYP3A4/5 substrates 
dronedarone 
alprazolam 
diazepam 
amlodipine 
diltiazem 
nifedipine 
nisoldipine 
nitrendipine 
capravirine 
ritonavir 
telaprevir 
atorvastatin 
everolimus 
clarithromycin 
erythromycin 
telithromycin 
aripiprazole 
haloperidol 
imatinib 
nilotinib 
methadone 
boceprevir 
brecanavir 
simvastatin 
quinine 
tamoxifen 
tolvaptan 
trazodone 
vincristine 
verapamil 
Moderate CYP3A4/5 inhibitors 
ciprofloxacin 
erythromycin 
amprenavir 
atazanavir 
darunavir 
fosamprenavir 
diltiazem 
verapamil 
grapefruit juice 
aprepitant 
casopitant 
cimetidine 
dronedarone 
tofisopam 
Moderate CYP3A4/5 inducers 
bosentan 
nafcillin 
efavirenz 
ritonavir 
etravirine 
talviraline 
modafinil 
tipranavir 
Proton pump inhibitors 
esomeprazole 
rabeprazole 
lansoprazole 
omeprazole 
pantoprazole 
This database 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 
(www.druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction Studies” 


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Table 14-15 
List of prohibited enzyme-inducing anti-epileptic drugs 
Prohibited enzyme-inducing anti-epileptic drugs 
carbamazepine 
phenobarbital 
ethotoin 
phenytoin 
felbamate 
primidone 
fosphenytoin 
topiramate 
Table 14-16 
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, .azcert.org/medical-pros/drug-lists/drug-lists.cfm 
14.17 
Appendix Q: Bayesian Adaptive Design 
14.17.1 Introduction 
This document outlines the adaptive design framework to be used for all trials within 
Novartis’s Modular phase II program designed to link targeted therapy to patients with 
pathway activated tumors.   
Although the selected tumor types may vary by trial, this document outlines the design and 
analysis approach based on 8 example tumor cohorts: 
• Lung NSCL 
• Bladder 
• Breast 
• Colorectal 
• GIST 
• HNSCC 
• Ovarian 
• Sarcoma 
Other tumor types may be considered for trials if 1) 4 or more patients are enrolled in the 
cohort, and 2) a reasonable estimate of the clinical benefit rate is available.   


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The primary endpoint is clinical benefit rate (CBR) in each cohort, with clinical benefit being 
assessed at 16 weeks.  All patients will receive the experimental treatment for that particular 
trial. 
14.17.1.1 Primary Analysis 
We let Yi be the response indicator for the ith subject, and let Rg be the assumed probability of 
response within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability 
of response for group g within the trial. We transform to the logit scale for modeling purposes. 
Let θg be the mean log odds treatment effect, i.e.: 
𝜃𝜃𝑔𝑔= log ቆ
𝜋𝜋𝑔𝑔
1 −𝜋𝜋𝑔𝑔
ቇ−log ቆ
𝑅𝑅𝑔𝑔
1 −𝑅𝑅𝑔𝑔
ቇ. 
Thus, θg is the group specific logistic regression coefficient for group g. The primary analysis 
is a set of group specific tests that θg>0, meaning that the experimental treatment is better than 
the assumed control rate for that group. Thus, we wish to test the set of hypotheses. 
H0g : θg≤0 
H1g : θg>0 
We proceed in a Bayesian fashion, assigning a prior distribution (discussed below) and 
computing the posterior probability of H1g within each group g. If, at the final analysis, 
Pr(θg>0 | data) > 0.80 
Then group g will be declared a success (thus, the final analysis produces a separate decision 
for each group). The trial also allows for early stopping of groups, described below. 
14.17.1.2 Trial Logistics 
Each trial will enroll all available subjects in all cohorts for 2 years unless a cohort cap is 
reached, or a cohort is stopped early, or the trial is stopped early by Novartis. Each trial will 
enroll no more than 30 evaluable subjects in each cohort. Interim monitoring will be 
conducted starting after the first 30 patients are enrolled overall (across all cohorts), and 
continuing each 13 weeks thereafter till study enrollment closure. After that, one CBR 
analysis will be done after database lock. At each interim data review, response information 
for the various cohorts will be evaluated to determine the current Pr(θg>0 | data) within each 
cohort, with sufficiently high/low values used to stop the cohort for success/futility. A 
minimum of 10 patients will be required in a cohort before it may discontinue enrollment for 
futility, and a minimum of 15 patients are required before discontinuing a cohort for efficacy. 
If a cohort stops enrolling early, the remaining cohorts will continue until the end of 2 years or 
until the other cohorts reach their own early stopping criteria. The final analysis will occur 
after the database lock for the primary CSR. 
Each trial will enroll subjects in all listed cohorts. In addition, should other cohorts be 
identified throughout the trial, the following mechanism will be used. If another cohort is 
identified, it will not be placed into the statistical analysis unless 3 subjects enroll within the 
cohort (thus, the trial may enroll multiple additional cohorts, but a cohort will only be added 
to the list if at least 3 patients enroll from that cohort). Thus, it is possible (but not viewed as 


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likely) that multiple additional cohorts may be added to the trial if the trial has sufficient 
enrollment in multiple additional cohorts. In addition to sufficient enrollment, the sponsor 
must have a reasonable estimate of the control clinical benefit rate. 
Subjects within any cohort which does not reach the minimum enrollment will be excluded 
from the interim and final analyses. As the study continues, early interim data reviews may be 
based on fewer cohorts than later interim data reviews, as the interim data reviews will 
include whatever cohorts have satisfied the criteria at the time of the data review. 
14.17.2 Statistical Modeling 
We let Yi be the response indicator for the ith subject, and let Rg be the probability of response 
within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability of 
response for group g within the trial. We transform to the logit scale for modeling purposes. 
Let θg be the mean log odds treatment effect, i.e.: 
𝜃𝜃𝑔𝑔= log ቆ
𝜋𝜋𝑔𝑔
1 −𝜋𝜋𝑔𝑔
ቇ−log ቆ
𝑅𝑅𝑔𝑔
1 −𝑅𝑅𝑔𝑔
ቇ 
The statistical design borrows information across groups with a hierarchical model. The 
hierarchical model allows dynamic borrowing of information between groups such that more 
borrowing occurs when the groups are consistent and less borrowing occurs when the groups 
differ.  In this way, the model is a compromise between the two alternate extremes of either a 
completely pooled analysis or a separate analysis in each group. We additionally incorporate a 
clustering mechanism that allows borrowing within clusters but treats clusters separately. This 
minimizes borrowing across groups that are quite different in terms of CBR. 
The purpose of such an analysis (discussed in more detail in the appendix) is to produce 
higher power or lower type I error in situations where we see some commonality (identical 
effects are not required) among the groups. The model will borrow more in situations where 
the groups appear similar than situations where the groups appear different. 
14.17.2.1 Hierarchical Model with Clustering 
Our hierarchical approach involves two stages. The goal of both stages is to allow the data to 
drive the amount of borrowing across groups. If the data indicate a large amount of borrowing 
is appropriate (due to similar results), the model will borrow more and thus increase the 
overall power of the trial within each group. In contrast, if the data indicate a small amount of 
borrowing is appropriate (due to dissimilar results) the model will adjust and each group will 
stand more on its own. This “dynamic” borrowing property is distinct from other approaches 
which use a fixed informative prior or apriori assume an amount of borrowing across groups. 
Here the approach includes two stages to identify the appropriate amount of borrowing based 
on the data. 
The first stage of model places the groups into distinct clusters. The purpose of this stage is to 
minimize borrowing of information across groups that appear to be quite different. Thus, for 
example, should 2 of the groups appear similar while the others differ significantly, the model 
may place a large probability on two clusters, one containing the two similar groups with the 
other containing the remaining groups. The model incorporates the uncertainty of the data in 


