Conditions: Chronic Myeloid Leukemia
Keywords: Chronic Myeloid Leukemia Nilotinib Molecular Response MR4.5
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 171
Healthy volunteers: no

Brief summary:
The main purpose of this study was to evaluate the rate of deep molecular response (MR4.5) after 24 months of therapy with nilotinib in newly diagnosed patients with chronic phase chronic myeloid leukemia (CML) using EUTOS (European Treatment and Outcome Study for CML)-standardized laboratories. All participants received nilotinib 300 mg twice daily (BID).

Detailed description:
This was a Phase IV open-label, multi-center, single-arm study in participants with newly diagnosed Philadelphia chromosome positive (Ph+) CML in chronic phase for who nilotinib is the appropriate treatment at the discretion of the investigator.

A screening period of 2 weeks was used to assess eligibility and to taper participants off disallowed medications. Participants whose eligibility was confirmed entered a 24 months treatment phase with nilotinib 300mg BID. Nilotinib was prescribed by the investigator according to the individual needs of the participants.

Arms:
arm 1: Participants with newly diagnosed CML in chronic phase received nilotinib 300 mg BID for 24 months

Interventions: intervention 1: Nilotinib
Intervention descriptions: intervention 1: A daily dose of 300 mg was given to all participants as two 150 mg capsules BID. The prescription of study drug was not study dependent and followed medical needs of the participant only. The study treatment was administered for 24 months.

Protocol document:
Prot_000.pdf: 
Novartis Pharma 
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Version 03, 15-Feb-2021 
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Clinical Development 
 AMN107 (Nilotinib, Tasigna®) 
Protocol number CAMN107ADE20 / NCT02546674
A Phase IV single arm, multicenter, open-label study 
assessing deep molecular response in adult patients with 
newly diagnosed Philadelphia chromosome positive CML 
in chronic phase after two years of treatment with nilotinib 
300mg BID 
Author(s): 
 
Document type: 
Amended Protocol Version 
EUDRACT number : 
2015‐000968‐34 
Development phase: 
IV 
Version No. 
v03 
Release date: 
15-Feb-2021


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Property of Novartis Pharma  
 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
 
 


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Compound name / number AMN107 
Protocol number CAMN107ADE20 
Approved by the following 
Signatures of Novartis Personnel: 
 
 
   
 
signature  
 
date 
 
 
(Trial Statistician)   
 
signature  
 
date 
 
   
 
 
signature  
 
date 
 


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Signature of Principal Investigator (Chief Investigator according to German 
Drug Law): 
 
Prof. Dr. med. 
 
(Principal Investigator) 
signature  
 
date 
 


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Signature Page for Investigator 
 
Compound name / number Nilotinib / AMN107 
Protocol number CAMN107ADE20 v03 
 
I have read this protocol and agree to conduct this trial in accordance with all 
stipulations of the protocol and in accordance with the principles outlined in the 
Declaration of Helsinki. Note: Any deviations from this protocol require a formal 
amendment to be approved by the responsible ethics committee. 
 
   
(Investigator) 
 
 
Center name / location: 
signature  
 
date 
 
institution (where applicable) 
 
city 
 
 


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Table of contents 
Table of contents ................................................................................................................. 6 
List of post-text supplements ............................................................................................... 9 
List of figures ...................................................................................................................... 9 
List of tables ........................................................................................................................ 9 
List of abbreviations .......................................................................................................... 10 
Glossary of terms ............................................................................................................... 14 
Amendmend 1 ................................................................................................................... 18 
1 
Background ........................................................................................................................ 20 
1.1 
Overview of disease pathogenesis, epidemiology and current treatments ............ 20 
1.2 
Overview of nilotinib (AMN107, Tasigna®) ......................................................... 20 
 
Non-clinical experience ........................................................................ 21 
 
Clinical experience ................................................................................ 21 
1.3 
Overview of Molecular Response ......................................................................... 23 
2 
Study purpose .................................................................................................................... 24 
3 
Objectives (and related endpoints) .................................................................................... 26 
3.1 
Primary objective(s) ............................................................................................... 26 
3.2 
Secondary objective(s) ........................................................................................... 26 
 
 27 
4 
Study design ...................................................................................................................... 27 
5 
Population .......................................................................................................................... 29 
5.1 
Inclusion/exclusion criteria .................................................................................... 29 
5.2 
Premature patient withdrawal ................................................................................ 31 
6 
Treatment ........................................................................................................................... 32 
6.1 
Patient numbering .................................................................................................. 32 
6.2 
Investigational drug ............................................................................................... 32 
6.3 
Treatment arms ...................................................................................................... 33 
6.4 
Treatment assignment ............................................................................................ 33 
6.5 
Treatment blinding ................................................................................................. 33 
6.6 
Treating the patient ................................................................................................ 33 
 
Dispensing the study drug ..................................................................... 33 
 
Instructions for use of study drug .......................................................... 33 
 
Study drug supply and resupply, storage, and tracking ........................ 33 
 
Study drug compliance and accountability ........................................... 34 


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Disposal and destruction ....................................................................... 34 
 
Permitted study drug dose adjustments and interruptions..................... 34 
 
Dose reduction guidelines for study drug-related non-
hematological toxicity and for ischemic vascular and 
cardiovascular events regardless of study drug relationship ................. 35 
 
Dose reduction guidelines for study drug-related hematologic 
toxicity................................................................................................... 39 
 
Guidelines for dose re-escalation .......................................................... 40 
 
Hepatitis B reactivation ......................................................................... 40 
 
Suggested management of cardiovascular risk factors and events ....... 40 
 
Follow-up for toxicities ......................................................................... 43 
 
Rescue medication ................................................................................ 44 
 
Other concomitant treatment ................................................................. 44 
 
Study drug discontinuation ................................................................... 46 
 
Definition of suboptimal response and treatment failure ...................... 46 
 
Progression ............................................................................................ 46 
 
Definition of intolerance ....................................................................... 47 
 
Emergency unblinding of treatment assignment ................................... 47 
 
Study completion and post-study treatment .......................................... 47 
 
End of treatment visit, including premature withdrawal and study 
discontinuation visit .............................................................................. 48 
 
Follow up period ................................................................................... 48 
7 
Visit schedule and assessments ......................................................................................... 48 
7.1 
Information to be collected on screening failures .................................................. 53 
7.2 
Patient demographics/other baseline characteristics ............................................. 53 
7.3 
Treatment exposure and compliance ..................................................................... 54 
7.4 
Efficacy .................................................................................................................. 54 
 
Molecular response ............................................................................... 54 
 56 
 
Cytogenetic response ............................................................................ 56 
 
Bone marrow analysis and cytogenetics ............................................... 57 
 
Hematologic response ........................................................................... 57 
7.5 
Safety ..................................................................................................................... 58 
 
Adverse events ...................................................................................... 58 
 
Physical examination ............................................................................ 58 


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Vital signs and weight ........................................................................... 59 
 
Performance status ................................................................................ 59 
 
Laboratory evaluations .......................................................................... 59 
 
Pregnancy test and assessments of fertility ........................................... 61 
 
Organ-specific safety monitoring .......................................................... 61 
 
Estimation and monitoring of the cardiovascular risk .......................... 61 
7.6 
Tolerability/acceptability ....................................................................................... 63 
7.7 
Resource utilization ............................................................................................... 63 
7.8 
Health-related Quality of Life (HRQOL) .............................................................. 63 
7.9 
Pharmacokinetics ................................................................................................... 64 
7.10 
Pharmacogenetics/pharmacogenomics .................................................................. 64 
7.11 
Other biomarkers ................................................................................................... 64 
8 
Safety monitoring .............................................................................................................. 64 
8.1 
Adverse events ....................................................................................................... 64 
 
Adverse event definition and reporting ................................................. 64 
 
Laboratory test abnormalities ................................................................ 66 
8.2 
Serious adverse events ........................................................................................... 67 
 
Serious adverse event definition, treatment and follow-up ................... 67 
 
Serious adverse event reporting ............................................................ 67 
8.3 
Pregnancy reporting ............................................................................................... 68 
8.4 
Reporting of adverse events and pregnancies after the last dose of study drug 
taken ....................................................................................................................... 68 
8.5 
Steering Committee ............................................................................................... 69 
9 
Data review and database management ............................................................................. 69 
9.1 
Site monitoring ...................................................................................................... 69 
9.2 
Data collection ....................................................................................................... 69 
9.3 
Database management and quality control ............................................................ 70 
10 Data analysis ...................................................................................................................... 70 
10.1 
Populations for analysis ......................................................................................... 71 
10.2 
Patient demographics/other baseline characteristics ............................................. 71 
10.3 
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance) ............................................................................................................ 71 
10.4 
Analysis of the primary objective(s) ...................................................................... 71 
 
Variable ................................................................................................. 71 


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Statistical hypothesis, model, and method of analysis .......................... 72 
 
Handling of missing values/censoring/discontinuations ....................... 72 
 
Supportive analyses ............................................................................... 72 
10.5 
Analysis of secondary objectives ........................................................................... 72 
 
Efficacy (secondary) ............................................................................. 72 
10.5.1.1 Secondary efficacy variables ................................................................. 72 
10.5.1.2 Methods of analyses .............................................................................. 73 
10.5.1.3 Handling of missing values ................................................................... 73 
 
Safety ..................................................................................................... 74 
 
Tolerability ............................................................................................ 74 
 
Resource utilization ............................................................................... 74 
 
Health-related Quality of Life ............................................................... 75 
 
Pharmacokinetics .................................................................................. 75 
 
Pharmacogenetics/pharmacogenomics ................................................. 75 
 
Biomarkers ............................................................................................ 75 
 
PK/PD ................................................................................................... 75 
 
 75 
10.7 
Interim analysis ...................................................................................................... 76 
10.8 
Sample size calculation .......................................................................................... 76 
10.9 
Power for analysis of critical secondary variables ................................................ 76 
11 Discussion and rationale for study design features ........................................................... 77 
12 References ......................................................................................................................... 78 
Appendix 1:  Ethical considerations and administrative procedures ........................................ 83 
Appendix 2: List of CYP3A4 inducers, inhibitors and substrates ............................................ 86 
13 Appendix 3: Quality of Life Questionnaires ..................................................................... 88 
14 Appendix 4: ESC Risk SCORE chart ................................................................................ 95 
 
List of post-text supplements 
List of figures 
No table of contents entries found. 
List of tables 
Table 4-1 
Study outline ......................................................................................... 28 


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Table 6-1  
Summary of nilotinib dose reduction guidelines for study drug-
related non-hematologic toxicity and for ischemic vascular and 
cardiovascular events regardless of study drug relationship ................. 35 
Table 6-2  
Summary of dose reduction guidelines for study drug-related 
hematologic toxicity .............................................................................. 40 
Table 6.6  
Summary of recommended threshold values (details see text) ............. 43 
Table 7-1 
Assessment schedule ............................................................................. 50 
Table 7-2  
Definition of Treatment failure, see also section 6.6.15 ....................... 55 
Table 7-3  
ECOG performance Criteria ................................................................. 59 
Medications that can induce CYP3A4...................................................................................... 86 
Medications that can inhibit CYP3A4 ...................................................................................... 87 
  
List of abbreviations 
ABL 
Abelson leukemia virus 
ACE 
Angiotensin-converting enzyme 
AE 
Adverse event 
ALL 
Acute lymphoid leukemia 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
Absolute Neutrophil count 
Anti HBc 
Antibody to hepatitis B core antigen 
AP 
Accelerated phase 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
AT 
Angiotensin 
AUC 
Area under curve 
BC 
Blast crisis 
BCR 
Break point cluster region 
BCR-ABL 
BCR-ABL oncoprotein, BCR-ABL fusion gene, BCR-ABL fusion transcript 
BID 
Bis In Die / twice a day 
BP 
Blood pressure 
CABG 
Coronary artery bypass graft 
CAD 
coronary artery disease  


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CCyR 
complete cytogenetic response 
CKD 
Chronic kidney disease 
CML 
Chronic myeloid leukemia 
CP 
Chronic phase 
CRF 
Case Report/Record Form 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CVD 
Cardiovascular disease 
CVE 
Cardiovascular event 
CYP3A4 
Cytochrome P450 3A4 
DS&E 
Drug Safety and Epidemiology 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
Event-free survival 
ELN 
European Leukemia Net 
EMA 
European Medicine Agency 
EMR 
Early molecular response 
EORTC 
European Organization for Research and Treatment of Cancer 
ESC 
European Society of Cardiology 
EUTOS 
European Treatment and Outcome Study for CML 
G-CSF 
Granulocyte colony-stimulating factor 
GFR 
Glomerular filtration rate 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
HbA1c 
Glycated hemoglobin 
HBs Ag 
Hepatitis B surface antigen 
HCT 
Hydrochlorothiazide 
HDL 
High-density lipoprotein 
HMG-CoA 
3-hydroxy-3-ethylglutaryl-coenzyme A 
HRQOL 
Health-related quality of life 


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IB 
Investigator brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
ICVE 
Ischemic cerebrovascular event 
i.v. 
Intravenous(ly) 
IHD 
Ischemic heart disease 
IRB 
Institutional Review Board 
IS 
International scale 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
LDL 
Low-density lipoprotein 
IVRS 
Interactive Voice Response System 
LVEF  
Left ventricular ejection fraction 
MR 
Molecular response 
MR4 
Molecular response 4 log reduction from standardized baseline  
MR4.5 
Molecular response 4.5 log reduction from standardized baseline 
MMR 
Major molecular response 
o.d. 
Omnia Die / once a day 
oGTT 
Oral glucose tolerance test 
PAES 
Post-authorisation efficacy studies 
PAOD 
Peripheral artery occlusive disease 
PASS 
Post-authorization safety study 
PCI 
Percutaneous coronary intervention 
PFS 
Progression free survival 
Ph 
Philadelphia chromosome 
Ph+ 
Philadelphia chromosome positive 
PK 
Pharmacokinetic 
p.o. 
per os / by mouth / orally 
QD 
Once a day 
QT 
QT interval 


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QTcF 
Fridericia-corrected QT interval 
Resp. 
Respectively 
RQ-PCR 
Real-time Quantitative - Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SmPC 
Summary of Product Characteristics 
TdP 
Torsade de pointes 
TKI 
Tyrosine kinase inhibitor 
TFR 
Treatment-free remission 
SPCS 
Study Protocol Concept Sheet 
WOCBP 
Women of child-bearing potential 
 
 


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Glossary of terms 
MMR 
≥3 log reduction from the standardized baseline or ≤ 0.1% BCR-
ABLIS 
MR4 
≥4-log reduction from IRIS baseline = either (i) detectable 
disease ≤0.01% BCR-ABLIS or  (ii) undetectable disease in 
cDNA with  
10 000–31 999 ABL1 transcripts or 24 000–76 999 GUSB 
transcripts. 
MR4.5 
≥4.5-log reduction from IRIS baseline = either (i) detectable 
disease ≤ 0.0032% BCR-ABLIS or (ii) undetectable disease in 
cDNA with 32 000–99 999 ABL1 transcripts or 77 000– 
239 999 GUSB transcripts. 
Assessment 
A procedure used to generate data required by the study 
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 drug whose properties are being tested in the study 
Investigational treatment 
Drug whose properties are being testing 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 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Patient number 
A number assigned to each patient who enrolls in the study; 
when combined with the center number, a unique identifier for 
each patient in the study is created. 
Phase 
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc. 
Period 
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, 
titration, washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study drug administration and 
assessments; at this time all study drug administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival 
Study drug 
Any drug administered to the patient as part of the required study 
procedures; includes investigational drug, combination of drugs 
and any control drugs including placebo 
Study drug discontinuation 
Point/time when patient permanently stops taking study drug for 
any reason; may or may not also be the point/time of premature 
patient withdrawal 


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Study treatment 
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins. In specific 
examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; 
study treatment in this case refers to the investigational and non-
investigational treatments in combination. 
Variable 
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified 
timepoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Amendmend 3 
Amendmend rational 
The protocol including amendment 2 is being amended in order to correct minor issues in 
previous versions and clarify 
 prior to DBL.  LPFV occurred on 20-Feb-2019.   
At the time of the amendment 169 patients have been included in the trial and 21 have been 
ongoing.  
 
Changes to the protocol: 
Clinical Trial Team 
• Changes in Clinical Trial Lead have been included 
Section 10.4.3 Handling of missing values/censoring/discontinuations 
•  Patients who miss to have an MR assessment at 24 month, but achieved MR4.5 before 
will be evaluated by last available MR assessment at month 21. Overall significance 
level of primary endpoint is not altered. 
 
 
 
 
 
 
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions 
 
Amendmend 2 
Amendmend rational 
The protocol including amendment 1 is being amended in order to add an Interim Analysis of 
the data to the planned procedures and to prolong the recruitment period.  LPFV is planned to 
happen until April 30th 2019. 
At the time of the amendment 53 patients have been included in the trial.  
 
Changes to the protocol: 
Clinical Trial Team 
• Changes in Clinical Trial Lead and Trial Statistician have been included 


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Section 10.7 Interim analysis 
• An interim analysis of baseline and follow-up until end of month 6 data has been added. 
As this analysis is purely descriptive in nature and does not include the primary 
endpoint, no adjustments with regards to the overall significance level will be made.  
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions 
 
A copy of this amended protocol will be sent to the Institutional Review 
Board (IRBs)/Independent Ethics Committee (IECs) and Health 
Authorities. The changes described in this amended protocol require 
IRB/IEC approval prior to implementation.


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Amendmend 1 
Amendmend rationale 
The primary purpose of this amendment is to include hepatitis B virus testing as one of the 
study procedures, to identify study patients who may be at risk of hepatitis B reactivation. 
Reactivation of hepatits B virus can occur in patients who are chronic carriers of this virus and 
are receiving a drug of the BCR-ABL TKI class such as nilotinib. Some cases involving BCR-
ABL TKI resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation 
or a fatal outcome. 
 
Changes to the protocol: 
Section 1.2.2 Clinical experience 
- 
Hepatitis B reactivation added to provide information that reactivation can occur in 
chronic carriers of this virus and receiving a drug of the BCR-ABL TKI class 
Section 6.6.10 Hepatitis B reactivation 
- 
This section was added to provide information on the next steps for patients tested 
positive for hepatitis B virus 
Section 7 Table 1 
- 
Visit schedule updated to include the hepatitis B testing at screening and once at the 
next possible visit when patient is on treatment 
Section 7.5.5 Laboratory evaluations 
- 
Hepatitis B serology added to provide information on hepatitis B testing 
List of abbreviations was updated to add HBs Ag and anti HBc. 
 
A copy of this amended protocol will be sent to the Ethics Committee and Health Authorities. 
 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatments 
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of transformed, 
primitive hematopoietic progenitor cells. The hallmark of CML is the Philadelphia (Ph) 
chromosome found in up to 95% of patients. It results from a reciprocal translocation 
t(9;22)(q34;q11) which adds a 3' segment of the ABL gene on chromosome 9 to the 5' part of 
the breakpoint cluster region (BCR) gene of chromosome 22. The resulting fusion gene encodes 
for a constitutively active tyrosine kinase, the BCR-Abelson (ABL) tyrosine kinase (Faderl et 
al., 1999), which has activity that imparts growth advantage to leukemic cells, increases 
proliferation and cytokine-independent growth, inhibits apoptosis, and inhibits alternate 
adhesion pathways (Sawyers, 1999, Deininger et al., 2000, Van Etten, 2004).  
With a constant incidence of 1,2-1,5/100.000 per year the prevalence of CML is steadily 
increasing (Hochhaus and La Rosee, 2013). Clinically, CML progresses through three distinct 
phases of increasing refractoriness to therapy: chronic phase (CP), accelerated phase (AP), and 
blast crisis (BC) (Enright H, 2000). Most patients, however, present in the CP, characterized by 
splenomegaly and leukocytosis with generally few symptoms. 
The gold standard for the treatment of CML was the tyrosine kinase inhibitor (TKI) Glivec® 
(imatinib). Nilotinib (Tasigna®, AMN107) is a second generation TKI with improved target 
specificity over imatinib. Its efficacy and safety in the treatment of patients who are resistant / 
intolerant to imatinib led to its registration in second-line treatment of CP-CML and AP-CML 
(Kantarjian et al., 2006, Kantarjian et al., 2007, le Coutre et al., 2008). Results of the ongoing 
pivotal ENESTnd trial (CAMN107A2303) demonstrate a superiority of a treatment of nilotinib 
300mg twice daily (BID) over imatinib 400mg once daily (QD) in newly diagnosed patients 
with superior rates of complete cytogenetic response CCyR), major molecular response (MMR) 
and deep molecular response (MR4.5), which led to approval of nilotinib 300mg BID for the 
first-line treatment of patients with chronic phase CML (Larson et al., 2012). 
The current European LeukemiaNet (ELN) recommendations for the management of chronic 
myeloid leukemia suggest continuing therapy with tyrosine kinase inhibitors (TKI) indefinitely 
in patients with optimal response. Nevertheless, the ELN and also NCCN guidelines highlight 
the possibility of treatment discontinuation for optimal responders in controlled studies, once a 
deep molecular response is achieved (Baccarani et al., 2013, NCCN, 2014). 
 
1.2 
Overview of nilotinib (AMN107, Tasigna®)  
Nilotinib (Tasigna®, AMN107) is a rationally designed second generation TKI with improved 
target specificity over imatinib. Tasigna® is approved for the treatment of adult patients with 
Ph+ CML-CP or AP resistant to or intolerant to at least one prior therapy including imatinib, 
and also for the treatment of adult patients with newly diagnosed Ph+ CML in CP. Nilotinib 


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was also shown to be effective in patients with myeloid and lymphoid blastic phase CML (Giles 
et al., 2012).  
Nilotinib is an adenosine triphosphate-competitive inhibitor of the tyrosine kinase activity of 
the native ABL as well as the chimeric fusion protein, BCR-ABL, and thereby prevents the 
activation of BCR-ABL dependent mitogenic and anti-apoptotic pathways (e.g. PI-3 kinase and 
STAT5), leading to the death of the BCR-ABL phenotype in CML (Manley et al., 2010). As 
well as being a highly potent and selective inhibitor of BCR-ABL, nilotinib also maintains 
activity against many imatinib-resistant mutant forms of BCR-ABL (Weisberg et al., 2005).  
 
Non-clinical experience  
Data from preclinical studies demonstrate that nilotinib achieves higher intracellular 
concentrations than imatinib, and that nilotinib inhibits BCR-ABL tyrosine kinase activity and 
induces apoptosis at lower concentrations than imatinib (le Coutre et al., 2004, White et al., 
2006). Therefore, based on the preclinical data, and observed efficacy of nilotinib in imatinib 
resistant and intolerant patients, nilotinib was predicted to have significant efficacy in newly 
diagnosed CML-CP patients. For more details on non-clinical experience, please refer to the 
latest nilotinib IB. 
 
Clinical experience 
Clinical safety and tolerability 
Overall, nilotinib has been found to be effective and well tolerated in patients with Philadelphia 
chromosome positive chronic myeloid leukemia (Ph+ CML)-CP, and AP who were resistant to 
imatinib or intolerant of imatinib as well as in patients with newly diagnosed Ph+ CML-CP. 
For detailed nilotinib clinical safety and tolerability, please refer to the latest nilotinib 
Investigator’s Brochure (IB). Safety data in newly diagnosed Ph+ CML-CP have been acquired 
from the Phase III ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials - 
newly diagnosed CML-CP), [CAMN107A2303] study. Additional safety data have been 
acquired from a Phase I/II open-label study [CAMN107A2101] in CML patients, and a Phase 
III study in gastrointestinal stromal tumor (GIST) patients, as well as from further clinical 
studies and post-marketing experience. The most commonly reported (>5%) all grade non-
hematologic adverse reactions in patients with CML were rash, headache, nausea, pruritus, 
alopecia, myalgia, fatigue, dry skin, arthralgia, vomiting, abdominal pain upper, muscle spasms, 
diarrhea, constipation, peripheral edema, dyspepsia, erythema, abdominal pain, and asthenia. 
Hematologic adverse drug reactions included myelosuppression (thrombocytopenia, 
neutropenia and 
anemia). Clinically relevant biochemical abnormalities included 
hyperglycemia, hyperbilirubinemia, hypophosphatemia, and increases in lipase, ALT, and AST. 
There are insufficient safety data for using nilotinib during pregnancy. 


