A Prospective, Randomized, Open Label, Two Arm Phase III Study to Evaluate Treatment Free Remission (TFR) Rate in Patients With Philadelphia-positive CML After Two Different Durations of Consolidation Treatment With Nilotinib 300mg BID.
Phase: PHASE3
Conditions: Philadelphia Chromosome Positive (PH+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)
Sponsor: Novartis Pharmaceuticals



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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 4 (01-Jun-2016) ............................................................................................11
Summary of previous amendments ...................................................................................12
Protocol summary..............................................................................................................19
1
Background........................................................................................................................25
1.1
Overview of disease pathogenesis, epidemiology and current treatments ............25
1.2
Introduction to investigational treatment(s) and other study treatment(s).............26
1.2.1
Overview of nilotinib............................................................................26
2
Rationale............................................................................................................................30
2.1
Study rationale and purpose...................................................................................30
2.2
Rationale for the study design ...............................................................................31
2.3
Rationale for dose and regimen selection..............................................................32
2.4
Rationale for choice of combination drugs............................................................32
2.5
Rationale for choice of comparators drug .............................................................33
2.6
Rationale for optional Stem cells ENESTPath substudy.......................................33
2.7
Rationale for ‘CML patient’s voice’ Italian Substudy ..........................................33
3
Objectives and endpoints...................................................................................................34
4
Study design ......................................................................................................................39
4.1
Description of study design ...................................................................................39
4.1.1
Description of optional Stem cells ENESTPath substudy ....................40
4.1.2
Description of ‘CML patient’s voice’ Italian substudy.........................41
4.2
Timing of interim analyses and design adaptations...............................................41
4.3
Definition of end of the study................................................................................42
4.4
Early study termination..........................................................................................42
5
Population..........................................................................................................................43
5.1
Patient population..................................................................................................43
5.2
Inclusion criteria ....................................................................................................43
5.3
Exclusion criteria...................................................................................................45
6
Treatment...........................................................................................................................47
6.1
Investigational treatment, other study treatment, supportive treatment ................47
6.1.1
Dosing regimen.....................................................................................47

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6.1.2
Ancillary treatments..............................................................................47
6.1.3
Rescue medication ................................................................................47
6.1.4
Guidelines for continuation of treatment ..............................................48
6.1.5
Treatment duration................................................................................48
6.2
Dose escalation guidelines.....................................................................................48
6.3
Dose modifications................................................................................................49
6.3.1
Dose modification and dose delay ........................................................49
6.3.2
Dose-reduction guidelines for study drug-related non-hematologic 
toxicity...................................................................................................49
6.3.3
Dose-reduction guidelines for study drug-related hematologic 
toxicity...................................................................................................54
6.3.4
Suggested management of selected adverse events ..............................55
6.3.5
Guidelines for dose-re-escalation..........................................................57
6.4
Concomitant medications ......................................................................................57
6.4.1
Permitted concomitant therapy .............................................................57
6.4.2
Permitted concomitant therapy requiring caution and/or action...........58
6.4.3
Prohibited concomitant therapy ............................................................58
6.5
Patient numbering, treatment assignment and randomization...............................59
6.5.1
Patient numbering .................................................................................59
6.5.2
Treatment assignment and randomization ............................................59
6.5.3
Treatment blinding................................................................................59
6.6
Study drug supply..................................................................................................60
6.6.1
Study drug preparation and dispensation..............................................60
6.6.2
Study drug packaging and labeling.......................................................60
6.6.3
Drug supply and storage........................................................................60
6.6.4
Study drug compliance and accountability ...........................................60
6.6.5
Disposal and destruction .......................................................................61
7
Visit schedule and assessments .........................................................................................61
7.1
Study flow and visit schedule................................................................................61
7.1.1
Pre-screening assessment......................................................................78
7.1.2
Screening...............................................................................................78
7.1.3
Run-in-period........................................................................................80
7.1.4
Induction/consolidation phase...............................................................80
7.1.5
Randomization/Eligibility visit.............................................................81
7.1.6
Treatment-free remission phase............................................................83
7.1.7
Nilotinib re-treatment phase (if applicable) ..........................................84

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7.1.8
End of Phase visit, including premature withdrawal and study 
discontinuation visit ..............................................................................84
7.1.9
Follow-up period...................................................................................86
7.2
Assessment types...................................................................................................87
7.2.1
Efficacy assessments.............................................................................87
7.2.2
Safety and tolerability assessments.......................................................88
7.2.3
Pharmacokinetics ..................................................................................93
93
7.2.5
Other assessments .................................................................................93
8
Safety monitoring and reporting........................................................................................93
8.1
Adverse events.......................................................................................................93
8.1.1
Definitions and reporting ......................................................................93
8.1.2
Laboratory test abnormalities................................................................95
8.1.3
Adverse events of special interest.........................................................95
8.2
Serious adverse events...........................................................................................96
8.2.1
Definitions.............................................................................................96
8.2.2
Reporting...............................................................................................96
8.3
Emergency unblinding of treatment assignment ...................................................97
8.4
Pregnancies............................................................................................................97
8.5
Warnings and precautions......................................................................................97
8.6
Data Monitoring Committee (DMC).....................................................................97
8.7
Scientific Study Management Committee.............................................................98
9
Data collection and management.......................................................................................98
9.1
Data confidentiality ...............................................................................................98
9.2
Site monitoring ......................................................................................................99
9.3
Data collection.....................................................................................................100
9.4
Database management and quality control..........................................................100
10 Statistical methods and data analysis ..............................................................................100
10.1
Analysis sets ........................................................................................................100
10.1.1
Full Analysis Set .................................................................................100
10.1.2
Patients entering the TFR phase..........................................................100
10.1.3
Safety Set ............................................................................................101
10.1.4
Per-Protocol Set ..................................................................................101
10.1.5
Other analysis sets...............................................................................101
10.2
Patient demographics/other screening characteristics .........................................101
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................101

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10.4
Primary objective.................................................................................................101
10.4.1
Variable...............................................................................................101
10.4.2
Statistical hypothesis, model, and method of analysis........................102
10.4.3
Handling of missing values/censoring/discontinuations.....................102
10.4.4
Supportive analyses.............................................................................102
10.5
Secondary objectives ...........................................................................................102
10.5.1
Key secondary objective(s).................................................................102
10.5.2
Other secondary efficacy objectives ...................................................104
10.5.3
Safety objectives .................................................................................105
10.6
Interim analysis....................................................................................................106
10.7
Sample size calculation........................................................................................106
10.8
Power for analysis of key secondary variables....................................................107
11 Ethical considerations and administrative procedures ....................................................107
11.1
Regulatory and ethical compliance......................................................................107
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................107
11.3
Informed consent procedures...............................................................................107
11.4
Discontinuation of the study................................................................................108
11.5
Publication of study protocol and results.............................................................108
11.6
Study documentation, record keeping, and retention of documents....................109
11.7
Confidentiality of study documents and patient records .....................................109
11.8
Audits and inspections.........................................................................................110
11.9
Financial disclosures............................................................................................110
12 Protocol adherence ..........................................................................................................110
12.1
Amendments to the protocol................................................................................110
13 References (available upon request)................................................................................111
14 Appendices ......................................................................................................................114
14.1
Appendix 1 List of CYP3A4 inducers and inhibitors..........................................114
14.1.1
List of medications metabolized by CYP3A4, strong, moderate and 
weak inhibitors of CYP3A4 to be used with caution..........................114
14.2
Edinburgh Claudication Questionnaire................................................................116

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List of figures
Figure 4-1
ENESTPath study design......................................................................39
Figure 4-2
Optional Stem cells ENESTPath substudy design................................41
List of tables
Table 3-1
Objectives and related endpoints ..........................................................35
Table 6-1
Dose and treatment schedule.................................................................47
Table 6-2
Summary of dose reduction guidelines for study drug-related 
clinically significant non-hematologic toxicity.....................................51
Table 6-3
Summary of dose reduction guidelines for study drug-related 
hematologic toxicity..............................................................................55
Table 6-4
Preparation and dispensing ...................................................................60
Table 6-5
Packaging and labeling .........................................................................60
Table 7-1
Visit evaluation schedule 1: screening and induction/consolidation 
phase......................................................................................................62
Table 7-2
Visit evaluation schedule 2: Nilotinib TFR phase (Arm 1) ..................71
Table 7-3
Visit evaluation schedule 3: Nilotinib TFR phase (Arm 2) ..................73
Table 7-4
Visit evaluation schedule 4: Nilotinib re-treatment phase (if 
applicable).............................................................................................76
Table 7-5
ECOG performance criteria ..................................................................90

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List of abbreviations
ABL
Abelson leukemia virus
AE
Adverse event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute neutrophil count
Anti HBc
Hepatitis B Core Antibody
AP
Accelerated phase
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area under curve
BC
Blast crisis
BCR
Break point cluster region
BCR-ABL
BCR-ABL oncoprotein product of BCR-ABL fusion gene
BID
bis in diem/twice a day
CBA
Chromosome banding analysis
CCyR
Complete cytogenetic response
CgR
Cytogenetic response
Cmax
Maximum plasma concentration
CML
Chronic myeloid leukemia
CP
Chronic phase
CRO
Contract research organization
CSR
Clinical study report
CTCAE
NCI Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
CVA
Cerebrovascular accident
CYP
Cytochrome P450
DDI
Drug-drug interaction
DMC
Data Monitoring Committee
DS&E
Drug Safety and Epidemiology
EC
European Commission
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
EDC
Electronic data capture
EOP
End of phase
EOS
End of study
EUTOS
European Treatment Outcome Study
FACS
Fluorescence activated cell sorting
FAS
Full Analysis Set
FDA
Food and Drug Administration (USA)
FISH
Fluorescent in-situ hybridization
GCP
Good Clinical Practice
GI
Gastrointestinal
GP
General practitioner
HBc Ab
Hepatitis B Core Antibody
HBs Ag
Hepatitis B Surface Antigen
IB
Investigator Brochure

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ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFN
Interferon
IHD
Ischemic heart disease
IN
Investigator Notification
INR
International normalized ratio
IRB
Institutional Review Board
IS
International scale
IVRS
Interactive voice response system
KM
Kaplan-Meier
LC-MS/MS
Liquid chromatography-tandem mass spectrometry
LLN
Lower limit of normal
LLOQ
Lower limit of quantification
LSC
Leukemic stem cell(s)
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MMR
Major molecular response
MR
Molecular response
MR4.0
4.0 log reduction on international scale (IS)
MR4.5
4.5 log reduction on international scale (IS)
OS
Overall survival
PAOD
Peripheral artery occlusive disease
PCR
Polymerase chain reaction
PD
Pharmacodynamics
PFS
Progression free survival
Ph
Philadelphia chromosome
Ph+ CML
Philadelphia chromosome-positive chronic myeloid leukemia
PHI
Protected health information
PI-3 kinase
Phosphatidylinositol-3-kinases
PK
Pharmacokinetic
PPS
Per-Protocol Set
QD
Once a day
RDC
Remote data capture
REB
Research Ethics Board
RQ-PCR
Real-time quantitative polymerase chain reaction
RT-PCR
Reverse transcriptase polymerase chain reaction
RU
Resource utilization
SAE
Serious adverse event
SD
Standard deviation
SS
Safety Set
SSMC
Scientific Study Management Committee
STAT5
Signal transducer and activator of transcription 5
t1/2
Half-life
TFR
Treatment-free remission
TFS
Treatment-free survival
TKI
Tyrosine kinase inhibitor