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this determination, producing a probability distribution over the possible clusterings. Thus, in 
our example, the model may consider it highly likely that the 2 similar groups are in one 
cluster with the remaining groups in another, but it would also retain lower probabilities on 
the possibility all groups are in one cluster (e.g. we are simply seeing differences in the two 
groups by chance) as well as other possibilities. The complete analysis averages over this 
uncertainty. This clustering approach is implemented through a Dirichlet Process Mixture 
(DPM) model, described in the appendix. 
At the second stage, we place hierarchical models over the groups within each cluster (thus, 
conditional on the clustering, there is no borrowing of information across clusters, only within 
clusters). The hierarchical model assumes that the 𝜃𝜃𝑔𝑔 have an across groups distribution 
θg ~ N(μ, τ2) 
The across group mean µ and variance τ2 are unknown, and hence have a prior distribution 
which is combined with the data to produce estimates of µ and τ2. 
The variance component τ controls the degree of borrowing among groups.  Small values of τ 
result in a greater degree of borrowing while large values of τ correspond to less borrowing. 
The parameter τ is estimated using the data, so the observed between group variation is a key 
component of the model behavior.  
Combined, the two stages allow groups with similar results to borrow information between 
them (they will have a high probability of being in the same cluster) while groups with 
different results with borrow far less information between them (they will have a low 
probability of being in the same cluster). 
Details of the two stages may be found in the appendix. 
14.17.3 Evaluation of Trial Success and Futility  
Interim monitoring will occur after the first 30 patients are on the study for 16 weeks (112 
days), then every 13 weeks thereafter till study enrollment closure. At each interim data 
review, the groups will be evaluated for early futility and early success by comparing 
posterior quantities for the response rate to pre-specified early stopping criteria. 
14.17.3.1 Early Futility  
If there is less than 10% probability that the response rate in a group exceeds the historical 
rate Rg, then the group will stop enrollment early for futility.  Formally, enrollment will stop 
early for futility if: 
Pr(πg > Rg) < 0.10. 
A group is only eligible for early stopping once a minimum of 10 patients has been evaluated 
for response in that group. 
14.17.3.2 Early Success 
If there is at least 95% probability that the response rate in a group exceeds the historical rate, 
then the group will stop enrollment early for success.  Formally, enrollment will stop early for 
success if: 


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Pr(πg > Rg) > 0.95. 
A minimum of 15 subjects will need to be evaluated prior to declaring a group to be 
efficacious. 
14.17.3.3 Final Analysis 
In addition, recall the final analysis will occur when both accrual and follow-up are complete 
in all groups, or after the database lock for the primary CSR. If, at the completion of the trial, 
there is at least 80% probability that the response rate in a group exceeds the historical rate, 
then the group will be considered a success. Formally: 
Pr(πg > Rg) > 0.80. 
14.17.4 Simulation 
We evaluated type I error and power for each of the 8 possible groups under a variety of 
possible “truths” indicating various possible true underlying probabilities within each group. 
14.17.4.1 Assumptions 
Accrual – Two scenarios for the assumed two-year expected accrual are investigated: 1) 10 
subjects per group and 2) 5 subjects per group.  Note that these are averages, the actual 
number of available patients is simulated as a Poisson distribution with the specified mean.  
Also note that the group cap of 30 applies, and thus if the number of available patients in a 
group exceeds 30, only the first 30 available patients in that group will be enrolled in the 
study. 
Dropouts – We assume no dropouts for the purpose of this simulation. 
Control Rates –Table 14-17 shows the assumed control clinical benefit rates for each group. 
Table 14-17 
Assumed control CBR values used in the simulations. 
Tumor Type 
Assumed Control Rate (Rg) 
Lung LSCL 
0.45 
Bladder 
0.47 
Breast 
0.50 
Colorectal 
0.38 
GIST 
0.50 
HNSCC 
0.45 
Ovarian 
0.47 
Sarcoma 
0.40 
We consider four possible scenarios, or possible “truths” in the simulation. These consisted of 
a null scenario (where the treatment has no effect for any group), an alternative scenario 
(where the treatment is effective in all groups), a scenario where the treatment was effective in 
two of the groups, and a scenario where the treatment was effective in half of the groups. 
Treatment Rates - The treatment rates for each scenario are shown in the table below. Values 
identical to the control are shown in bold, while values greater than the assumed control rate 
are shown in italics. 


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Null 
Alternative 
Two 
Half 
Lung LSCL 
0.45 
0.71 
0.45 
0.45 
Bladder 
0.47 
0.73 
0.47 
0.47 
Breast 
0.50 
0.75 
0.50 
0.50 
Colorectal 
0.38 
0.65 
0.38 
0.38 
GIST 
0.50 
0.75 
0.50 
0.75 
HNSCC 
0.45 
0.71 
0.45 
0.71 
Ovarian 
0.47 
0.73 
0.73 
0.73 
Sarcoma 
0.40 
0.67 
0.67 
0.67 
Simulation Details – For each scenario we simulated 1000 trials. For each interim within each 
trial, we ran 50,000 MCMC iterations after a 1,000 MCMC iteration burnin. 
14.17.4.2 Results 
A total of 8 scenarios were simulated (two accrual scenarios and four possible ‘truths’ for the 
clinical benefit rate).  The probability of group success for each group is provided for each 
scenario in the below two tables. 
Table 14-18 provides the probability of group success for each of the cohort – assuming 
expected accrual of 10 subjects/cohort and 5 subjects/cohort separately. 
Table 14-18 
Probability of group success 
Two-year expected accrual: 10 subjects/cohort 
Group 
Null 
Alternative 
Two 
Half 
Lung LSCL 
0.158 
0.915 
0.208 
0.305 
Bladder 
0.131 
0.918 
0.232 
0.322 
Breast 
0.147 
0.909 
0.233 
0.312 
Colorectal 
0.138 
0.921 
0.200 
0.276 
GIST 
0.162 
0.921 
0.233 
0.826 
HNSCC 
0.139 
0.906 
0.217 
0.834 
Ovarian 
0.145 
0.929 
0.786 
0.829 
Sarcoma 
0.135 
0.939 
0.758 
0.852 
 
Two-year expected accrual: 5 subjects/cohort 
Group 
Null 
Alternative 
Two 
Half 
Lung LSCL 
0.132 
0.803 
0.204 
0.258 
Bladder 
0.140 
0.830 
0.196 
0.265 
Breast 
0.160 
0.807 
0.232 
0.261 
Colorectal 
0.135 
0.794 
0.194 
0.278 
GIST 
0.155 
0.826 
0.212 
0.688 
HNSCC 
0.140 
0.820 
0.190 
0.657 
Ovarian 
0.151 
0.819 
0.587 
0.652 
Sarcoma 
0.139 
0.799 
0.579 
0.667 