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Ischemic Vascular and Ischemic Cardiovascular Events Reported for 
CAMN107A2303 (ENESTnd Study) 
Newly-diagnosed or worsened Ischemic Vascular and Ischemic Cardiovascular Events such as 
Ischemic Heart Disease (IHD), Ischemic Cerebrovascular Events (ICVE) or Peripheral Artery 
Occlusive Disease (PAOD) have occurred in a relatively small number of CML-CP patients 
while on study medication. However, such events have been reported with higher frequency on 
the nilotinib treatment arms compared with the imatinib treatment arm. Up to the data cut-off 
for the 60 Month analysis (30-Sep-2013), the number of patients reported with these events is 
as follows: 
• Nilotinib 300 mg BID: IHD, 11 (3.9%); ICVE, 4 (1.4%); PAOD, 7 (2.5%) 
• Nilotinib 400 mg BID: IHD, 24 (8.7%); ICVE, 9 (3.2%); PAOD, 7 (2.5%) 
• Imatinib 400 mg QD: IHD, 5 (1.8%); ICVE, 1 (0.4%); PAOD, 0 (0.0%) 
The majority of reported ischemic vascular and ischemic cardiovascular events were in patients 
with associated risks (e.g., advanced age, hypertension, hyperlipidemia, hypercholesterolemia, 
smoking, diabetes mellitus, pre-existing peripheral vascular disease). The background 
incidence of these events has not been established for the CML patient population. 
Hepatitis B reactivation 
Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus and are 
receiving a BCR-ABL tyrosine kinase inhibitor, such as nilotinib. Some cases involving drugs 
of the BCR-ABL TKI class resulted in acute hepatic failure or fulminant hepatitis leading to 
liver transplantation or a fatal outcome. 
Clinical Efficacy 
Nilotinib is approved by US Food and Drug Administration (FDA) and European Medicines 
Agency (EMA) to treat newly diagnosed adult patients with Ph+ CML in CP, and to treat CP 
and AP Ph+ CML in adult patients resistant to or intolerant to prior therapy that included 
imatinib. The recommended adult dosage of nilotinib is 300 mg orally twice daily for newly 
diagnosed Ph+ CML-CP and 400 mg orally twice daily for resistant or intolerant Ph+ CML-CP 
and CML-AP. 
The results of the pivotal ENESTnd study [CAMN107A2303] demonstrated superiority of 
nilotinib vs. imatinib in the CML-CP frontline setting (Saglio et al., 2010, Larson et al., 2012). 
This ongoing study was designed to determine whether the treatment of newly diagnosed, 
previously untreated Ph+ CML-CP patients, with either nilotinib 300 mg BID or 400 mg BID 
demonstrated improved efficacy, compared to imatinib 400 mg QD. Data cut-off for the latest, 
the 60-months analysis, was 30-Sep-2013. A total of 846 newly diagnosed CML-CP patients 
were randomized into the study. The study met its primary efficacy endpoint at the 12-month 
analysis time point with significantly higher MMR rates in the nilotinib arms compared to the 
imatinib arm (44.3% in nilotinib 300mg BID arm versus 22.3% in imatinib 400mg QD arm). 
By 60 months, the MMR rate remained higher in the nilotinib arms than in the imatinib arm, 


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indicating that the superiority of both nilotinib arms over the imatinib arm persists with longer 
follow-up. Furthermore, the proportions of patients achieving deep molecular response MR4 
(BCR-ABLIS ≤ 0.01%) and MR4.5 (BCR-ABLIS ≤ 0.0032%) by 60 months were significantly 
higher in the nilotinib arms than in the imatinib arm. For more efficacy data, please refer to the 
latest version of the AMN107 IB. 
Pharmacokinetic 
Approximately 30% of a nilotinib dose is absorbed after oral administration, with peak 
concentrations reached at 3 hours after dosing. Plasma protein binding is high (approximately 
98%) and independent of dose. 
Nilotinib is metabolized in the liver via oxidation and hydroxylation pathways, mediated 
primarily by CYP3A4. Nilotinib was identified as the main circulating component in the serum, 
while none of the metabolites was found to contribute significantly to the pharmacological 
activity of nilotinib. In humans, excretion of nilotinib occurred exclusively through the fecal 
route, with no renal elimination of the drug or its metabolites observed. The average elimination 
half-life (t1/2) of nilotinib is 17 hours. The bioavailability of nilotinib is increased by food: 
healthy volunteer studies showed increases in Cmax and AUC (area under curve) of up to 112% 
and 82%, respectively (30 hours after high-fat meal, versus fasting conditions).  
1.3 
Overview of Molecular Response  
The methodology used for identifying and quantifying BCR-ABL transcripts has evolved over 
the years.  
A basic method for expressing results of novel and effective treatment for CML was introduced 
by Hughes and colleagues in 2003, who monitored the response to imatinib in previously 
untreated patients with CML entered in the International Randomized Study of Interferon 
versus STI571 (IRIS study); in order to normalize results of measuring reductions in BCR-ABL 
transcripts in geographically dispersed laboratories, the investigators introduced the concept of 
log10 reduction from a standardized baseline for untreated patients. At the same time, the first 
description of “major molecular response” (MMR) was published and defined to be a three-log 
reduction from the standardized baseline (Hughes et al., 2003). Three years later, the 
International Scale (IS) for BCR-ABL measurement was proposed. The IS further standardized 
the real time PCR methodology and expresses detectable disease levels as percentage with 
100% IS as the standardized baseline and 0.1% IS corresponding to MMR (Hughes et al., 2006).  
More recently, the terms MR4, MR4.5 and MR5 have been introduced to harmonize results and 
to reflect the proceedings in PCR sensitivity. These values represent threshold levels for BCR-
ABL transcripts at 4, 4.5 and even 5 log reductions, independent of the negativity of the PCR 
reaction. In relation to the International Scale, MR4 corresponds to ≤0.01% BCR-ABLIS, MR4.5 
corresponds to ≤0.0032% BCR-ABLIS and MR5 corresponds to ≤0.001% BCR-ABLIS (Cross et 
al., 2015). Unfortunately, there are still some concerns about the comparability of PCR results 
between different laboratories, even if these are expressed in % IS, because variations in the 
PCR methodology make it difficult to compare the actual results. For this reason, the European 


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Treatment and Outcome Study (EUTOS) group is doing an international performance 
evaluation with the aim of recommending specific laboratory definitions, protocols and internal 
quality assurance that will facilitate standardization of MR and provide greater comparability 
between centers (Muller et al., 2009).   
Since the treatment of CML patients with especially second and third generation TKIs has 
proven to lead to deep molecular responses in a majority of patients (Savona, 2014), the need 
for accurate and standardized molecular monitoring has gained even more importance. 
Achieving a deeper molecular response than MMR (MR4 or MR4.5) is associated with a stable 
response after discontinuation of TKI therapy for at least a group of patients (Rousselot et al., 
2007) and it is generally associated with better event-free and failure-free survival (Etienne et 
al., 2014). Different concepts for treatment discontinuation after achieving deep molecular 
responses are currently being tested in clinical trials [CAMN107I2201, CAMN107AIC05 and 
CAMN107A2408] and the prerequisite for entering a treatment free remission phase of these 
studies is the deep and stable molecular response (Cross et al., 2015).   
The benefit to patients of regular molecular analysis is a reassurance of ongoing response using 
the most sensitive of techniques or a potential improvement in outcome for those where relapse 
is indicated early (Branford et al., 2007).  
2 
Study purpose 
The therapy and management of chronic myeloid leukemia (CML) has advanced through recent 
years and has been revolutionized by the advent of tyrosine kinase inhibitors (TKI). TKIs 
transformed the status of the disease from an indolent yet progressive cancer with limited 
prognosis to that of a highly treatable and potentially curable cancer (Mauro, 2013, Baccarani 
et al., 2013).  
Previous studies have shown that deeper response, particularly when attained early during 
treatment, is associated with better long-term clinical outcomes (Mahon and Etienne, 2014). In 
ENESTnd, 91% of the patients with nilotinib 300mg BID achieved a BCR-ABL level of ≤ 10% 
after 3 months of therapy versus 67% in the imatinib arm. Landmark analysis has shown a 
significantly worse PFS and OS after 5 years for patients with BCR-ABL > 10% after 3 months. 
In addition, significantly more patients with deep early response achieve higher rates of MR4.5 
after 5 years (Saglio 2013). 
Several studies have shown that a further reduction of residual leukemic cells (i.e. achieving a 
deeper response compared to an MMR) is associated with the most favorable outcome for 
patients in CML-CP (Branford, 2008, Press et al., 2007, Kantarjian et al., 2008). In the German 
CML study IV life expectancy in patients with MR4 or MR4.5 was the same as that in an age 
matched population (Mahon and Etienne, 2014). No patient who has achieved MR4.5 has 
progressed to advanced disease in large independent clinical trials (Hehlmann et al., 2014, 
Kantarjian et al., 2011, Kantarjian et al., 2012). A recent report has shown that patients who 
achieved a deep molecular response MR4.5 have a statistically significant superior survival rate 
to that in patients with only a 2-log reduction in BCR-ABL transcript level, which has been 


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suggested to be the minimal molecular response equivalent of complete cytogenetic response 
(CCyR), (Hehlmann et al., 2014). This identifies MR4.5 as a predictor of survival and the first 
molecular marker shown to be more predictive of long-term survival than CCyR (Hehlmann et 
al., 2014). These results provide encouraging evidence that achievement of deep molecular 
response MR4.5 is an important clinical goal.  
Although CML is now a chronic disease and many patients can anticipate a normal life 
expectancy, physicians and patients have shown a strong interest to explore treatment-free 
remission (TFR) strategies for BCR-ABL inhibitors. Second generation TKIs for the treatment 
of newly diagnosed patients have increased the proportion of patients who achieve profound 
molecular response and could increase the number of patients who can safely stop treatment or 
could discontinue treatment earlier (Breccia and Alimena, 2014, Mauro, 2013). The potential 
benefits of successful TFR include elimination of TKI-induced chronic and/or acute side 
effects, minimization of drug-drug interactions, and the possibility of a pregnancy without 
exposure to TKIs. Deep molecular response (MR4.5) defines a subgroup of patients with CML 
who may stay in maintained remission after treatment discontinuation (Hehlmann et al., 2014).  
Currently, different concepts for discontinuing treatment with TKIs are under investigation. The 
EURO-SKI, TIGER and ENESTpath trials are all designed for patients with a response of at 
least MR4 after TKI treatment. ENESTop and ENESTfreedom however are studies for patients 
with a response of at least MR4.5. To date there is no consensus about the question whether there 
is a difference in outcome for patients who stop treatment after a response of MR4 or MR4.5, 
therefore the proportion of patients with a response of at least MR4 will be assessed as a 
secondary endpoint. 
Standardized molecular monitoring has become widely available in Europe through the efforts 
of EUTOS cooperation (Muller et al., 2009) and now allows for the generation of comparable 
data on the residual disease using recalculation on the international scale despite these data 
being analyzed in many different laboratories. Standardization of deeper levels of molecular 
response is urgently needed to facilitate improved interpretation of clinical results. The ongoing 
EUTOS (European Treatment and Outcome Study) collaboration aims to facilitate 
standardization 
of 
deep 
molecular 
response 
across 
laboratories 
by 
establishing 
recommendations for response definitions and quality control (Mahon and Etienne, 2014). 
In conclusion, nilotinib has proved superiority in reducing the leukemic burden and achieving 
clinical relevant parameters as well as preparing patients for TFR. The reported studies support 
the goal of therapy for newly diagnosed CML-CP as being an attainment of deep molecular 
response, as this is associated with the most favorable outcome for patients. Monitoring of 
molecular response provides a straightforward opportunity to assess patients' response and 
possible prognosis in the use of targeted therapy. Advances in the standardization of molecular 
responses and the improvement of targeted therapy have allowed for comparable response 
assessment across Europe and early treatment optimization of patients. Thus the further 
evaluation of deep molecular response and corresponding standardized monitoring seems 
justified. 


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The main purpose of this study is evaluating of deep molecular response (MR4.5; BCR-ABLIS 
< 0.0032%) after 24 months of therapy with nilotinib in newly diagnosed patients with chronic 
phase CML. Via the use of MR4.5 EUTOS (‘European Treatment and Outcome Study for CML’) 
laboratories adequate and reliable molecular monitoring as a key parameter for assessing 
molecular milestones is fostered. For definition of MR4.5 please see section 7.4. 
 
 
 
 
 
 
 
 
 
 
 
 
As modern therapy turned CML in a chronic disease where patients need to tolerate and adhere 
to continuing treatment for many years, assessing health-related quality of life (HRQOL) and 
managing side effects of TKI became a key issue for CML management (Efficace et al., 2014). 
The impact of TKIs on the HRQOL of CML-patients has been poorly investigated and the few 
studies available show that patients’ HRQOL is impaired in many respects. This study will 
evaluate the HRQOL by using the internationally developed CML-specific QLQ-CML 24 
(Efficace et al., 2014) questionnaire, which is used in conjunction with the EORTC QLQ C30 
questionnaire (Aaronson et al., 1993).  
In addition the study seeks to give guidance for the assessment and treatment of cardiovascular 
risk factors. This guidance can be applied at the discretion of the investigator based on the 
individual needs of the patient.  
3 
Objectives (and related endpoints) 
3.1 
Primary objective(s) 
- 
To evaluate the proportion of patients who are in deep molecular response MR4.5 (IS) at 
24 months of study treatment, measured in a standardized EUTOS MR4.5 laboratory.   
3.2 
Secondary objective(s) 
- 
to determine the proportion of patients who are in deep molecular response MR4 (IS) at 
24 months of study treatment 
- 
to determine the proportion of patients who are in MMR at 12 months of study treatment 


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- 
to determine the proportion of patients who are in CCyR at 6 months of study treatment 
- 
to evaluate progression-free survival (PFS) and time to progression to AP/BC 
- 
to evaluate quality of life of 300mg nilotinib BID therapy 
 
 
 
 
 
 
 
 
 
 
4 
Study design 
 
This is a Phase IV open-label, multicenter, single-arm trial of nilotinib 300mg BID in newly 
diagnosed patients with chronic phase CML to primarily evaluate the rate of deep molecular 
response (MR4.5) at 24 months of study treatment using EUTOS standardized laboratories. 171 
evaluable patients will be included in at least 50 sites in Germany. All patients will receive 
nilotinib 300mg BID. Nilotinib will be prescribed by the investigator according to the individual 
needs of the patients. 
A screening period of 2 weeks will be used to assess eligibility and to taper patients off 
disallowed medications.  Patients whose eligibility is confirmed will then enter a 24 months 
treatment phase.  The assessment to address the primary objective will be performed at the end 
of the treatment phase.  
For efficacy analysis, only patients with typical b2a2 or b3a2 BCR-ABL transcripts at baseline 
will be considered. Other variants will be analyzed separately. 
 


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Table 4-1 
Study outline 
 
 
 
End of study 
Screening  
2 Weeks 
Treatment Phase 
24 Months 
30 Day  
Safety FU 
 EUTOS RQ-PCR 
           M3           M6          M9 
        M12           M15          M18          M21           M24 
N = 171 


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5 
Population 
 
The study population will consist of a representative group of adult patients with newly 
diagnosed Philadelphia chromosome positive (Ph+) CML in chronic phase for who nilotinib is 
the appropriate treatment at the discretion of the investigator. 171 evaluable patients will be 
included in at least 50 sites in Germany. The decision for treatment of the patient will be made 
independently of the study. Prescription of nilotinib will also be independent of the study and 
exclusively follows the patient’s medical need. 
5.1 
Inclusion/exclusion criteria  
Patients must meet all inclusion criteria and none of the exclusion criteria to enter the study. 
Patients must meet all inclusion criteria within 2 weeks of study start (bone marrow 
examinations may be within 12 weeks). The investigative site must have all documentation of 
eligibility on file at the investigative site for confirmation by study monitors. 
Inclusion Criteria: 
1. Male or female patients at least 18 years of age 
2. ECOG 0, 1, or 2. 
3. Patients within 6 months of diagnosis of CML in chronic phase with cytogenetic 
confirmation of Ph+ [t(9;22) translocation]; if the bone marrow sample is taken within 12 
weeks of the start of study treatment but before the patient consents, the bone marrow should 
not be repeated after the patient formally consents to the study. 
4. Documented chronic phase CML will meet all the criteria defined by: 
1. < 15% blasts in peripheral blood and bone marrow, 
2. < 30% blasts plus promyelocytes in peripheral blood and bone marrow, 
3. < 20% basophils in the peripheral blood, 
4. ≥ 100 x 109/L (≥ 100,000/mm3) platelets, 
5. No evidence of extramedullary leukemic involvement, with the exception of 
hepatosplenomegaly. 
5. Patients must be previously untreated for CML with the exception of 6 months treatment 
with hydroxyurea and a maximum of 6 weeks treatment with imatinib 
6. Adequate end organ function as defined by: 
• Total bilirubin < 1.5 x ULN (upper limit of normal) except know Mb. Gilbert 
• AST (SGOT), ALT (SGPT) < 3 x ULN or ≤ 5.0 x ULN if considered due to leukemia 
• Creatinine < 1.5 x ULN 
• Serum amylase and lipase ≤ 1.5 x ULN 
• Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related. 


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7. Normal serum levels ≥ LLN (lower limit of normal) of potassium, magnesium, total 
calcium corrected for serum albumin or phosphorus, or correctable to within normal limits 
with supplements, prior to the first dose of study medication 
8. Ability to provide written informed consent prior to any study related screening procedures 
being performed. 
 
Exclusion Criteria: 
1. Contraindication to excipients in study medication 
2. Known impaired cardiac function, including any of the following: 
• 
Congenital long QT syndrome or a known family history of long QT syndrome 
• 
History of or presence of clinically significant ventricular or atrial tachyarrhythmias 
• 
Clinically significant resting bradycardia (<50 beats per minute)  
• 
QTcF >450 msec (using the QTcF formula). If   QTcF > 450 msec and electrolytes are not 
within normal ranges, electrolytes should be corrected and the patient re tested for the QTc 
• 
History of clinically documented myocardial infarction within 12 months prior to study entry 
• 
History of unstable angina during the last 12 months 
• 
Other clinical significant heart disease (congestive heart failure) 
3. History of acute (within 1 year of starting study medication) or chronic pancreatitis 
4. Severe and/or uncontrolled concurrent medical conditions that in the opinion of the 
investigator could cause unacceptable safety risks or compromise compliance with the 
protocol (e.g., acute artherothrombotic events (such as ischemic heart disease, acute 
peripheral arterial occlusive disease, symptomatic carotid stenosis/cerebrovascular 
accident), uncontrolled diabetes mellitus, active or uncontrolled infections, uncontrolled 
severe hypertension, and uncontrolled severe dyslipidemia, acute or chronic liver or severe 
renal disease.  
5. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of study drug  
6. History of significant congenital or acquired bleeding disorder unrelated to cancer 
7. Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers  
(see http://medicine.iupui.edu/clinpharm/ddis/main-table/)     
or medications that have the potential to prolong the QT interval  
(see https://www.crediblemeds.org/pdftemp/pdf/CombinedList.pdf this list may not be 
exhaustive) which cannot be either discontinued or switched to a different medication prior 
to starting study drug 
8. Patients who have not recovered from prior surgery 
9. Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a 
negative pregnancy test prior to baseline and (d) female of childbearing potential unwilling 
to use contraceptive precautions throughout the trial (post-menopausal women must be 
amenorrheic for at least 12 months to be considered of non-childbearing potential). 


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Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for 14 days after the final dose of nilotinib. Patients using an oral hormonal 
contraception method should complete their monthly treatment course. 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 (surgical bilateral oophorectomy with or without hysterectomy) or tubal 
ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow up hormone level 
assessment 
• 
Male sterilization (at least 6 months prior to screening). For female subjects on the study the 
vasectomized male partner should be the sole partner for that subject. 
• 
Combination of any two of the following (a+b or a+c, or b+c) listed below:  
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 
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. 
10. Patients with a history of another primary malignancy that is currently clinically 
significant or currently requires active intervention with the exception of previous or 
concomitant basal cell skin cancer and previous carcinoma in situ treated curatively 
11. Treatment with other investigational agents within 30 days of Day 1 
12. Patients not able to understand and to comply with study instructions and requirements 
13. Refusal to give informed consent 
 
5.2 
Premature patient withdrawal 
Patients must be withdrawn from the study for any of the following reasons: 
• Withdrawal of informed consent 
• Pregnancy  
• Study termination by the sponsor 
• Disease progression (see section 6.6) 
• Lost to follow up 
• Death 
• Permanent study drug discontinuation  


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Patients also should be withdrawn at any time if the investigator concludes that it would be in 
the patient’s best interest for any reason. Protocol violations should not lead to patient 
withdrawal unless they indicate a significant risk to the patient’s safety. 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, or fail to return for visits, or 
become lost to follow up for any other reason.  
If a study withdrawal occurs, or if the patient fails to 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 Disposition CRF page. 
For patients who are lost to follow-up (i.e., those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show "due diligence" by documenting in the source documents steps taken to contact the 
patient, e.g., dates of telephone calls, registered letters, etc.  
Patients who are prematurely withdrawn from the study will not be replaced by newly enrolled 
patients.   
6 
Treatment 
6.1 
Patient numbering 
Each patient in the study is uniquely identified by a 9 digit patient number which is a 
combination of his/her 4-digit center number and 5-digit subject number. The center number is 
assigned by Novartis to the investigative site. Upon signing the informed consent form, the 
patient is assigned a patient number by the investigator. At each site the first patient is assigned 
patient number 1, and subsequent patients are assigned consecutive numbers (e.g., the second 
patient is assigned patient number 2, the third patient is assigned patient number 3). For studies 
using eCRFs, only the assigned patient number should be entered in the field labeled “Subject 
ID” on the EDC data entry screen. Once assigned to a patient, a patient number will not be 
reused for any other patient and the patient no. for that individual must not be changed, even if 
the patient is re-screened. If the patient fails to be assigned to treatment for any reason, the 
reason for not being assigned to treatment will be entered on the Screening Log.  
6.2 
Investigational drug 
Tasigna® (Nilotinib:AMN107) is the study drug.  
Nilotinib will be prescribed as 150 mg hard gelatin capsule (commercial packs with blisters).  
The decision for treatment of the patient will be made independently of the study. Prescription 
of the study drug will also be independent of the study and exclusively follows the patient’s 
medical need. 
Nilotinib will not be dosed by weight or body surface area. 


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6.3 
Treatment arms 
This is a single arm study, therefore all patients will be treated with nilotinib (AMN107) 300 
mg BID, given as two 150 mg capsules twice daily. 
6.4 
Treatment assignment 
No randomization and no IVRS/IWRS will be used in this study. 
6.5 
Treatment blinding 
This is an open-label study. 
6.6 
Treating the patient 
 
Dispensing the study drug 
Nilotinib will be prescribed by the investigator according to the patient’s medical need.  
Patients will receive a prescription for the respective amount to cover the period until the next 
study visit or a period to be decided at the discretion of the investigator. For patients entering 
the study, the prescription will be dispensed on Day 1 (Visit 2). If, at the investigators discretion, 
it is decided to dispense the prescription drug for a shorter or longer period, then the patient 
must be rescheduled for an interim visit to ensure continuous medication can be given. These 
interim visits will not be recorded as study visits, and every attempt must be made to follow the 
visit schedule as stipulated in the protocol. It is recommended to prescribe a 1-month supply at 
Day 1 and a 3-month supply at every subsequent visit. Patients will be asked to return all unused 
study drug at each visit to check compliance. 
 