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ULN
Upper limit of normal
VAP
Validation and Planning
WBC
White blood cell
WOCBP
Women of childbearing potential

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Glossary of terms
CHR
Complete hematologic response = normalization of hematopoiesis
CCyR
Complete cytogenetic response = 0% Ph+ metaphases in a review of a minimum of 20 
metaphases in the bone marrow
MMR
Major Molecular Response, MMR is defined as a ≥3.0 log reduction in BCR-ABL transcripts 
compared to the standardized baseline or ≤ 0.1% BCR-ABL according to the international 
scale as measured by RQ-PCR
MR4.0
Defined as either (i) detectable disease ≤0.01% BCR-ABL IS; or (ii) undetectable disease in 
cDNA with ≥10,000 ABL transcripts (numbers of ABL transcripts in the same volume of 
cDNA used to test for BCR-ABL)
MR4.5
Defined as either (i) detectable disease ≤0.0032% BCR-ABL IS; or (ii) undetectable disease 
within cDNA with ≥32,000 ABL transcripts (numbers of ABL transcripts in the same volume 
of cDNA used to test for BCR-ABL)
MR 5
Defined as either (i) BCR-ABL (IS) ≤0.001%; or (ii) undetectable disease with Total ABL 
≥100.000
Assessment
A procedure used to generate data required by the study
Control drug
A study treatment used as a comparator to reduce assessment bias, preserve blinding of 
investigational drug, assess internal study validity, and/or evaluate comparative effects of the 
investigational drug
Enrollment
Point/time of patient entry into the study; the point at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational 
drug
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational new drug”
Investigational 
treatment
Drug whose properties are being 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
Medication 
number
A unique identifier on the label of each study treatment package which is linked to one of the 
treatment groups of a study
Other study 
treatment
Any drug administered to the patient as part of the required study procedures that was not 
included in the investigational treatment
Subject Number 
(Subject No.)
A unique identifying number assigned to each patient/healthy volunteer who enrolls in the 
study
Period
A subdivision of the study timeline; divides stages into smaller functional segments, such as 
screening, baseline, titration, washout, etc.
Premature patient 
withdrawal
Point/time when the patient exits from the study prior to the planned completion of all study 
treatment administration and/or assessments; at this time all study treatment administration 
is discontinued and no further assessments are planned, unless the patient will be followed 
for progression and/or survival
Randomization 
number
A unique treatment identification code assigned to each randomized patient, corresponding 
to a specific treatment arm assignment
Stage related to 
study timeline
A major subdivision of the study timeline; begins and ends with major study milestones such 
as enrollment, randomization, completion of treatment, etc.
Stop study 
participation
Point/time at which the patient came in for a final evaluation visit
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.

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Amendment 4 (01-Jun-2016)
Amendment rationale
The recruitment of this study has been completed (LPFV 30-Apr-2015) and 621 patients have 
been enrolled.
The primary purpose for the 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 hepatitis 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 protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

List of abbreviations updated.

Protocol Summary was updated to add serology in the panel of Safety assessments.

Section 6.3.4 Hepatitis B reactivation was added to provide information on next steps for 
patients tested positive for hepatitis B virus.

Section 7-1 Hepatitis B testing was added to the visit schedule to be performed once and 
only once at the next possible visit when patient is on treatment or before treatment is re-
initiated.

Section 7.2.2.4.5 Hepatitis B testing was added to provide information on hepatitis B 
testing.

Section 8.6 Data Monitoring Committee (DMC) regular and specific reports have been 
updated

Section 10.6 Interim analysis minor update

All other sections, to correct minor inconsistencies and typos
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.

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Summary of previous amendments
Amendment 3
Amendment Rationale
The primary purpose for this substantial amendment is:

To update the protocol with the latest changes in the Investigator Brochure Edition 11.

To update the protocol including the ‘CML patient’s voice’ Italian substudy to evaluate 
the emotional aspects in patients participating to a nilotinib Treatment-free remission 
(TFR) trial. This substudy aims to examine patients’ psycho-emotional characteristics, 
quality of life and experiences of being involved in CAMN107AIC05 trial and its 
discontinuation using a qualitative-quantitative mixed method. The ‘CML patient’s voice’
Italian substudy will be conducted in Italy only. It will be coordinated by the Chair of 
Clinical Psychology, San Paolo Hospital, University of Milan. Further details can be 
found in the Post Text Supplement 1.
Changes to the protocol

Section 1.2.1.1: Updated with the mouse carcinogenicity study

Section 2.7: Updated with the rationale of the ‘CML patient’s voice’ Italian substudy

Section 4.1.2: Updated with the Italian ‘CML patient’s voice’ Italian substudy

Section 5.4 and Section 5.5: Updated with the inclusion and exclusion criteria for the 
‘CML patient’s voice’ Italian substudy

Sections 6.4.2 and 6.4.3 are updated with the information on permitted concomitant 
therapy (CYP3A4 and Antacid drugs)

Section 11.3: ICF procedure updated with safety data from pre-clinical study

All other sections: minor typos corrections

Addition of references to support rationale for ‘CML patient’s voice’ Italian substudy

IRB/IECA copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.

Appendix 14.1.1 (List of medications metabolized by CYP3A4, strong, moderate and 
weak inhibitors of CYP3A4 to be used with caution) is updated.

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Amendment 2
Amendment rationale
The primary purpose for this substantial amendment is:

To modify the study sample size based on new data from the ENESTcmr and STIM 
studies and a number of recently published clinical trials (Hughes TP, et al. Blood. 
2014;124: 729-36; Mahon FX, et al. Blood. 124(21);151; Rea D, et al. Blood. 
2014;124(21) [abstract 811])

To amend the secondary objectives of the study and related endpoints

To incorporate the safety recommendations provided by the DMC on patients with severe 
cardiovascular ischemic events experienced before entering the study or while on study
i.e.:

Patients with prior PAOD, or severe ischemic cardiovascular disease for whom in the 
opinion of the investigator other treatments might have a more favorable benefit/risk 
profile will be excluded from the study

Patients who experience severe Ischemic vascular or cardiovascular events have to be 
discontinued from the study whenever in the opinion of the investigator the AE is 
related to the study drug and other treatments could have a more favorable benefit/risk 
profile

To update the efficacy and safety data of nilotinib according to the Investigator’s Brochure 
Edition 10 (April 2014)

To implement requests of Health Authorities and Ethics Committees/Institutional Review 
Boards (ECs/IRBs) raised during review of the protocol version number 01

To update the visit numbering according to the new eCRF design

To correct minor inconsistencies and typos in the protocol
Changes to the protocol

Table 3-1: Update of secondary objectives and related endpoints

Section 4.1: Update of sample size

Figure 4-1: update of visit numbering

Section 4.1.1: Addition of time point for determination of PH+ stem cells in bone marrow
for patients enrolled in the optional Stem cells ENESTath substudy

Section 4.2: Addition of information about publication of results

Section 5.2: Corrections of inclusion criteria numbering and other minor corrections

Section 5.3: Update of exclusion criteria relating to history PAOD or severe ischemic 
cardiovascular disease; deletion of refusal to give consent for the optional Stem cells 
ENESTath substudy from exclusion criteria for main study

Table 6-2: Update QTc criteria for study discontinuation; update of action to be taken for 
grade 3 or 4 ischemic vascular or cardiovascular events; update of action to be taken for 
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
Table 7-1, Table 7-2, Table 7-3, and Table 7-4: Update of assessments schedule and 
numbering

Section 7.1.4: Clarification and update of assessments to be done during the induction 
/consolidation phase

Section 7.1.5: Clarification on procedures to be done at the randomization and at 
eligibility visits

Section 7.1.6: Update of action patient to take with remaining study drug

Section 7.1.7: Clarification of procedures to be done during the re-treatment phase

Section 7.1.8: Update of EOP visits definition

Section 7.1.8.1: Update of criteria for premature patient withdrawal

Section 7.2.1.1: Update of methodology to be used to assess molecular response according 
to the latest EUTOS working guidelines

Section 7.2.1.3: Clarification of when CgR assessment should be performed

Section 7.2.2.4.4: Update of when urine analysis is to be performed

Section 7.2.2.7: Clarification of when the questionnaire is to be administered and action to 
be taken if questionnaire results are positive

Section 8.1.1: Update of when adverse event monitoring is to be done

Section 8.6: Added information about timing of DMC meetings

Section 10.4.2: Amendment of statistical hypotheses based on new assumptions

Section 10.4.3: Update of method to handle missing values

Section 10.5.1: Amendment of the secondary endpoints and corresponding statistical 
methods

Section 10.5.2: Amendment of the statistical methods to be applied for the Stem cells 
ENESTPath substudy.

Section 10.7: Amendment of assumptions used for sample size calculation for main study 
and Stem cells substudy

All other sections: minor typos corrections

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Amendment 1
Amendment rationale
The primary purpose for this substantial amendment is:

Inclusion of the optional Stem cells ENESTpath substudy “Leukemic stem cells 
quantification in patients with chronic myeloid leukemia included in the ENESTpath trial”;
the purpose of this substudy is to evaluate the importance of leukemic stem cells (LSC) in 
the long-term maintenance of the disease and their role in the relapse of patients during the 
TFR phase. Participation in this “stem cells" substudy is optional and requires separate 
specific consent. Patients not wishing to participate in the stem cells substudy may still 
participate in the main (ENESTpath) study

To update the efficacy and safety data of nilotinib according to the Investigator’s Brochure 
Edition 9 (June 2013), focusing on the 48-month update of the CAMN107A2303 study in 
newly diagnosed CML-CP patients

To include cholesterol testing in the assessment schedule. Elevations in total serum 
cholesterol and low density lipoprotein cholesterol have been observed very commonly in 
patients treated with nilotinib or imatinib. Most of the cholesterol elevations were grade 1 
(> ULN - 300 mg/dL; > ULN - 7.75 mmol/L) or 2 (> 300 - 400 mg/dL; > 7.75 - 10.34 
mmol/L), and some elevations were present prior to initiation of CML therapy. Lipid 
profiles, including total cholesterol, LDL-C and HDL-C will be assessed at baseline and
during the conduct of this study. If test results warrant intervention, investigators should 
follow their local standards of practice or treatment guidelines, which may recommend 
treatment even for grade 1 cholesterol elevation. Before prescribing a lipid-lowering 
medication, the possibility of drug-drug interactions should be considered as some HMG-
CoA reductase inhibitors are also metabolized via the CYP3A4 pathway

To include glucose testing in the assessment schedule. Elevations of blood glucose levels 
have been observed in CML patients treated with nilotinib. Blood glucose will be assessed 
at baseline and during the conduct of this study. If test results warrant intervention, 
investigators should follow their local standards of practice and treatment guidelines

To provide a harmonization on dose reductions guidelines across Novartis-sponsored 
Tasigna study protocols

To incorporate guidance for the management of:

Serum cholesterol increases

Blood glucose increases

Other cardiac risk factors

Ischemic vascular or ischemic cardiovascular events occurring in patients treated with 
nilotinib

To define ischemic vascular and ischemic cardiovascular events as adverse events of 
special interest, and their reporting