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Entries in bold represent groups where the treatment effect is 0 (e.g. the treatment is 
ineffective). Thus, entries in bold are type I errors. Entries in italics appear where the 
treatment is effective, and thus indicate the power of the design. 
Generally, type I error is controlled below 0.20 under the null scenario (the borrowing 
compensates for the multiple interim data reviews) and power is an increasing function of the 
expected sample size (power is higher in the higher accrual situation across treatment rate 
scenarios).  In the alternative scenario there remains decently high probability of success even 
in the lower accruing situations. When fewer groups are effective in truth, the scenarios “half” 
and “two” are harder to discern. Note in any particular trial there should be a mix of high and 
low enrolling groups, thus some groups may enroll closer to 10 subjects while others may 
only enroll five. This would produce a power value somewhere between the two tables. 
Power is reduced and type I error is inflated when the truth is a mixture of effective and 
ineffective treatment effects across the groups. Generally power is a function of the sample 
size. 
Appendix 1 - Modeling Details 
Recall at the first stage the groups are clustered according to a Dirichlet Process Mixture 
Model. 
The number of clusters is not assumed to be known in advance but will instead be inferred 
from the data using Dirichlet Process Mixtures (DPM). The DPM looks across all the possible 
clusterings of the groups and assigns a probability to each based on the data. The prior 
distribution in a DPM is governed by a parameter α. When α is small, the prior favors large 
clusters. As α tends to zero, the prior tends to place all its mass on a single cluster containing 
all the groups. As α increases, the prior places more mass on clusterings with a large number 
of clusters. As α becomes very large, the prior places all of its mass on having a separate 
cluster for each group (that is, no borrowing across groups). Thus, by specifying extreme 
values of the prior one could force the groups into one cluster or force the groups to be 
analyzed in separate clusters. Here we choose a moderate version of α=2 (common values 
might be anywhere between 0.5 and 5) and allow the data more control over the clustering.  
The details of the prior are as follows. Let zg represent the cluster to which group g belongs.  
Then zg ~ Categorical(p), where p is the vector such that pk is the probability that a group 
belongs to cluster k and ∑
𝑝𝑝𝑘𝑘
∞
𝑘𝑘=1
= 1. We construct p using a stick-breaking process: 
𝑝𝑝𝑘𝑘= 𝛽𝛽𝑘𝑘ෑ(1 −𝛽𝛽𝑖𝑖)
𝑘𝑘−1
𝑖𝑖=1
 
and 
βk ~ Beta(1, α). 
A large value of α thus removes a very small amount of probability for p, resulting in many 
clusters, while a small value of α tends to produce probabilities near 1 for the first cluster.  
Conditional on the clustering, we fit a hierarchical model which has an across groups 
distribution  


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θg ~ N(μ, τ2) 
As discussed above, this across group distribution states that within a cluster we expect to see 
some variation in the parameters, with that variation governed by τ. When τ is small, there is 
minimal variation across groups within a cluster, and thus within the cluster the model would 
approach pooling. In contrast, when τ is large we expect large amount of across group 
variation, and thus even though the groups are in the same cluster the θg values may be quite 
different. Apriori we have no way of knowing τ, so we estimate it using the data combined 
with the prior distributions 
μ ~ N(0, 1.82) 
and 
τ2 ~ IG(3,0.5), 
where IG(α, β) is the inverse gamma distribution defined by: 
𝑓𝑓(𝑥𝑥|𝛼𝛼, 𝛽𝛽) = 𝛽𝛽𝛼𝛼𝑒𝑒−𝛽𝛽𝑥𝑥
⁄
𝑥𝑥𝛼𝛼+1Γ(𝛼𝛼). 
When the entire model is implemented (via Markov Chain Monte Carlo) we consider the full 
joint distribution of the clustering combined with the hierarchical model parameters. We 
average over the entire range of the uncertainty in the parameters to produce the posterior 
distribution for each group parameter θg, which is then used to drive the decisions in the 
model. 

SAP_000.pdf: 
Clinical Development & Medical Affairs 
LDK378 
Protocol CLDK378AUS23 / NCT02186821 
Modular phase II study to link targeted therapy to patients with 
pathway activated tumors: 
Module 7 – Ceritinib (LDK378) for patients whose tumors have 
aberrations in ALK or ROS1 
RAP Module 3 – Detailed Statistical Methodology 
Author: 
 
Document type: 
RAP Documentation 
Document status: 
Final v2.0 
Release date: 
09Apr2017 
Number of pages: 
23 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous version of RAP module 3. 
Version 
Date 
Changes 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1 
Statistical methods planned in the protocol and determination of sample size ................... 5 
2 
Statistical and analytical plans ............................................................................................. 5 
2.1 
Change in planned analyses from the protocol ........................................................ 6 
 
 7 
3 
Subjects and treatments ....................................................................................................... 7 
3.1 
Analysis sets ............................................................................................................ 7 
3.2 
Subject disposition ................................................................................................... 8 
3.3 
Study Treatment and other concomitant medications ............................................. 8 
4 
Patient demographics and other baseline characteristics ..................................................... 9 
5 
Study treatment exposure and other medications .............................................................. 10 
5.1 
Study treatment ...................................................................................................... 10 
5.2 
Prior and concomitant medications/non-drug therapies ........................................ 10 
6 
Efficacy and PRO evaluation ............................................................................................ 11 
6.1 
Clinical Benefit Rate (CBR) .................................................................................. 11 
6.2 
Overall Response Rate (ORR) ............................................................................... 11 
6.3 
Progression Free Survival (PFS) ........................................................................... 12 
6.4 
Overall Survival (OS) ............................................................................................ 12 
6.5 
Clinical Benefit Rate by Gene Mutations .............................................................. 12 
7 
Safety evaluation ............................................................................................................... 12 
7.1 
Adverse events ....................................................................................................... 12 
7.1.1 
Specific safety event categories ............................................................ 13 
7.2 
Deaths .................................................................................................................... 14 
7.3 
Vital signs .............................................................................................................. 14 
7.4 
Laboratory evaluations .......................................................................................... 14 
7.5 
Other safety evaluations ........................................................................................ 15 
8 
Interim analyses ................................................................................................................. 15 
9 
Determination of sample size ............................................................................................ 15 
10 Bayesian Adaptive Design ................................................................................................ 17 
10.1 
Introduction ............................................................................................................ 17 
10.1.1 
Primary Analysis ................................................................................... 17 
10.1.2 
Trial Logistics ....................................................................................... 18 
10.2 
Statistical Modeling ............................................................................................... 18 
10.2.1 
Hierarchical Model with Clustering ...................................................... 19 
10.3 
Evaluation of Trial Success and Futility ................................................................ 20 
10.3.1 
Early Futility ......................................................................................... 20 


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10.3.2 
Early Success ........................................................................................ 20 
10.3.3 
Final Analysis........................................................................................ 20 
10.4 
Simulation .............................................................................................................. 20 
10.4.1 
Assumptions .......................................................................................... 21 
10.4.2 
Results ................................................................................................... 21 
10.5 
Modeling Details ................................................................................................... 22 
11 References ......................................................................................................................... 23 


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1 
Statistical methods planned in the protocol and 
determination of sample size 
The primary efficacy variable, clinical benefit rate, will be analyzed by a Novartis designated 
Contract Research Organization (CRO), 
 Analysis details are provided in 
Appendix Q of the protocol, which is also included in Section 10 of this Report Analysis Plan 
(RAP).  
 
 
All other data will be analyzed by a different Novartis-designated CRO, 
 
 according to Section 10 of the study protocol which will be available in 
Appendix 16.1.1 of the Clinical Study Report (CSR).  Important information is given in the 
following sections and details will be provided, as applicable, in Appendix 16.1.9 of the CSR.  
All statistical analyses will be performed using SAS® Version 9.3 (or higher).   
2 
Statistical and analytical plans 
Data from all centers that participate in this protocol will be used.  The analyses stated in this 
document will be based on all subjects’ data upon data base lock. The study is early 
terminated by sponsor. Last subject’s survival follow-up was closed on August 4, 2016.  
All statistical analyses presented in this document are related to subject background 
information, efficacy, and safety variables collected for the study.  All analyses are descriptive 
and no hypothesis testing is planned (except for the primary efficacy variable, which is 
described in Section 10).  Data from all centers will be combined for any analysis.  In general, 
there is no stratification factor being considered for the analysis with the exception of tumor 
type in the primary efficacy variable analyses.  Missing data will not be imputed unless 
otherwise specified.  All data collected in the study will be presented in the listings.  In 
general, this document will detail the methods used in summaries/tabulations.  
The study population consists of adult subjects with a diagnosis of a solid tumor or 
hematological malignancy that have been pre-identified as having ALK or ROS1 positive 
mutations, translocations, rearrangements or amplifications. Pre-identification of the 
mutation or activation in the pathway will be performed locally at a Clinical Laboratory 
Improvement Amendments (CLIA) certified laboratory prior to participation in the study.  
Subject must have archival or fresh tissue available for submission to a central laboratory 
selected by Novartis to allow for molecular testing related to pathway regulation.  If the 
tissue is not available or is insufficient, the subject must be willing to undergo a fresh tumor 
biopsy to allow for this analysis.  Mutation types from both local and central laboratories will 
be analyzed. 
To be eligible for enrollment to this study, subjects must have received at least one prior 
treatment for their recurrent, metastatic and/or locally advanced disease and have no 
remaining standard therapy options anticipated to result in a durable response.  Subjects 
must have progressive and measurable disease (per RECIST 1.1 or appropriate 
hematological response criteria) and are in need of treatment. 