Instructions for use of study drug 
Nilotinib should be taken according to the SmPC (Summary of Product Characteristics). 
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient should be instructed to contact the investigator if he/she is 
unable for any reason to take the study drug as prescribed. 
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF. 
 
Study drug supply and resupply, storage, and tracking 
Patients will receive a prescription for the respective amount at the discretion of the investigator. 
The patients will get the medication at a pharmacy. The patient will be advised to present the 
blisters at the subsequent study visit, to review compliance and allow the investigator to 
complete a drug accountability check.  
Storage conditions will be described in the patient leaflet (Summary of Product Characteristics). 


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Study drug compliance and accountability 
Study drug compliance 
Dosing frequency and compliance will be assessed by the investigator and/or study personnel 
at each patient visit and information provided by the patient will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit. 
Study drug accountability 
The investigator will prescribe nilotinib in the approved indication. The patient will be advised 
to present the blisters at the subsequent study visits to review compliance and allow the 
investigator to complete a drug accountability check. 
 
Disposal and destruction 
n.a. 
 
Permitted study drug dose adjustments and interruptions 
For patients who are unable to tolerate the protocol-specified dosing scheme, dose adjustments 
and interruptions are permitted in order to keep the patient on study drug. The following 
guidelines should be followed. 
For the purpose of these dose reduction guidelines, toxicity is defined as any adverse event (AE) 
which is, with reasonable likelihood according to Investigator’s judgment, caused by study 
drug. 
According to International Conference on Harmonization (ICH) E6 the Investigator is 
responsible for all trial-related medical decisions. During and following a patient’s participation 
in a trial, the Investigator should ensure that adequate medical care is provided to a patient for 
any adverse events, including clinically significant laboratory values, related to the study drug. 
Any dose change must be recorded on the Dosage Administration Record electronic case report 
form (eCRF). Dose escalation is not allowed above the study dose of 300 mg BID (total 600 
mg) nilotinib.  
Drug adjustment should take place as soon as possible, as clinically indicated. Patients do not 
need to wait for a scheduled visit once clinical need has been determined. If multiple dose-
reducing toxicities are present, the greatest dose reduction schedule should be used. 
This study will use the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
version 4.0 for toxicity and AE reporting. The NCI Common Toxicity Criteria version 4.0 can 
be downloaded from the following website: http://ctep.info.nih.gov/reporting/ctc.html. The 
highest reported AE grade should be used to determine the dose modification action. 


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Dose reduction guidelines for study drug-related non-hematological 
toxicity and for ischemic vascular and cardiovascular events 
regardless of study drug relationship 
A summary of dose reduction guidelines for study drug-related non-hematological toxicity and 
for ischemic vascular and cardiovascular events regardless of study drug relationship is 
presented in Table 6-1. 
These guidelines provide general principles and recommendations intended to support the 
investigator’s judgment and decisions about appropriate management of toxicity in the 
individual patient. 
However, for those toxicities detailed in Table 6-1, the following rules (as detailed in the bullet 
points below) must be strictly followed: 
• Any non-hematological toxicity Grade 3 or 4 must be resolved within 28 days to ≤ Grade 
2 in order to resume study drug at the reduced dose. If a non-hematological toxicity Grade 
3 or 4 does not resolve after 28 days, the patient must be discontinued from the study. 
• If Grade 4 toxicity of the same type recurs despite nilotinib dose reduction to 450 mg QD 
the patient must be discontinued from the study. 
• In case of Grade 3 pancreatitis, study drug treatment must be held and Novartis must be 
consulted immediately. 
• In case of Grade 4 pancreatitis, study drug treatment must be permanently stopped and the 
patient must be discontinued from study. 
• In case of Grade 4 liver toxicity, study drug treatment must be held and Novartis must be 
consulted immediately. 
• In case of Grade 4 cardiac toxicity, study drug treatment must be permanently stopped and 
the patient must be discontinued from study. 
• In case of recurrent QTcF prolongation to > 480 msec despite dose reduction the patient 
must be discontinued unless the reason for QTcF prolongation can be corrected (such as 
discontinuing or replacing of QT-prolonging concomitant drugs) 
 
Table 6-1  
Summary of nilotinib dose reduction guidelines for study drug-related 
non-hematologic toxicity and for ischemic vascular and 
cardiovascular events regardless of study drug relationship 
 
Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) 
General non-hematological toxicity 
Grade 2 
(persisting > 7 days with 
optimal supportive care) 
The dose of nilotinib may be reduced to 450 mg at the discretion of the investigator 
if clinically appropriate and in the best overall interest of the patient 


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Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) 
≥ Grade 3 
Hold study drug and resume nilotinib at next lower dose level after recovery to ≤ 
Grade 2 is seen 
 
l→ 450 mg. 
 
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be discontinued 
from the study. 
 
If Grade 4 toxicity recurs despite dose reduction to 450 mg  
 
 
l→ discontinue from the study. 
Serum hypophosphatemia 
Grade 2-3 
Continue nilotinib at 300 mg BID and start phosphate supplementation. 
Grade 4 
Hold study drug and consult Novartis. 
Serum creatinine 
Grade 2 
> 1.5 -3.0 x ULN 
The dose of nilotinib may be reduced to 450 mg at the discretion of the investigator 
if clinically appropriate and in the best overall interest of the patient. 
≥ Grade 3 
≥ 3.0 x ULN 
Hold study drug and resume nilotinib at next lower dose level after recovery to ≤ 
Grade 2 is seen 
 
l→ 450 mg. 
 
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be discontinued 
from the study. 
 
If Grade 4 toxicity recurs despite dose reduction to 450 mg  
 
 
l→ discontinue from the study. 
Hepato-biliary [bilirubin, AST (SGOT), ALT (SGPT)] 
Note: If hyperbilirubinemia is primarily due to the indirect bilirubin [with indirect bilirubin > direct bilirubin and 
direct bilirubin ≤ 1.5 x ULN and ALT ≤ Grade 1, AST ≤ Grade 1, ALP ≤ Grade 1, and hemolysis has been ruled 
out as per institutional guidelines (e.g. by determination of hepatoglobin)], nilotinib may be continued at the 
same dose, at the discretion of the investigator. 
Grade 2 
The dose of nilotinib may be reduced to 450 mg at the discretion of the investigator 
if clinically appropriate and in the best overall interest of the patient. 
≥ Grade 3 
Hold study drug and resume nilotinib at next lower dose level after recovery to ≤ 
Grade 2 is seen 
 
l→ 450 mg. 
 
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be discontinued 
from the study. 
 
If Grade 4 toxicity recurs despite dose reduction to 450 mg 
 
 
l→ discontinue from the study. 
Pancreatitis (with abdominal symptoms plus lipase elevation) 


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Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) 
Grade 2 
Hold study drug and perform abdominal CT with contrast to exclude pancreatic 
pathology. 
 
If CT is positive, continue to hold therapy and repeat CT, at investigator’s 
discretion. 
 
If CT is negative, re-start nilotinib at 450 mg after recovery to ≤ Grade 1 is seen. 
 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be discontinued 
from the study. 
 
If toxicity recurs 
 
l→ discontinue from the study. 
Grade 3 
Hold study drug and consult Novartis. 
Grade 4 
Stop study drug. The patient must be discontinued from study. 
Elevated lipase without symptoms 
≥ Grade 3 
Hold study drug. 
 
Re-start nilotinib at 450 mg after recovery to ≤ Grade 2 is seen. 
 
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be discontinued 
from the study. 
 
If toxicity recurs without symptoms consider appropriate diagnostic procedures 
such as abdominal CT or ultrasound to exclude pancreatitis. After recovery to ≤ 
Grade 2, 
l→ continue dosing at 450 mg QD based on investigator’s discretion. 
Diarrhea 
Note: Anti-diarrheal medication is recommended at the first sign of loose stools or overt diarrhea. If diarrhea 
cannot be controlled with optimal anti-diarrheal treatments, take the following actions: 
≥ Grade 3 
Hold study drug and resume nilotinib at next lower dose level after recovery to ≤ 
Grade 2 is seen 
 
l→ 450 mg. 
 
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be discontinued 
from the study. 
Vomiting 
Note: Antiemetic medication should be withheld until the patient experiences ≥ grade 1 vomiting then institute 
symptomatic therapy as appropriate. Antiemetics with the potential to prolong QT such as domperidone must 
be avoided. If nausea and vomiting cannot be controlled with optimal antiemetic treatment take the following 
actions:  
≥ Grade 3 
Hold study drug and resume nilotinib at next lower dose level after recovery to ≤ 
Grade 2 is seen 
 
l→ 450 mg. 
 
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be discontinued 
from the study. 
Skin rash 
Note: Institute symptomatic therapy as appropriate. If skin rash does not resolve with optimal treatments, take 
the following actions: 
Grade 2 
The dose of nilotinib may be reduced to 450 mg at the discretion of the investigator 
if clinically appropriate and in the best overall interest of the patient. 


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Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) 
≥ Grade 3 
Hold study drug and resume nilotinib at next lower dose level after recovery to ≤ 
Grade 2 is seen 
 
l→ 450 mg. 
 
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be discontinued 
from the study. 
 
If Grade 4 toxicity recurs despite dose reduction to 450 mg 
 
 
l→ discontinue from the study. 
Cardiac QTc prolongation 
QTcF > 480 msec 
Hold study drug when an ECG with a QTcF > 480 msec.  
 
In addition to the procedures below, the investigator should follow their local 
standards of practice and treatment guidelines for treating prolonged QT intervals.  
 
• Perform an analysis of serum potassium and magnesium, and if below lower limit 
of normal, correct with supplements to within normal limits. 
 
• Concomitant medication usage must be reviewed for their potential to inhibit 
CYP3A4 and/or to prolong the QT-interval. 
 
• Perform a repeat ECG within one hour of the first QTcF of > 480 msec. 
 
• If QTcF remains > 480 msec, repeat ECG as clinically indicated, but at least once 
a day until the QTcF returns to < 480 msec. 
 
Study drug may be restarted, at same dose, if reason for elevation of QTcF is 
identified and corrected so that QTcF returns to < 450 msec and to within 20 msec 
of baseline within 2 weeks. 
 
ECGs must be repeated 7 days after dose re-start for all patients who had therapy 
held due to QTcF > 480 msec. 
 
If the QTcF is repeated and is more than 20 msec greater than baseline or 
between 450 msec and 480 msec, the dose of study drug should be reduced to 
450 mg QD. 
 
If QTcF of > 480 msec recurs, the patient is to be discontinued from the study.  
 
The investigator should contact Novartis regarding any questions that arise if a 
patient with QTcF prolongation should be maintained on study. 
 
Note: QTcB can be used in centers that do not have the ability to automatically 
measure QTcF for QTc prolongation. In patients with a heart rate lower than 60 
per minute decisions are always based on QTcF because QTcB underestimates 
QT prolongation at heart rates below 60 per minute.  
Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) 
Ischemic vascular or cardiovascular events 


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Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) 
Grade 2* 
Hold study drug and refer patient for assessment by a vascular or cardiovascular 
specialist.   
Resume nilotinib at next lower dose level after recovery to ≤ Grade 1 is seen 
 
     l→ 450 mg.       
 
If another recurrence 
     l→ discontinue from the study.       
 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be discontinued 
from the study. 
Grade 3* or 4* 
Hold study drug and refer patient for assessment by a vascular or cardiovascular 
specialist. Consideration should be given for discontinuation from the study. The 
patient must be discontinued from the study if recovery to ≤ Grade 2 is greater 
than 28 days. 
* Patient should be assessed for potential risk factors for the event including causality secondary to CML 
therapy. 
Cardiac “other” 
Grade 2 or Grade 3 
Hold study drug and resume nilotinib at next lower dose level after recovery to ≤ 
Grade 1 is seen 
 
l→ 450 mg. 
 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be discontinued 
from the study. 
 
If Grade 3 toxicity recurs despite dose reduction to 450 mg 
 
 
l→ discontinue from the study. 
Grade 4 
Stop study drug. The patient must be discontinued from the study. 
 
Patients who experience Grade 2/3/4 ischemic vascular or cardiovascular events should be 
referred for a cardiac or cardio-vascular consult and management decisions (e.g. continue 
current treatment, dose reduction or study discontinuation). Patients should be assessed for 
potential risk factors for the event including causality secondary to CML therapy. 
The SC will be informed on regular basis on the Grade 2/3/4 ischemic vascular or 
cardiovascular events occurring to the patients enrolled in the trial. 
 
Dose reduction guidelines for study drug-related hematologic toxicity 
A summary of dose reduction guidelines for ≥ Grade 3 study drug-related hematologic toxicity 
as determined by the Investigator is presented in Table 6-2. No dose adjustments should be 
made for Grade 1 or 2 hematologic toxicities. These guidelines provide some general principles 
as well as recommendations which are intended to support the investigator’s judgment and 
decision about the appropriate management of toxicity in the individual patient. Please note that 
proceeding according to the SmPC is sufficient. However, if a hematological toxicity does not 
resolve to ≤ Grade 2 within 28 days, the investigator should consult with Novartis or the SC.  
 


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Table 6-2  
Summary of dose reduction guidelines for study drug-related 
hematologic toxicity 
 
Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) 
≥ Grade 3 
● Grade 3/4 1st and 2nd time: Stop nilotinib, check at least weekly, resume 600mg 
daily dose when Grade <3  
● Grade 3/4 3rd time: Stop nilotinib, check at least weekly, resume nilotinib at 450 
mg daily dose when Grade <3 and at 600 mg daily dose after 1 week; 
● Grade 3/4 4th time: Stop nilotinib, check at least weekly, resume nilotinib at 300 
mg daily dose when Grade <3 and at 600 mg daily dose after 1 month; 
● Grade 3/4 5th or subsequent time: Stop nilotinib until Grade <3, then contact 
Novartis. It will be discussed with the SC if nilotinib can be resumed or should be 
discontinued permanently. 
Note: Dose of study drug need not be reduced or interrupted for hematological toxicity of Grade 2 or lower. 
 
Guidelines for dose re-escalation 
Re-escalation of the dose of nilotinib to the 300 mg BID is permitted at the discretion of the 
investigator, if the following criterion is met at least one month on treatment on the reduced 
dose: 
All ≥ Grade 3 toxicities have resolved to ≤ Grade 2 
 
Hepatitis B reactivation 
Patients should be tested for hepatitis B infection before initiating treatment with nilotinib as 
indicated in table 7.1. and section 7.5.5. Patients included before protocol amendment 1 should 
be tested during the study to identify patients who may be at risk for hepatitis B reactivation. 
Experts in liver disease should be consulted before treatment is initiated in patients with positive 
hepatitis B serology (including those with active disease) and for patients who test positive for 
HBV infection during treatment. Carriers of HBV who require treatment with nilotinib should 
be closely monitored for signs and symptoms of active hepatitis B infection throughout therapy 
and for several months following termination of therapy. 
 
Suggested management of cardiovascular risk factors and events 
Newly-diagnosed or worsened ischemic vascular or cardiovascular events have occurred in a 
relatively small number of CML-CP patients while on study medication. If a patient experiences 
such an adverse event, the Investigator should ensure that the patient is assessed by a vascular 
or cardiovascular specialist. Further recommendations for the management of ischemic vascular 
or cardiovascular-related events are outlined below and in Table 6.1 (dose modifications). 
The guidance provided here is not mandatory for the conduct of the study and is meant to be 
used as assistance at the discretion of the investigator. Assessment and management of 
cardiovascular risk factors is based on “The 2012 European Guidelines on Cardiovascular 
Disease Prevention in Clinical Practice”, the Joint ESC Guidelines, (Perk et al., 2012) and 
applies to all patients independently of the leukemic disease and its treatment.  


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Suggested management of cardiovascular risk factors 
The consequent management and minimization of cardiovascular risk factors should be an 
important accompanying measure as the risk of cardiovascular events can possibly be reduced. 
Cooperation with the primary care physician and specialists (cardiologist, angiologist) is 
suggested, beginning from the start of the study medication. Management should be performed 
according to current guidelines and in regard of possible drug-drug interactions (e.g. some 
statins are metabolized via the CYP450 34A isoenzyme, recommendations see below). 
Lifestyle factors  
Basis for the minimization of cardiovascular risk are modifications of lifestyle factors. 
- 
All smoking is a strong and independent risk factor for CVD and has to be avoided. All 
smokers should be given advice to quit and be offered assistance  
- 
A healthy diet is recommended as being the cornerstone of CVD prevention  
- 
Weight reduction in overweight and obese people is recommended as this is associated 
with favorable effects on blood pressure and dyslipidemia 
- 
Patients should be encouraged for physical activity and exercise 
For more in-depth information consultation of the ESC guidelines or of a cardiovascular 
specialist is recommended (Perk et al., 2012). 
 
Blood pressure (BP) 
Arterial hypertension is assumed when several regular measurements show systolic BP > 140 
mmHg resp. diastolic BP > 90 mmHg (Mancia et al., 2013). During TKI-therapy it should be 
aimed for a BP < 140 mmHg systolic resp. < 90 mmHg diastolic. For patients > 80 years systolic 
BP < 150 mmHg is acceptable. Patients with diabetes should have a diastolic blood pressure 
<85 mmHg. 
For patients without increased cardiovascular risk systolic BP up to 160 mmHg systolic is 
temporarily tolerable.  
If through modification of lifestyle factors through a period of 3-6 months optimization of BP 
is not achieved, drug therapy is suggested with the aim of a BP systolic < 140 mmHg (Kiani et 
al., 2015). 
For initiation of antihypertensive treatment thiazide diuretics, beta-blockers, calcium channel 
blockers, ACE-inhibitors or AT-receptor inhibitors are suitable, which are usually used as a 
monotherapy. Alternatively or if not sufficient a combination therapy can be used (Mancia et 
al., 2013). Please pay attention to drug-drug-interactions with the study medication; HCT, 
Ramipril, Lisinopril and Candesartan are examples for drugs where no interactions are to be 
feared (Haouala et al., 2011).  


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Lipids 
Blood lipid panel tests should be performed at baseline and throughout the study as indicated 
in the visit schedule. If test results warrant intervention, investigators should follow their local 
standards of practice or treatment guidelines. Before prescribing a lipid lowering medication, 
the possibility of drug-drug interactions should be considered due to the moderate inhibitory 
effect of nilotinib on CYP3A4 isoenzyme that is involved in the metabolic pathway of some 
statins (HMG-CoA reductase inhibitors).  
Based on the ESC guidelines (Perk et al., 2012) LDL cholesterol should be  
- 
For very high risk patients < 70mg/dl resp. <1.8 mmol/l or at least ≤ 50% of the initial 
value  
- 
for high risk patients < 100mg/dl resp. < 2.6 mmol/l 
- 
for all other patients < 115mg/dl resp. <3.0 mmol/l 
Next to dietary measures statins are used for lowering LDL-cholesterol. In regard of drug-drug 
interactions with the study drug pravastatin and rosuvastatin can be safely used, whereby 
rosuvastatin is especially recommended for high risk patients. If target-values are not achieved 
a combination therapy with ezetimib and statin can be considered (Haouala et al., 2011, 
Authors/Task Force et al., 2013, Reiner et al., 2011). 
Elevated triglycerides are mostly an accompanying phenomenon of elevated cholesterol and 
glucose levels and should be finally assessed after optimal management of cholesterol and 
glucose. In this situation moderate triglyceride elevations do not necessitate intervention. For 
high risk patients with significant (> 500mg) elevations therapy should be considered. In this 
special situation in the context of interactions an expert for metabolic diseases should be 
consulted (Kiani et al., 2015). 
Blood glucose 
Blood glucose tests should be performed at baseline and throughout the study as indicated in 
the visit schedule. If blood glucose results warrant intervention, investigators should follow 
their local standards of practice and treatment guidelines in order to normalize blood glucose 
levels. 
A fasting glucose level of > 125mg/dl resp. > 7mmol/l or HbA1c value > 6.5% indicate the 
presence of diabetes mellitus (Authors/Task Force et al., 2013). These parameters should be 
assessed on a regular basis accordingly, for borderline results an oral glucose tolerance test 
(oGTT) can be conducted. If there are indications for a disturbed glucose tolerance or present 
diabetes further clarification and possibly treatment can be necessary. Consultation of a 
diabetologist is suggested. 
Initial therapy should comprise life-style modifications and dietary measures. Regarding 
medical treatment interactions must be taken into account. Insulin and metformin can be safely 
used in this context (Haouala et al., 2011).  


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For patients with diabetes type 1 intensified blood glucose treatment is necessary. For patients 
with diabetes type 2 the HbA1c value should be ≤ 7% (Authors/Task Force et al., 2013). For 
patients where intensive control of glucose levels can be risky (e.g. very old age, cognitive 
deficits) a target value for HbA1c can be tolerated up to 7.5-8% (Stone et al., 2014). During 
TKI-therapy impaired glucose tolerance should be treated primarily through lifestyle 
modification and also by employing glucose lowering medication if lifestyle modification is not 
sufficient. 
Platelet aggregation inhibitors 
Platelet aggregation inhibitors are generally indicated for persons with cardiovascular disease 
in their medical history and absent contraindications. For all patients with increased 
cardiovascular risk the use of platelet aggregation inhibitors can be considered after individual 
risk-benefit evaluation. Drugs of choice are acetyl salicylic acid (ASS) with a dosage of 100mg 
daily or alternatively clopidogrel 75mg daily. Patients without signs for atherosclerosis and 
without increased cardiovascular risk should not receive platelet inhibitors (Kiani et al., 2015). 
 
Table 6.6  
Summary of recommended threshold values (details see text) 
Parameter 
High & very high risk Patients 
Moderate & low risk Patients 
Systolic BP 
<140mmHg 
<140(160)mmHg 
Diastolic BP 
<90(85)mmHg 
<90mmHg 
LDL 
Very high risk: <70mg/dl / <1.8mmol/l 
High risk: <100mg/dl / <2.6mmol/l 
<115mg/dl / <3.0mmol/l 
HbA1C 
≤7(8)% 
≤7(8)% 
 
Management of cardiovascular events 
In case of occurrence of cardiovascular events (e.g. claudication, peripheral arterial disease, 
limp ischemia, coronary heart disease, myocardial infarction or cerebrovascular event) please 
refer the patient to a vascular expert. Close monitoring and minimization of risk factors will be 
necessary and simultaneous treatment of angiologists/cardiologists is suggested if medication 
is not to be discontinued. 
 
Follow-up for toxicities 
All patients who permanently terminate the study at any time due to a study drug related AE or 
abnormal laboratory value must be followed at least once a week for 4 weeks, until resolution 
or stabilization of the event, whichever comes first. All patients will be followed for serious 


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adverse events (SAEs) for 30 days following premature discontinuation from any phases of the 
study or following end of participation as per protocol. 
 
Rescue medication 
n.a. 
 