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
To implement modifications as requested from different Health Authorities and Ethics
Committees/Institutional Review Boards (ECs/IRBs) during review of the original
protocol

To address feedback from investigators received during the study startup

To correct minor inconsistencies and typos in the protocol
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol, and include the following:

Section 1.2.1.2.1: Addition of a session on “Ischemic Vascular and Ischemic 
Cardiovascular Events Reported for CAMN107A2303 (ENESTnd Study)”

Section 2.6: New section providing rationale for optional Stem cells ENESTpath substudy 
included in Protocol Amendment 1

Section 3: Addition of objectives, endpoints, and analyses for optional Stem cells 
ENESTpath substudy included in Protocol Amendment 1

Section 4.1: Addition of visit/month information to Figure 4-1 to improve clarity

Section 4.1.1: Addition of new subsection with study description for the optional Stem 
cells ENESTpath substudy included in Protocol Amendment 1

Section 4.4: Changes to early study termination criteria

Section 5.1: Update of screening criteria for patient population, and addition of details of 
patient population for the optional Stem cells ENESTpath substudy

Section 5.2: Update of definition of chronic phase CML, update of inclusion criterion for 
patients in treatment with imatinib for a minimum of 24 calendar months (even not 
continuously) and in imatinib treatment at time of enrolment, and addition of requirement 
for separate specific informed consent for the optional Stem cells ENESTpath substudy

Section 5.3: Addition/amendment of the following exclusion criteria:

Definition of atypical BCR-ABL transcripts

Previous anticancer agents for CML except for imatinib, and/or for cytoreduction 
after CML diagnosis, and/or interferon treatment whose duration was shorter than
1 year

Known impaired cardiac function, including any of the following:

Inability to determine the QT interval on electrocardiogram [ECG]

Complete left bundle branch block

Right bundle branch block plus left anterior or posterior hemiblock

Use of a ventricular-paced pacemaker

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)

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
QTc > 450 msec on the average of three serial baseline ECGs (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 1 year prior to 
study entry

History of unstable angina during the last 12 months

Other clinically significant heart disease (e.g. congestive heart failure or 
uncontrolled hypertension)

Severe and/or uncontrolled concurrent medical disease that in the opinion of the 
investigator could cause unacceptable safety risks or compromise compliance with the 
protocol (e.g. atherothrombotic events [such as ischemic heart disease, peripheral 
arterial occlusive disease, symptomatic carotid stenosis/cerebrovascular accident 
(CVA)], uncontrolled diabetes, active or uncontrolled infection, uncontrolled severe 
hypertension, or uncontrolled severe dyslipidemia). If appropriate measures (e.g. diet, 
exercise, appropriate therapy) are taken to control blood glucose, or cholesterol LDL 
levels, or hypertension, the patient can be re-screened for the study

Unwillingness to use specified highly efficient forms of contraception in women of
childbearing potential (WOCBP)

Refusal to provide separate specific consent for the optional Stem cells ENESTpath 
substudy included in Protocol Amendment 1 (eligibility for the main ENESTpath 
study remains unaffected)

Section 6.3: Amendment of dose modification guidelines, and in Section 6.3.2: 
Amendment of dose reduction guidelines to include ischemic vascular or cardiovascular 
events, and arrhythmical cardiac toxicity

Section 6.3.4: Update of suggested management of selected adverse events

Section 6.4.2: Update to permitted concomitant therapy to include management of 
hyperglycemia and/or hypertriglyceridemia in some patients

Section 6.4.3: Update to prohibited concomitant therapy

Section 7: Addition of assessments in flowcharts and assessments subsections (Edinburgh 
Claudication Questionnaire, smoking history, and family history of cardiovascular events, 
urine pregnancy tests, HbA1C, HDL and LDL, microalbuminuria, determination of Ph+ 
stem cells in bone marrow); addition of two extra optional visits (Day 15 and Month 1 in 
first trimester of induction/consolidation phase) for hematology/clinical chemistry 
assessments, plus renumbering of all subsequent visits

Section 7.1.1: Amendment of screening assessments to include the decision tree for 
protocol entry based on the molecular response

Section 7.1.7.1: Expansion of withdrawal criteria relating to pregnancy (occurring during 
nilotinib treatment or during TFR phase or within 30 days of last dose of nilotinib)

Section 7.2.2.1: Update of the “Physical Examination” section with the addition of the
extramedullary involvement

Section 7.2.2.4.2: Update of clinical chemistry

Section 7.2.2.4.3: Update of pregnancy assessments according to the IB Edition 9

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
Section 7.2.2.7: Addition of a section regarding the Edinburgh Claudication Questionnaire

Section 7.2.5: Addition of bone marrow assessments for patients who participate in the 
Stem cells ENESTpath substudy

Section 8.1.3: Addition of a section regarding adverse events of special interest (ischemic 
vascular and cardiovascular events)

Section 8.4: Expanded statements about pregnancy

Section 8.6: Changes to data monitoring committee constitution and possible DMC 
recommendations

Section 10.1: Update of the “Analysis sets” section

Section 10.5.1: Update of key secondary objectives

Section 10.5.2: Addition of secondary objectives for optional Stem cells ENESTpath 
substudy

Section 10.5.3: Update of safety objectives

Section 10.7: Addition of sample size calculation for optional Stem cells ENESTpath 
substudy

Section 11.3: Addition of specific informed consent for optional Stem cells ENESTpath 
substudy

Section 11.5: Adaptation of authorship rules to comply with SSMC charter

Addition of references to support rationale for optional Stem cells ENESTpath substudy

Addition of Appendix containing the lists of CYP3A4 inducers and inhibitors and the 
Edinburgh Claudication Questionnaire

Changes to protocol summary to match main protocol

Minor changes and corrections for clarity
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.

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Protocol summary
Protocol number
AMN107AIC05
Title
A prospective, randomized, open-label, two-arm Phase III study to evaluate treatment-
free remission (TFR) rate in patients with Philadelphia chromosome-positive CML after
two different durations of consolidation treatment with nilotinib 300 mg BID
Brief title
A randomized phase III study to assess the effect of a longer duration of consolidation 
treatment with nilotinib on TFR in patients with CML in the chronic phase (CML-CP)
Sponsor and
Clinical Phase
Novartis
Phase III
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
Purpose:
This study aims to assess the optimal duration of nilotinib 300 mg twice daily (BID, bis in 
die) consolidation treatment, in order that patients remain in TFR (≥molecular response 
[MR]4.0) 12 months after starting the TFR phase of the study.
Rationale:
The natural history of chronic myeloid leukemia (CML) was changed dramatically by the 
introduction of TKIs (tyrosine kinase inhibitors), which have increased patient survival 
and consequently have prolonged the duration and increased the prevalence of the 
disease. It is estimated that the number of CML cases will continue to increase over the 
next half century, with the number of patients expected to exceed 250,000 in the USA 
alone. In this context, TFR studies may serve to both provide a new treatment paradigm 
for patients (in respect to the minimization of drug-drug interactions, elimination of 
chronic side effects, and benefit of pregnancy without exposure to TKIs), and also 
potentially have a positive impact on health economics, considering the expected 
increase in the numbers of patients with the disease.
CML-CP patients who have received 24 or more months of first-line imatinib treatment, 
and who have failed to achieve the molecular response threshold for treatment cessation 
(equal to or more than MR4.0, ≥MR4.0) have a 50% greater chance of achieving this level 
of molecular response by switching to nilotinib; however, the optimal duration of 
consolidation treatment with nilotinib to ensure the highest rate of patients remaining in 
≥MR4.0 after suspending treatment is not yet known. This protocol therefore aims to 
assess the potential impact of two durations of consolidation treatment with nilotinib, i.e. 
12 months versus 24 months, on molecular relapse rate in the first 12 months of the TFR
phase.
Rationale for optional Stem cells ENESTPath substudy - “Leukemic stem cells 
quantification in patients with chronic myeloid leukemia included in the ENESTPath trial”: 
The focus of this optional Stem cells ENESTPath substudy is to evaluate the importance 
of leukemic stem cells (LSC) in the long-term maintenance of the disease and their role 
in the relapse of patients during the TFR phase. This optional Stem cells ENESTPath 
substudy evaluates:
●
The presence and number of LSC and their progenitors in the bone marrow of all 
patients participating in this substudy before and after completing induction and the first 
year of the consolidation phase (at Visit 8).
●
Whether prolonging the treatment period of consolidation with nilotinib (patients in 
Arm 2) induces a reduction in the percentage of patients presenting LSC and progenitor 
cells in bone marrow at the end of the second year of the consolidation phase.
Rationale of ‘CML patient’s voice’ Italian substudy - The inner psycho-emotional 
experiences of CML patients during consolidation and TFR phases are unknown.The 
‘CML patient’s voice’ Italian substudy aims to examine patients’ psycho-emotional 
characteristics, quality of life and experiences of being involved in the ENESTPath study
and its discontinuation using a mixed method design qualitative-quantitative. This
substudy will be conducted in Italy only. For further details, please refer to the [Post-text 
Supplement 1]

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Primary objective
To assess the optimal duration of consolidation treatment with nilotinib 300 mg BID in 
order that patients remain in treatment-free remission (≥MR4 0) without molecular relapse 
12 months after entering the TFR phase
Secondary 
objectives
●
To evaluate the proportion of patients who are eligible to suspend nilotinib therapy by 
achieving and maintaining sustained ≥MR4 0 for at least 12 months during consolidation 
treatment with 300 mg BID nilotinib
●
To assess the achievement of MMR, MR4 0, and MR4 5 during induction/consolidation 
treatment with nilotinib 300 mg BID at the different time points in patients without that 
response at study entry
●
To assess the molecular response in patients during induction/consolidation 
treatment with nilotinib 300 mg BID at the different time points
●
To assess the proportion of patients in TFR at 3, 6, 12, 18, and 24 months after 
nilotinib cessation in the two treatment arms
●
To assess the molecular response in patients after randomization in the two 
treatment arms
●
To assess the kinetics of BCR-ABL transcript during induction/consolidation 
treatment with 300 mg BID nilotinib, during the TFR phase and during the nilotinib re-
treatment phase.
●
To assess the progression-free survival (PFS) rate after randomization in both 
treatment arms
●
To assess the treatment-free survival (TFS) rate after the start of TFR phase in the 
two treatment arms
●
To assess the overall survival (OS) rate after randomization in the two treatment 
arms
●
To assess the safety profile of nilotinib during the induction/consolidation phase, the 
TFR phase, and the re-treatment phase
For those patients consenting to participate in the optional Stem cells ENESTPath 
substudy, the following objectives will be also evaluated:
●
To evaluate the presence and number of LSC and their progenitors in the bone 
marrow before and after completing induction and the first year of the consolidation 
phase (at Visit 8);
●
To evaluate whether prolonging the treatment period of consolidation with nilotinib 
(patients in Arm 2 versus patients in Arm 1) induces a reduction in the percentage of 
patients presenting LSC and progenitor cells in bone marrow at the end of the second 
year of the consolidation phase (Visit 204 for Arm 2 versus Visit 8 for Arm 1).
●
To perform an exploratory analysis in order to evaluate whether relapse in patients 
during the TFR phase in either arm correlates with the presence of LSC and progenitor 
cells in bone marrow at the end of consolidation phase and at the time of relapse during 
TFR
For those patients consenting to participate to the ‘CML patient’s voice’ Italian substudy, 
please refer to the [Post-text Supplement 1].