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Subjects are administered with ceritinib at 750 mg once daily.  A complete treatment cycle 
is defined as 28 days.  Subjects may continue on study treatment until disease progression, 
withdrawal of consent, unacceptable toxicity, death, or any other reasons (e.g., physician’s 
decision).  After discontinuation of study treatment, subjects, regardless of reason for study 
treatment discontinuation will be followed for safety for 30 days after the last dose.  
Survival information will be collected every 3 months until 2 years after the last subject has 
enrolled in the study regardless of treatment discontinuation reason (except if consent is 
withdrawn).  Additional survival assessments may be performed outside the 3 months 
follow-up schedules if a survival update is required for an interim assessment to meet safety 
or regulatory needs.  Note that, survival follow-up has been terminated for this study on 
August 4, 2016. 
The primary efficacy objectives of the study, clinical benefit (definition details see Section 
6.1) associated with ceritinib treatment based on local investigator assessment, will be 
summarized.  The clinical benefit rate will be analyzed using a Bayesian hierarchical model to 
evaluate trial success and futility, and the relationship between relevant pathway regulation 
and the response to treatment with ceritinib (if applicable).  Analysis details are documented 
in Section 10. 
Duration of response (DOR) based on local investigator assessment will be analyzed.  In the 
event of a low response rate, DOR will be listed only without frequency summaries.  Overall 
response (OR) will be summarized with the number and percentages of subjects for each 
response category (e.g., for solid tumor - CR, PR, SD, PD, Not evaluable).  Progression-free 
survival (PFS) will be summarized using Kaplan-Meier (KM) methodology.  Due to limited 
survival follow-up for the study, overall survival will only be descriptively summarized, ie, 
only the frequency of deaths will be provided. 
Subject demographics, disease characteristics (including mutation analyses), ceritinib 
treatment, and safety variables will be summarized descriptively, by nominal visit (if 
applicable), and/or overall. 
Data used for the analyses specified in this document will come from the Electronic Data 
Capture (EDC) system. In addition, the mutation data from the central laboratory will be 
collected in an Excel spreadsheet format and subsequently be uploaded to a secure FTP site 
by Novartis. 
2.1 
Change in planned analyses from the protocol 
The protocol specifies that analyses are to be conducted by “patient group” which is formed 
by the types of cancer at study entry.  That is, subjects with the same tumor type will be 
considered as in the same “patient group”.  For efficacy analyses, with exception of the 
primary analysis of clinical benefit rate (i.e., summarized by ‘patient group’), other 
descriptive summaries in general will be produced overall for all ceritinib-treated subjects.  
Separate summaries may be produced for those groups with at least 10 subjects.  All subjects 
will be combined for any safety analyses. 
In the event of a low response rate, DOR will only be listed, and not tabulated. Subjects who 
had no disease progression/death will be censored at last adequate tumor assessment on or 
before the discontinuation/completion of the study.  


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For determination of PFS events, due to tumor assessments post study treatment are not 
collected, deaths occurred more than 30 days post treatment without prior progressive 
disease/relapse of disease will not be considered as an event. 
For overall survival analysis, no KM method will be used due to early study termination.  
Descriptive summaries will be provided instead. 
For vital signs, values will be descriptively summarized by nominal visit. Separate summaries 
of significant abnormalities will not be provided, but will be reflected in adverse events 
(AEs).  
For cardiac imaging, due to data collection is only as clinically indicated, thus only listing will 
be provided. 
3 
Subjects and treatments  
3.1 
Analysis sets 
The following analysis data sets will be used in the analyses: 
Full analysis set (FAS): The FAS will include all subjects who have received at least one 
dose of the study drug.  The FAS will be the primary set for efficacy analyses.  
Safety set (SS): The SS will include all subjects who have received at least one dose of the 
study treatment and had at least one post-baseline safety assessment.  A subjects who has 
received a dose of study treatment and who has no post-treatment safety data of any kind (i.e., 
no AE assessment, no vitals, no ECG, no cardiac imaging, no ECOG performance status, and 
no laboratory assessment) will be excluded from the SS.  Note that the statement ‘no adverse 
event’ is considered as an assessment of AE. 


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3.2 
Subject disposition 
The number and percentage of subjects who completed study treatment or prematurely 
discontinued from the study treatment will be summarized with reasons for premature 
discontinuation.  The reasons for study treatment discontinuation are as follows: 
1. Adverse events 
2. Lost to follow-up 
3. Death 
4. Disease progression 
a. Radiological assessment 
b. Clinical assessment 
5. Protocol deviation 
6. Non-compliance with study treatment 
7. Pregnancy 
8. Physician’s decision 
9. Subject/guardian decision 
10. Study terminated by sponsor 
In addition, the number and percentage of subjects who consent to be followed for survival 
will be presented. 
For subjects who were screened but did not take the study treatment, a listing with reasons for 
screen failure will be provided.  The reasons collected for screen failure are as follows: 
1. Unacceptable past medical history/concomitant diagnosis 
2. Intercurrent medical event 
3. Unacceptable laboratory value(s) 
4. Unacceptable test procedure result(s) 
5. Did not meet diagnostic/severity criteria 
6. Unacceptable use of excluded medications/therapies 
7. Subject withdrew consent 
8. Unknown 
9. Other 
In addition, a listing of subjects’ deviations/violations during the study will be provided. 
3.3 
Study Treatment and other concomitant medications 
Subjects receive ceritinib at 750 mg once daily.  A complete treatment cycle is 28 days.  
There is no break between dosing cycles. For subjects who are unable to tolerate the protocol-
specified dosing schedule, dose adjustments are permitted in order to allow these subjects to 
continue study treatment.  Protocol section 6.3 provides the details.   
In general, concomitant medications and therapies deemed necessary for the care of the 
subject are permitted (see Protocol Section 6.4.1 and 6.4.2), except as specifically prohibited 


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(see Protocol Section 6.4.3). All medications, procedures and significant non-drug therapies 
(including physical therapy, oxygen and blood transfusions) administered within 30 days prior 
to the administration of ceritinib and through 30 days after the last dose of study treatment 
will be recorded in the corresponding CRF page.  
Detailed summaries of study treatment and other concomitant medications are described in 
Section 5 below. 
4 
Patient demographics and other baseline characteristics 
Demographic data, medical history, disease characteristics and other baseline characteristics 
are collected at the screening visit. 
In general, the baseline value will be considered as the last measurement observed prior to the 
first dose of study treatment, and includes assessments taken on the date of the first dose of 
study treatment.   
Unless specified otherwise, for continuous data, the mean, standard deviation, median, 25th 
and 75th percentiles, minimum, and maximum will be presented.  For categorical data, 
frequencies and percentages will be presented.   
Demographic characteristics 
Demographic variables include:  
• Age (years), age group (<65, ≥65-<75, ≥75 years) 
• Sex (Male, Female – able to bear children, premenarche, post menopausal, sterile of 
child bearing age) 
• Race (Caucasian, Black, Asian, Native American, Pacific Islander, Other) 
Medical history 
Number and percentage of subjects with relevant and/or current medical history/conditions 
will be summarized by categories of conditions.  For ongoing conditions, grade of condition 
(i.e., 1-4) will also be summarized. Medical history/current medical conditions will be coded 
using Medical Dictionary for Regulatory Activities (MedDRA). The MedDRA version used 
for reporting the study will be specified as a footnote in the tables/listings. 
Disease characteristics 
Disease characteristics variables include: 
• Gene mutations as detected by local and central labs in pre-defined per-protocol 
mutation categories 
• Primary tumor type (Sponsor adjudicated) 
Note: The tumor type adjudication is made based on the combination of the primary 
site of tumor with the tumor histology/cytology as collected in the CRFs. 
• Time (in months) from initial diagnosis to the first dose of ceritinib 