Other concomitant treatment 
Use of the following treatments is NOT allowed after the start of study drug: 
The concomitant administration of investigational drugs other than nilotinib is not allowed. The 
administration of any other anticancer agents including chemotherapy and biologic agents is 
not permitted except for anti-cancer treatments of newly diagnosed solid cancers (e.g. prostate 
cancer) that would not impact the level of minimal residual disease of patients. These patients 
may remain in study after consultation with Novartis. The administration of other tyrosine 
kinase inhibitors indicated for treatment of Ph+ CML is not allowed. 
Every effort should be made NOT to administer strong CYP3A4 inhibitors. CYP3A4 
inhibitors may decrease the metabolism of nilotinib and thereby increase serum concentrations 
and increase exposure. If administration of a strong CYP3A4 inhibitor cannot be avoided during 
the study and cannot be switched to an alternative therapy, study treatment must be STOPPED. 
Furthermore, increased awareness should be exercised when administering moderate inhibitors 
and/or multiple weak inhibitors. A list of these medications and inhibitor classifications can be 
found in the appendix; however, this list may not be comprehensive. 
Every effort should be made NOT to administer strong CYP3A4 inducers however, if 
administration of a CYP3A4 inducer cannot be avoided during the study, temporary 
discontinuation of study treatment is NOT required. A list of these medications and inducer 
classifications can be found in Appendix, however this list may not be comprehensive. 
Every effort should be made NOT to administer a QT prolonging agent when a patient is 
on nilotinib treatment. If a patient is on nilotinib treatment, concomitant administration 
of an agent known to prolong the QT interval is required and cannot be switched to an 
alternative therapy, nilotinib must be STOPPED. Please see for a list of agents that prolong 
the QT interval at 
https://www.crediblemeds.org/pdftemp/pdf/CombinedList.pdf  
Please be aware that this list may not be exhaustive. In case of doubt, please consult the clinical 
trial team and the SmPC. Concomittant medication with “conditional risk of TdP” (Torsade de 
pointes) is contraindicated in case of possible interactions with nilotinib. 
Cardiac monitoring is required upon re-initiation of nilotinib therapy if either study drug is 
stopped due to administration of any of the above medications (agents known to prolong the 
QT interval or strong CYP3A4 inhibitors). An ECG must be obtained both 24 to 48 hours and 
one week after re-initiation of nilotinib therapy. A minimum washout period of 72 hours or 
longer is required (depending on the half-life of the CYP3A4 inhibitor or QT interval 
prolonging agent) prior to study drug re-initiation. 


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All patients must avoid grapefruit, star fruit, pomegranate, and Seville oranges during the study. 
The juices and products containing these fruits must also be avoided. 
Concomitant therapy requiring caution and/or action: 
Cytochrome P450 3A4 substrates 
Nilotinib is a moderate CYP3A4 inhibitor in vivo. Because of the potential risk for drug-drug 
interactions, the systemic exposure of other drugs known to be sensitive substrates of CYP3A4 
and also to have a narrow therapeutic index should be used with caution. A list of these drugs 
is listed in Appendix 2 via link. 
Antacid drugs: 
Nilotinib has a pH-dependent solubility; therefore, in order not to impact nilotinib 
pharmacokinetics, administration of the following antacid drugs (if necessary) should be as 
follows: 
- 
H2 blocker (famotidine) may be administered approximately 10 hours before or 
approximately 2 hours after the dose of nilotinib, 
- 
Antacid (hydroxide/magnesium hydroxide/simethicone) may be administered 
approximately 2 hours before or approximately 2 hours after the dose of nilotinib. 
 
Permitted concomitant therapy: 
In general, concomitant medications and therapies deemed necessary for the supportive care 
and safety of the patient are allowed, provided their use is documented in the patient records 
and on the appropriate case report form, including the medication’s duration (start and end dates 
or if continuing at final visit). These include blood and platelet transfusions for patients with 
anemia and with thrombocytopenia.  
The routine use of systemic corticosteroid therapy, except dexamethasone (as it is a strong 
CYP3A4 inducer), is permitted.  
The use of prophylactic medication for vomiting is not recommended; however, antiemetic 
medication can be used as clinically indicated or in the patient’s best interest. 
The use of loperamide may be initiated for patients experiencing ≥ Grade 2 diarrhea, before 
dose interruption (e.g. Imodium®, with suggested dosing to start as 4 mg PO x 1, then 2 mg PO 
after each loose stool, up to a maximum of 16 mg/day). 
The use of hormonal contraception is permitted. 
Note that previously the use of therapeutic coumarin derivatives (i.e. warfarin, acenocoumarol, 
phenprocoumon) was not permitted while taking nilotinib but it is now allowed. There is new 
data demonstrating the lack of effect of nilotinib on PK and pharmacodynamics (PD) of 
warfarin, suggesting nilotinib does not inhibit CYP2C9 activity in human patients. These 
findings suggest that warfarin may be used with nilotinib concurrently if needed (Yin et al., 


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2011). Low molecular weight heparin and heparin may be substituted for coumarin and other 
medications for anticoagulation may also be considered at the investigator’s discretion. 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study drug. All medications and significant non-drug therapies 
(including physical therapy and blood transfusions) administered after the patient starts 
treatment with study drug must be listed on the Concomitant medications/Significant non-drug 
therapies after start of study drug (e)CRF. 
 
Study drug discontinuation 
Study drug must be discontinued for a given patient if the investigator determines that 
continuing it would result in a significant safety risk for that patient. Permanent study drug 
discontinuation will lead to study withdrawal, see section 5.2. For allowed temporarily study 
drug interruptions please refer to section 6.6.6, Table 6.1 and 6.2. 
Patients who discontinue study drug should be considered withdrawn from the study after the 
final visit assessments are performed or when it is clear that the patient will not return for these 
assessments. 
 
Definition of suboptimal response and treatment failure 
The management recommendations of the European LeukemiaNet (Baccarani et al., 2013) 
define treatment failure as no CHR and/or Ph+ > 95% at 3 months, BCR-ABL > 10% and/or 
Ph+ > 35% at 6 months, BCR-ABL > 1% and/or Ph+ > 0 at 12 months and then and at any time 
loss of CHR, loss of CCyR, loss of confirmed MMR (in 2 consecutive tests, of which one with 
a BCR-ABL1 transcripts level ≥1%) as well as mutations and clonal chromosome abnormalities 
in Ph+ cells. Warning is defined as BCR-ABL > 10% and/or Ph+ 36-95% at 3 months, BCR-
ABL 1-10% and/or Ph+ 1-35% at 6 months and BCR-ABL 0.1-1% at 12 months and then and 
at any time clonal chromosome abnormalities in Ph negative cells.  
The response can be assessed with either a molecular or a cytogenetic test, but both are 
recommended whenever possible. Failure means that the patient should receive a different 
treatment to limit the risk of progression and death. Warning implies that more frequent 
monitoring is required by the characteristics of the disease and the response to treatment to 
allow timely changes in therapy in case of failure. The conclusion of the ELN-panel is, however, 
that a single measurement of BCR-ABL level is not sufficient to define as failure necessitating 
a change of treatment, whereas 2 tests (at 3 and 6 months) and supplementary tests in between 
provide more support for the decision to change treatment. 
 
Progression 
The following events are considered disease progression 
- 
Death due to disease under study 
- 
Accelerated phase (AP) as defined by any of the following:  


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• ≥ 15% blasts in the peripheral blood or bone marrow aspirate, but < 
30% blasts in both the peripheral blood and bone marrow aspirate 
• ≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow 
aspirate 
• ≥ 20% basophils in the peripheral blood or bone marrow 
• Thrombocytopenia (<100 x 109/L) that is unrelated to therapy 
• Evidence of clonal evolution (with consensus of SC only) 
- 
Blast crisis (BC) as defined by any of the following: 
• ≥ 30% blasts in peripheral blood or bone marrow aspirate 
• Appearance of extramedullary involvement other than 
hepatosplenomegaly proven by biopsy (i.e., chloroma). 
 
Definition of intolerance 
Intolerance is defined as: 
- 
Recurrent Grade 3 or 4 AEs persisting in spite of optimal supportive care measures and 
necessitating discontinuation of therapy 
- 
Grade 2 AEs related to nilotinib that persist ≥ 1 month or recurs > three times despite 
dose reduction or discontinuation. 
 
Emergency unblinding of treatment assignment 
This is an open-label study, emergency unblinding does not apply. 
 
Study completion and post-study treatment 
The study will be considered completed for an individual patient when he/she completes the 
30-Day FU Visit. The study will be considered completed when the last evaluable patient 
completes the 30-Day FU Visit.  
Once planned enrollment is met, patients already in screening should be offered to enter the 
study. As the study drug is prescribed independent of the study, it is up to the investigator and 
his patient to decide this. 
The study can be terminated for reasons stipulated in the study contract. Should this be 
necessary, the patients should be contacted and scheduled for their end of treatment assessments 
as described in Section 7. Novartis will be responsible for informing IRBs and/or IECs of the 
early termination of the study.  
Treatment decision following the study is at the discretion of the investigator. Patients 
discontinued from the study should be given the opportunity to benefit from other therapies. 
The investigator also must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.  


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End of treatment visit, including premature withdrawal and study 
discontinuation visit 
At the time patients discontinue from the study, including premature withdrawal for any reason, 
a visit should be scheduled as soon as possible, at which time all of the assessments listed for 
the End of Study (EOS) visit will be performed (Table 7.1). An EOS eCRF page should be 
completed, giving the date and reason for stopping the study period prematurely (if applicable). 
All relevant information that relates to the reason for discontinuation of study including 
contributory factors must be included on the CRF. 
At a minimum, all patients who discontinue from the study, including those who refuse to return 
for a final visit, will be contacted for safety evaluations during the 30 days after a patient ends 
his/her participation in the study (prematurely or as per protocol). Documentation of attempts 
to contact the patient should be recorded in the patient record.  
Patients who discontinue from the study should be considered withdrawn from the study after 
the final visit assessments are performed or when it is clear that the patient will not return for 
these assessments. 
Patients who discontinue the study due to a study drug-related AE must be followed weekly for 
4 weeks, or until resolution or stabilization of the event, whichever occurs first. 
 
Follow up period 
All patients must have safety evaluations for 30 days after the last dose of study treatment.  
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 
Any patient who discontinues from the study prematurely will be followed for survival, 
antineoplastic therapies after discontinuation of study treatment and progression to AP/BC 
every 3 months for up to 2 years after the patient’s start in the study. 
7 
Visit schedule and assessments 
Table 7-1 lists all of the assessments and indicates with an “X” the visits when they are 
performed.  
The definition of a month is a calendar month. Patient visits for all visits during the first month 
of the study should be completed on the designated day (with an allowed “visit window” of ± 
5 days). Patients visits for all subsequent visits should be seen on the designated day (with an 
allowed “visit window” of ± 7 days). If a visit was not possible within the requested time frame 
Novartis should be informed and further procedure discussed with the steering committee. 
All data obtained from the assessments listed in Table 7.1 and described in detail in the 
subsections below must be supported in the patient’s source documentation. Assessments that 


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generate data for database entry and which are recorded on eCRF are listed using the eCRF 
name. Assessments that are transferred to the database electronically (e.g., laboratory data) are 
listed by test name.   
Written informed consent must be obtained before any study specific medical procedures are 
performed. 


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Table 7-1 
Assessment schedule 
 
Screening/ 
Baseline 
(D-14 to 0) 
Day 1 
End of 
month 
1 
End of 
month 
3 
End of 
month 
6 
End of 
month 
9 
End of 
month 
12 
End of 
month 
15 
End of 
month 
18 
End of 
month 
21 
End of 
month 
24 /  
EOS 
30-Day 
safety 
FU 
Visit Number 
1  
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical 
history, history of 
disease 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior antineoplastic 
therapy  and 
medication 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs / heart 
rate / blood pressure 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Extramedullary 
involvement 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance 
Status 
X 
 
 
 
 
 
 
 
 
 
X 
 
Sokal and EUTOS 
Score at diagnosis1 
X 
 
 
 
 
 
 
 
 
 
 
 
ESC score 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Smoking status 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
ECG 
X 
 
X 
 
 
 
 
 
 
 
 
 


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Screening/ 
Baseline 
(D-14 to 0) 
Day 1 
End of 
month 
1 
End of 
month 
3 
End of 
month 
6 
End of 
month 
9 
End of 
month 
12 
End of 
month 
15 
End of 
month 
18 
End of 
month 
21 
End of 
month 
24 / 
EOS  
30-Day 
safety 
FU 
Visit Number 
1  
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Hematology5 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistry 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hepatitis B serology6 
X6 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
test (if applicable) 
X 
X3 
 
 
 
 
 
 
 
 
X 
 
Bone marrow 
assessment/ 
Cytogenetics (until 
CCyR is reached)4 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 
Peripheral blood 
BCR-ABL PCR  
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Mutational analysis2 
 
In case of treatment failure 
QoL Questionnaire 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 
Nilotinib dispensing 
 
Continuous 
Drug compliance 
check 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
Continuous 
Concomitant Med. 
Continuous 
 
 
(1) For Calculation of SOKAL and EUTOS Score at Diagnosis, spleen size is defined as maximum distance from costal margin in [cm]; Blood 
counts for Basophils, Eosinophils and Blasts must be expressed in % for calculation of both Scores. 
(2) In the event that a patient shows treatment failure, a study visit must be performed within 4-6 weeks. If needed, an unscheduled visit may 
be completed.   A physical examination including assessment of extramedullary involvement, body weight, vital signs (including heart rate, 


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blood pressure, and body temperature), and blood work will be performed. Blood samples for PCR and mutational analysis will be taken. 
If needed, additional bone marrow for confirmation of cytogenetic response may also be taken. 
(3) These assessments should be performed only if the Day 1 visit occurred >8 days after the Screening visit. 
(4) Bone marrow aspirates and/or biopsies for cytogenetics to evaluate response are strongly recommended and will be performed at 3 
months, and at the end of every 6 months until CCyR is achieved, referring to the ELN Guidelines. 
(5) Additional complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter, or as clinically 
indicated. 
(6) Patients will be tested for hepatitis B serology at screening. Patients included before protocol amendment 1 and currently on study 
treatment should have testing performed at the next possible visit in order to identify chronic carriers 
 


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7.1 
Information to be collected on screening failures 
Only demography data and the reason for failing (screening failure log) are collected for those 
patients who fail to enter the treatment phase.  
Potential adverse events and hospitalizations which may have occurred from time of signing 
informed consent/written assent until screening failure time should be documented in the patient 
medical records. Reporting of potential SAE during this time period should be followed as 
described in Part 8.2. 
7.2 
Patient demographics/other baseline characteristics 
Screening assessments to confirm eligibility must be performed prior to the first dose of study 
drug, patient eligibility is to be established by confirming all inclusion/exclusion criteria. A 
relevant record (e.g., checklist) must be stored with the source documentation at the study site. 
Violation of any entry criterion excludes a subject from enrolment into the study. 
The bone marrow aspirate can be done up to 12 weeks prior to first dose of study treatment. A 
minimum of 20 marrow cell metaphases are required for all follow-up cytogenetic evaluations 
but not at baseline. FISH analysis alone will not be accepted. 
All further screening assessments must be performed within 2 weeks prior to first dose of study 
treatment. Patients with potassium, magnesium, calcium and/or phosphorus levels that are < 
LLN at screening, must have their levels replenished through supplementation. 
A peripheral blood sample will be drawn before start of treatment and sent to the allocated 
central EUTOS standardized molecular laboratory for multiplex PCR analysis (transcript type 
analysis). 
The patient’s year of birth and sex will be recorded. 
Relevant medical history and current medical conditions, including those symptoms related to 
CML, are recorded on the respective CRF until the start of the study drug. 
Prior antineoplastic medications, radiotherapy, and surgeries, including surgical biopsies, will 
be collected as well as prior doses and duration of imatinib and hydroxyurea. 
Date of initial diagnosis of CML will be collected. EUTOS and Sokal score will be calculated 
retrospectively from the data collected at diagnosis or at screening, if data is not available. 
Physical examination including extramedullary involvement, performance status, vital signs, 
ECG and laboratory assessments will be performed at screening. 
Significant findings that were present prior to the signing of informed consent must be included 
in the Relevant Medical History/Current Medical Conditions CRF. Significant new findings 
that begin or worsen after informed consent must be recorded on the AE page of the patient’s 
eCRF. 


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7.3 
Treatment exposure and compliance 
Dosage administration record 
Date and time of nilotinib (morning or evening doses as appropriate) dose 
administration/prescription 
will 
be 
recorded 
in 
the 
respective 
Dosage 
administration/prescription record and the patient diary. 
Any changes in study drug dose administration including interruption or reduction in dosing 
due to an AE must be reflected on the Dosage administration/prescription record and the patient 
diary. 
Concomitant medications/significant non-drug therapies 
All prescription medications and over-the-counter drugs including vitamins, herbal and 
alternative treatments and blood transfusions taken within 30 days prior to the start of and 
throughout the study must be recorded on the Prior/Concomitant Medications/Non-Drug 
Therapies eCRF. Medication entries should include the trade name, the start and discontinuation 
dates and the reason for therapy. 
Compliance 
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the patient. The patient will be advised to present the 
blisters at the study visits, to review compliance and allow the investigator to complete a drug 
accountability check. In addition, detailed information about drug intake will be captured in the 
patient diary. 
7.4 
Efficacy 
 
Molecular response 
Molecular response (MR) will be assessed in all patients every 3 months until the end of study 
visit. 
At baseline, type of BCR-ABL transcripts will be determined by multiplex PCR, levels by RQ-
PCR. In subsequent samples BCR-ABL transcripts will be determined by RQ-PCR testing of 
peripheral blood. Samples will be analyzed at the designated EUTOS reference laboratory.  
MR4 is defined in this study as: 
• ≥ 4-log reduction from IRIS baseline = either (i) detectable disease ≤0.01% BCR-ABLIS 
or  (ii) undetectable disease in cDNA with 10 000–31 999 ABL1 transcripts or 24 000–
76 999 GUSB transcripts. 
 
 


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MR4.5 is defined as: 
• ≥4.5-log reduction from IRIS baseline = either (i) detectable disease ≤ 0.0032% BCR-
ABLIS or (ii) undetectable disease in cDNA with 32 000–99 999 ABL1 transcripts or 77 
000–239 999 GUSB transcripts.  
Major molecular response is defined as: 
• ≥3 log reduction from the standardized baseline or ≤ 0.1% BCR-ABLIS.  
At baseline a 20 mL sample of peripheral blood will be taken for multiplex PCR and RQ-PCR.  
In order to monitor molecular response under study treatment (and perform mutational analyses 
as required), 20 mL of peripheral blood will be collected at each sampling time point in all 
patients. The sample will be sent to the designated EUTOS MR4.5 reference laboratory for 
molecular response for evaluation of BCR-ABL transcript levels by RQ-PCR. 
Mutational analysis should be done in case of treatment failure or of progression to AP/BC 
according to the ELN recommendations (Baccarani et al., 2013) and if clinically indicated by 
the investigator.  
Mutational analysis is also recommended for patients in a warning zone between optimal 
response and treatment failure (Baccarani et al., 2013). 
Table 7-2  
Definition of Treatment failure, see also section 6.6.15 
timepoint 
Response 
3 months 
no CHR and/or Ph+ >95% 
6 months 
BCR-ABL > 10%  and/or Ph+ >35% 
12 months 
BCR-ABL > 1%  and/or Ph+ > 0 
Then and at any time 
loss of CHR,  
loss of CCyR,  
loss of confirmed MMR*  
mutations and clonal chromosome 
abnormalities in Ph+ cells 
* in 2 consecutive tests, of which one with a BCR-ABL1 transcripts level ≥1% 
 
If patients demonstrate treatment failure, mutational analyses will be performed on the cDNA 
available from the RQ-PCR at the respective time point. Continued mutational analyses may be 
performed following relapse at a frequency of every 3 months as needed. 


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If a ≥ 5-fold increase in BCR-ABL transcripts from the lowest value achieved on study is 
identified and confirmed by duplicate analysis of the same sample and the result corresponds 
to loss of MMR, the result has to be further confirmed by a subsequent sample within 4-6 weeks.  
Sites will use standard materials for sample collection and shipment. Collection, storage, and 
shipment of samples for molecular response assessment and mutational analysis will follow the 
standard practice of the designated EUTOS MR4.5 laboratory.  
If a suitable peripheral blood sample for RQ-PCR testing was not obtained during the normal 
visit schedule then a subsequent sample must be collected at an unscheduled visit within 4 
weeks.  
 
 
 
 
 
 
 
. 
 
Cytogenetic response 
Cytogenetic response will be assessed as the percentage of Ph+ metaphases in the bone marrow 
and is defined as the following (a review of a minimum of 20 metaphases is required) and will 
be calculated for the Ph+ population: 
• Complete (CCyR) - 0% Ph+ metaphases 
• Partial (PCyR) - >0 to 35% Ph+ metaphases 
• Major (MCyR) - 0 to 35% Ph+ metaphases 
• Minor (mCyR) - >35 to 65% Ph+ metaphases 
• Minimal - >65 to 95% Ph+ metaphases 
• None - >95 to 100% Ph+ metaphases 
A major response (0 to 35% Ph+ metaphases) combines both complete and partial responses. 
For patients who do not achieve MCyR at 6 months mutational analysis should be obtained.  
Loss of complete cytogenetic response is defined as an increase in the Ph+ bone marrow cells 
to >0%. 


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Bone marrow analysis and cytogenetics 
Bone marrow aspiration and/or biopsy and bone marrow cytogenetics to evaluate Ph+ 
metaphases will be performed within 12 weeks prior to the first dose of study drug. The date of 
diagnosis will be considered as the date of sample from which cytogenetic diagnosis for CML-
CP was made. Results from a cytogenetic analysis that was done before a patient has signed 
informed consent can be used. Bone marrow aspirates and/or biopsies for cytogenetics to 
evaluate response are strongly recommended and will be performed at 3 months, and at the end 
of every 6 months until CCyR is achieved, referring to the ELN Guidelines (Baccarani et al., 
2013).  
Bone marrow aspirates with cytogenetics will also be performed at the time there is a ≥ 5-fold 
increase in BCR-ABL transcripts from the lowest level achieved on study by PCR in association 
with either not achieving MMR or confirmed loss of MMR during therapy or when there is any 
other clinical indication of disease progression (e.g. progression to AP/BC based on peripheral 
blood and/or extramedullary assessment, loss of CHR). Standard cytogenetics are to be 
performed locally by the site using standard methods. A minimum of 20 metaphases must be 
examined in each bone marrow sample (except baseline). Cytogenetics must be performed by 
chromosome banding analysis (CBA) of marrow cell metaphases. 
Quantification of the percentage of Ph+ chromosome metaphases, number of metaphases, 
number positive for Ph chromosome, cellularity, and percent of blasts and promyelocytes will 
be recorded on the Bone Marrow CRF. These exams will be performed and analyzed locally. 
If the bone marrow is of poor quality (such as a dry tap) and makes evaluation of cytogenetic 
response not evaluable, the bone marrow assessment should be repeated within one month. 
If additional bone marrow evaluations are performed, the results should be captured on the CRF 
as an unscheduled visit. 
 
Hematologic response 
Hematologic response includes any of the following: 
• Complete hematologic response. 
A CHR is defined as all of the following present for ≥ 4 weeks: 
- 
WBC count < 10 x 109/L 
- 
Platelet count < 450 x 109/L 
- 
No circulating peripheral blood blasts, promyelocytes, myelocytes or metamyelocytes 
in the peripheral blood 
- 
The presence of less than 5% basophils in peripheral blood 
- 
No evidence of disease-related symptoms and extramedullary disease, including spleen 
and liver. 
Loss of CHR is defined as the appearance of any of the following in the absence of other causes: 


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- 
WBC count that rises to > 10.0 x 109/L in the absence of growth factor use or acute 
infections 
- 
Platelet count that rises to ≥ 450 x 109/L 
- 
Any palpable spleen 
- 
Appearance of any myelocytes, metamyelocytes, or any promyelocytes or blasts in the 
peripheral blood 
Increasing WBC count for patients not achieving a CHR is a hematologic progression defined 
as a doubling of WBC count at least 1 month apart with at least the second value > 20 x 109/L. 
7.5 
Safety 
Safety assessments will consist of evaluating AEs and SAEs and concomitant 
medications/therapies used to treat them, laboratory parameters including hematology and 
chemistry, body weight, physical examinations, ECG monitoring and estimation, as well as 
monitoring of the cardiovascular risk. 
 
Adverse events 
For details on adverse event collection and reporting, refer to section 8. 
 