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Study design
This is a prospective, randomized, open-label, multicenter, two-arm Phase III study that 
includes a 12-month induction phase, followed by a 12 or 24-months consolidation phase 
(dependent on randomization) and a 36 or 24-months TFR phase, respectively, totaling a 
5-year study duration for the individual patient.
Eligible patients are adults with a confirmed diagnosis of CP Philadelphia chromosome-
positive (Ph+) and/or BCR-ABL+ CML who have been treated with first-line imatinib for 
24 months or more, and are in complete cytogenetic response (CCyR). Patients must not 
have achieved ≥MR4.0 at study entry, as assessed by a EUTOS laboratory.
Approximately 565 patients will be enrolled into the study and will be treated with nilotinib 
300 mg BID for 24 months. Following 24 months of treatment, patients in sustained 
molecular response for at least the last 12 months will be randomized on a 1:1 basis to 
either:
●
Suspend nilotinib treatment immediately and enter the TFR phase (Arm 1; the 
nilotinib 24-month treatment arm), or
●
Continue nilotinib treatment for a further 12 months then suspend treatment and 
enter the TFR phase (Arm 2; the nilotinib 36-month treatment arm).
Patients not achieving a sustained molecular response at 24 months (and subsequently 
at 36 months if previously randomized to the treatment arm with 1 year additional 
consolidation) will exit the study and will be treated at the discretion of the investigator 
according to standard practice. Information on survival, stem cell transplant, and the 
status of the patient’s disease (i.e. disease progression to AP (accelerated phase)/BC 
(blast crisis) according to protocol definition, TKI treatment) will be collected until death, 
or until 5 years from study entry, whichever comes first.
Patients relapsing during the TFR phase will enter the nilotinib re-treatment phase of the 
study, and will be re-treated with the same dose of nilotinib as they were on before the 
TFR phase (i.e. the re-treatment dose will be nilotinib 300 mg BID or a lower dose of 
nilotinib if the dose was reduced in the consolidation phase before entering the TFR
phase).
These patients will remain on study until the completion of the 5-year study period
Optional Stem cells ENESTPath substudy:
The Stem cells ENESTPath substudy adds the determination of Ph+ stem cells in bone 
marrow in those patients consenting to participate in this substudy, at the following time 
points:
a)
At the screening visit, before starting nilotinib treatment
b)
After 2 years of nilotinib treatment at Visit 8
c)
After 3 years of nilotinib treatment, only in patients with 2 years’ consolidation 
treatment (Arm 2) at Visit 204
d)
If the patient relapses during the TFR phase, before re-starting the treatment 
with nilotinib
A 10 mL bone marrow sample will be collected and sent to 
 
 for immunophenotype analysis, FACS 
(fluorescence activated cell sorting) cell purification, in situ hybridization, and RT-PCR. 
Measurement and quantification will be performed by flow cytometry in a bone marrow 
purified population of stem cells in order to detect the presence of leukemic Ph+ cells or 
BCR-ABL transcript levels (evaluated by fluorescent in situ hybridization [FISH] or RT-
PCR).
‘CML patients’ voice’ Italian substudy:
Please refer to the [Post-text Supplement 1]

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Key inclusion 
criteria
●
Male or female patients, aged ≥ 18 years
●
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
●
Confirmed diagnosis of Ph+ and/or BCR-ABL+ CML-CP
●
Previous first-line treatment with imatinib for a minimum of 24 months (even not 
continuously) in total and in imatinib treatment at time of enrollment
●
Patient in CCyR
For those patients consenting to participate in the optional Stem cells ENESTPath 
substudy, the same inclusion criteria as for the main ENESTPath study will be 
applicable, plus the following:
●
A separate specific written informed consent for the Stem cells ENESTPath substudy 
must be obtained prior to extraction of additional bone marrow samples.
For those patients consenting to participate in the ‘CML patient’s voice’ Italian substudy , 
the same inclusion inclusion criteria as for the main ENESTPath study will be applicable.
This substudy will be conducted in Italy only.
Key exclusion 
criteria
●
Achievement of ≥MR4 0 at study entry as assessed by a EUTOS standardized 
laboratory
●
Previous treatment with BCR-ABL inhibitors other than imatinib
●
Patients with detectable atypical BCR-ABL transcripts, defined as absence of typical 
BCR-ABL transcripts for CML of the types b2(e13)-a2 or b3(e14)-a2 or both of them 
simultaneously documented at CML diagnosis or at any time before the screening 
procedure
●
Previous anticancer agents for CML except:
●
imatinib, and/or
●
cytoreduction after CML diagnosis, and/or
●
interferon for less than 1 year
●
Known second chronic phase of CML after previous progression to AP/BC;
●
Known impaired cardiac function, including any of the following:
●
Inability to determine the QT interval on ECG
●
Complete left bundle branch block
●
Right bundle branch block plus left anterior or posterior hemiblock
●
Use of a ventricular-paced pacemaker
●
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)
●
QTc > 450 msec on the average of three serial baseline ECG (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 severe PAOD or severe ischemic 
cardiovascular disease (e.g. myocardial infarction, ischemic cerebral vascular 
disease) whenever in the opinion of the investigator other treatments could have a 
more favorable benefit/risk profile.
●
Other clinically significant heart disease (e.g. congestive heart failure or 
uncontrolled hypertension)
●
Severe and/or uncontrolled concurrent medical disease that in the opinion of the 
investigator could cause unacceptable safety risks or compromise compliance with the 
protocol (e.g. uncontrolled diabetes, active or uncontrolled infection, uncontrolled severe 
hypertension, uncontrolled severe dyslipidemia). If appropriate measures (e.g. diet, 
exercise, appropriate therapy) are taken to control blood glucose or cholesterol LDL 
levels, or hypertension, the patient can be re-screened for the study.
●
History of acute pancreatitis within 12 months of study entry, or a medical history of 
chronic pancreatitis

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●
Known presence of significant congenital or acquired bleeding disorder unrelated to 
cancer
●
History of other active malignancies within 5 years prior to study entry, with the 
exception of previous or concomitant basal cell skin cancer, or previous cervical 
carcinoma in situ treated curatively 
●
Patients who have not recovered from prior surgery
●
Treatment with other investigational agents within 30 days of Day 1
●
Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers or 
medications that have the potential to prolong the QT interval that cannot be either 
discontinued or switched to a different medication prior to starting study drug
●
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter 
the absorption of study drug
●
Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential 
without a negative pregnancy test prior to baseline, or (d) of childbearing potential 
unwilling to use highly effective contraceptive precautions (as detailed below) throughout 
the trial (post-menopausal women must be amenorrheic for at least 12 months to be 
considered of non-childbearing potential)
●
Women of child-bearing potential (WOCBP), 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 or imatinib. 
Patients using an oral hormonal contraception method should complete their monthly 
treatment course. Highly effective contraception methods include:
I.
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
II.
Female sterilization (surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least 6 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
III.
Male sterilization (at least 6 months prior to screening). For female subjects on 
the study, the vasectomized male partner should be the subject’s sole partner
IV.
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%), e.g. 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
●
Patients not able to understand and comply with study instructions and requirements
For those patients consenting to participate in the optional Stem cells ENESTPath
substudy, the same exclusion criteria as for the main ENESTPath study will apply
For those patients consenting to participate in the ‘CML patient’s voice’ Italian substudy, 
the same exclusion criteria as for the main ENESTPath study will apply. This substudy 
will be conducted in Italy only.
Investigational 
therapy
Nilotinib 300 mg BID
Efficacy 
assessments
●
Molecular Response (RQ-PCR, optional mutational analysis)
●
Bone marrow assessments and cytogenetics, including evaluation of LSC and 
progenitor cells in the optional Stem cells ENESTPath substudy

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Safety assessments
●
Physical examination
●
Vital signs
●
ECOG performance status
●
Laboratory evaluations (clinical chemistry, hematology, urine analysis);
●
Serology (Hep B)
●
ECG
●
Echocardiography
●
Edinburgh Claudication Questionnaire
●
Adverse events
●
Concomitant medication
●
Serum and urine pregnancy test (for WOCBP)
Other assessments
Optional Stem cells ENESTPath substudy:
●
Presence of Ph+ LSC in bone marrow (CD34+/CD38+ progenitor cells, 
CD34+/CD38−stem cells, and CD34+/CD56+ aberrant stem cells [the last ones only if 
detectable])
●
Percentage of total CD34+ cells
●
Percentage of Ph+ cells evaluated by FISH
●
BCR-ABL transcript levels on sorted cells by RT-PCR
●
Percentage of subpopulations (CD34+/CD38+, CD34+/CD38−, and CD34+/CD56+ [if 
detectable]) 
Data analysis
Based on new data from the ENESTcmr study, it is expected that 40% of the patients 
switched from imatinib to nilotinib will achieve MR4.0 or better at the end of the 12-month 
induction phase, and will maintain this level of molecular response by the end of the 12-
month consolidation phase prior to randomization. Furthermore, if the patients treated 
with nilotinib for 24 months before entering the TFR phase (Arm 1) have a similar relapse 
rate as the patients in the STIM trial (Mahon et al 2011), it is expected that 40% of 
patients randomized to Arm 1 will not have relapsed after the 12 months TFR phase. 
Based on new information from a number of recently published studies (Hughes TP et al 
2014 Blood;124:729-36; Mahon FX et al 2014 Blood;124(21):151; Rea D et al 2014
Blood.;124(21) [abstract 811]), it is reasonable to assume that a 12-month longer 
consolidation period with nilotinib (Arm 2) may reduce the molecular relapse rate in the 
first 12 months TFR phase by approximately 20% (from 60% to 40%, absolute difference 
of 20%).
Therefore it is assumed that the percentage of patients without relapse will be 40% in 
Arm 1, and 60% in the Arm 2. Considering this, a sample size of 107 patients per group 
(a total of 214) is needed to detect such a difference. These calculations are based on a 
two-sided chi-square test at 0.05 alpha level with a power of 80%. Assuming that 5% of 
patients will be unevaluable after randomization, a total of 226 patients will need to be 
randomized in order to adequately power the study. Finally, as explained above, 
assuming that 40% of the patients switched from imatinib to nilotinib will achieve ≥MR4.0
at the end of the 12-month induction phase, and will maintain this level of molecular 
response by the end of the 12-month consolidation phase prior to randomization, a total 
of 565 patients are required for this study.
Primary analysis: The proportion of patients who are in TFR (≥MR4.0) without molecular 
relapse at the end of 12 months in the TFR phase will be calculated by dividing the 
number of patients who remain in ≥MR4.0 at the end of 12 months in the TFR phase 
(without re-starting nilotinib therapy) by the number of patients who entered the TFR 
phase. A chi-square test will be applied to compare the two treatment arms. A two sided 
test with alpha = 0.05 will be used. The rate of successful TFR will be presented together 
with an exact 95% Clopper Pearson confidence interval. 
No formal interim analyses are planned.
Key words
Phase III, two-arm, open-label, nilotinib, treatment-free remission, sustained MR4.0, stem 
cells, confirmed loss of M R4.0, loss of MMR, Ph+ CML-CP.