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• Time (in months) from date of most recent recurrence/relapse to the first dose of 
ceritinib 
• Stage at initial diagnosis 
• Age of biopsy samples (in months) calculated from date of biopsy sample date to the 
first dose of ceritinib 
Other baseline assessments 
• Vital signs (height, weight, body temperature, respiratory rate, sitting pulse, sitting 
systolic/diastolic blood pressures [SBP/DBP]) 
• 12 lead ECG (QTcF, heart rate, PR duration, QT duration, QRS duration) 
• Cardiac imaging (LVEF) 
• ECOG performance status 
• Prior lines of antineoplastic medication therapy 
• Prior antineoplastic radiotherapy (yes/no) 
• Prior antineoplastic surgery (yes/no)   
5 
Study treatment exposure and other medications 
5.1 
Study treatment 
Duration of ceritinib treatment (in months) and actual total dose (sum of daily ceritinib 
treatment) will be summarized with mean, standard deviation, median, 25th percentile, 75th 
percentile, minimum and maximum.  Duration of the treatment is defined as the last dose date 
of ceritinib minus the first dose date of ceritinib + 1.  The number and percentage of subjects 
with ceritinib exposure for the following categories will be presented as well: day 1 – day 61 
(≤ 2 month), day 62 – day 122 (> 2 months - ≤ 4 months), day 123 – day 183 (> 4 months - ≤ 
6 months), day 184 – day 244 (> 6 months - ≤ 8 months), day 245 – day 365 (> 8 months - ≤ 
12 months), and ≥ day 366 (> 12 months). 
Actual dose intensity and relative dose intensity of ceritinib will be summarized. Dose 
intensity is defined as the total dose of ceritinib (mg) divided by duration of ceritinib (in 
days).  Relative dose intensity (in percent) is the actual dose intensity divided by planned dose 
intensity (i.e., 750 mg/day), and expressed in percent. 
In addition, the number and percentage of subjects who had a dose change will be 
summarized with reasons for the change (as per protocol: AE, dosing error, lab test 
abnormality, scheduling conflict, or dispensing error).   
5.2 
Prior and concomitant medications/non-drug therapies 
Prior and concomitant medications will be coded according to the World Health Organization-
Drug Dictionary (WHO-DD). The WHO-DD version will be specified as a footnote in the 
tables/listings. Prior and concomitant medications are mutually exclusive, as defined below:  


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• Prior medications are defined as any medications with an end date prior to the first 
dose of ceritinib; 
• Concomitant medications are defined as any medications taken during the treatment 
period (from the first dose date and on).  Prior medications that are ‘ongoing’ at the 
time of first study treatment or whose end date is after first study treatment will be 
considered concomitant medication. 
The number and percentage of subjects with prior medications, concomitant medications that 
started prior to ceritinib initiation, as well as concomitant medications that started after 
ceritinib initiation, will be summarized by preferred term.  Non-drug therapies (surgical and 
medical procedures) will be listed for each subject. A standard imputation method will be 
used for partial start/stop date of medications. 
6 
Efficacy and PRO evaluation 
6.1 
Clinical Benefit Rate (CBR) 
Clinical benefit is determined by investigator assessment for each tumor assessment and is 
defined as responses of CR or PR or SD ≥ 16 weeks. In addition to tumor-specific 
measurements (e.g., radiological assessment of tumor response for solid tumors), progressive 
disease will also be considered when it was indicated either as a reason based on clinical 
assessment for the study treatment discontinuation or as a cause of on-treatment death.  CR 
and PR (for solid tumors) require a confirmation that is at least a minimum of 4 weeks after 
the initial observation of response.  Subjects who had a confirmed CR/PR or SD prior to 16 
weeks, but discontinued prior to 16 weeks for reasons other than progressive disease, will 
have their clinical benefit defined as non-evaluable; subjects who had a confirmed CR/PR or 
SD prior to 16 weeks, but progressed prior to 16 weeks, will be considered as not achieving 
clinical benefit; subjects who had CR/PR/SD occurred prior to 16 weeks, but progressed at or 
after 16 weeks without evidence of CR/PR/SD at or after 16 weeks, will also be considered as 
not achieving clinical benefit.  CBR will be analyzed by comparing achieved CBR with a 
historical control rate of each tumor type, and if there is at least 90% probability that the 
response rate in a tumor type exceeds the historical rate, then the tumor type will be 
considered a success; it will be considered as promising if the probability is between 80% and 
90%.  Details for the analyses of CBR are located in Section 10. 
6.2 
Overall Response Rate (ORR) 
Overall response is determined by investigator assessment for each tumor assessment in the 
study.  For subjects with solid tumors (other than lymphoma) the assessment criteria will be 
RECIST 1.1 and will include responses of CR and/or PR; for lymphoma, Cheson criteria will 
be used; for hematologic tumors, other appropriate hematological response criteria will apply.  
The number and percentage of subjects for different categories of overall response (e.g., for 
solid tumors – CR, PR, SD, PD, Not Evaluable) will be provided for solid tumors (non-
lymphoma), lymphoma (if applicable), and each hematological tumor type (if applicable).  
Ninety-five percent (95%) exact confidence intervals (CIs) will be provided for the response 
rate(s) (e.g., for solid tumors – CR and/or PR) as well.  For cohorts with at least 10 subjects, 


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overall responses will be summarized separately.  Components of tumor assessments (e.g., for 
solid tumors – target lesion response, non-target lesion response, new lesion [yes/no]) will 
also be listed.  In addition, Cancer Antigen-125 (CA-125) (if applicable) in the assessment of 
ovarian cancer response, Prostate-specific Antigen (PSA) (if applicable) in the assessment of 
prostate cancer will be listed. 
The above analyses will be performed for the FAS. 
6.3 
Progression Free Survival (PFS) 
PFS is defined as the time from the date of first dose of ceritinib to the date of the first 
documented disease progression/relapse or death due to any cause within 30 days of the last 
dose, and is calculated as PFS = (date of progression/relapse or death – date of first study 
treatment + 1).  Disease progression noted as the reason for discontinuation of treatment will 
be considered as a progression, thus will be considered as an event for PFS. 
Subjects who discontinue or complete study treatment without disease progression will be 
censored at last adequate tumor assessment on or before the discontinuation/completion of the 
study.  If there is no tumor assessment for the subject, the PFS will be censored at Day 1.  
PFS will be summarized and graphed using the Kaplan-Meier product-limit method1.   The 
estimated median survival time, the corresponding 95% CIs2, and 25th and 75th percentiles 
will be provided.  In addition, survival rate estimates at 1, 2, 3, 4, 5, 6, and 12 months with 
95% CIs will also be provided.  For cohorts with at least 10 subjects, separate PFS analyses 
will be conducted for each cohort. 
The above analyses will be performed for the FAS. 
6.4 
Overall Survival (OS) 
Due to limited overall survival follow-up, only the number and percentage of all deaths will 
be presented. 
6.5 
Clinical Benefit Rate by Gene Mutations 
The concordance between gene mutations detected by local and central labs will be 
summarized on protocol pre-defined mutations. A frequency summary will be provided for 
summarizing clinical benefit rate per gene mutation using mutation data provided by the 
central lab (on protocol pre-defined mutations only) as well as by the local lab. The data will 
also be presented in a listing.  This analysis will be performed for the FAS. 
7 
Safety evaluation 
7.1 
Adverse events 
Adverse events data will be collected at each visit.  They will be assessed according to the 
most current version of the Common Toxicity Criteria for Adverse Events (CTCAE).  If 
CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 