Physical examination 
A physical examination will be performed according to the visit schedule (refer to Table 7.1), 
i.e. during screening and at every visit. Information about the physical examination must be 
included in the source documentation at the study site and will not be recorded in the eCRF.  
A complete physical examination will include the assessment of weight and an examination of 
general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular and neurological.  
Height will be measured at screening only. 
Extramedullary involvement 
Presence of extra-medullary leukemic involvement will be checked with each physical 
examination as outlined above. Findings on physical examination consistent with 
extramedullary leukemic involvement will be recorded (e.g. lymph nodes, liver and spleen 
size). With regards to lymph nodes, only those palpable lymph nodes should be considered to 
be CML related if leukemic blast infiltration has been confirmed via biopsy/histology or by 
technically adequate (not contaminated with peripheral blood) aspiration cytology. When extra-
medullary involvement other than of the spleen or liver is the only evidence of blast crisis, this 
finding must be confirmed by technically adequate (not contaminated with peripheral blood) 
aspiration cytology and /or biopsy (especially for isolated lymph nodes) and data entered into 
the extramedullary involvement eCRF. 


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Vital signs and weight 
Vital signs and weight should be performed during screening and at every visit. Pulse rate 
(sitting, after two minutes of rest), blood pressure (sitting, after two minutes of rest), body 
temperature, and weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) 
as specified in Table 7-1 must be present in the patient’s chart, and captured on the eCRF. 
Height will be measured only at screening and recorded on the eCRF. 
To detect early signs of fluid retention, patients should be weighed according to the visit 
schedule, and should also weigh themselves regularly at home. Patients are encouraged to report 
to the study Investigator any body weight change of more than 2 kg as compared to their pre-
study body weight. Rapid weight gain of ≥ 2 kg should be carefully investigated and other 
measures considered as appropriate. 
 
Performance status 
Performance status will be recorded in the eCRF according to Table 7-1 and as defined by the 
following ECOG criteria, published by the Eastern Cooperative Oncology Group (Oken et al., 
1982): 
Table 7-3  
ECOG performance Criteria 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
 
 
Laboratory evaluations 
The laboratory evaluations will be performed by a local laboratory. Novartis must be provided 
with a copy of the certification and tabulation of the normal ranges for all local laboratories 
used. 
At any time during the study, abnormal laboratory parameters which are clinically relevant (e.g. 
require dose modification and/or interruption of study drug, lead to clinical symptoms or signs 


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or require therapeutic intervention), whether specifically requested in the protocol or not, must 
be recorded on the appropriate comment CRF page in addition to the appropriate laboratory 
CRF page. 
When abnormal laboratory values or test results constitute an adverse event (i.e. induces clinical 
signs/symptoms or requires therapy) they must be recorded on the Adverse Events CRF. 
Abnormal laboratory values or test results constitute adverse events only if they induce clinical 
signs or symptoms, are considered clinically significant (e.g. cause study discontinuation or 
constitutes in and of itself a Serious Adverse Event) or require therapy (e.g., any hematologic 
abnormality that requires transfusion or cytokine treatment); and should be recorded on the 
Adverse Events CRF under the signs, symptoms or diagnosis associated with them. 
Hematology 
Hematology labs are to be done locally at the site. Hematology includes assessment of 
hemoglobin, platelets count, total white blood cell count (WBC) and a full differential count in 
percentage or absolute values including neutrophils, lymphocytes, eosinophilis, basophils, 
monocytes, promyelocytes, myelocytes, metamyelocytes, and blast cells. In laboratories where 
manual differentials are not routinely performed, automated differential counts will be accepted. 
Additional complete blood counts should be performed every 2 weeks for the first 2 months 
and then monthly thereafter, or as clinically indicated. 
Biochemistry 
Clinical chemistry tests will include AST (SGOT), ALT (SGPT), direct bilirubin, total bilirubin, 
alkaline phosphatase, lipase, amylase (optional), lactate dehydrogenase (LDH), albumin, 
triglycerides, high-density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol, 
fasting glucose, HbA1c, serum creatinine, sodium, potassium, magnesium, calcium, GFR and 
inorganic phosphorus. Potassium, calcium, magnesium, and/or sodium supplements may be 
given to correct values that are < LLN. Regarding substitution please proceed according to 
general standards in internal medicine. Post-correction values must not be deemed to be a 
clinically significant abnormality prior to patients being dosed. 
Glucose, HDL, LDL, total cholesterol and triglycerides should be assessed under fasting 
conditions.  
Hepatitis B serology 
Patients will be tested at screening for the following hepatitis B serologic markers: hepatitis 
surface antigen (HBs Ag) and antibodies to hepatitis B core antigen (anti HBc).  
Patients included before protocol amendment 1 and already on study treatment should have 
testing performed at the next possible visit in order to identify chronic carriers. 


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Urinanalysis 
At Screening, a standard urine test will be performed. Additionally the presence of micro 
albuminuria should be tested. 
 
Pregnancy test and assessments of fertility 
A serum pregnancy test is mandatory at screening and at end of study or at early discontinuation 
visits for female patients of child-bearing potential (definition see section 5).  
Pregnancy testing is not required for patients who are determined to be post-menopausal. 
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) or have had surgical bilateral oophorectomy with or without hysterectomy or tubal 
ligation at least 6 weeks prior to enrolling. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone level assessment 
is she considered to be not of childbearing potential. 
 
Organ-specific safety monitoring 
Cardiac assessment 
After the subject has rested approximately 10 minutes in a semi-supine position, a single 12-
lead ECG must be obtained at the time points indicated in Table 7.1 and whenever clinically 
indicated at Investigator’s discretion, e.g. when concomitant medication is changed. 
Interpretation of all ECGs must be done by a qualified physician. Each ECG tracing should be 
labeled with the study number, subject number, date, and kept in the source documents at the 
study site. Clinically significant abnormalities present prior to the start of study drug should be 
reported on the Medical History eCRF page. Clinically significant findings must be discussed 
with Novartis prior to enrolling the patient in the study. New or worsened clinically significant 
findings occurring after the start of study drug must be recorded on the Adverse Events eCRF 
page. 
QTc will be calculated according to Fridericia’s formula. 
The patient should not be dosed if the ECG confirms a QTcF >480 ms (please refer to Table 6-
1 for dose modification instructions related to QTcF prolongation) or >450 ms at screening. 
In case of a grade 3 QT prolongation, a cardiologist opinion should be requested and an 
appropriate and closer cardiac monitoring of the patient must be put in place until the QTcF 
decreases to <500ms. 
 
Estimation and monitoring of the cardiovascular risk 
The basis for the estimation of the individual cardiovascular risk of a patient is “The 2012 
European Guidelines on Cardiovascular Disease Prevention in Clinical Practice” (Perk et al., 


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2012). In these guidelines patients are divided in four risk groups: very high, high, moderate 
and low risk.  
Part of the ESC risk estimation is calculation of the SCORE (Systematic Coronary Risk 
Evaluation), where through several parameters the 10-year risk of a first fatal atherosclerotic 
event is estimated. The SCORE can be calculated using an online calculator 
(http://www.heartscore.org/) or using the chart in Appendix 4. The following parameters are 
needed to calculate the ESC Risk-Score: 
• Age 
• Sex 
• Systemic blood pressure 
• Cholesterol [mmol/l or mg/dl] 
• Smoking status 
Given that some risk factors are modifiable, the SCORE will be newly calculated at baseline 
and every six months during the treatment. 
The individual cardiovascular risk estimation for a patient is defined as follows: 
 1. Very high risk - Subjects with any of the following: 
• Documented CVD by invasive or non-invasive testing (such as coronary angiography, 
nuclear imaging, stress echocardiography, carotid plaque on ultrasound), previous 
myocardial infarction, ACS, coronary revascularization (PCI, CABG), and other arterial 
revascularization procedures, ischaemic stroke, peripheral artery disease (PAD). 
• Diabetes mellitus (type 1 or type 2) with one or more CV risk factors and/or target organ 
damage (such as microalbuminuria: 30–300 mg/24 h). 
• Severe chronic kidney disease (CKD) (GFR <30 mL/min/1.73 m2). 
• A calculated SCORE ≥10%. 
 
2. High risk - Subjects with any of the following: 
• Markedly elevated single risk factors such as familial dyslipidaemias and severe 
hypertension. 
• Diabetes mellitus (type 1 or type 2) but without CV risk factors or target organ damage. 
• Moderate chronic kidney disease (GFR 30–59 mL/min/1.73 m2). 
• A calculated SCORE of  ≥5% and <10% for 10-year risk of fatal CVD. 
 
3. Moderate risk 
Subjects are considered to be at moderate risk when their SCORE is ≥1 and <5% at 10 years. 
Many middle-aged subjects belong to this category. This risk is further modulated by factors 
mentioned above. 
 
4. Low risk 


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The low-risk category applies to individuals with a SCORE <1% and free of qualifiers that 
would put them at moderate risk. 
 
Persons with established CVD need prompt intervention on all risk factors, while in apparently 
healthy persons total risk should be assessed by using the score system.  
The higher the risk, the greater is the benefit from preventive efforts. Low-risk persons should 
be offered advice to maintain their low-risk status. While no threshold is universally applicable, 
the intensity of advice should increase with increasing risk. In general, those with a risk of CVD 
death of ≥5% qualify for intensive advice, and may benefit from drug treatment. At risk levels 
>10%, drug treatment is more frequently required. In persons older than 60, these thresholds 
should be interpreted more leniently, because their age-specific risk is normally around these 
levels, even when other cardiovascular risk factor levels are ‘normal’. 
Especially patients with increased cardiovascular risk should be under close monitoring and 
their risk factors should be strictly controlled. Patients in risk group 1 (very high risk) should 
be referred to a cardiovascular specialist. Ongoing minimization of modifiable risk factors is 
suggested for all patients. Through close monitoring early detection of impairment of the 
glucose and lipid metabolism and occurrence of CVE is supported. 
7.6 
Tolerability/acceptability 
Not applicable 
7.7 
Resource utilization  
Not applicable 
7.8 
Health-related Quality of Life (HRQOL) 
In CML, the introduction of TKI treatment led to a decisive extension of survival time. As a 
consequence, issues such as reducing side effects, symptom relief and patients’ satisfaction 
have moved into focus in order to assess the adequacy of medical strategies. 
Patients will be asked to complete the EORTC QLQ-CML 24, an internationally developed 
disease specific HRQOL questionnaire for CML patients, together with the EORTC-QLQ C30 
questionnaire. The QLQ-CML 24 has been developed according to the EORTC guidelines 
involving a large sample of patients (655 CML patients in 10 countries). The questionnaire is 
composed of four mulit-item scales and two single-item scales. The module consists of 24 items 
assessing symptom burden, impact on daily life and on worry/mood, body image problems, and 
satisfaction with care and social life. The items are measured on four levels: not at all, a little, 
quite a bit and very much. The EORTC QLQ-CML 24 is a supplement to the EORTC-QLQ 
C30 and intended to be used in conjunction (Efficace et al., 2014, Aaronson et al., 1993). 
QoL will be evaluated at Screening/Baseline (within 7 days prior to study inclusion), and at 3, 
6, 12, 18, 24 months.  


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The patient informed consent form explains the patients that they will have a regular QoL 
assessment while involved in the trial. The questionnaires will be handed out to the patients by 
the investigator or a study nurse prior to seeing the doctor for clinical evaluations. Patients will 
be asked to fill out the questionnaires as completely and accurately as possible. Patient’s refusal 
to complete all or any part of a questionnaire should be documented in the study data capture 
system and should not be captured as a protocol deviation.  
The site personnel should check the questionnaire for completeness and ask the patient to 
complete any missing responses. The original questionnaire will be kept with the patient’s file 
as the source document. 
Completed questionnaire(s) and any unsolicited comments written by the patient should be 
reviewed and assessed by the investigator for responses which may indicate potential AEs or 
SAEs. 
7.9 
Pharmacokinetics 
n.a. 
7.10 
Pharmacogenetics/pharmacogenomics 
n.a. 
7.11 
Other biomarkers 
n.a. 
8 
Safety monitoring 
8.1 
Adverse events 
 
Adverse event definition and reporting 
An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s), or medical condition(s) that occur after patient’s signed informed consent has been 
obtained. Abnormal laboratory values or test results occurring after informed consent constitute 
AEs only if they induce clinical signs or symptoms, are considered clinically significant, require 
therapy (e.g. hematologic abnormality that requires transfusion or hematological stem cell 
support), or require changes in study medication(s). 
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 laboratory 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 


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rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate AE.  
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 AE, the severity of mild, 
moderate, severe, and life-threatening, corresponding to Grades 1 to 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 AEs should be sought by non-directive questioning of the patient during the 
screening process after signing informed consent and at each visit during the study.  In addition 
to direct questioning of the patient, the Investigator should review the patient diary and discuss 
potential AEs with the patient during each visit. Adverse events also may be detected when they 
are volunteered by the patient during the screening process or between visits, or through 
physical examination, laboratory test, or other assessments. As far as possible, each AE should 
be evaluated to determine: 
• The severity grade (CTCAE Grade 1-4); 
• Its duration (Start and end dates); 
• Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes); 
• Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable); 
• Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy); 
• 
Outcome 
(not 
recovered/not 
resolved, 
recovered/resolved, 
recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown); 
• Whether it is serious, where a SAE is defined as in 8.2.1 
All AEs should be treated appropriately. If a concomitant medication or non-drug therapy is 
given, this action should be recorded on the Adverse Event eCRF.  
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Natural progression or deterioration of the malignancy under treatment (including progression 
to accelerated phase or blastic phase and death due to disease progression) will be recorded as 
part of the efficacy evaluation and should not be reported as an AE/SAE.  
Signs and symptoms clearly associated with the disease under study should NOT be reported 
as AEs unless they are newly emergent (i.e. not previously observed in the patient), judged by 
the Investigator to be unusually severe or accelerated, or if the Investigator considers 
deterioration of disease-related signs and symptoms to be caused directly by the study drug. If 


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there is any uncertainty about an AE being due solely to the disease under study, it should be 
reported as an AE or SAE as appropriate. 
Adverse events of special interest 
Ischemic vascular and ischemic cardiovascular events include (but are not limited to) the events 
listed below. Patients should be educated on the clinical symptoms of such events to ensure 
accurate reporting to the Investigator. 
• Ischemic Heart Disease (IHD): angina pectoris, coronary artery disease, acute myocardial 
infarction and coronary artery stenosis 
• Ischemic Cerebrovascular Events (ICVE): ischemic cerebrovascular accident, and transient 
ischemic attack 
• Peripheral Artery Occlusive Disease (PAOD): intermittent claudication, arterial stenosis of a 
limb  
If patients experience ischemic vascular or ischemic cardiovascular events, carefully consider 
protocol guidance for dose reduction or study drug discontinuation (Protocol Table 6.1). 
The Investigator should ensure that the patient is assessed by a vascular or cardiovascular 
specialist. It is recommended that the standard of care for concurrent ischemic vascular or 
cardiovascular events should be given to the patients while they are receiving nilotinib therapy. 
All patients should have their risk factors for such diseases appropriately managed and follow 
the current recommendations (please see also section 6.6.8).  
The Study Steering Committee will be informed on regular basis on the Grade 2/3/4 ischemic 
vascular or cardiovascular events occurring to the patients enrolled in the trial. 
 
Laboratory test abnormalities 
Laboratory abnormalities that constitute an Adverse Event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require dose reduction or temporary 
or permanent study drug discontinuation or require concomitant therapy), should be recorded 
on the Adverse Event CRF page. Whenever possible, a diagnosis, rather than a symptom should 
be provided. Laboratory abnormalities that meet the criteria for an Adverse Event 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 or laboratory abnormality (severe) as per 
CTCAE (if applicable) 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 AE. 


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8.2 
Serious adverse events 
 
 Serious adverse event definition, treatment and follow-up 
An SAE is defined as an event which: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
• 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 
• 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 
 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 30 days after the patient has stopped study 
participation (defined as time of last dose of study drug taken or last visit whichever is later) 
must be reported to Novartis within 24 hours of learning of its occurrence.  
Any SAEs experienced after this 30 day period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. Recurrent episodes, complications, 
or progression of the initial SAE must be reported as follow-up to the original episode, 
regardless of when the event occurs. This report must be submitted within 24 hours of the 
investigator receiving the follow-up information. An SAE that is considered completely 
unrelated to a previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess the relationship to study drug, complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the German 
Novartis Clinical Safety & Epidemiology Department. Causality for each reported serious event 
on the SAE report form must be assessed as either as “Suspected” or “Not Suspected” to the 
study drug. No other term such as “Probable”, “Plausible”, “May be” or “Could be” etc. should 
be used for causality assessment. The telephone and telefax number of the contact persons in 
the German department of Clinical Safety and Epidemiology, are listed in the investigator folder 


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provided to each site. The original copy of the SAE Report Form and the fax confirmation sheet 
must be kept with the case report form documentation at the study site. 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. Each re-occurrence, complication, or progression 
of the original event should be reported as a follow-up to that event regardless of when it occurs. 
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated and whether the patient continued or withdrew from study participation.  
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study drug, a Clinical Safety & 
Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same drug that this 
SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. 
8.3 
Pregnancy reporting 
To ensure patient safety, each pregnancy in a patient on study drug 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.  
Instances of pregnancies and positive pregnancy tests should be collected for all patients who 
have conceived after receiving study medication. Pregnancies that are noted prior to 
administration of study medication but after signing informed consent may require reporting if 
they are considered to be associated to the conduct of the study by the investigator. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the German Novartis Clinical Safety & Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
8.4 
Reporting of adverse events and pregnancies after the last dose 
of study drug taken 
All AEs, SAEs, and pregnancies which occurred within 30 days after intake of last dose of study 
drug should be reported.  


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8.5 
Steering Committee 
The Steering Committee (SC) will be established comprising external experts in the field of 
CML, one cardiologist/angiologist and Novartis representatives from the Clinical Trial Team. 
The SC will be supported and advised by a patient advocate. 
The SC will suggest modifications to the trial protocol, ensure transparent management of the 
study according to the protocol through recommending and approving modifications as 
circumstances require and consider patient cases where further discussion is required. The SC 
will review protocol amendments as appropriate. Together with the clinical trial team, the SC 
will also develop recommendations for publications of study results including authorship rules. 
9 
Data review and database management 
9.1 
Site monitoring 
Before study initiation, at a site initiation visit, a Novartis representative will review the protocol 
and eCRF with the investigators and their staff. During the study, the field monitor will visit 
the site regularly to check the completeness of patient records, the accuracy of entries on the 
eCRF, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that drug is being 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 on eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (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, documentation 
of SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the eCRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the patients will be disclosed.  
9.2 
Data collection 
The designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will not 
be given access to the Remote Data Capture (RDC) system until they have been trained. 
Designated investigator staff will enter the data required by the protocol into the Novartis 


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eCRFs using the Investigator’s own computer. Automatic validation programs check for data 
discrepancies in the eCRFs and, by generating appropriate error messages, 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. After database 
lock, the investigator will receive a CD-ROM or paper copies of the patient data for archiving 
at the investigational site.  
9.3 
Database management and quality control 
Novartis staff (or designated CRO) review the eCRFs entered by investigational staff for 
completeness and accuracy and instruct the site personnel to make any required corrections or 
additions. Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff is required to respond to the query and make any necessary changes to the 
data.  
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples for molecular monitoring will be processed centrally and the results will be 
sent electronically to Novartis (or a designated CRO) and the investigational site. 
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the database has been declared to be complete and 
accurate, it will be locked. Any changes to the database after that time can only be made by 
joint written agreement between the Trial Statistician and Statistical Reporting and the Clinical 
Trial Leader. 
10 
Data analysis 
The data will be analyzed by Novartis and/or by the designated CRO. Any data analysis carried 
out independently by the investigator(s) should be submitted to Novartis before publication or 
presentation. 
It is planned that the data from all centers that participate in this protocol will be used, so that 
an adequate number of patients will be available for analysis. 
Data will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements and safety observations and measurements. 


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10.1 
Populations for analysis 
The Full Analysis Set (FAS) will consist of all patients that entered study and received at least 
one dose of study drug and have at least one post-baseline assessment of the primary efficacy 
variable. 
The Safety Set will consist of all patients that received at least one dose of study drug and had 
at least one post-baseline safety assessment. Of note, the statement that a patient had no adverse 
events also constitutes a safety assessment. 
The Per-Protocol Set will consist of all patients who did not show major deviations from the 
protocol procedures that might have an impact on the study outcome. Criteria that are 
assumed to have such an impact will be defined in the data validation document (VAP). 
The key efficacy analysis will be performed for both, the FAS and the PPS set. The FAS is 
regarded as primary. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data will be summarized descriptively for both the Safety Set 
and the FAS. Categorical data will be presented as frequencies and percentages. For continuous 
data, mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum will 
be presented. 
10.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
All study medication data will be summarized using the safety set.  
Time on treatment, duration of exposure, percentage of days on treatment, average dose 
intensity, actual daily dose and relative dose intensity will be summarized for these above safety 
subsets. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized. 
10.4 
Analysis of the primary objective(s) 
The primary objective of the study is to evaluate the proportion of patients that achieve deep 
molecular response MR4.5 (IS) at 24 months of study treatment, measured in a standardized 
EUTOS MR4.5 laboratory 
 
Variable 
The primary efficacy variable is the rate of MR4.5 at 24 months of study treatment measured in 
a standardized EUTOS MR4.5 laboratory. MR4.5 is defined as either (i) detectable disease ≤ 
0.0032% BCR-ABLIS or (ii) undetectable disease in cDNA with 32 000 – 99 999 ABL1 
transcripts or 77 000 – 239 999 GUSB transcripts. 


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Molecular response (MMR, MR4 and MR4.5) will be calculated for patients with b2a2 and/or 
b3a2 BCR-ABL transcripts only. Patients with alternative transcripts will be excluded for the 
analysis, because their transcripts cannot be used for deep MR or MMR determination. 
 
Statistical hypothesis, model, and method of analysis 
The rate of MR4.5 (IS) at 24 months of study treatment will be computed by dividing the number 
of patients who fit the definition of response at 24 months by the total number of patients in the 
analysis set. The corresponding 95% confidence interval will be computed as well. 
 
Handling of missing values/censoring/discontinuations 
Only patients with a MR4.5 at 24 months of study treatment, or if the assessment at this time 
point is missing, with a MR4.5 at 21 months are considered responders. Patients dropping out 
early or not providing sufficient data for any other reason will be considered as early 
discontinuation or not evaluable, respectively, and will be included in the analysis set as non-
responders, even if a MR4.5  was previously achieved. Any patient who achieves MR4.5 before 
24 months, but is no longer in MR4.5 at 24 months or progressed (or is no longer in MR4.5  at 21 
months if evaluation at 24 months is missing), will be considered as a non-responder. 
 
Supportive analyses 
The primary analysis will also be repeated on per-protocol population as a sensitivity analysis 
of robustness of the results. Additionally, primary analysis will be stratified for gender. 
10.5 
Analysis of secondary objectives 
For all computations on molecular endpoints, patients with atypical transcripts will not be 
considered, i.e. will be excluded from the analysis, because they cytogenetically respond as 
normal patients, but their transcripts cannot be used for molecular response determination. 
 