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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatments
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder of transformed, 
primitive hematopoietic progenitor cells. The hallmark of CML is the Philadelphia (Ph) 
chromosome, which is 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 on 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 2000; van Etten 2004).
Clinically, CML progresses through three distinct phases of increasing refractoriness to 
therapy: chronic phase (CP; median duration 3 to 4 years; median survival up to 10 years with 
allogeneic bone marrow transplant, and 5 to 6 years with interferon), accelerated phase (AP; 
median duration 3 to 9 months; median survival 8 to 18 months), and blast crisis (BC; median 
survival 3 to 6 months) (Enright and McGlave 2000). Most patients, however, present in the 
CP, characterized by splenomegaly and leukocytosis with generally few symptoms.
The objectives of CML-CP treatment are the normalization of hematopoiesis (complete 
hematologic response), the elimination of the Ph+ cells from the bone marrow (complete 
cytogenetic response [CCyR]), and the reduction of the BCR-ABL transcript levels from 
samples of peripheral or bone marrow blood by a factor of 3.0 logs compared to the 
standardized baseline (major molecular response [MMR] international scale [IS]: 0.1%).
Several studies have shown that a further reduction of residual leukemic cells of 4.0 logs or 
more (i.e. achieving a complete molecular response [MR4.0 or better, i.e. ≥MR4.0] compared to 
an MMR) is associated with the most favorable outcome for patients in CML-CP. In a study 
of 90 patients with a CCyR, only one out of 28 patients with a ≥MR4.0 subsequently lost their 
CCyR, whereas 11 out of 48 with an MMR subsequently lost their CCyR (Press 2007). In a 
study by Kantarjian (2008) of 276 patients treated with imatinib, 100 patients achieved a 
≥MR4.0, with no treatment failures (classified as sustained ≥MR4.0 for 6 months or more). A 
third study published by Branford (2008) demonstrated in a series of 144 patients treated with 
imatinib who achieved an MMR, that the lowest frequency of recurrence occurred in the 
55 patients with a ≥MR4.0 (1.8%) compared with 89 patients with an MMR but not a ≥MR4.0
(7.9%). These studies support the goal of therapy for newly diagnosed CML-CP as being 
attainment of ≥MR4.0, as this is associated with the most favorable outcome.
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 (Kantarjian 2006; Kantarjian 2007; le Coutre 2008) led to its 
registration for the second-line treatment of CML-CP and CML-AP. More recently, nilotinib 
has been approved for the first-line treatment of newly diagnosed CML-CP patients. The 

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5-year follow-up from the pivotal nilotinib study [CAMN107A2303] in this indication 
(Larson 2014) confirmed the superiority of nilotinib 300 mg twice daily (BID) or 400 mg BID 
over imatinib 400 mg once daily (QD) in terms of the MMR rates (77%, 77%, and 60%, 
respectively) and in achieving MR4.5 (54%, 52%, and 31%) by 5 years. In particular, the 
estimated rate of progression to AP/BC was also significantly lower in both nilotinib 
treatment arms (0.7%, 1.1%) than in the imatinib treatment arm (4.2%).
The National Comprehensive Cancer Network guidelines on CML (version 2, 2012) and the 
European Leukemia Net guidelines (Baccarani et al 2013) recommend continuing TKI 
treatment (i.e. imatinib or nilotinib) indefinitely in all responding patients. There are currently 
no recommendations or provisions for temporary or permanent treatment-free remission (TFR) 
phases with any TKI.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of nilotinib
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-CP. Efficacy data 
in patients with CML-BC are not available.
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. 
phosphatidylinositol-3kinase [PI-3K] and signal transducer and activator of transcription 
[STAT5]), leading to the death of the BCR-ABL phenotype in CML (Manley 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 2005). In murine 
models of CML, sole treatment with oral nilotinib reduces tumor burden and prolongs 
survival. In primary Ph+ leukemia cell lines from CML patients, nilotinib selectively inhibits 
proliferation and induces apoptosis. Nilotinib has little or no effect against the majority of 
other protein kinases examined, including Src, except for the platelet-derived growth factor, 
Kit, and ephrin receptor kinases, which it inhibits at concentrations within the range achieved 
following oral administration at therapeutic doses recommended for the treatment of CML.
1.2.1.1
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 
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In a mouse study, skin growth or skin cancer were detected at doses representing
approximately 30 to 40 times the human exposure at the maximum approved dose. At doses
that were approximately 10 to 20 times the human exposure at the maximum approved dose,
no observed overgrowth of the skin was detected. In this study the major non-cancer lesions
were in the skin, the growing teeth (degeneration/atrophy of the enamel and inflammation of
the gingiva) and the thymus (low lymphocytes). There are currently no clinical data
suggesting an increased risk of skin cancer in patients treated with Tasigna.
For more details on non-clinical experience, please refer to the latest [AMN107 Investigator 
Brochure].
1.2.1.2
Clinical experience
1.2.1.2.1 Clinical safety and tolerability
Overall, nilotinib has been found to be well tolerated in patients with Ph+ CML-CP, and -AP 
who were resistant to or intolerant of imatinib, as well as in patients with newly diagnosed 
Ph+ CML-CP.
While adverse events (AEs) are common in patients with CML treated with nilotinib, they are 
generally mild to moderate, reversible, and manageable with dose interruption and/or dose 
reduction. The most common grade 3 or 4 toxicities are hematologic, which are not 
unexpected in the CML population and are generally manageable. Hematotoxicity is more 
frequent in patients with imatinib-resistant or -intolerant CML and in particular in patients 
with CML-AP and CML-BC. The most commonly reported non-hematologic adverse 
reactions in patients with newly diagnosed Ph+ CML-CP, resistant or intolerant Ph+ CML-CP, 
or resistant or intolerant Ph+ CML-AP are rash, pruritus, headache, nausea, fatigue, myalgia, 
nasopharyngitis, constipation, diarrhea, abdominal pain, vomiting, arthralgia, pyrexia, upper 
urinary tract infection, back pain, cough, and asthenia. Hematologic adverse drug reactions 
include myelosuppression: thrombocytopenia, neutropenia, and anemia. In comparison to 
first-line patients, grade 3/4 AEs were more frequently observed in CML patients resistant to 
or intolerant of prior therapy, including imatinib. Other significant drug effects reported with 
nilotinib include modest QTc prolongation, elevations of blood glucose, bilirubin, lipase, and 
transaminases, which are manageable with dose interruptions and reductions.
No major differences in safety or efficacy have been observed in patients ≥65 years of age. 
Clinical studies have not been performed in patients with impaired renal function.
For detailed information regarding nilotinib clinical safety and tolerability, please refer to the 
latest [AMN107 Investigator Brochure].
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 
in the nilotinib treatment arms compared with the imatinib treatment arm. Up to the data cut-

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off for the 60-month analysis (30-Sep-2013), the number of patients reported with 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.
1.2.1.2.2 Pharmacokinetics/pharmacodynamics of nilotinib
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.
With multiple oral doses of nilotinib, steady-state conditions were achieved by Day 8 after 
starting treatment. There were 2-fold and 3.8-fold accumulations with QD and BID dosing, 
respectively. Inter-patient variability (coefficient of variation [CV%]) in nilotinib 
pharmacokinetics (PK) was moderate to high, with CV% being 32% to 64% in area under the 
serum concentration-time curve (AUC) and 34% to 72% in maximum plasma concentration 
(Cmax), respectively.
The bioavailability of nilotinib is increased by food: healthy volunteer studies showed 
increases in Cmax and AUC of up to 112% and 82%, respectively (30 hours after high-fat meal, 
versus fasting conditions). Concurrent intake of grapefruit juice increased the nilotinib Cmax
and AUC0-∞, but the median time to reach peak concentration and the mean t1/2 were not 
altered.
With QD dosing of nilotinib from 50 to 1200 mg at steady state, Cmax and AUC increased 
with increasing dose from 50 to 400 mg in a generally dose-proportional manner, but 
appeared to plateau at dose levels above 400 mg. Dividing the daily dose into a BID schedule 
partially overcame the dose-limiting absorption; exposure to nilotinib with 400 mg BID was 
approximately 35% greater than with 800 mg QD.
Systemic exposure (AUC) of nilotinib at steady state at a dose level of 400 mg BID was 
approximately 13.4% higher than at a dose level of 300 mg BID. The average nilotinib Cmax
and minimum plasma concentration (Cmin) over 12 months were approximately 15.7% and 
14.8% higher, respectively, following 400 mg BID dosing compared to 300 mg BID, 
suggesting a less than proportional dose-exposure relationship between nilotinib 300 mg BID 

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and 400 mg BID. Bioavailability and systemic exposure may be lower in male patients;
studies have shown 10% to 20% lower systemic exposure in males versus females.
Hepatic impairment has a modest effect on nilotinib PK, increasing AUC0-∞by 35%, 35%, 
and 19% in patients with mild, moderate, and severe hepatic impairment, respectively, versus 
patients with normal hepatic function. Impaired renal function is not expected to influence 
nilotinib PK. Nilotinib absorption (relative bioavailability) may be reduced by approximately 
48% and 22% in patients with total gastrectomy and partial gastrectomy, respectively.
The administration of nilotinib with agents that are strong cytochrome P450 (CYP)3A4 
inhibitors (including, but not limited to ketoconazole, itraconazole, voriconazole, 
clarithromycin, telithromycin, and ritonavir) should be avoided. Concomitant use of nilotinib 
with medicinal products that are potent inducers of CYP3A4 (e.g. phenytoin, rifampicin, 
carbamazepine, phenobarbital, and St. John’s wort) is likely to reduce exposure to nilotinib to 
a clinically relevant extent. For further information, see the [AMN107 Investigator Brochure].
1.2.1.2.3 Efficacy of nilotinib
Overall, approximately 11,764 patients have been exposed to nilotinib in clinical trials as of 
31 January 2015.
Nilotinib is approved by US Food and Drug Administration (FDA) and European 
Commission to treat newly diagnosed adult patients with Ph+ CML-CP, and to treat Ph+ 
CML-CP and CML-AP in adult patients resistant to or intolerant of prior therapy, including 
imatinib. The recommended adult dosage of nilotinib is 300 mg orally BID for newly 
diagnosed Ph+ CML-CP patients and 400 mg orally BID for patients with resistant or 
intolerant Ph+ CML-CP or CML-AP.
The results of study ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–
Newly Diagnosed Patients) demonstrated superiority of nilotinib versus imatinib in the CML-
CP first-line setting (Saglio et al 2010; Larson et al 2012). More patients treated with nilotinib 
achieved deeper molecular responses, and the differences were significantly superior at each 
of the analyzed time points to date. The rate of MMR at 12 months was 44% in the nilotinib 
300 mg BID treatment arm and 22% in the imatinib treatment arm p<0.001 (primary 
endpoint). The cumulative incidence of MR4.5 log reduction from standardized baseline was 
11%, 25%, and 32% by 12, 24, and 36 months in the nilotinib 300 mg BID arm. In the 
imatinib arm, the rates were 1%, 9%, and 15% at the same time points. The differences 
between the rates of MR4.5 in the nilotinib and imatinib arms increased over time.
For additional details human studies in CML, see the [AMN107 Investigator Brochure].