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and life-threatening, or grades 1-4 were used.  CTCAE grade 5 (death) was not used in this 
study; rather, this information was collected in the End of Treatment/Study or Survival 
Information CRF page. 
All AEs will be coded by Preferred Term (PT) and associated primary System Organ Class 
(SOC) using MedDRA (Medical Dictionary for Regulatory Activities, version 19.0 or above).  
The CRF collects the verbatim term for MedDRA coding. 
Summaries of AE will be based on treatment emergent adverse events (TEAEs), which is 
defined as all new or worsening events collected from first study treatment date to last 
treatment date + 30.  Novartis standard partial date imputation methods will be used for 
imputation of partial AE onset/resolution dates. 
Analysis of Adverse Events 
In general, the subject incidence of TEAEs will be summarized for all tables, unless otherwise 
noted, by SOC and PT.  TEAEs will be shown in alphabetical order for SOCs and in 
decreasing frequencies for PTs within each SOC.  Subject frequencies and percentages will be 
presented. 
All summaries will be based on subject counts (i.e., the number and percentage of subjects 
who satisfy the criteria), and will depict all AEs and all grade 3/4 AEs at minimum.  Each 
subject will be counted at most once per category.  For subjects with multiple grades for the 
same event, only the worst grade will be counted. 
The following summary tables will be provided for the SS: 
• Summary of TEAEs by SOC, PT, and maximum severity 
• Summary of serious TEAEs by SOC and PT 
• Summary of the most common TEAEs (10% or more of subjects) by PT and 
decreasing frequency 
• Summary of suspected TEAEs by SOC and PT 
• Summary of TEAEs associated with permanent discontinuation of study drug 
• Summary of TEAEs associated with dosage adjusted/temporarily interrupted of study 
drug 
• Summary of adverse events of special interest (see details below in Section 7.1.1) 
Individual records of AEs will also be listed alphabetically by the SOC/PT and then in 
chronological order (i.e., by start date of the event as recorded in the CRF).  The listing will 
include subject identifier, age, race, gender, and all related event status information (e.g., 
grade, relationship to study medication, etc.).  For the overall AE listing, AEs that are non-
treatment emergent will be included.  Separate AE listings that include only TEAEs (e.g., 
suspected AEs, serious TEAEs) will also be presented. 
7.1.1 
Specific safety event categories 
Specific Safety Event Categories (SEC) consists of adverse events for which there is a 
specific clinical interest in connection with ceritinib treatment (i.e. where ceritinib may 


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influence a common mechanism of action responsible for triggering them) or adverse events 
which are similar in nature (although not identical).  
Each of these SECs uses MedDRA categories (Standard MedDRA Query [SMQ], Novartis 
MedDRA Query [NMQ], High Level Group Term [HLGT], etc.) to group preferred terms for 
which there is a specific clinical interest. One SEC can be defined by one or several MedDRA 
categories. These SECs are defined in the current version of the ceritinib Safety profiling 
plan/ceritinib Case Retrieval Strategy (CRS) document. 
Standard data of analysis for all SECs will be conducted as follows: 
- The number and percentage of subjects will be reported by SEC, by MedDRA 
category and by preferred term.  
- All AEs of subjects having at least one AE in that SEC will be listed. 
7.2 
Deaths 
A subject listing of deaths with recorded principal cause of death (if available) will be 
provided. 
7.3 
Vital signs 
Actual raw values and changes from baseline for vital sign results (sitting systolic and 
diastolic blood pressure, sitting pulse, body temperature, respiratory rate, and weight) 
obtained for each scheduled visit will be summarized using descriptive statistics (number of 
subjects, mean, standard deviation, median, 25th percentile, 75th percentile, minimum, and 
maximum).  Baseline is defined as the last non-missing measurement prior to the first 
ceritinib dose.  Vital signs will also be presented in a listing.  These analyses will be 
performed using the SS. 
7.4 
Laboratory evaluations 
Laboratory assessment will be collected at screening and post baseline (at scheduled visits 
outlined in the protocol or as clinically indicated).  The collected laboratory values will be 
converted into standard units and the severity grade will be calculated using CTCAE v4.03.  
A severity grade of 0 will be assigned when the value is within normal limits. For laboratory 
parameters where severity grades are determined both through normal limits and absolute cut-
offs, in the unlikely case that a local laboratory normal range overlaps into the higher (i.e., 
non-zero) CTCAE grade, the laboratory value will still be taken as within normal limits and 
assigned a CTCAE grade of zero.  Baseline is defined as the last non-missing measurement on 
or prior to the first ceritinib treatment.  On-treatment laboratory evaluations are defined as 
laboratory values collected post baseline and no later than 30 days after the last study 
treatment. 
Abnormal on-treatment laboratory values will be summarized using shift tables (from baseline 
to any abnormal laboratory value post baseline) by each laboratory parameter at its worst 
severity grade.  The number and percentage of subjects with abnormal laboratory values will 
be presented by CTCAE grade for each laboratory parameter that is CTCAE gradable.  For 
laboratory parameters where CTCAE grades are not defined, shift tables using the 


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low/normal/high/(low and high) classification to compare baseline to the worst on-treatment 
value will be provided.  Listings of all laboratory values (Blood chemistry, 
Hematology/Coagulation parameters separately) in chronologic order will be provided for 
each laboratory parameter.  Laboratory values collected more than 30 days after study 
treatment discontinuation will be flagged in the listing.  A separate listing will also be 
provided for notable laboratory abnormalities (i.e., grade 3 or 4 laboratory toxicities post start 
of study treatment).  In addition, other labs such as urinalysis and pregnancy tests will be 
listed separately.  These presentations will be performed for the SS. 
7.5 
Other safety evaluations 
ECOG performance status will be summarized by visit for SS.  The number and percentage of 
subjects in each score (0-5) will be displayed.  In addition, the shift table of ECOG value from 
baseline to the worst score post baseline will be presented.  
ECG values will be summarized descriptively by visit for the SS.  Change from baseline for 
each collected parameter will also be summarized.  The ECG parameters to be summarized 
include: QTcF, HR, PR, QT, and QRS. 
Cardiac imaging evaluations will only be listed.  
Baseline for the safety evaluation is defined as the last non-missing measurement on or prior 
to the first ceritinib dose. 
8 
Interim analyses 
Scheduled interim analysis is planned for the primary endpoint of clinical benefit rate only as 
required by the Bayesian Hierarchical design. The first interim analysis performs after the first 
30 patients have been dosed for at least 16 weeks or discontinued then every 13 weeks 
thereafter until study enrollment closure. After that, one CBR analysis will be done after 
database lock. Interim analyses may be performed more frequently dependent on enrollment 
rate to avoid over-enrollment in any of the disease groups. At each interim analysis, the 
groups will be evaluated for early futility and early success by comparing posterior quantities 
for the response rate to pre-specified early stopping criteria. 
There is no plan for a formal interim analysis of safety or other secondary endpoints for this 
study. However, for publication or other purposes, interim data review of clean data will be 
performed as necessary. At these interim reviews, patient demographics/baseline 
characteristics, the primary and secondary endpoints as applicable, and all important safety 
endpoints will be summarized. No formal report will be issued for these interim data reviews.   
9 
Determination of sample size 
The sample size was chosen by the usual criteria of obtaining adequate power for the 
alternative hypothesis of interest as shown in the protocol Tables 4.2 of Appendix Q (same as 
Table 2 as shown below in Section 10.4.2).  This hypothesis corresponds to a generally 
effective treatment across groups and incorporates variation in treatment effects to reflect the 
realistic expectation that treatment effects may differ by group. In this setting, analytical 
power calculations are not possible, but the design was simulated to obtain the power of the 


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study as shown in Section 10 below.  The sample size shown (minimum of 10 for futility 
stopping, minimum of 15 for early success and maximum of 30 as group cap) achieve 
adequate power for the alternative hypothesis.  The simulations included the expected variable 
accrual by simulating a Poisson process with expected accrual also shown in the protocol 
Appendix Q (same as Section 10 below). 
Given the exploratory nature of the study design, there is no power consideration for 
secondary objectives. 