 
Efficacy (secondary) 
10.5.1.1 Secondary efficacy variables 
MR4 (IS)  
- 
MR4 (IS) is defined in this study as either (i) detectable disease ≤0.01% BCR-ABLIS or 
(ii) undetectable disease in cDNA with 10 000 – 31 999 ABL1 transcripts or 24.000 – 
76 999 GUSB transcripts. 
- 
The rate of MR4 (IS) at 24 months of study treatment will be computed by dividing the 
number of patients who fit the definition of response at 24 months by the total number 
of patients in the analysis set. 
MMR 


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- 
MMR is defined as a ≥3 log reduction from the standardized baseline or ≤ 0.1% BCR-
ABLIS 
- 
The rate of MMR at 12 months of study treatment will be computed by dividing the 
number of patients who fit the definition of response at 12 months by the total number 
of patients in the analysis set 
CCyR 
- 
Complete cytogenetic response is defined as 0% Ph+ metaphases 
- 
Rate of CCyR at 6 months of study treatment will be calculated by dividing the number 
of patients who fit the definition of response at 6 month by the total number of Ph+ 
patients in the analysis set  
Outcome 
- 
Time to progression to AP/BC is defined as the time from the date of start of study 
treatment to the date of earliest transformation to AP/BC, or CML-related death. Rates 
of progression at various time points will also be provided. 
- 
Progression-free survival is defined as the time from the date of start of study treatment 
to the date of event defined as the first documented disease progression to AP/BC or the 
date of death from any cause, whichever is earlier. 
10.5.1.2 Methods of analyses 
The rate of molecular responses at certain time points will be presented together with an exact 
95% confidence interval. 
Kaplan Meier’s product limit estimates will be used for time to event endpoints, such as time 
to progression to AP/BC and progression-free survival (PFS). The estimated rates by Kaplan 
Meier’s method at various time points will also be provided. 
For time to progression to AP/BC and PFS patients will be censored if one of the following 
situations occurs: 
- 
If a patient does not experience an event before the cut-off date for the analysis, 
censoring time will be the last assessment date before the cut-off date 
- 
If a patient discontinues study treatment prior to experiencing an event, then the patient 
will be censored at the date of last assessment prior to the date of discontinuation. 
10.5.1.3 Handling of missing values 
For MMR and CCyR assessment at a specific time point, only patients with response which 
occurs or is sustained at the specific time point are considered responders; e.g. a patient who 
achieves MMR  before 12 months but is no longer in MMR  at 12 months (or progressed), will 
be considered as a non-responder at 12 months. The same applies for all time points and 
response variables. Patients dropping out early or not providing sufficient data for any other 


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reason will be considered as early discontinuation or not evaluable, respectively, and will be 
included in the analysis set as non-responders. 
 
Safety 
All the safety analyses will be based on the Safety Population.  
Adverse Events 
The incidence of treatment-emergent AEs (new or worsening from screening visit) will be 
summarized by MedDRA System Organ Class and Preferred Term, severity (based on CTCAE 
grades), type of AE, and relation to study treatment. 
Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated by type 
of AE. 
Laboratory abnormalities 
For laboratory tests covered by the CTCAE version 4.03, the study’s biostatistican will grade 
laboratory data accordingly. Grade 0 will be assigned for all non-missing values not graded as 
1 or higher. Grade 5 will not be used. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
The following summaries will be generated separately for hematology and clinical chemistry: 
• Number and percentage of patients with laboratory abnormalities, by parameter and 
worst post-baseline CTCAE grade. Each patient will be counted only for the worst grade 
observed post-baseline, regardless of the baseline status; 
• Shift tables using CTCAE grades 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. 
In addition to the above mentioned tables and listings, 
 might be 
specified in the RAP. 
Other safety data 
Other safety data collected (e.g. ECG, vital signs etc.) will be listed and summarized using 
descriptive statistics as appropriate. Notable values may be flagged. Notable/abnormal values 
for safety data will be further specified in the RAP. 
 
Tolerability 
n.a. 
 
Resource utilization 
n.a. 


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Health-related Quality of Life 
Descriptive statistics will be provided for the EORTC QLQ-C30 in combination with the 
EORTC QLQ-CML 24 questionnaire (including absolute change from baseline) up to the end 
of study for the FAS. Additional analysis may be performed and details will be prescribed in 
the analysis plan. 
 
Pharmacokinetics 
n.a. 
 
Pharmacogenetics/pharmacogenomics 
n.a. 
 
Biomarkers  
n.a. 
 
PK/PD  
n.a. 


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10.7 
Interim analysis 
An interim analysis of baseline and follow-up data is planned after the first 38 patients included 
in the study reach the end of month 6 visit, as of April 2017 in order to evaluate the integrity of 
the collected data. No evaluation of the primary endpoint will be conducted and therefore no 
adjustments with regard to the alpha level will be made. The rational for interim analysis is to 
check the integrity of the data. 
The interim analysis will be purely descriptive in nature and include patient characteristics, vital 
signs, Sokal risk score, EUTOS score, ESC risk score, ECOG performance status, hematologic 
and blood chemistry laboratory values, RQ-PCR results, medical history and adverse events. 
These parameters are described in panels DM, ZC, VS, SRS, QSEUT, QSESC, QSECOG, 
LBLGH, B2, B1, MH, FACM, SU, EG, LBLGC, AE and LBLGU. For panel VS, QSESC, 
LBLGH, B2, B1, FACM, SU, EG, LBLGC, AE and LBLGU analysis will be performed for 
initial visit and all sub sequential visits till end of month 6. 
10.8 
Sample size calculation 
The aim of the current study is to confirm the MR4.5 rates of nilotinib in a broad population 
using the EUTOS MR4.5 (‘European Treatment and Outcome Study for CML’) standardized 
molecular laboratories. 
Therefore sample size is based on the precision of estimate computation; i.e. the 95% 
confidence interval of the proportion of patients with MR4.5 at month 24. 
Assuming a MR4.5 rate at 24 months to be 25%, a total of 171 patients will allow for a precision 
of +/- 6,5 %. 
10.9 
Power for analysis of critical secondary variables 
n.a. 
 
 


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11 
Discussion and rationale for study design features  
Objectives and treatment design: 
Primary objective of this Phase-IV study is to determine the rate of MR4.5 in newly diagnosed 
CML patients after 2 years of nilotinib treatment and is investigated in an open-label single arm 
design. The defined secondary objectives can be assessed through a single arm design 
accordingly. 
Population criteria: 
This study is open to all newly diagnosed patients with CML in chronic phase which the 
investigator intends to treat with nilotinib 300mg BID in accordance with treatment guidelines 
(e.g. ELN-Guidelines, (Baccarani et al., 2013)) and the label of the drug. For reasons of the 
study conduct and patient safety these patients will furthermore have to comply with the stated 
in- and exclusion criteria in Section 5.  
Study drug dose: 
Nilotinib 300mg BID is the approved dose for newly diagnosed CML patients in chronic phase 
and is recommended as one of three possible TKIs for the first-line treatment of CML-CP by 
ELN guidelines (Baccarani et al., 2013). 
Assessments: 
BCR-ABL expression in peripheral blood will be assessed by RQ-PCR, performed in EUTOS 
laboratories. The EUTOS laboratories are certified for performing this assessment reproducibly 
with the most accuracy to identify MR4.5.  The relevance for assessing deep molecular response 
MR4.5 is provided in Section 2. 
 


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12 
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MAURO, M. J. 2013. Striving to achieve safe, permanent treatment discontinuation in chronic myeloid 
leukemia. Leuk Res, 37, 1395-403. 
MULLER, M. C., CROSS, N. C., ERBEN, P., SCHENK, T., HANFSTEIN, B., ERNST, T., HEHLMANN, 
R., BRANFORD, S., SAGLIO, G. & HOCHHAUS, A. 2009. Harmonization of molecular 
monitoring of CML therapy in Europe. Leukemia, 23, 1957-63. 
NCCN, N. C. C. N. 2014. Clinical Practice Guidelines in Oncology [Online]. Available: 
http://www.nccn.org/. 
OKEN, M. M., CREECH, R. H., TORMEY, D. C., HORTON, J., DAVIS, T. E., MCFADDEN, E. T. & 
CARBONE, P. P. 1982. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol, 5, 649-55. 
PERK, J., DE BACKER, G., GOHLKE, H., GRAHAM, I., REINER, Z., VERSCHUREN, M., ALBUS, C., 
BENLIAN, P., BOYSEN, G., CIFKOVA, R., DEATON, C., EBRAHIM, S., FISHER, M., 
GERMANO, G., HOBBS, R., HOES, A., KARADENIZ, S., MEZZANI, A., PRESCOTT, E., 
RYDEN, L., SCHERER, M., SYVANNE, M., SCHOLTE OP REIMER, W. J., VRINTS, C., 
WOOD, D., ZAMORANO, J. L., ZANNAD, F., EUROPEAN ASSOCIATION FOR 
CARDIOVASCULAR, P., REHABILITATION & GUIDELINES, E. S. C. C. F. P. 2012. European 
Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth 
Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular 
Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by 
invited experts). Eur Heart J, 33, 1635-701. 
PRESS, R. D., GALDERISI, C., YANG, R., REMPFER, C., WILLIS, S. G., MAURO, M. J., DRUKER, B. 
J. & DEININGER, M. W. 2007. A half-log increase in BCR-ABL RNA predicts a higher risk of 
relapse in patients with chronic myeloid leukemia with an imatinib-induced complete cytogenetic 
response. Clin Cancer Res, 13, 6136-43. 
REINER, Z., CATAPANO, A. L., DE BACKER, G., GRAHAM, I., TASKINEN, M. R., WIKLUND, O., 
AGEWALL, S., ALEGRIA, E., CHAPMAN, M. J., DURRINGTON, P., ERDINE, S., HALCOX, J., 
HOBBS, R. H., KJEKSHUS, J. K., PERRONE FILARDI, P., RICCARDI, G., STOREY, R. F., 
DAVID, W. & CLINICAL PRACTICE GUIDELINES COMMITTEE OF THE SPANISH SOCIETY 


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OF, C. 2011. [ESC/EAS Guidelines for the management of dyslipidaemias]. Rev Esp Cardiol, 
64, 1168 e1-1168 e60. 
ROUSSELOT, P., HUGUET, F., REA, D., LEGROS, L., CAYUELA, J. M., MAAREK, O., BLANCHET, 
O., MARIT, G., GLUCKMAN, E., REIFFERS, J., GARDEMBAS, M. & MAHON, F. X. 2007. 
Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete 
molecular remission for more than 2 years. Blood, 109, 58-60. 
SAGLIO, G., KIM, D. W., ISSARAGRISIL, S., LE COUTRE, P., ETIENNE, G., LOBO, C., PASQUINI, 
R., CLARK, R. E., HOCHHAUS, A., HUGHES, T. P., GALLAGHER, N., HOENEKOPP, A., 
DONG, M., HAQUE, A., LARSON, R. A. & KANTARJIAN, H. M. 2010. Nilotinib versus imatinib 
for newly diagnosed chronic myeloid leukemia. N Engl J Med, 362, 2251-9. 
SAVONA, M. R. 2014. Molecular monitoring and minimal residual disease in the management of chronic 
myelogenous leukemia. J Community Support Oncol, 12, 171-8. 
SAWYERS, C. L. 1999. Chronic myeloid leukemia. N Engl J Med, 340, 1330-40. 
STONE, N. J., ROBINSON, J. G., LICHTENSTEIN, A. H., BAIREY MERZ, C. N., BLUM, C. B., ECKEL, 
R. H., GOLDBERG, A. C., GORDON, D., LEVY, D., LLOYD-JONES, D. M., MCBRIDE, P., 
SCHWARTZ, J. S., SHERO, S. T., SMITH, S. C., JR., WATSON, K., WILSON, P. W., 
EDDLEMAN, K. M., JARRETT, N. M., LABRESH, K., NEVO, L., WNEK, J., ANDERSON, J. L., 
HALPERIN, J. L., ALBERT, N. M., BOZKURT, B., BRINDIS, R. G., CURTIS, L. H., DEMETS, 
D., HOCHMAN, J. S., KOVACS, R. J., OHMAN, E. M., PRESSLER, S. J., SELLKE, F. W., 
SHEN, W. K., SMITH, S. C., JR., TOMASELLI, G. F. & AMERICAN COLLEGE OF 
CARDIOLOGY/AMERICAN HEART ASSOCIATION TASK FORCE ON PRACTICE, G. 2014. 
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic 
cardiovascular risk in adults: a report of the American College of Cardiology/American Heart 
Association Task Force on Practice Guidelines. Circulation, 129, S1-45. 
VAN ETTEN, R. A. 2004. Mechanisms of transformation by the BCR-ABL oncogene: new perspectives 
in the post-imatinib era. Leuk Res, 28 Suppl 1, S21-8. 
WEISBERG, E., MANLEY, P. W., BREITENSTEIN, W., BRUGGEN, J., COWAN-JACOB, S. W., RAY, 
A., HUNTLY, B., FABBRO, D., FENDRICH, G., HALL-MEYERS, E., KUNG, A. L., MESTAN, J., 
DALEY, G. Q., CALLAHAN, L., CATLEY, L., CAVAZZA, C., AZAM, M., NEUBERG, D., 
WRIGHT, R. D., GILLILAND, D. G. & GRIFFIN, J. D. 2005. Characterization of AMN107, a 
selective inhibitor of native and mutant Bcr-Abl. Cancer Cell, 7, 129-41. 
WHITE, D. L., SAUNDERS, V. A., DANG, P., ENGLER, J., ZANNETTINO, A. C., CAMBARERI, A. C., 
QUINN, S. R., MANLEY, P. W. & HUGHES, T. P. 2006. OCT-1-mediated influx is a key 
determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 
activity is the cause of low in vitro sensitivity to imatinib. Blood, 108, 697-704. 
YIN, O. Q., GALLAGHER, N., FISCHER, D., ZHAO, L., ZHOU, W., LEROY, E., GOLOR, G. & SCHRAN, 
H. 2011. Effects of nilotinib on single-dose warfarin pharmacokinetics and pharmacodynamics: 
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31, 169-79. 
 
 
 


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Appendix 1:  Ethical considerations and administrative procedures 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including 
European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of Helsinki.  
Responsibilities of the investigator and IRB/IEC/ 
The protocol and the proposed informed consent form must be reviewed and approved by a properly 
constituted Institutional Review Board / Independent Ethics Committee (IRB/IEC) before study start.  
Approval letters concerning protocol and informed consent will be filed by Novartis. 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, and regulatory 
authorities as required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made. 
Informed consent procedures  
Eligible patients may only be included in the study after providing written, IRB/IEC-approved informed 
consent. 
Women of child bearing potential should be informed that taking the study drug 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. 
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.   
Novartis will provide to investigators in a separate document a proposed informed consent form that 
complies with the ICH GCP guideline and regulatory requirements and is considered appropriate for this 
study. 
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 trial 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 
it cannot be implemented. All significant protocol deviations will be recorded and reported in the CSR. 
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. Only amendments that are 
required for patient safety may be implemented prior to IRB/IEC 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 


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from the protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed within 10 working days. 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical trial 
agreement. 
Publication of study design 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. 
Study documentation, record keeping and retention of documents 
Each participating site will maintain appropriate medical and research records for this trial, in compliance 
with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements for the protection of 
confidentiality of subjects. As part of participating in a Novartis-sponsored study, each site will permit 
authorized representatives of the sponsor(s) and regulatory agencies to examine (and when required 
by applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits and 
evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Examples of these original 
documents and data records include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
Principal Investigator. The study case report form (CRF) is the primary data collection instrument for the 
study. The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported in the CRFs and all other required reports. Data reported on the CRF, that are derived from 
source documents, should be consistent with the source documents or the discrepancies should be 
explained. All data requested on the CRF must be recorded. Any missing data must be explained. Any 
change or correction to a paper CRF should be dated, initialed, and explained (if necessary) and should 
not obscure the original entry. For electronic CRFs an audit trail will be maintained by the system. The 
investigator should retain records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential Documents for 
the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable regulations and/or 
guidelines. The investigator/institution should take measures to prevent accidental or premature 
destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than fifteen (15) 
years from the completion of the Clinical Trial unless Sponsor provides written permission to dispose of 
them or, requires their retention for an additional period of time because of applicable laws, regulations 
and/or guidelines. 


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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. 
 
Audits and inspections  
Source data/documents must be available to inspections by Novartis or designee or Health Authorities 
 
 


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Appendix 2: List of CYP3A4 inducers, inhibitors and substrates 
Medications that can induce CYP3A4 
Strong Inducers 
Moderate inducers 
Weak inducers 
Unclassified 
inducers 
avasimibe 
bosentan 
amprenavir 
topiramate 
carbamazepine 
efavirenz 
aprepitant 
 
dexamethasone* 
etravirine 
armodafinil (R-modafinil) 
 
phenobarbital 
modafinil 
echinacea 
 
phenytoin 
nafcillin 
garlic 
 
rifabutin 
ritonavir 
ginkgo 
 
rifampin 
talviraline 
glycyrrhizin 
 
rifapentin* 
tipranavir 
methylprednisolone 
 
St. John's wort 
 
nevirapine 
 
 
 
oxcarbazepine 
 
 
 
pioglitazone 
 
 
 
prednisone 
 
 
 
pleconaril 
 
 
 
rufinamide 
 
 
 
troglitazone 
 
* Discrepancies on the level of induction of these drugs exist in the literature, however, they are listed 
in the“strong inducers” group in order to be consistent with the Tasigna Labeling. 
Note: 
Inducer classification: 
• 
Strong inducers may result in a substrate area under curve (AUC) decreased by ≥ 80%. 
• 
Moderate inducers may result in a substrate AUC decreased by 50-80%. 
• 
Weak inducers may result in a substrate AUC decreased by 20-50%. 
This list is compiled based on 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. This list may not be comprehensive and may be updated periodically. Refer to 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ for updates or more details, as well as the 
complete list of Cytochrome P450 substrates. 
 
 


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Medications that can inhibit CYP3A4 
Strong inhibitors 
Moderate inhibitors 
Weak inhibitors 
clarithromycin 
amprenavir 
alprazolam 
conivaptan 
aprepitant 
AMD070 
Indinavir 
atazanavir 
amlodipine 
itraconazole 
cimetidine 
azithromycin 
ketoconazole 
ciprofloxacin 
bicalutamide 
lopinavir 
darunavir 
cranberry juice 
mibefradil 
diltiazem 
chlorzoxazone 
nefazodone 
elvitegravir 
cilostazol 
nelfinavir 
erythromycin 
cyclosporine 
posaconazole 
fluconazole 
fluvoxamine 
ritonavir 
grapefruit juice 
ginkgo 
saquinavir 
imatinib 
goldenseal 
telithromycin 
schisandra sphenanthera 
isoniazid 
troleandomycin 
tipranavir 
lacidipine 
voriconazole 
tofisopam 
M100240 
 
verapamil 
nilotinib 
 
 
oral 
contraceptives 
(e.g. 
drospirenone, 
norgestimate, 
and ethinyl estradiol) 
 
 
peppermint oil 
 
 
propiverine 
 
 
ranitidine 
 
 
ranolazine 
 
 
roxithromycin 
 
 
Seville orange juice 
 
 
sitaxentan 
 
 
tabimorelin 
Note: 
Inhibitor classification: 
• 
Strong inhibitors may result in a substrate AUC > 5-fold increase. 
• 
Moderate inhibitors may result in a substrate AUC ≥ 2-fold increase and < 5-fold increase. 
• 
Weak inhibitors may result in a substrate AUC ≥ 1.25-fold increase and < 2-fold increase. 


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This 
list 
may 
not 
be 
comprehensive 
and 
may 
be 
updated 
periodically. 
Refer 
to 
http://medicine.iupui.edu/clinpharm/ddis/main-table/  for updates or more details, as well as the 
complete list of Cytochrome P450 substrates. 
13 
Appendix 3: Quality of Life Questionnaires 
 


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14 
Appendix 4: ESC Risk SCORE chart 

SAP_001.pdf: 
Clinical Development
AMN107/Nilotinib/Tasigna®
Oncology Clinical Protocol CAMN107ADE20 / NCT02546674
A Phase IV single arm, multicenter, open-label study 
assessing deep molecular response in adult patients with 
newly diagnosed Philadelphia chromosome positive CML 
in chronic phase after two years of treatment with nilotinib 
300mg BID
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Lead Statistician, 
Document type:
SAP Documentation
Document status:
Addendum v1.0
Release date:
19-Nov-2021
Number of pages:
37
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for update
Sectio
n and 
title 
impact
ed 
(Curre
nt)
18-Sep-
2020
Prior to 
DB 
lock
Creation of final 
version
N/A - First version
NA
26-Nov-
2020
Prior to 
DB 
lock
Vital sign abnormality 
table updated
Updated the table for criteria 
for notable vital sign 
abnormalities
Sectio
n 5.3.1
30-Nov-
2020
Prior to 
DB 
lock
Patient-reported
outcomes updated
PRO updated EORTC QLQ-
C30 scoring procedure and 
EORTC QLQ-C24
Sectio
n 2.11
14-Jan-2021
Prior to 
DB 
lock
AE end date imputation
AE end date imputation added
Sectio
n 
5.1.2.2
14-Jan-2021
Prior to 
DB 
lock
Added TEAE 
definition added
Added TEAE definition added 
Sectio
n 2.8.1
22-Jan-2021
Prior to 
DB 
lock
Team decided to update 
more about Handling of 
missing value
/censoring
/discontinuations
Added more details for the 
handling of missing 
value/censoring/discontinuatio
ns. Added the definition for 
responder and non-responder
Sectio
n 2.5.3


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SAP 
CAMN107ADE20
Date
Time 
point
Reason for update
Outcome for update
Sectio
n and 
title 
impact
ed 
(Curre
nt)
17-Feb-
2021
19-Nov-
2021
Prior to 
DB 
lock
After 
DBL
Visit window updated
Inconsistancy
of age 
group
Assessment windows
table updated
Updated  Change to protocol-
specified analyses
Sectio
n 2.1.2
Sectio
n 4 


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SAP 
CAMN107ADE20
Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
General definitions................................................................................11
Visit windows........................................................................................11
2.2
Analysis sets ..........................................................................................................14
Subgroup of interest ..............................................................................14
2.3
Patient disposition, demographics and other baseline characteristics ...................14
Number and percentage of missing observations in each category 
will be summarized. Patient disposition................................................14
Patient demographics ............................................................................14
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................15
Study treatment / compliance................................................................15
Prior, concomitant and post therapies...................................................16
2.5
Analysis of the primary objective..........................................................................17
Primary endpoint...................................................................................17
Statistical hypothesis, model, and method of analysis..........................17
Handling of missing values/censoring/discontinuations.......................17
Supportive analyses...............................................................................17
2.6
Analysis of the key secondary objective ...............................................................17
2.7
Analysis of secondary efficacy objective(s)..........................................................18
Secondary efficacy variables.................................................................18
Secondary endpoints .............................................................................18
Statistical hypothesis, model, and method of analysis..........................19
Handling of missing values/censoring/discontinuations.......................20
2.8
Safety analyses.......................................................................................................20
Adverse events (AEs)............................................................................20
Deaths....................................................................................................21
Laboratory data .....................................................................................21
Other safety data ...................................................................................22
2.9
Pharmacokinetic endpoints....................................................................................23


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2.10
PD and PK/PD analyses.........................................................................................23
2.11
Patient-reported outcomes .....................................................................................23
2.12
Absolute change from baseline will also be provided by visit. Biomarkers .........25
25
25
26
 
.26
2.14
Mutational Analysis...............................................................................................26
2.15
Interim analysis......................................................................................................27
3
Sample size calculation .....................................................................................................27
4
Change to protocol-specified analyses ..............................................................................27
5
Appendix ...........................................................................................................................27
5.1
Imputation rules.....................................................................................................27
Study drug.............................................................................................27
AE date imputation ...............................................................................28
Concomitant medication date imputation .............................................29
5.2
AEs coding/grading ...............................................................................................31
5.3
Laboratory parameters derivations ........................................................................32
Criteria for notable vital sign abnormalities..........................................32
5.4
Statistical models...................................................................................................32
Primary analysis....................................................................................32
Secondary analysis................................................................................33
5.5
Rule of exclusion criteria of analysis sets..............................................................34
6
Reference...........................................................................................................................37


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List of abbreviations
ABL 
Abelson leukemia virus
ACE
Angiotensin-converting enzyme
AE
Adverse event
ALL
Acute lymphoid leukemia
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute Neutrophil count
Anti HBc
Antibody to hepatitis B core antigen
AP
Accelerated phase
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AT
Angiotensin
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
BC
Blast crisis
BCR
Break point cluster region
BCR-ABL
BCR-ABL oncoprotein, BCR-ABL fusion gene, BCR-ABL fusion transcript
bid
bis in diem/twice a day
BP
Blood pressure
CCyR
complete cytogenetic response
CKD
Chronic kidney disease
CML
Chronic myeloid leukemia
CP
Chronic phase
CRF
Case Report/Record Form
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CVD
Cardiovascular disease
CYP3A4
Cytochrome P450 3A4
DMC
Data Monitoring Committee 
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EFS
Event-free survival
ELN
European Leukemia Net
EMA
European Medicine Agency
EMR
Early molecular response
EORTC
European Organization for Research and Treatment of Cancer
ESC
European Society of Cardiology
EUTOS
European Treatment and Outcome Study for CML
FAS
Full Analysis Set
G-CSF
Granulocyte colony-stimulating factor
GFR
Glomerular filtration rate
GM-CSF
Granulocyte-macrophage colony-stimulating factor