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2
Rationale
2.1
Study rationale and purpose
The natural history of CML was changed dramatically by the introduction of TKIs, which 
have increased patient survival and consequently have prolonged the duration and increased 
the prevalence of the disease. It is estimated that the number of CML cases will continue to 
increase over the next half century, with the number of patients expected to exceed 250,000 in 
the USA alone.
The TKI imatinib has been the gold standard in the treatment of Ph+, BCR-ABL+ CML for 
more than 10 years, with approximate cumulative responses of 70% of patients achieving a 
CCyR and 50% achieving a 3-log reduction in BCR-ABL IS or an MMR following treatment 
(Clark et al 2012). Studies have demonstrated that the survival of imatinib-treated patients is 
similar to that of non-CML patients; however, the proportion of patients who achieve a stable 
molecular response of below 4-log or more (i.e. MR4.0, MR4.5, and MR5.0) is much smaller, 
and ranges between 26% for MR4.0 and 15% for MR4.5 after 3 years of follow-up (Clark et al 
2012).
Several results from independent study groups have proven that discontinuation of patients 
from imatinib treatment is possible, with the risk of relapse being between 40% and 60% and 
occurring most frequently within the first year of discontinuation (Mahon et al 2010). As a 
prerequisite for any discontinuation attempt however, patients must have achieved a sustained 
deep molecular response for an extended duration of time. The depth of molecular remission 
is not consistent among the trials conducted; however, it is felt that a sustained molecular 
remission of ≥MR4.0 will provide adequate protection from relapse after cessation of treatment 
for at least a notable proportion of the population. (Cross et al 2012)
Studies have demonstrated that patients who achieve a low level of BCR-ABL can 
subsequently show fluctuations of their molecular responses due to individual patient biology. 
Indeed, data from the ENESTnd study ([CAMN107A2303]), a pivotal phase III study of 
nilotinib versus imatinib in first-line treatment; Novartis, Larson, R, et al. Blood. 2014 
[abstract 4541] suggest that approximately 30% of patients will have fluctuations in 
BCR-ABL above the given threshold of a 4.5-log reduction in BCR-ABL. Therefore a 
sustained molecular remission of ≥MR4.0 serves to reduce the number of patients eligible for 
treatment cessation further.
From the considerations above, it is recognized that only a small proportion of 
imatinib-treated patients are eligible for an attempt at treatment cessation; and data have 
shown that almost 50% of patients undergo a molecular relapse upon treatment interruption. 
For patients not achieving a deep molecular response on imatinib treatment after 2 years, the 
chances of doing so at a later date is very small, and therefore the chances of participating in a 
cessation attempt is further reduced.
Nilotinib is an imatinib derivative that has a greater activity on the kinase activity of 
BCR-ABL, either wild type or with most mutations associated with imatinib resistance
(Weisberg et al 2005), that has been proven to induce a CCyR in about 50% of the patients 
who were resistant to imatinib treatment (Kantarjian et al 2006). Subsequently, it was 

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demonstrated that nilotinib induced CCyR and MMR to a greater extent than imatinib in 
first-line treatment (Saglio et al 2010). Nilotinib is registered for the second-line treatment of 
CML at a dose of 400 mg BID and for the first-line treatment of CML at a dose of 300 mg 
BID. The data from the ENESTnd study showed that the molecular response to nilotinib is not 
only higher and faster, but also deeper, with an MR4.0 rate of approximately 30% by 2 years 
and 50% by 3 years (Clark et al 2012).
In addition, data from the ongoing Evaluating Nilotinib Efficacy and Safety in Clinical Trials-
Complete Molecular Response (ENESTcmr) study shows that patients with a lack of deep 
molecular response on imatinib can benefit from treatment with nilotinib by reaching deeper 
levels of molecular response compared to continuation of treatment with imatinib (Cervantes 
et al 2012). In this study the primary endpoint, defined as undetectable BCR-ABL in two 
consecutive samples was not reached; however, twice as many patients who switched to 
nilotinib achieved MR4.5 versus patients who continued on imatinib. Overall, 9% of patients 
who were switched to nilotinib discontinued the study prematurely due to AEs, in comparison 
to 1% of patients who continued on imatinib.
In the context of the increasing prevalence of CML, TFR studies may serve to both provide a 
new treatment paradigm for patients (with respect to the minimization of drug-drug 
interactions, elimination of chronic side effects, and benefit of pregnancy without exposure to 
TKIs), but may also have a positive impact on health economics considering the expected 
increase in the numbers of patients with the disease.
CML-CP patients who have received 24 or more months of imatinib treatment and have failed 
to achieve the MR threshold for treatment cessation have a 50% greater chance of achieving
this level of MR by switching to nilotinib; however, the optimal duration of consolidation 
treatment with nilotinib to ensure the highest rate of patients remaining in ≥MR4.0 after 
suspending treatment is not yet known. Several attempts were made to assess the impact of 
the duration of sustained molecular remission (e.g. Mahon et al 2010, Ross et al 2010) with
inconclusive results. Therefore within the current protocol, it is planned to assess this duration 
as an integral part of the study design, randomizing the patients to either a 12-month or a 24-
month consolidation phase before treatment cessation and assessing the potential impact of a 
longer duration of consolidation treatment with nilotinib on molecular relapse rate in the first 
12 months of the TFR phase.
2.2
Rationale for the study design
This is an open-label, multicenter, randomized, two-arm study aiming to identify the duration 
of nilotinib treatment that enables a highest percentage of patients to remain in TFR (≥MR4.0) 
12 months after starting the TFR phase of the study.
In a previous study (ENESTcmr), MR4.5 was achieved after 24 months of treatment with 
nilotinib in 43% of CML-CP patients lacking a deep MR after having been on imatinib for at 
least 2 years. For this reason, it is expected that 24 and 36 months of treatment with nilotinib 
300 mg BID may induce greater percentages of patients to achieve sustained ≥MR4.0.
The primary efficacy parameter of the number of patients remaining in TFR (≥MR4.0) will be 
determined 12 months after starting the TFR phase in both randomized treatment arms. An 
additional analysis at 24 months will also be performed. Updated results from the STIM study 

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were reported (Mahon et al 2011), which demonstrated that 39 out of 100 off-treatment 
patients remained without detectable BCR-ABL transcript levels after a median 34 months of 
follow-up. Of the 61 patients who had molecular relapses, 58 (95%) relapsed in the first 
7 months of the study, and three molecular recurrences occurred at later time points (months 
19, 20, and 22). This observation is in line with the molecular recurrence patterns described 
by both Mahon et al (2010) and Branford et al (2012). It is therefore anticipated that even if 
patients have a 1- to 2-log lower residual leukemic disease burden at the time of starting the 
TFR phase (as opposed to patients treated with imatinib in previous studies), those who 
experience molecular recurrence during this phase will do so within the same time frame as 
observed in previous discontinuation studies. Assessments of relapse rate at 12 and 24 months 
in the TFR follow-up period are therefore deemed to be sufficient to detect any clinically 
significant difference between the two randomized arms.
Patients who are eligible to enter the TFR phase will be monitored every 4 weeks during the
first 6 months of the phase, with assessments occurring less frequently in the following 18 
months. Studies have shown that in case of molecular recurrence, the increase is on average 1
log per month (Brandford et al 2012; Mahon et al 2010). The monthly monitoring during the
first 6 months of the TRF phase (when most recurrences are anticipated) will therefore ensure 
that impending recurrence is identified early enough to avoid loss of CCyR by timely 
re-initiation of nilotinib treatment.
It is also hypothesized, primarily from the STIM study, that virtually all patients with 
molecular recurrence after the TFR phase will regain MMR, as well as ≥MR4.0, within 
approximately 3 months of re-initiating treatment. Therefore, patients with molecular 
recurrence during the TFR phase will be re-treated immediately with nilotinib 300 mg BID 
and will remain on study until they complete the 5-year study period.
No formal interim analyses are planned during the study; however, as this study will be 
overseen by a Data Monitoring Committee (DMC), DMC reports will be provided on a 
regular basis (see Section 8.6).
2.3
Rationale for dose and regimen selection
In the first 12 months following the switch from imatinib to nilotinib 400 mg BID treatment in 
the ENESTcmr study, 9% of patients discontinued due to AEs. It is therefore suggested that 
administration of the currently marketed nilotinib 300 mg BID dose will result in similar 
efficacy and fewer discontinuations in the current trial due to AEs. Additionally, 
administration of nilotinib 300 mg BID appears justified, as CML-CP patients on imatinib 
who have achieved CCyR but less than MR4.0 are not considered to be treatment failure 
patients according to current treatment recommendations. The selection of the 300 mg BID 
dose is therefore considered appropriate in order to minimize the occurrence of AEs when 
moving from imatinib to nilotinib, and to provide the best long-term efficacy.
2.4
Rationale for choice of combination drugs
Not applicable.

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2.5
Rationale for choice of comparators drug
Not applicable.
2.6
Rationale for optional Stem cells ENESTPath substudy
“Leukemic stem cells quantification in patients with chronic myelogenous leukemia included 
in the ENESTPath trial”:
In two randomized studies ([CAMN107A2303] and [CAMN107A2405]), nilotinib has been 
shown to be significantly more effective than imatinib in inducing deep MR in CML-CP
patients. In ENESTnd [CAMN107A2303], nilotinib allowed a higher number of newly
diagnosed patients to achieve deeper MR (MR4.0 or MR4.5) compared to imatinib. In 
ENESTcmr [CAMN107A2405] in CML-CP patients after prolonged treatment with imatinib, 
twice as many patients in the nilotinib arm than in the imatinib arm achieved MR4.5 after 
12 months of treatment. It is then possible that a deeper MR is a marker for a decreased 
number or eradication of leukemic stem cells (LSC), and that subsequent relapse after 
treatment discontinuation may be correlated with the presence and/or the number of persisting 
LSC.
Taking this hypothesis into account, the focus of this substudy is to evaluate the importance of 
LSC (CD34+/CD38+ progenitor cells, CD34+/CD38−stem cells and CD34+/CD56+ aberrant 
stem cells [the last ones only if detectable]) in the long-term maintenance of the disease and 
their role in the relapse of patients in the TFR phase. This substudy is based on the possibility 
of detection and quantification of LSC and their progenitors by flow cytometry, and also the 
possible differential effect of nilotinib compared to imatinib in these cell populations (Defina 
et al 2012, Janssen et al 2012, Corbin et al 2011).
The hypothesis will be tested by:
1. Evaluating the presence and number of LSC and their progenitors in the bone marrow of 
all patients participating in this substudy before and after completing induction and the 
first year of the consolidation phase (at Visit 8).
2. Evaluating, by descriptive statistics, whether prolonging the treatment period of 
consolidation with nilotinib (patients in Arm 2) causes a reduction in the percentage of 
patients presenting LSC and progenitor cells in bone marrow at the end of the second year 
of the consolidation phase.
3. Performing an exploratory analysis in order to evaluate whether relapse in patients during 
the TFR phase in either arm correlates with the presence of LSC and progenitor cells in 
bone marrow at the end of the consolidation phase and at the time of relapse during TFR.
2.7
Rationale for ‘CML patient’s voice’ Italian Substudy
The ‘CML patient’s voice’ Italian substudy aims to examine patients’ psycho-emotional 
characteristics, quality of life and experiences of being involved in CAMN107AIC05l trial 
and its discontinuation using the following mixed method design (qualitative-quantitative). 
This sub-study will be conducted in Italy only. [Post-text Supplement 1].