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10 
Bayesian Adaptive Design 
10.1 
Introduction 
This document outlines the adaptive design for Novartis’s P2P trial of LDK378. 
This trial will enroll patients from at least 6 histologic groups: 
• Breast 
• Colorectal 
• B-Cell Lymphoma 
• Melanoma 
• ALCL 
• Ovarian 
In addition, another group currently simply referred to as “Other” may be identified and 
enrolled throughout the study (e.g. “Other” will be a focused histologic group, but may not be 
explicitly identified until the trial is ongoing due to recruitment issues). We discuss the 
logistics in more detail below, but a decision will only be made for a group other than the 6 
listed if 1) more than 3 patients are enrolled in the group, and 2) a reasonable estimate of the 
clinical benefit rate is available. 
The primary endpoint is clinical benefit rate (CBR) in each group, with clinical benefit being 
assessed at 16 weeks. All patients will be assigned LDK378. 
10.1.1 
Primary Analysis 
We let Yi be the response indicator for the ith subject, and let Rg be the assumed probability of 
response within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability 
of response for group g within the treatment group. We transform to the logit scale for 
modeling purposes. Let θg be the mean log odds treatment effect, i.e.: 
 
Thus, θg is the group specific logistic regression coefficient for the treatment within group g. 
The primary analysis is a set of group specific tests that θg>0, meaning that the treatment is 
better than the assumed control rate within that group. Thus, we wish to test the set of 
hypotheses 
H0g : θg≤0 
H1g : θg>0 


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We proceed in a Bayesian fashion, assigning a prior distribution (discussed below) and 
computing the posterior probability of H1g within each group g. If, at the final analysis, 
Pr(θg>0 | data) > 0.90 
Then group g will be declared a success (thus, the final analysis produces a separate decision 
for each group). The trial also allows for early stopping of groups, described below. 
10.1.2 
Trial Logistics 
The trial will enroll all available subjects in all groups for 2 years unless a group cap is 
reached or a group is stopped early. The trial will enroll no more than 30 evaluable subjects in 
each group. Interim monitoring will be conducted starting after the first 30 patients enrolled 
overall (across all groups) have been dosed for at least 16 weeks or discontinued, then 
continuing each 13 weeks thereafter. At each interim analysis, response information for the 
various groups will be evaluated to determine the current Pr(θg>0 | data) within each group, 
with sufficiently high/low values used to stop the group for success/futility. A minimum of 10 
patients will be required in a group before it may discontinue enrollment for futility, and a 
minimum of 15 patients are required before discontinuing a group for efficacy. If a group 
stops enrolling early, the remaining groups will continue until the end of 2 years or until the 
other groups reach their own early stopping criteria. The final analysis will occur after 2 years 
of trial duration, with all subjects enrolled at 2 years followed up to their endpoint. 
The trial will enroll subjects in all listed groups. In addition, should other groups be identified 
throughout the trial, the following mechanism will be used. If another group is identified, it 
will not be placed into the statistical analysis unless 3 subjects enroll within the group (thus, 
the trial may enroll multiple possible groups within the “other” category, but a group will only 
be added to the list if at least 3 patients enroll from that group. Thus, it is possible (but not 
viewed as likely) that multiple “other” groups may be added to the trial if the trial has 
sufficient enrollment in multiple “other” groups. In addition to sufficient enrollment, the 
sponsor must have a reasonable estimate of the control clinical benefit rate. 
Subjects within the “other” category which do not reach the minimum 3 subject enrollment 
will be excluded from the interim and final analyses. Thus, in the statistical analysis below, 
the number of groups may be 4 (if no other groups meet the requirements for inclusion in the 
study) or more if other groups are identified throughout the course of the study. As the study 
continues, early interim analyses may be based on fewer groups than later interim analyses, as 
the interim analyses will include whatever groups have satisfied the criteria at the time of the 
analysis. 
10.2 
Statistical Modeling 
We let Yi be the response indicator for the ith subject, and let Rg be the probability of response 
within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability of 
response for group g within the trial. We transform to the logit scale for modeling purposes. 
Let θg be the mean log odds treatment effect, i.e.: 
 


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The statistical design borrows information across groups with a hierarchical model. The 
hierarchical model allows dynamic borrowing of information between groups such that more 
borrowing occurs when the groups are consistent and less borrowing occurs when the groups 
differ.  In this way, the model is a compromise between the two alternate extremes of either a 
completely pooled analysis or a separate analysis in each group. We additionally incorporate a 
clustering mechanism that allows borrowing within clusters but treats clusters separately. This 
minimizes borrowing across groups that are quite different in terms of CBR. 
The purpose of such an analysis is to produce higher power or lower type I error in situations 
where we see some commonality (identical effects are not required) among the groups. The 
model will borrow more in situations where the groups appear similar than situations where 
the groups appear different. 
10.2.1 
Hierarchical Model with Clustering 
Our hierarchical approach involves two stages. The goal of both stages is to allow the data to 
drive the amount of borrowing across groups. If the data indicate a large amount of borrowing 
is appropriate (due to similar results), the model will borrow more and thus increase the 
overall power of the trial within each group. In contrast, if the data indicate a small amount of 
borrowing is appropriate (due to dissimilar results) the model will adjust and each group will 
stand more on its own. This “dynamic” borrowing property is distinct from other approaches 
which use a fixed informative prior or apriori assume an amount of borrowing across groups. 
Here the approach includes two stages to identify the appropriate amount of borrowing based 
on the data. 
The first stage of model places the groups into distinct clusters. The purpose of this stage is to 
minimize borrowing of information across groups that appear to be quite different. Thus, for 
example, should 2 of the groups appear similar while the others differ significantly, the model 
may place a large probability on two clusters, one containing the two similar groups with the 
other containing the remaining groups. The model incorporates the uncertainty of the data in 
this determination, producing a probability distribution over the possible clusterings. Thus, in 
our example, the model may consider it highly likely that the 2 similar groups are in one 
cluster with the remaining groups in another, but it would also retain lower probabilities on 
the possibility all groups are in one cluster (e.g. we are simply seeing differences in the two 
groups by chance) as well as other possibilities. The complete analysis averages over this 
uncertainty. This clustering approach is implemented through a Dirichlet Process Mixture 
(DPM) model, described in the appendix. 
At the second stage, we place hierarchical models over the groups within each cluster (thus, 
conditional on the clustering, there is no borrowing of information across clusters, only within 
clusters). The hierarchical model assumes that the 
 have an across groups distribution 
θg ~ N(μ, τ2) 
The across group mean µ and variance τ2 are unknown, and hence have a prior distribution 
which is combined with the data to produce estimates of µ and τ2. 
The variance component τ controls the degree of borrowing among groups. Small values of τ 
result in a greater degree of borrowing while large values of τ correspond to less borrowing. 