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HbA1c
Glycated hemoglobin
HBs Ag
Hepatitis B surface antigen
HCT
Hydrochlorothiazide
HDL
High-density lipoprotein
HMG-CoA
3-hydroxy-3-ethylglutaryl-coenzyme A
HRQOL
Health-related quality of life
IB
Investigator brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
ICVE
Ischemic cerebrovascular event
i.v.
Intravenous(ly)
IHD
Ischemic heart disease
IRB
Institutional Review Board
IS
International scale
IUD
Intrauterine device
IVR
Interactive Voice Response
IVRS
Interactive Voice Response System
IWR
Interactive Web Response
LDL
Low-density lipoprotein
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MR
Molecular response
MR4
Molecular response 4 log reduction from standardized baseline
MR4.5
Molecular response 4.5 log reduction from standardized baseline
MMR
Major molecular response
o.d.
Once Daily
OS
Overall Survival
PFS
Progression-Free Survival
Ph
Philadelphia chromosome
Ph+
Philadelphia chromosome positive
p.o.
per os / by mouth / orally
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
QT
QT interval
QTcF
Fridericia-corrected QT interval
RAP
Report and Analysis Process
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
TKI
Tyrosine kinase inhibitor


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1
Introduction
This statistical analysis plan (SAP) module describes the planned statistical methods for all 
safety and efficacy analyses to be used in Phase IV clinical study CAMN107ADE20. Any 
changes made to the statistical plan and methodology after the clinical database lock will be 
documented as an addendum.
The main purpose of this document is to provide summary of the statistical methodology that 
will be used for this clinical study; this includes a detailed description of data summaries. 
Analyses plan in this document refers to the related statistical analysis sections in clinical study 
report.
The analysis described here will be conducted by Novartis using statistical software SAS®
Version 9.4 according to the Statistical methods and data analysis Section 10 of the study 
protocol which will be available in Appendix 16.1.1 of the CSR. Important information will 
be given in the following sections and further details are provided, as applicable, in the 
Appendix 16.1.9 of the CSR.
Data will be analyzed by Novartis according to the data analysis Section 10 of the clinical study 
protocol. That statistical methodology is described below and any deviations from the protocol 
are documented. Additional detailed information regarding the analysis methodology is 
contained in the Appendix section.
Unless otherwise specified, the statistical methodologies including the analysis sets, analysis 
models, algorithms and conventions are following the Oncology study protocol 
CAMN107ADE20 final version.
1.1
Study design
This is a Phase IV open-label, multicenter, single-arm trial of nilotinib 300mg twice a day (BID)
in newly diagnosed patients with chronic phase CML to primarily evaluate the rate of deep 
molecular response (MR4.5) at 24 months of study treatment using European Treatment and 
Outcome Study for CML (EUTOS) standardized laboratories. Patients will undergo up to 2 
weeks of screening period and if deemed eligible, will receive nilotinib 300mg BID formulation 
for 24 weeks. 
The experiment is planned to be take place at 50 sites in Germany and 171 patients are planned 
to be included. All patients will be given nilotinib 300mg BID. Nilotinib will be prescribed by 
the investigator according to the individual needs of the patients. 
The overall study design is as the following:

A screening period of 2 weeks will be used to assess eligibility and to taper patients off 
disallowed medications. 

Patients whose eligibility is confirmed will then enter a 24 months treatment phase. The 
assessment to address the primary objective will be performed at the end of the treatment 
phase. 
For efficacy analysis, only patients with typical b2a2 or b3a2 BCR-ABL transcripts at baseline 
will be considered. Other variants will be analyzed separately.


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Following figure gives overall study design:
Figure 1.1
1.2
Study objectives and endpoints
The primary, secondary 
objectives and endpoints are presented in Table 1.1.
Table 1-1
Objectives and related endpoints
Objectives
Endpoints
Primary objective
To evaluate the proportion of patients who are in 
deep molecular response MR4.5 (IS) at 24 months 
of study treatment, measured in a standardized 
EUTOS MR4.5 laboratory. 
Number and proportion of patients with 
deep molecular response MR4.5 (IS) at 
24 months of study treatment
Secondary objectives 
To determine the proportion of patients who are 
in deep molecular response MR4 (IS) at 24 
months of study treatment 
Number and proportion of patients with 
deep molecular response MR4 (IS) at 
24 months of study treatment
To determine the proportion of patients who are 
in MMR at 12 months of study treatment 
Number and proportion of patients with 
MMR at 12 months of study treatment 
To determine the proportion of patients who are 
in CCyR at 6 months of study treatment 
Number and proportion of patients who 
fit the definition of response at 6 month 
by the total number of Ph+ patients in 
the analysis set. 


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Objectives
Endpoints
To evaluate progression-free survival (PFS) and 
time to progression to AP/BC 
Kaplan Meier’s product limit estimates 
and estimated rates by Kaplan Meier’s 
method at various time points in the 
analysis set
To evaluate quality of life of 300mg nilotinib 
BID therapy 
Absolute change from baseline up to 
the end of study for the FAS in the 
analysis set
2
Statistical methods
2.1
Data analysis general information
The data will be analyzed by PLS, Novartis. Analysis datasets and statistical outputs will be 
produced using the most recent SAS® Version 9.4 (SAS Institute Inc., Cary, NC, USA), and 
stored in Novartis global programming & statistical environment (GPS).
Once all data including the final visit (containing the primary and secondary endpoints) are 
complete and clean, the database for that study period will be locked and analyzed. It is planned 
that the data from all centers that participate in this protocol will be used, so that an adequate 
number of patients will be available for analysis. Data will be summarized with respect to 
demographic and baseline characteristics, efficacy observations and safety observations.
Data will be summarized descriptively for both the Safety Set and the Full Analysis Set (FAS). 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation (SD), median, 25th and 75th percentiles, minimum, maximum will be 
provided. Also, 95% C.I of proportion will be presented, wherever applicable.


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General definitions
Study treatment
In this and subsequent analysis plan module (TFL and PDS), the terms “investigational drug”, 
“study drug” and “study treatment” refers to nilotinib 300mg BID throughout the study.
Study treatment start and end date
Study treatment start date is defined as the first date when a non-zero dose of study drug is 
administered and recorded on the Drug Administration Record (DAR) CRF page. Similarly, 
study drug end date is defined as the last study drug administration date.
Study day
Study day will be calculated as (event date – study drug start date + 1 day) for events that 
occurred on or after study drug start date (e.g. Visit, lab samples, AEs). 
For events prior to study drug start date (e.g., time of diagnosis), study day will be negative 
and calculated as (event date – study drug start date). Note that study drug start date is study 
day 1.
Due to the study drug dosing schedule, one month will be considered as 28 days. However, 
for “time since event” data (e.g., medical history), one month will be considered as 365.25/12 
days for events that occurred prior to study Day 1. 
Baseline
The last available assessment before start of study of study treatment (study day 1) will be 
taken as baseline. For Patient-reported outcomes, the last available assessment before or on 
start of study of study treatment (study day 1) will be taken as baseline. Further, if several 
assessments are taken on the same day, the last assessment will be used for that time point.
Post Baseline assessment
A post-baseline value refers to a measurement taken in the Treatment phase from Day 1 
onwards. For patients who discontinued study treatment, all assessments listed in End of 
Study (EOS) visit will be performed.
Change from baseline:
When change from baseline is of interest, the following formula will be used for each scheduled 
visit where baseline and post-baseline values are both available:
Change from baseline = post-baseline value – baseline value.
Visit windows
In the protocol assessment schedules, one month is considered as a 4-weekly period. For each 
parameter (i.e. hematologic, cytogenetic and molecular response), time windows will be used 
to identify data to be considered for the specific analysis at a specific time point as well as the 


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cut-off for the analysis of response by a specific time point. The time windows are defined so 
that there are no gaps between the planned assessments, i.e. every assessment – including 
additional unscheduled assessments - would be assigned to one specific time point. If there is 
more than one assessment within the time window, the last available assessment in that time 
window will be used. 
For all time windows after baseline, only values after first dose of study drug will be used. Time 
windows are defined based on the first dose of treatment for the analyses.


Table 2-1
Assessment windows
Analysis visit
Target 
day
Analysis visit 
window
MR
CCyR / 
QoL
ECOG
ESC / smoking 
status
ECG
Baseline
Day 0
-14 – 0
-14 - 1
-14 – 0
-14 – 0
-14 – 0
-14 – 0
Visit 2
Day 1
1 – 8
Visit 3
Month 1
Day 28
9 - 42
1 - 56
Visit 4
Month 3
Day 84
43 – 126
2 – 126
1 -126
Visit 5
Month 6
Day 168
127 – 210
127 – 210
127 – 252
1 – 252
Visit 6
Month 9
Day 252
211 – 294
211 – 294
Visit 7
Month 12
Day 336
295 – 378
295 – 378
253 – 420
253 – 420
Visit 8
Month 15
Day 420
379 – 462
379 – 462
Visit 9
Month 18
Day 504
463 – 546
463 – 546
421 – 588
421 – 588
Visit 10
Month 21
Day 588
547 – 630
547 – 630
Visit 11
Month 24
Day 672
631 – 686
631 – 758
589 - 728
1 - 716
589 - 728
Visit 12
Follow-up
Day 702
687 - 732
For assessments captured at all visits up to Month 24, follow the visit windows as mentioned in “Analysis visit window” column of Table 2-
1. For calculation of dose exposure and dose intensity, the following visit windows will be applied (counting from first dose administration 
(treatment start)):
Table 2-2
Assessment windows for treatment information
Assessment
Window
< 3 months
Day 1 – Day 83
>=xx - <yy months
Trt day (xx*28) included up to day (yy*28) 
excluded


2.2
Analysis sets
Full Analysis Set (FAS): The Full Analysis Set (FAS) will consist of all patients who have
entered study and received at least one dose of study drug and have at least one post-baseline 
assessment of the primary efficacy variable. 
Safety Set: The Safety Set will consist of all patients who received at least one dose of study 
drug and had at least one post-baseline safety assessment. Of note, the statement that a patient 
had no adverse events also constitutes a safety assessment. 
Per-Protocol Set: The Per-Protocol Set will consist of all patients who did not show major 
deviations from the protocol procedures that might have an impact on the study outcome. 
Criteria that are assumed to have such an impact will be defined in the data validation document 
(VAP).
The key efficacy analysis will be performed for both, the FAS and the PPS. The FAS is regarded 
as primary. Any major protocol deviation will lead to exclusion of patients from PPS. The list 
of PDs is defined in Section 5.5.
Subgroup of interest
To evaluate efficacy of nilotinib in the elderly patients, the population (FAS) will be stratified 
by age, assessing patients ≥ 65 years versus < 65 years, using the cutoff according to the median 
age at diagnosis in western populations (Gugliotta et al., 2014), regarding time to assessing 
cytogenetic and molecular response as well as rates of progression to AP and BC. 
2.3
Patient disposition, demographics and other baseline 
characteristics
Descriptive statistics will be provided for patient disposition, demographics and all baseline 
characteristics including baseline values of main efficacy endpoints. Categorical data will be 
presented as frequencies and percentages. For continuous data, mean, standard deviation, 
median, 25th and 75th percentiles, minimum, and maximum will be presented.
Number and percentage of missing observations in each category will 
be summarized. Patient disposition
The Full Analysis Set will be used for the summary and listing of patient disposition. The 
overall number and percentage of patients who were screened, completed and discontinued 
the study along with reasons for discontinuation will be summarized.
Patient demographics
Summary statistics will be presented for continuous demographic variables for all patients in 
both the Safety Set and Full Analysis Set. For categorical variables, number and percentage of 
patients in each category will be presented.
The following demographic variables will be summarized:


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Continuous variable:

Age (years)
Categorical variables

Age category (<65 and ≥65 years)

Sex (male, female)

Is subject of child bearing status (Able to bear children, Premenarche, Post-
menopausal, Sterile - of child bearing age)

Race (Caucasian, Black, Asian, Other, Native American)
Baseline characteristics
Sokal risk score, EUTOS score, extramedullary involvement and vital signs at baseline will be 
summarized descriptively.
Medical history
Relevant medical history and current medical conditions will be summarized by system organ 
class and preferred term of the Medical Dictionary for Drug Regulatory Affairs (MedDRA)
dictionary. ESC Risk related medical history/conditions will be listed.
In addition, time since initial diagnosis of CML will be summarized descriptively.
Also, smoking history will be tabulated with descriptive statistics.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
Study treatment / compliance
All study medication data will be summarized using the Safety set.
Time on treatment, duration of exposure, percentage of days on treatment, average dose 
intensity, and actual daily dose will be summarized by treatment group. In addition, 95% 
distribution-free confidence intervals for the median time on treatment and duration of exposure 
will be provided.
Date of first dose is defined as the date of first intake of any of the study drug. This will be 
considered as treatment day 1.
Date of the last dose is defined as follows:

For patient who discontinued study treatment, the date of last dose is defined as the date 
of the last non-zero dose of any of the study drug reported in the dose administration 
CRF page.

For patients still ongoing on treatment, the date of last dose is defined as the last 
available date reported on any of the following CRF pages: visit, dose administration, 
PCR, bone marrow,


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The following definitions are used:
Time on treatment (in days) = date of last dose – date of first dose + 1 day
Duration of exposure (in days) = (date of last dose – date of first dose) + 1 day - (days of zero 
total daily dose)
Percentage of days exposed = (duration of exposure / time on treatment) * 100
Actual dose intensity (mg/day) = total dose / time on treatment (periods of zero dose are 
included)
Average daily dose (mg/day) = total dose / duration of exposure (periods of zero dose are 
excluded)
The following quantities will be derived in relation to the treatment group assigned for safety
analysis:
Relative dose intensity (%) = (actual dose intensity / assigned total daily dose)*100
Relative daily dose = average daily dose / assigned total daily dose
Dose changes
The number and percentage of patients with dose interruption and/or dose reduction along with 
reasons for dose interruption/reduction will be summarized in the Safety set.
Dose interruption and dose reduction are defined as follows:

Interruption is defined as any period of zero daily dose.

Reduction is defined as any decrease from the immediate prior daily dose. Zero daily 
doses are not regarded as reduction.
Prior, concomitant and post therapies
Prior and concomitant medications/significant non-drug therapies will be listed and 
summarized in the Safety set.

Prior medications are defined as treatments taken and stopped prior to first dose of 
study treatment. 

Concomitant medications are medications that started on or after the first dose of study 
drug, or started before the first dose of study drug and continued after the first dose of 
study drug.
The number and percentage of patients receiving prior and concomitant medication or 
significant non-drug therapy will be presented separately, by Anatomical Therapeutic 
Classification (ATC) class and preferred term.
Medications will be presented in alphabetical order, by ATC codes and grouped by 
anatomical main group. Tables will show the overall number and percentage of patients 
receiving at least one treatment of a particular ATC code and at least one treatment in a 
particular anatomical main group.


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Surgical and medical procedures will be summarized by primary system organ class and 
MedDRA preferred term.
2.5
Analysis of the primary objective
Primary endpoint
The primary objective of the study is to evaluate the proportion of patients who achieve deep 
molecular response MR4.5 (IS) at 24 months of study treatment, measured in a standardized 
EUTOS MR4.5 laboratory. The rate of MR4.5 (IS) at 24 months of study treatment will be 
computed by dividing the number of patients who fit the definition of response at 24 months by 
the total number of patients in the analysis set.
MR4.5 is defined as either (i) detectable disease ≤0.0032% BCR-ABL (IS) or (ii) undetectable
disease in cDNA with 32 000 – 99 999 ABL1 transcripts or 77 000 – 239 999 GUSB transcripts. 
Molecular response will be calculated for patients with b2a2 and/or b3a2 BCR-ABL transcripts 
only. Patients with alternative transcripts will be excluded from the analysis, because their 
transcripts cannot be used for deep MR or MMR determination.
Statistical hypothesis, model, and method of analysis
The rate of MR4.5 (IS) at 24 months of study treatment will be computed by dividing the 
number of patients who fit the definition of response at 24 months by the total number of 
patients in the analysis set. The corresponding 95% confidence interval will be computed by 
Clopper-Pearson method.
Handling of missing values/censoring/discontinuations
Only patients with a MR4.5 at 24 months of study treatment, or if the assessment at this time 
point is missing, with a MR4.5 at 21 months are considered responders. Patients dropping out 
early or not providing sufficient data for any other reason will be considered as early 
discontinuation or not evaluable, respectively, and will be included in the analysis set as non-
responders, even if a MR4.5 was previously achieved. Any patient who achieves MR4.5 before 
24 months, but is no longer in MR4.5 at 24 months or progressed (or is no longer in MR4.5 at 
21 months if evaluation at 24 months is missing), will be considered as a non-responder.
Supportive analyses
The primary analysis the proportion of patients who are in deep molecular response MR4.5 (IS) 
at 24 months of study treatment will be repeated on per-protocol population as a sensitivity 
analysis of robustness of the results. Additionally, primary analysis will be stratified for gender.
2.6
Analysis of the key secondary objective
Not applicable.


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2.7
Analysis of secondary efficacy objective(s)
Secondary efficacy variables
MR4 (IS) 
- MR4 (IS) is defined in this study as either (i) detectable disease ≤0.01% BCR-ABLIS or (ii) 
undetectable disease in cDNA with 10 000 – 31 999 ABL1 transcripts or 24.000 – 76 999 GUSB 
transcripts. 
- The rate of MR4 (IS) at 24 months of study treatment will be computed by dividing the number 
of patients who fit the definition of response at 24 months by the total number of patients in the 
analysis set. 
MMR 
- MMR is defined as a ≥3 log reduction from the standardized baseline or ≤ 0.1% BCR-ABLIS 
- The rate of MMR at 12 months of study treatment will be computed by dividing the number of 
patients who fit the definition of response at 12 months by the total number of patients in the 
analysis set 
CCyR 
- Complete cytogenetic response is defined as a value of 0% Ph+ metaphases in bone marrow. 
- Rate of CCyR at 6 months of study treatment will be calculated by dividing the number of 
patients who fit the definition of response at 6 month by the total number of Ph+ patients in the 
analysis set 
Cytogenetic response will be assessed as the percentage of Ph+ metaphases in the bone marrow (a 
review of a minimum of 20 metaphases is required).
Outcome 
- Time to progression to AP/BC is defined as the time from the date of start of study treatment to 
the date of earliest transformation to AP/BC, or CML-related death. Rates of progression at 
various time points will also be provided. 
- Progression-free survival is defined as the time from the date of start of study treatment to the 
date of event defined as the first documented disease progression to AP/BC or the date of death 
from any cause, whichever is earlier. 
Secondary endpoints
The following secondary outcome measures will be analyzed on FAS: 
1. Proportion and percentage of patients with deep molecular response MR4 (IS).
2. Proportion and percentage of patients with MMR at 12 months. 
3. Proportion and percentage of patients with complete cytogenetic response defined as 0% 
Ph+ metaphases in bone marrow.
4. Kaplan Meier’s product limit estimates and estimated rates by Kaplan Meier’s method 
at various time points.


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5. Absolute change from baseline in HR-QoL, up to the end of study.
Statistical hypothesis, model, and method of analysis
1. Proportion and percentage of patients with deep molecular response MR4 (IS)
The rate of MR4 (IS) at 24 months of study treatment will be computed by dividing the 
number of patients who fit the definition of response at 24 months by the total number of 
patients in the analysis set. The corresponding 95% confidence interval will be computed 
by Clopper-Pearson method.
2. Proportion and percentage of patients with MMR at 12 months of study
The rate of MMR at 12 months of study treatment will be computed by dividing the number 
of patients who fit the definition of response at 12 months by the total number of patients in 
the analysis set. The corresponding 95% confidence interval will be computed by Clopper-
Pearson method.
3. Proportion of patients who are in CCyR at 6 months of study treatment.
Proportion of CCyR at 6 months of study treatment will be calculated by dividing the 
number of patients who fit the definition of response at 6 month by the total number of 
patients in the analysis set.
4. To evaluate progression-free survival (PFS) and time to progression to AP/BC
Kaplan Meier’s product limit estimates will be used for time to event endpoints - time to 
progression to AP/BC and progression-free survival (PFS). The estimated rates by Kaplan 
Meier’s method at various time points will be provided. Percentiles (25%, median, 75%) of the 
event time distribution will be presented along with their two-sided 95% confidence interval.
The Kaplan-Meier curve will also be displayed. The plots will display the number of patients
at risk every 3 months. Time to progression and death will be listed per patient presenting the
start and end date of treatment, the progression status (Y/N), progression date, last progression-
free date, death status (Y/N), date of death along with principal cause of death and date of last 
adequate AP/BC assessment which is used for censoring.

Time to progression to AP/BC is defined as the time from the date of start of study 
treatment to the date of earliest transformation to AP/BC, or CML-related death. Rates 
of progression at various time points will also be provided.

Progression-free survival is defined as the time from the date of start of study treatment 
to the date of event defined as the first documented disease progression to AP/BC or the 
date of death from any cause, whichever is earlier.
For time to progression to AP/BC and PFS patients will be censored if one of the following 
situations occurs:
- If a patient does not experience an event before the cut-off date for the analysis, censoring 
time will be the last assessment date before the cut-off date 
- If a patient discontinues study treatment prior to experiencing an event, then the patient will 
be censored at the date of last assessment prior to the date of discontinuation.


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5. To evaluate quality of life of 300mg nilotinib BID therapy
Refer to Section 2.11 for details.
Handling of missing values/censoring/discontinuations
For MMR and CCyR assessment at a specific time point, only patients with response which 
occurs or is sustained at the specific time point are considered responders; e.g. a patient who 
achieves MMR before 12 months but is no longer in MMR at 12 months (or progressed), will 
be considered as a non-responder at 12 months. The same applies for all time points and 
response variables. Patients dropping out early or not providing sufficient data for any other 
reason will be considered as early discontinuation or not evaluable, respectively, and will be 
included in the analysis set as non-responders.
2.8
Safety analyses
All the safety analyses will be based on the Safety Set Population.
Adverse events (AEs)
Adverse events (AE) will be coded using the MedDRA dictionary that provides the system 
organ class and preferred term information. CTCAE version 4.0 will be used for reporting AE 
severity. Treatment-emergent AEs starting on or after the date of first study medication 
(including AEs that start after the discontinuation of the study medication regardless of the 
number of days after discontinuation) will be reported and summarized. Treatment Emergent 
Adverse Events are those, which start in on-treatment period, or which start in pre-treatment 
period but worsen in on-treatment period, last day of treatment + 30 days.
Adverse events will be summarized by presenting the number and percentage of patients having 
any adverse event, having an adverse event in each primary system organ class, and having an 
adverse event with a particular preferred term within a system organ class.
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 AE, the severity of mild, moderate, 
severe, and life-threatening, corresponding to Grades 1 to 4, will be used. CTCAE Grade 5 (death) 
will not be used in this study.
The following selection of AEs will be summarized separately. 

AEs, by toxicity grade

AEs suspected to be study drug related

AEs reported as serious AEs (SAEs)

AEs reported as non-serious

AEs associated with discontinuation of study drug 

AEs requiring dose adjustment or study drug interruption


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Deaths will also be also be summarized similarly by MedDRA System Organ Class and 
Preferred Term. Listings for all AEs, SAEs and deaths will also be provided.
2.8.1.1
Adverse events of special interest / grouping of AEs
The crude incidence for SPP risks will be summarized. In addition, listings will be provided 
presenting which subjects experienced which risk.
The incidence of following AEs of special interest will be summarized by MedDRA System
Organ Class and Preferred Term...