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3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.

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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4.
To assess the optimal duration of consolidation 
treatment with nilotinib 300 mg BID in order that 
patients remain in TFR (≥MR4 0) without molecular 
relapse 12 months after entering the TFR phase.
The number of patients who remain in TFR (≥MR4.0) 
without molecular relapse at the end of 12 months in 
the TFR phase of the study, in the nilotinib 12-month 
consolidation treatment arm versus the nilotinib 24-
month consolidation treatment arm. Molecular relapse 
during TFR is defined as the loss of MMR, or the 
confirmed loss of MR4.0 (defined by 3 consecutive 
tests less than MR4.0 assessed at 3 consecutive visits 
according to the visit schedule of the TFR phase) (see 
Section 4.1).
The proportion of patients who are in TFR (≥MR4 0) 
without molecular relapse at the end of 12 months in 
the TFR phase will be calculated by dividing the 
number of patients who remain in ≥MR4.0 at the end of 
12 months in the TFR phase (without re-starting 
nilotinib therapy) by the number of patients who 
entered the TFR phase. A chi-square test will be 
applied to compare the two treatment arms.
Secondary
Refer to Section 10.5.
To evaluate the proportion of patients who are eligible 
to suspend nilotinib therapy by achieving and 
maintaining a sustained ≥MR4.0 for at least 12 months 
during consolidation treatment with nilotinib 300 mg 
BID.
The proportion of patients who achieve a sustained 
≥MR4.0 (defined as having 4 out of 5 quarterly 
assessments of ≥MR4.0 by a (EUTOS) standardized 
laboratory over the last 12 months and the last 
assessment before randomization is at least MR4 0) 
during the consolidation phase of the study.
The proportion of patients who are in sustained ≥MR4 0
at 24 months after completing the 
induction/consolidation phase will be calculated by 
dividing the number of patients who have achieved 
sustained ≥MR4 0 over at least the last 12 months of 
the consolidation phase by the number of patients 
enrolled.

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Objective
Endpoint
Analysis
To assess the achievement of MMR, MR4 0, and MR4 5 
during induction/consolidation treatment with nilotinib 
300 mg BID at the different time points in patients 
without that response at study entry.
To assess the molecular response in patients during 
induction/consolidation treatment with nilotinib 300 mg 
BID at the different time points.
The proportion of patients who achieve MMR, MR4 0,
or MR4.5 on the study at selected time points (every 3 
months until Month 24 or Month 36 depending on the 
randomized arm) during the induction/consolidation 
phase of the study.
The proportion of patients who are in MMR, MR4.0, or 
MR4.5 on the study at selected timepoints (every 3 
months until Month 24 or Month 36 depending of the 
randomized arm) during the induction/consolidation 
phase of the study.
The proportion of patients who achieve MMR, MR4 0 or 
MR4 5 at selected timepoints during the 
induction/consolidation phase (every 3 months until 
Month 24 or Month 36 depending on the randomized 
arm) will be calculated by dividing the number of 
patients who are in MMR, MR4.0 or MR4 5 by the 
number of patients without that response at baseline.
The proportion of patients who are in MMR, MR4.0, or 
MR4 5 at selected timepoints during the TFR phase 
(every 3 months until Month 24 or Month 36 
depending on the randomized arm) will be calculated 
by dividing the number of patients who are in MMR, 
MR4 0, or MR4 5 by the number of enrolled patients.
To assess the proportion of patients in TFR at 3, 6, 12, 
18 and 24 months after nilotinib cessation in the two 
treatment arms
The proportion of patients in TFR, i.e. with no 
confirmed loss of MR4.0, no loss of MMR and no 
restarting of nilotinib therapy within the first 3, 6, 12, 
18, and 24 months following nilotinib cessation. 
The proportion of patients in TFR will be calculated by 
dividing the number of patients with no confirmed loss 
of MR4 0, no loss of MMR, and no re-starting of nilotinib 
therapy in the first 3, 6, 12, 18, and 24 months 
following nilotinib cessation by the number of patients 
who entered the TFR phase
To assess the molecular response in patients after 
randomization in the two treatment arms.
The proportion of patients who are in MMR, MR4.0, or 
MR4.5 at selected time points (at Month 3, 6, 12, and
every 3 months thereafter until Month 24 or Month 36 
depending on the randomized arm) during the TFR 
phase in each one of the two treatment arms.
The proportion of patients who are in MMR, MR4.0, or 
MR4 5 at selected time points (at Month 3, 6, 12, and 
every 3 months thereafter until Month 24 or Month 36 
depending on the randomized arm) will be calculated 
by dividing the number of patients who are in MMR, 
MR4 0 or MR4.5 by the number of patients in the TFR 
phase in each one of the two treatment arms.
To assess the kinetics of BCR-ABL transcript during 
induction/consolidation treatment with nilotinib 300 mg 
BID
BCR-ABL transcript levels (IS) during the 
induction/consolidation phase
Descriptive statistics of BCR-ABL transcript levels (IS) 
over time during the induction/consolidation phase
To assess the kinetics of BCR-ABL transcript during 
the TFR phase in the two treatment arms
BCR-ABL transcript levels (IS) during the TFR phase
Descriptive statistics of BCR-ABL transcript levels (IS) 
over time during the TFR phase

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Objective
Endpoint
Analysis
To assess the kinetics of BCR-ABL transcript during 
the nilotinib re-treatment phase
BCR-ABL transcript levels (IS) during the nilotinib re-
treatment phase
Descriptive statistics of BCR-ABL transcript levels (IS) 
over time during the nilotinib re-treatment phase
To assess the progression-free survival (PFS) rate 
after randomization in the two treatment arms.
PFS is defined as progression to AP/BC or death from 
any cause, where the “failure” event is the earliest 
occurrence of either of these events.
Kaplan-Meier (KM) estimation of PFS. PFS is 
measured from the date of randomization to the date 
of the earliest failure event. Patients not known to 
have progressed or died on or before the cut-off date 
for the KM analysis will have their PFS censored at the 
earlier of the date of their last assessment 
(cytogenetic, hematology, or extramedullary) for 
patients who are still on study and at the date of last 
contact for patients who are in follow-up.
To assess treatment-free survival (TFS) after start of 
the TFR phase in the two treatment arms.
TFS is defined as lack of any of the following events: 
loss of MMR, confirmed loss of MR4.0, re-start of 
nilotinib treatment for any reason, progression to 
AP/BC, or death from any cause.
KM estimation of TFS, which is measured from the 
start of the TFR phase to the date of the earliest of the 
following: loss of MMR, confirmed loss of MR4.0, (see 
Section 4.1) re-start of nilotinib treatment, progression 
to AP/BC, or death from any cause. Patients not 
known to have had any of the events on or before the 
cut-off date for the KM analysis will have their TFS 
censored at the earlier of the date of their last 
assessment (PCR, cytogenetic, hematology, or 
extramedullary) for patients who are still on study and 
the date of last contact for patients who are in 
follow-up.
To assess the overall survival (OS) rate after 
randomization in the two treatment arms.
Overall survival is defined as the time from 
randomization to the time of death due to any cause.
KM estimation of OS, which is measured from the date 
of randomization to the date of death due to any 
cause. For patients not known to have died on or 
before the cut-off date, survival time will be censored 
at the date of last contact.

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Objective
Endpoint
Analysis
To assess the safety profile of nilotinib during the 
induction/consolidation phase, the TFR phase, and 
during the re-treatment phase.
Safety will be monitored through assessment of 
Adverse Events, laboratory data, ECG, vital signs.
Descriptive statistics on AEs, laboratory abnormalities,
and clinically notable ECG and other safety 
parameters during the nilotinib induction/consolidation 
phase, during the TFR phase, and during re-initiation 
of treatment with nilotinib.
For those patients consenting to participate in the 
optional Stem cells ENESTPath substudy, the 
following objectives will be also applicable:
To evaluate the presence and number of LSC and 
their progenitors in the bone marrow of all patients 
participating in this substudy before and after 
completing induction and first year of consolidation 
phase (at Visit 8 ).
To evaluate whether prolonging the treatment period 
of consolidation with nilotinib (patients in Arm 2 versus 
patients in Arm 1) induces a reduction in the 
percentage of patients presenting LSC and progenitor 
cells in bone marrow at the end of the second year of 
the consolidation phase (Visit 204 for Arm 2 versus 
Visit 8 for Arm 1);
To perform an exploratory analysis in order to evaluate 
whether relapse in patients during the TFR phase in 
either arm correlates with the presence of LSC and 
progenitor cells in bone marrow at the end of the 
consolidation phase and at the time of relapse during 
TFR.
The following endpoints are applicable to all the 
objectives detailed for the optional Stem cells 
ENESTPath substudy: 
Proportion of patients with presence of Ph+ LSC in 
bone marrow (CD34+/CD38+ progenitor cells, 
CD34+/CD38−stem cells, and CD34+/CD56+ 
aberrant stem cells [the last ones only if detectable]) at 
screening and at Visit 8.
Proportion of patients with presence of Ph+ LSC in 
bone marrow (CD34+/CD38+ progenitor cells, 
CD34+/CD38−stem cells, and CD34+/CD56+ 
aberrant stem cells [the last ones only if detectable]) at 
the end of consolidation arm (Visit 8 for Arm 1 and 
Visit 204 for Arm 2).
Proportion of patients with or without molecular 
relapse in the first year of TFR in either arm by 
presence of LSC in bone marrow (CD34+/CD38+ 
progenitor cells, CD34+/CD38−stem cells, and 
CD34+/CD56+ aberrant stem cells [the last ones only 
if detectable]) at Visit 8 and at the time of relapse 
during TFR.
The percentage of patients presenting Ph+ LSC in 
bone marrow will be calculated at each time point and 
descriptively analyzed. 
Descriptive statistics.
Descriptive statistics.
For the ‘CML patient’s voice’ Italian substudy please refer to [Post-text Supplement 1]

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4
Study design
4.1
Description of study design
This is a prospective, randomized, open-label, multicenter, two-arm Phase III study aiming to 
assess the optimal duration of nilotinib 300 mg BID consolidation treatment, in order that 
patients remain in TFR (MR4.0 or better [≥MR4.0]) 12 months after entering the TFR phase of 
the study.
The study design includes a 12-month induction phase, followed by a 12- or 24-month 
consolidation phase, and a 24- or 36-month TFR phase depending on randomization
(Figure 4-1).
Figure 4-1
ENESTPath study design
Eligible patients are adults with a confirmed diagnosis of chronic phase Ph+ and/or 
BCR-ABL+ CML who have been treated with first-line imatinib for 24 months or more, and 
are at least in CCyR. Patients must not have achieved ≥MR4.0 at study entry, as assessed by a 
EUTOS standardized laboratory.