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The parameter τ is estimated using the data, so the observed between group variation is a key 
component of the model behavior.  
Combined, the two stages allow groups with similar results to borrow information between 
them (they will have a high probability of being in the same cluster) while groups with 
different results with borrow far less information between them (they will have a low 
probability of being in the same cluster). 
Details of the two stages may be found in the appendix. 
10.3 
Evaluation of Trial Success and Futility  
Interim monitoring will occur after the first 30 patients, then every 13 weeks thereafter. At 
each interim analysis, the groups will be evaluated for early futility and early success by 
comparing posterior quantities for the response rate to pre-specified early stopping criteria. 
10.3.1 
Early Futility  
If there is less than 10% probability that the response rate in a group exceeds the historical 
rate Rg, then the group will stop enrollment early for futility. Formally, enrollment will stop 
early for futility if: 
Pr(πg > Rg) < 0.10. 
A group is only eligible for early stopping once a minimum of 10 patients has been evaluated 
for response in that group. 
10.3.2 
Early Success 
If there is at least 95% probability that the response rate in a group exceeds the historical rate, 
then the group will stop enrollment early for success. Formally, enrollment will stop early for 
success if: 
Pr(πg > Rg) > 0.95. 
A minimum of 15 subjects will need to be evaluated prior to declaring a group to be 
efficacious. 
10.3.3 
Final Analysis 
In addition, recall the final analysis will occur when both accrual and follow-up are complete 
in all groups. If, at the completion of the trial, there is at least 90% probability that the 
response rate in a group exceeds the historical rate, then the group will be considered a 
success. Formally: 
Pr(πg > Rg) > 0.90. 
10.4 
Simulation 
We evaluated type I error and power for each of the 7 possible groups (including one “other” 
category) under a variety of possible “truths” indicating various possible true underlying 
probabilities within each group. Note as described above the 7th “other” group is only 
included in the analysis if it enrolls at least 3 subjects. 


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10.4.1 
Assumptions 
Accrual - Table 1 shows the assumed two year expected accrual number as well as the 
assumed control rates for the 7 histologic groups (including “other”). Note these are averages, 
the actual number of available patients is simulated as a Poisson distribution with the 
specified mean. Also note that the group cap of 30 applies, and thus if the number of available 
patients in a group exceeds 30, only the first 30 available patients in that group will be 
enrolled in the study. Note given the low assumed enrollment rate for “other” (2), there a high 
likelihood these subjects will not enroll sufficiently to enter the main analysis. 
Dropouts – We assume no dropouts for the purpose of this simulation. 
Control Rates –Table 1 also shows the assumed control rates. 
Histology 
Assumed 2 year accrual 
Assumed Control Rate (Rg) 
Breast 
20 
0.69 
Colorectal 
15 
0.26 
B-cell Lymphoma 
6 
0.60 
Melanoma 
8 
0.30 
ALCL 
6 
0.90 
Ovarian 
15 
0.65 
Other (where applicable) 
2 
0.50 
Table 1 – Assumed 2 year accrual rates (accrual is simulated as a Poisson process with these 
means) and assumed control CBR values used in the simulations. 
We consider four possible scenarios, or possible “truths” in the simulation. These consisted of 
a null scenario (where the treatment has no effect for any group), an alternative scenario 
(where the treatment is effective in all groups), a scenario where the treatment was effective in 
two of the groups, and a scenario where the treatment was effective in half of the groups.  
Treatment Rates - The treatment rates for each scenario are shown in the table below. Values 
identical to the control are shown in bold, while values greater than the assumed control rate 
are shown in italics. 
 
 
Null 
Alternative 
Two 
Half 
Breast 
0.69 
0.88 
0.88 
0.69 
Colorectal 
0.26 
0.50 
0.26 
0.50 
B-cell Lymphoma 
0.60 
0.82 
0.60 
0.60 
Melanoma 
0.30 
0.55 
0.55 
0.55 
ALCL 
0.90 
0.97 
0.90 
0.90 
Ovarian 
0.65 
0.85 
0.65 
0.85 
Other (where 
applicable) 
0.50 
0.75 
0.50 
0.75 
Simulation Details – For each scenario we simulated 1000 trials. For each interim within each 
trial, we ran 50,000 MCMC iterations after a 1,000 MCMC iteration burnin. 
10.4.2 
Results 
Table 2 below provides the probability of group success for each of the groups 
 


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Group (Exp N) 
Null 
Alternative 
Two 
Half 
Breast (20) 
0.126 
0.924 
0.815 
0.246 
Colorectal (15) 
0.059 
0.813 
0.116 
0.743 
B-cell Lymphoma (6) 
0.063 
0.692 
0.125 
0.180 
Melanoma (8) 
0.052 
0.698 
0.517 
0.627 
ALCL (6) 
0.003 
0.611 
0.045 
0.148 
Ovarian (15) 
0.082 
0.839 
0.151 
0.771 
Other (where applicable) (2) 
0.011 
0.509 
0.069 
0.294 
Entries in bold represent groups where the treatment effect is 0 (e.g. the treatment is 
ineffective). Thus, entries in bold are type I errors. Entries in italics appear where the 
treatment is effective, and thus indicate the power of the design. 
Generally, type I error is controlled at 0.10 under the null scenario (the borrowing 
compensates for the multiple interim analyses) and power is an increasing function of the 
expected sample size (power for Breast, Colorectal, and Ovarian are generally high, 
particularly in the alternative case). In the alternative scenario there remains decently high 
probability of success even in the lower enrolling groups. When fewer groups are effective in 
truth, the scenarios “half” and “two” are harder to discern, however the model still retains 
around 75-80% power to isolate the highest enrolling groups. In these scenarios identifying 
the lower enrolling groups becomes more problematic, with power between 50-65%. 
Power is reduced and type I error is inflated when the truth is a mixture of effective and 
ineffective treatment effects across the groups. Generally power again is a function of the 
sample size. 
10.5 
Modeling Details 
Recall at the first stage the groups are clustered according to a Dirichlet Process Mixture 
Model. 
The number of clusters is not assumed to be known in advance but will instead be inferred 
from the data using Dirichlet Process Mixtures (DPM). The DPM looks across all the possible 
clusterings of the groups and assigns a probability to each based on the data. The prior 
distribution in a DPM is governed by a parameter α. When α is small, the prior favors large 
clusters. As α tends to zero, the prior tends to place all its mass on a single cluster containing 
all the groups. As α increases, the prior places more mass on clusterings with a large number 
of clusters. As α becomes very large, the prior places all of its mass on having a separate 
cluster for each group (that is, no borrowing across groups). Thus, by specifying extreme 
values of the prior one could force the groups into one cluster or force the groups to be 
analyzed in separate clusters. Here we choose a moderate version of α=2 (common values 
might be anywhere between 0.5 and 5) and allow the data more control over the clustering. 
The details of the prior are as follows. Let zg represent the cluster to which group g belongs. 
Then zg ~ Categorical(p), where p is the vector such that pk is the probability that a group 
belongs to cluster k and 
. We construct p using a stick-breaking process: 
 


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and 
βk ~ Beta(1, α). 
A large value of α thus removes a very small amount of probability for p, resulting in many 
clusters, while a small value of α tends to produce probabilities near 1 for the first cluster. 
Conditional on the clustering, we fit a hierarchical model which has an across groups 
distribution 
θg ~ N(μ, τ2) 
As discussed above, this across groups distribution states that within a cluster we expect to see 
some variation in the parameters, with that variation governed by τ. When τ is small, there is 
minimal variation across groups within a cluster, and thus within the cluster the model would 
approach pooling. In contrast, when τ is large we expect large amount of across group 
variation, and thus even though the groups are in the same cluster the θg values may be quite 
different. Apriori we have no way of knowing τ, so we estimate it using the data combined 
with the prior distributions 
μ ~ N(0, 1.82) 
and 
τ2 ~ IG(3,0.5), 
where IG(α, β) is the inverse gamma distribution defined by: 
 
 
 
When the entire model is implemented (via Markov Chain Monte Carlo) we consider the full 
joint distribution of the clustering combined with the hierarchical model parameters. We 
average over the entire range of the uncertainty in the parameters to produce the posterior 
distribution for each group parameter θg, which is then used to drive the decisions in the 
model. 
11 
References 
                                                 
1 Kaplan EL, Meier P.  Nonparametric Estimation from Incomplete Observations.  J Am Stat 
Assoc. 1958; 53: 457-81. 
2 Brookmeyer R., Crowley, J.  A Confidence Interval for the Median Survival Time.  
Biometrics, 1982; 38: 29-41