Ischemic Heart Disease (IHD): angina pectoris, coronary artery disease, acute 
myocardial infarction and coronary artery stenosis 

Ischemic Cerebrovascular Events (ICVE): ischemic cerebrovascular accident, and 
transient ischemic attack 

Peripheral Artery Occlusive Disease (PAOD): intermittent claudication, arterial 
stenosis of a limb
Deaths
Deaths which occurred, within the treatment phase of the study, or within 30 days after 
discontinuation of the treatment phase of the study will be summarized and listed.
Laboratory data
Laboratory values analyzed using the CTCAE grades version 4.03. Grade 0 will be assigned 
for all non-missing values not graded as 1 or higher. Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
The following summaries will be generated separately for hematology and clinical chemistry: 

Summary statistics for change from baseline for the parameters will be presented;

Number and percentage of patients with laboratory abnormalities, by parameter and 
worst post-baseline CTCAE grade. Each patient will be counted only for the worst grade 
observed post-baseline, regardless of the baseline status; 

Shift tables using CTCAE grades 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.
Newly observed or worsened laboratory abnormalities with grade 3 or 4 will be presented 
separately. Any laboratory toxicity will be defined as being newly occurring or worsening grade 
3/4 if:

patients have baseline result missing or a grade 0, 1 or 2 and then develop grade ≥ 3, or

patients have baseline result of a grade 3 and then develop grade 4.
Summary statistics will be presented for urinalysis at screening and serum pregnancy test results 
by visit.


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Other safety data
2.8.4.1
European Society of Cardiology (ESC) Risk Score
Calculated ESC Risk score will be summarized descriptively by visit.
2.8.4.2
Smoking Status
Following variables will be summarized for smoking status using safety set:

Subject’s usage status( Never/Current/ Former)

Number of cigarettes smoked everyday

Years as smoker

Estimated amount consumed on average (Pack year(s)) 
2.8.4.3
ECG and cardiac imaging data
The following quantitative variables will be summarized: 

Fridericia (QTcF) corrections (msec), 

maximum heart rate (beats/min), 

PR interval duration (msec), 

QT duration (msec) 

QRS Duration (msec) 
Summary statistics will be presented for ECG variables by visit.
In addition, shift tables comparing baseline ECG interpretation (normal, abnormal, not 
available, total) with the worst on-study interpretation (normal, abnormal, not available, total) 
will be provided.
A listing of all newly occurring or worsening abnormalities will be provided, as well as a by-
subject listing of all quantitative ECG parameters.
2.8.4.4
Vital signs
Following vital signs will be summarized:

Weight (kilogram)

Temperature (Celsius)

Sitting Pulse (Beats/ Min)

Systolic Blood Pressure ( mmHg)

Diastolic Blood Pressure (mm Hg)
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit will be performed. These descriptive summaries will be 


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presented by vital sign and treatment group. Change from baseline will only be summarized 
for patients with both baseline and post-baseline values and will be calculated as:
                        change from baseline = post-baseline value – baseline value 
The number and percentage of patients with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in section 5.3.1
2.8.4.5
ECOG performance status
For ECOG performance status, shift tables will be provided comparing baseline with post-
baseline assessment at end of study.
2.9
Pharmacokinetic endpoints
Not applicable.
2.10
PD and PK/PD analyses
Not applicable.
2.11
Patient-reported outcomes
The following PROs will be summarized using FAS.
EORTC QLQ-C30 in combination with the EORTC Quality of Life Questionnaire 
(QLQ)-CML 24 questionnaire
EORTC QLQ-CML 24 is an internationally developed disease specific health-related quality 
of life (HRQOL) questionnaire for CML patients, together with the EORTC-QLQ C30 
questionnaire. The QLQ-CML 24 has been developed according to the EORTC guidelines 
involving a large sample of patients (655 CML patients in 10 countries). The questionnaire is 
composed of four multi-item scales and two single-item scales. The module consists of 24 items 
assessing symptom burden, impact on daily life and on worry/mood, body image problems, and 
satisfaction with care and social life. The items are measured on four levels: not at all, a little, 
quite a bit and very much. The EORTC QLQ-CML 24 is a supplement to the EORTC-QLQ 
C30 and intended to be used in conjunction (Efficace et al., 2014, Aaronson et al., 1993). 
Mean and standard deviation will be provided for the EORTC QLQ-C30 scales in combination 
with the EORTC QLQ-CML 24 questionnaire
up to the end of study at 
Baseline/Screening(within 7 days prior to study inclusion), and at 3, 6, 12, 18, 24 months. No 
total score is calculated on the EORTC QLQ questionnaire. Each item will be scored as the 
proportion of patients who select each response option.
Descriptive statistics for baseline and change from baseline in EORTC QLQ-C30 and EORTC 
QLQ CML 24 will be provided at each visit. In addition to this, Descriptive statistics for 
baseline and change from baseline will be provided for EORTC QLQ-CML24 scales by 
response to molecular response at each visit
Score procedure for EORTC QLQ-C30 and EORTC QLQ CML 24.
For Mapping item to the EORTC QLQ-C30 and EORTC QLQ CML 24 scale use table 2.11.1 
and 2.11.2 respectively.


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Table 2.11.1: Scoring the QLQ-30 version 3.0
Table 2.11.2: Scoring the QLQ- CML 24
EORTC QLQ CML 24: First four scale (Symptom burden, Impact on worry/mood, Impact on 
daily life and Body image problems) will be considered under Symptom scale/item. Last two 
scale or item (Satisfaction with care and information and Satisfaction with social life) will be 
derived as Function scale. Range for all scale/item will be 3 (4-1); 


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Refer SC manual for more detail explanation.
2.12
Absolute change from baseline will also be provided by visit. 
Biomarkers
Not applicable   


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2.14
Mutational Analysis
A listing will be provided for patients who undergo mutational analysis and assessments are 
recorded “Mutational Analysis – Summary” CRF page.


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2.15
Interim analysis
An interim analysis of baseline and follow-up data is planned after the first 38 patients included 
in the study reach the end of month 6 visit, as of April 2017 in order to evaluate the integrity of 
the collected data. No evaluation of the primary endpoint will be conducted and therefore no 
adjustments with regard to the alpha level will be made. The rational for interim analysis is to 
check the integrity of the data.
The interim analysis will be purely descriptive in nature and include patient characteristics, vital 
signs, Sokal risk score, EUTOS score, ESC risk score, ECOG performance status, hematologic 
and blood chemistry laboratory values, RQ-PCR results, medical history and adverse events. 
These parameters are described in panels DM, ZC, VS, SRS, QSEUT, QSESC, QSECOG, 
LBLGH, B2, B1, MH, FACM, SU, EG, LBLGC, AE and LBLGU. For panel VS, QSESC, 
LBLGH, B2, B1, FACM, SU, EG, LBLGC, AE and LBLGU analysis will be performed for 
initial visit and all sub sequential visits till end of month 6.
3
Sample size calculation
The aim of the current study is to confirm the MR4.5 rates of nilotinib in a broad population 
using the EUTOS MR4.5 (‘European Treatment and Outcome Study for CML’) standardized 
molecular laboratories. 
Therefore, the sample size is based on the precision of estimate computation; i.e. the 95% 
confidence interval of the proportion of patients with MR4.5 at month 24. 
Assuming a MR4.5 rate at 24 months to be 25%, a total of 171 patients will allow for a precision 
of +/- 6.5 %.
4
Change to protocol-specified analyses
 
 
 
 
5
Appendix
5.1
Imputation rules
This section will be used later for drafting CSR Appendix 16.1.9.
Study drug
Not applicable.


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AE date imputation     
5.1.2.1
AE Start Date Imputation 
Imputation is based only on a comparison of the partial AE start date to the treatment start 
date as mentioned in the Table 5.1-2 below.  
1. If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set to 
NULL.
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment.  Therefore:
a.
If the AE year is less than the treatment year and the AE month is missing, the 
imputed AE start date is set to the mid-year point (01JulYYYY).
b. Else if the AE year is less than the treatment year and the AE month is not missing, 
the imputed AE start date is set to the mid-month point (15MONYYYY).
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore:
a.
If the AE year is greater than the treatment year and the AE month is missing, the 
imputed AE start date is set to the year start point (01JanYYYY).
b. Else if the AE year is greater than the treatment year and the AE month is not 
missing, the imputed AE start date is set to the month start point (01MONYYYY).
4. If the AE start date year value is equal to the treatment start date year value:
a.
And the AE month is missing or the AE month is equal to the treatment start 
month, the imputed AE start date is set to one day after treatment start.
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY).
c.
Else if the AE month is greater than the treatment start month, the imputed AE 
start date is set to the start month point (01MONYYYY).
Table 5.1-2: AE date imputation
MON
MON < CFM
MON = CFM
MON > CFM
MISSING
YYYY 
MISSING NULL
NULL
NULL
NULL
Uncertain
Uncertain
Uncertain
Uncertain
YYYY < 
CFY
( D ) = 01JULYYYY
( C )= 15MONYYYY ( C )= 15MONYYYY ( C )= 15MONYYYY
Before Treatment Start Before Treatment Start Before Treatment Start Before Treatment Start
YYYY = 
CFY
(B)= TRTSTD+1
( C )= 15MONYYYY (A)= TRTSTD+1
(A)= 01MONYYYY
Uncertain
Before Treatment Start Uncertain
After Treatment Start


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YYYY > 
CFY
(E)= 01JANYYYY
(A)= 01MONYYYY
(A)= 01MONYYYY
(A)= 01MONYYYY
After Treatment Start After Treatment Start After Treatment Start After Treatment Start 
Before Treatment Start 
Partial indicates date prior to Treatment Start Date
After Treatment Start 
Partial indicates date after Treatment Start Date
Uncertain
Partial insufficient to determine relationship to Treatment Start Date
LEGEND:
(A)
         MAX(01MONYYYY,TRTSTD+1)
(B)
         TRTSTD+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
5.1.2.2
AE End Date Imputation 
Rules for imputing the AE end date:

Rules for imputing the AE end date:

If AE day is missing but year and month are available, then the AE end date is set to 
minimum of (end date of follow-up period (treatment end date + 30 days), last day of 
the month, date of death, cutoff date).

If AE month and day are missing but year is available, then it is set to minimum of 
(end date of follow-up period, Dec-31 of the year, date of death, cutoff date).

If AE year is missing the end date will not be imputed. 

If complete (imputed) AE end date is available and the imputed AE start date is 
greater than the (imputed) AE end date, then imputed AE start date should be set to the 
(imputed) AE end date. If patient has not yet started study treatment, no imputation 
will be done for AE end date.
Concomitant medication date imputation
Concomitant medication (CMD) date imputation uses both a comparison of the partial CMD 
start date to the treatment start date, and the value of the CMDTYP1C flag (1, 2, or 3).  Event 
date comparisons to treatment start date are made based on the year and month values only 
(any day values are ignored) in Table 5.1-3 below.
1. If the CMD start date year value is missing, the date will be imputed based on the 
CMDTYP1C flag value.  If the flag value is 1 or 3, the imputed CMD start date is set to 
one day before the treatment start date.  Else, if the flag value is missing or 2, the imputed 
CMD start date is set to one day after the treatment start date.  (Note that for some legacy 


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data, the CMDTYP1C variable may not exist in the data.  When this happens and the 
CMD start date year value is missing, the imputed date value will be NULL.)
2. If the CMD start date year value is less than the treatment start date year value, the CMD 
started before treatment.  Therefore:
a.
if the CMD year is less than the treatment year and the CMD month is missing, the 
imputed CMD start date is set to the mid-year point (01JulYYYY).
b. Else if the CMD year is less than the treatment year and the CMD month is not 
missing, the imputed CMD start date is set to the mid-month point 
(15MONYYYY).
If the CMD start date year value is greater than the treatment start date year value, the CMD 
started after treatment. Therefore:
a.
If the CMD year is greater than the treatment year and the CMD month is missing, 
the imputed CMD start date is set to the year start point (01JanYYYY).
b. Else if the CMD year is greater than the treatment year and the CMD month is not 
missing, the imputed CMD start date is set to the month start point 
(01MONYYYY).
3. If the CMD start date year value is equal to the treatment start date year value:
a.
and the CMD month is missing or the CMD month is equal to the treatment start 
month,
i.
If the flag value is 1 or 3, the imputed CMD start date is set to one day 
before the treatment start date.
ii.
Else, if the flag value is missing or 2, the imputed CMD start date is set to 
one day after the treatment start date.
a.
Else if the CMD month is less than the treatment start month, the imputed CMD 
start date is set to the mid-month point (15MONYYYY).
b. Else if the CMD month is greater than the treatment start month, the imputed 
CMD start date is set to the start month point (01MONYYYY).
Table 5.1-3:  CMD date imputation
MON MISSING
MON < CFM
MON = CFM
MON > CFM
YYYY 
MISSING (F)
(F)
(F)
(F)
Uncertain
Uncertain
Uncertain
Uncertain
YYYY < 
CFY
(D)=01JULYYYY
(C)=15MONYY
(C)=15MONYY
(C)=15MONYY
Before Treatment Start
Before Treatment Start Before Treatment Start
Before Treatment Start
YYYY = 
CFY
(B)
(C)=15MONYY
(B)
(A)=01MONYYYY
Uncertain
Before Treatment Start Uncertain
After Treatment Start
YYYY > 
CFY
(E)= 01JANYYYY
(A)=01MONYYYY
(A)=01MONYYYY
(A)=01MONYYYY
After Treatment Start
After Treatment Start
After Treatment Start
After Treatment Start


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Before Treatment Start 
Partial indicates date prior to Treatment Start Date
After Treatment Start 
Partial indicates date after Treatment Start Date
Uncertain
Partial insufficient to determine relationship to Treatment Start Date
         LEGEND:
(A)
MAX(01MONYYYY,TRTSTD+1)
(B)
IF CMDTYP1C IN (1,3) THEN TRTSTD-1
     ELSE IF CMDTYP1C in(. , 2) THEN TRTSTD+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
(F)
IF CMDTYP1C IN (1,3) THEN TRTSTD-1
    ELSE IF CMDTYP1C in  (. , 2) THEN TRTSTD+1
5.1.3.1
Prior therapies date imputation
Not applicable.
5.1.3.2
Post therapies date imputation
Not applicable.
5.1.3.3
Other imputations
Not applicable.
5.2
AEs coding/grading
The verbatim term recorded on CRF will be identified as adverse event and will be coded by 
primary system organ class and preferred term using MedDRA version 18.1 and above.


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5.3
Laboratory parameters derivations
Criteria for notable vital sign abnormalities
Very high risk 
Patient
High risk Patient
Moderate Patient
Low risk patient
Normal 
sbp
<140
<140
<140
<140
<160
If ( all “ESC Risk 
related medical 
history/conditions”) 
are marked as  “NO”   
<160
If ( all “ESC Risk 
related medical 
history/conditions”) 
are marked as  “NO”   
Normal 
DBP
<90
<90
<90
<90
<85
if (Diabetes mellitus 
(type 1 or type 2) 
but without CV risk 
factors or target 
organ damage ,
Diabetes mellitus 
(type 1 or type 2) 
with one or more CV 
risk factors and/or 
target organ 
damage (such as
microalbuminuria: 
30-300 mg/24 h)) 
are “YES”
<85
if (Diabetes mellitus 
(type 1 or type 2) 
but without CV risk 
factors or target 
organ damage ,
Diabetes mellitus 
(type 1 or type 2) 
with one or more CV 
risk factors and/or 
target organ 
damage (such as
microalbuminuria: 
30-300 mg/24 h)) 
are “YES”
Normal 
ldl
<70mg/dl / 
<1.8mmol/l
<100mg/dl / 
<2.6mmol/l
<115mg/dl / 
<3.0mmol/l
<115mg/dl / 
<3.0mmol/l
Normal 
HbA1C
<7
<7
<7
<7
<8
(if very old age (age 
>=65))
<8
(if very old age (age 
>=65))
<8
(if very old age (age 
>=65))
<8
(if very old age (age 
>=65))
5.4
Statistical models
Primary analysis
5.4.1.1
Clopper-Pearson CI for response rate
The 100 × (1 – alpha level) % Pearson-Clopper CI for the proportion of responders (binary 
outcome = 1 or “Yes”), for a given treatment group X, is obtained from the following:
proc freq data = dataset;
where treatment group = X;


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table binary event / binomial(exact level = ”Yes”) alpha = alpha level;
When there are no responders for treatment group X, SAS does not produce a CI by default. To
obtain a CI in this situation, PROC FREQ is used as specified above except changing 
level=”No”.
From the results of this modified procedure, the values in percent of the LCL and UCL of a 0% 
response rate are calculated as follows:

LCLLEVEL=”Yes” (%) = 100% - UCLLEVEL=”No” (%)

UCLLEVEL=”Yes” (%) = 100% - LCLLEVEL=”No” (%)
Secondary analysis
5.4.2.1
Log-rank test
The log-rank test will be conducted for selected time to event analyses. The p-value for this test 
is obtained from the following:
proc lifetest data = dataset;
where treatment group = X or Y;
strata <group> / group = treatment group;
time time to event * censor(1);
5.4.2.3
Kaplan-Meier CI for estimated median time to event and estimated rate
The 100 × (1 – alpha level) % CI for the Kaplan-Meier estimated median time to event and 
estimated rate of an event at different time points, using the linear transformation, is obtained 
from the following:
proc lifetest data = dataset alpha = estimated rate alpha level alphaqt
= estimated median alpha level conftype = linear;
where treatment group = X;
time time to event * censor(1);
Note that all these codes are for reference purpose.


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5.5
Rule of exclusion criteria of analysis sets 
Table 5.5.1
Protocol deviations that cause subjects to be excluded
Deviation 
Id
Deviation description
Exclusion from 
analyses
Severity 
code
Major or 
Minor
INCL01
Subject is less than 18 years or age 
is missing
Defined 
individually 
Refer 
DRM 
minutes
To be 
categorized 
individually 
case by 
case
INCL02
Subject is not having ECOG as 0,1 
or 2 
Include in 
everything
0
Minor
INCL03
Patients within 6 months of 
diagnosis of CML in chronic 
phase with cytogenetic 
confirmation of Ph positive 
[t(9,22) translocation]
Include in 
everything
0
Minor
INCL04
Subject does not meet the criteria 
defined for Chronic phase CML
Defined 
individually 
Refer 
DRM 
minutes
To be 
categorized 
individually 
case by 
case
INCL05
Patients must be previously 
untreated for CML with the 
exception of 6 months treatment 
with hydroxyurea and a maximum 
of 6 weeks treatment with 
imatinib.
Exclude from 
PPS
4
Major
INCL06
Adequate end organ function as 
defined in protocol
Include in 
everything
0
Minor
INCL07
Serum level to be greater than or 
equal to lower limit of normal or 
corrected to normal by 
supplements for potassium, 
magnesium, total calcium  or 
phosphorus prior to first dose of 
study medication
Include in 
everything
0
Minor
INCL08
Subject did not provided Informed 
Consent prior to any study related 
procedures
Include in 
everything
0
Minor
EXCL01
Contraindication to excipients in 
study medication
Include in 
everything
0
Minor
EXCL02
Known impaired cardiac function 
as per protocol
Include in 
everything
0
Minor


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EXCL03
History of acute (within 1 year of 
starting study medication) or 
chronic pancreatitis
Include in 
everything
0
Minor
EXCL04
Severe and/or uncontrolled 
concurrent medical conditions that 
in the opinion of the investigator 
could cause unacceptable safety 
risks or compromise compliance 
with the protocol
Include in 
everything
0
Minor
EXCL05
Impairment of gastrointestinal 
(GI) function or GI disease that 
may significantly alter the 
absorption of study drug
Exclude from 
PPS
4
Major
EXCL06
History of significant congenital 
or acquired bleeding disorder 
unrelated to cancer
Include in 
everything
0
Minor
EXCL07
Patients on strong CYP3A4 
inhibitors and or inducers or 
medications with potential to 
prolong QT interval not 
discontinued before start of study 
drug
Include in 
everything
0
Minor
EXCL08
Patients who have not recovered 
from prior surgery
Include in 
everything
0
Minor
EXCL09
Pregnant, Breast feeding, 
Childbearing potential without a -
ve pregnancy test prior to baseline 
and female of childbearing 
potential unwilling to use 
contraceptive precautions 
throughout the trial
Include in 
everything
0
Minor
EXCL10
Patients with history of another 
primary malignancy that is 
currently clinically significant or 
currently requires active 
intervention with exception of 
previous or concomitant basal cell 
skin cancer
Include in 
everything
0
Minor
EXCL11
Treatment with other 
investigational agents within 30 
days of Day 1
Defined 
individually 
Refer 
DRM 
minutes
To be 
categorized 
individually 
case by 
case


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EXCL12
Patients not able to understand and 
to comply with study instructions 
and requirements
Include in 
everything
0
Minor
TRT01
Subject should start study drug 
with a dose of 300 mg BID
Defined 
individually 
Refer 
DRM 
minutes
To be 
categorized 
individually 
case by 
case
TRT02
Subject not compliant with 
prescribed study drug dose and 
regimen
Defined 
individually 
Refer 
DRM 
minutes
To be 
categorized 
individually 
case by 
case
TRT03
Subject took total daily dose of 
Nilotinib less than 450 mg
Defined 
individually 
Refer 
DRM 
minutes
To be 
categorized 
individually 
case by 
case
TRT04
Subject took dose of 
Nilotinib=>450 mg and regimen 2 
times per dayfor more than 28 
days or Subject took dose of 
Nilotinib>600 mg and regimen 
1times per day for more than 28 
days
Defined 
individually 
Refer 
DRM 
minutes
To be 
categorized 
individually 
case by 
case
TRT06
Drug supply method changed due 
to COVID-19
Include in 
everything
0
Minor
TRT07
Treatment not given due to 
COVID-19
Include in 
everything
0
Minor
TRT08
Subject took dose of Nilotinib 
greater than 600mg daily dose for 
more than 28 days
Defined 
individually 
Refer 
DRM 
minutes
To be 
categorized 
individually 
case by 
case
OTH01
Hepatitis assessment not 
performed for the subject
Include in 
everything
0
Minor
OTH02
Subject enrolled in the study 
without completing key 
assessments per protocol 
eligibility criteria
Include in 
everything
0
Minor
OTH03 
Subject completed Screening 
assessments prior to signing ICF
Include in 
everything
0
Minor
OTH04
Missed Visit due to COVID-19
Include in 
everything
0
Minor


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OTH05
Assessment related to assessing 
Inclusion criteria and Exclusion 
criteria not performed
Include in 
everything
0
Minor
OTH06
Visit not done at Study site due to 
COVID-19
Include in 
everything
0
Minor
OTH07
Assessment / procedure changed 
due to COVID-19
Include in 
everything
0
Minor
OTH08
Discontinuation due to COVID-19
Include in 
everything
0
Minor
COMD01
Use of anticancer agents including 
chemotherapy and biologic agents
Defined 
individually 
Refer 
DRM 
minutes
To be 
categorized 
individually 
case by 
case
COMD02
Subject took concomitant 
medication excluded as per 
protocol during study treatment
Defined 
individually 
Refer 
DRM 
minutes
To be 
categorized 
individually 
case by 
case
Table 5.5.2
Analysis set exclusions based on population codes
Analysis set 
Population codes that cause a subject to be 
excluded
RAN 
NA
SAF 
2, 3
FAS
1, 3
PPS
4
Table 5.5.3
Population code text
Population Code
Population code text
0
INCLUDE IN EVERYTHING
1
EXCLUDE FROM FULL ANALYSIS SET (FAS)
2
EXCLUDE FROM SAFETY SET (SAF)
3
EXCLUDE FROM FAS AND SAF
4
EXCLUDE FROM PPS
Unless otherwise stated, summary tables, figures and listings will be on all subjects included in 
the analysis set under consideration.
6
Reference
1. Study protocol: Oncology study protocol CAMN107ADE20.