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Approximately 565 patients will be enrolled into the study and will be treated with nilotinib 
300 mg BID for 24 months. Following 24 months of treatment, patients in sustained 
molecular response for at least the last 12 months will be randomized on a 1:1 basis to either:

Suspend nilotinib treatment immediately and enter the TFR phase (the nilotinib 24-month 
treatment arm; Arm 1), or

Continue nilotinib treatment for a further 12 months, then suspend treatment and enter the 
TFR phase (the nilotinib 36-month treatment arm; Arm 2).
Patients will be deemed to be in sustained molecular response if:

Four out of the preceding five quarterly real-time quantitative polymerase chain reaction 
(RQ-PCR) assessments were ≥MR4.0, and

The last assessment was ≥MR4.0.
Patients not achieving a sustained molecular response at 24 months from treatment start (and 
subsequently at 36 months from treatment start depending on the randomization arm) will exit 
the study and will be treated at the discretion of the investigator according to standard practice. 
Information on survival, stem cell transplantation, status of the patient’s disease (i.e. disease 
progression to AP/BC according to protocol definition, TKI treatment) will be collected until 
death or until 5 years from study entry, whichever comes first.
Patients relapsing during the TFR phase will enter the nilotinib re-treatment phase of the study 
and will be re-treated with the same dose of nilotinib as they were on before the TFR phase 
(i.e. the re-treatment dose will be nilotinib 300 mg BID or a lower dose of nilotinib if the dose
was reduced in the consolidation phase before entering the TFR phase). The patient will
subsequently remain on study until the completion of the 5-year study period.
Relapse is defined as the loss of MMR, or the confirmed loss of MR4.0 (defined by three
consecutive tests less than MR4.0 assessed at three consecutive visits according to the visit 
schedule of the TFR phase). If during the three consecutive tests, one of the tests shows loss 
of MMR, this patient will be declared as relapsing and will start the nilotinib re-treatment 
phase immediately even if the definition of confirmed loss of MR4.0 is not yet fulfilled.
Loss of MMR is considered a more clinically relevant criterion for re-initiating nilotinib 
treatment than loss of MR4.0 due to the anticipated fluctuations in BCR-ABL transcript levels 
at low levels without systematic rise in patients with minimal residual disease.
4.1.1
Description of optional Stem cells ENESTPath substudy
The Stem cells ENESTPath substudy adds the determination of Ph+ stem cells in bone 
marrow at the following time points, in patients providing separate specific consent to 
participate in the substudy (Figure 4-2):
a) During the screening, before starting nilotinib 300 mg BID treatment
b) After 2 years of nilotinib treatment at Visit 8
c) After 3 years of nilotinib treatment, only in patients with 2 years of consolidation treatment 
(Arm 2) at Visit 204
d) If the patient relapses during the TFR phase, before re-starting the treatment with nilotinib

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A 10-mL bone marrow sample will be obtained and sent to 
 
 for immunophenotype analysis, FACS cell purification, 
fluorescent in situ hybridization (FISH) and RT-PCR. Measurement will be performed by 
flow cytometry in a bone marrow purified population of stem cells in order to detect the 
presence of leukemic Ph+ cells (evaluated by FISH) or BCR-ABL transcripts (evaluated by 
RT-PCR).
Figure 4-2
Optional Stem cells ENESTPath substudy design
4.1.2
Description of ‘CML patient’s voice’ Italian substudy
Italian CAMN107AIC05 patients in consolidation phase consenting to participate will be 
included in the ‘CML patient’s voice’ Italian substudy. See [Post-Text Supplement 1]
4.2
Timing of interim analyses and design adaptations
No formal interim analyses are planned. There will be no publication of results until
enrollment has been completed.
If Novartis decides to publish interim data after enrollment is completed, details will be 
specified in the analysis plan.

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As this study will be overseen by a Data Monitoring Committee (DMC), DMC reports will be 
provided on a regular basis.
Should a predetermined number of patients fulfill the criteria of molecular relapse within the 
TFR phase, the further conduct of the study will be evaluated by the DMC. Any events of 
progression to AP/BC, loss of CCyR, or failure to regain MMR in case of re-initiation of 
treatment for molecular recurrence will be closely monitored by the Novartis Clinical Trial 
Team and the DMC during the entire TFR phase. General stopping rules during the first 
12 months of the TFR phase have been predetermined and are presented in Section 4.4.
4.3
Definition of end of the study
The study will continue until the last patient who was eligible for randomization has 
completed 5 years from study entry, or has been withdrawn from the study. The total maximal 
study duration is therefore 5 years for every patient.
4.4
Early study termination
Predefined stopping rules during the first 12 months of the TFR phase will trigger an 
immediate DMC teleconference. It is the DMC’s responsibility to take the final decision on 
the conduct of this trial.
The stopping rules are based on the frequency of specific events occurring in the ENESTnd 
study [CAMN107A2303]. It is considered crucial that patients treated on this study have 
outcomes during the TFR phase that are comparable or better than those of patients who were 
treated with continuous nilotinib therapy (300 mg BID or 400 mg BID) in the ENESTnd study 
[CAMN107A2303].
Therefore, the following stopping rules for this study will apply to the first 12 months of the 
TFR phase:
1. More than 2 cases of progression to AP/BC, or
2. More than 2 cases of loss of CCyR without re-achievement of CCyR within 6 months of 
nilotinib re-treatment, or
3. More than 9 cases of loss of MMR without re-achievement of MMR within 3 months of 
nilotinib re-treatment
and despite full compliance with BCR-ABL monitoring during the TFR phase for all three 
groups described above and despite full compliance with nilotinib treatment during the 
nilotinib re-treatment phase for groups 2 and 3 (patients with loss of CCyR and patients with 
loss of MMR) according to protocol.
Novartis can terminate the study at any time for appropriate reasons. Should this be necessary, 
the patient should be seen as soon as possible, and the same assessments should be performed 
as described in Section 7.1.8 for a prematurely withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or IECs of the early termination of the trial.

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5
Population
5.1
Patient population
The study population will consist of adult patients (male or female, aged ≥18 years) with a 
confirmed diagnosis of chronic phase Ph+ and/or BCR-ABL+ CML who have been treated 
first-line with imatinib for 24 months or more, and are at least in CCyR. Patients who have 
previously discontinued imatinib could be enrolled in the trial provided that they have been 
treated with imatinib for 24 months (even not continuously) in total and are in imatinib 
treatment at the time of enrollment. Patients must not have achieved ≥MR4.0 at study entry, as 
confirmed by a EUTOS standardized laboratory with validated PCR technology.
The investigator or designee must ensure that only patients who meet all of the following 
inclusion and none of the exclusion criteria are offered enrollment into the study. Written 
informed consent must be obtained prior to any screening procedures. All data for the 
inclusion/exclusion criteria must be verifiable in the patient’s source documents.
Patients enrolled into this study are not permitted to participate in additional parallel 
investigational drug or device studies.
Optional Stem cells ENESTPath substudy
The study population in the Stem cells ENESTPath substudy will consist of those patients 
participating in the ENESTPath trial who consent to participate in this substudy and who sign 
separate specific informed consent for the stem cells substudy.
There is no cap on patient accrual in each single center; accrual is competitive and will 
continue until the target patient number based on statistical sample size calculation is 
achieved.
‘CML patient’s voice’ Italian substudy
Italian CAMN107AIC05 patients in consolidation phase consenting to participate will be 
included in this substudy. [Post-text Supplement 1]
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Male or female patients, aged ≥ 18 years
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
3. Documented confirmed diagnosis of chronic phase Ph+ and/or BCR-ABL+ CML-CP. 
Documented chronic phase CML must meet all of the following criteria:

< 15% blasts in peripheral blood and bone marrow

< 30% blasts plus promyelocytes in peripheral blood and bone marrow

< 20% basophils in the peripheral blood

≥100 x 109/L (≥ 100,000/mm3) platelets

No evidence of extramedullary leukemic involvement, with the exception of hepato-
and/or splenomegaly

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4. Previous first-line treatment with imatinib for a minimum of 24 months (even not 
continuously) in total and in imatinib treatment at time of enrollment
5. Patient in CCyR (A patient with MMR is considered to be in CCyR. Therefore,
cytogenetic response [CgR] assessment has to be done if a patient has less than MMR in 
the local laboratory result and/or in the blood sample that was sent to the EUTOS 
standardized laboratory at the screening visit [patient will be considered screening failure 
if not in CCyR] see Section 7.1.2 for details);
6. Adequate end-organ function as defined by:

Total bilirubin < 1.5 x upper limit of normal (ULN). Does not apply to patients with 
isolated hyperbilirubinemia (e.g. Gilbert’s disease) grade < 3

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN

Serum lipase ≤2 x ULN

Alkaline phosphatase ≤2.5 x ULN

Serum creatinine < 1.5 x ULN
7. Patients must have the following electrolyte values within normal limits at screening
analysis, or corrected to within normal limits with supplements prior to the first dose of 
study medication:

Potassium

Magnesium

Total calcium
8. Patients must have normal marrow function as defined below:

Absolute Neutrophil Count (ANC) ≥1.5 x 109/L

With the exception of people of North African descent for whom the threshold 
for ANC will be ≥1.0 x 109/L due to an increase in the marginal pool of 
neutrophils

Hemoglobin ≥9.0 g/dL

Platelets ≥100 x 109/L
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests,
and other study procedures;
10. Written informed consent must be obtained prior to any screening procedures.
For those patients consenting to participate in the optional Stem cells ENESTPath substudy or 
in the ‘CML patient’s voice’ Italian substudy, the same inclusion criteria for the ENESTPath 
study will be applicable, plus the following:

Separate specific written informed consent for the Stem cells ENESTPath substudy or 
for the ‘CML patient’s voice’ Italian substudy must be obtained before starting any 
sub-study related assessment like but not limited to extraction of additional bone 
marrow samples for stem cells sub-study.

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5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1.
Achievement of ≥MR4.0 at study entry as assessed by a EUTOS standardized laboratory
2.
Previous treatment with BCR-ABL inhibitors other than imatinib
3.
Patients with detectable atypical BCR-ABL transcripts, defined as absence of typical
BCR-ABL transcripts for CML of the types b2(e13)-a2 or b3(e14)-a2 or both 
simultaneously documented at CML diagnosis or at any time before the screening 
procedure
4.
Previous anticancer agents for CML except for:

Imatinib, and/or

Cytoreduction after CML diagnosis, and/or

Interferon for less than 1 year
5.
Known second chronic phase of CML after previous progression to AP/BC
6.
Known impaired cardiac function, including any of the following:

Inability to determine the QT interval on ECG

Complete left bundle branch block

Right bundle branch block plus left anterior or posterior hemiblock

Use of a ventricular-paced pacemaker

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)

QTc > 450 msec confirmed on the average of three serial baseline ECGs (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 severe peripheral occlusive disease or severe 
ischemic cardiovascular disease (e.g. myocardial infarction, ischemic cerebral 
vascular disease) whenever in the opinion of the investigator other treatments could 
have a more favorable benefit/risk profile.

Other clinically significant heart disease (e.g. congestive heart failure or uncontrolled 
hypertension)
7.
Severe and/or uncontrolled concurrent medical disease that in the opinion of the 
investigator could cause unacceptable safety risks or compromise compliance with the 
protocol (e.g. uncontrolled diabetes, active or uncontrolled infection, uncontrolled severe 
hypertension, or uncontrolled severe dyslipidemia). If appropriate measures (e.g. diet, 
exercise, appropriate therapy) are taken to control blood glucose or cholesterol (LDL)
levels or hypertension, the patient can be re-screened for the study
8.
History of acute pancreatitis within 12 months of study entry, or a past medical history of 
chronic pancreatitis
9.
Known presence of significant congenital or acquired bleeding disorder unrelated to 
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10. History of other active malignancy within 5 years prior to study entry with the exception 
of previous or concomitant basal cell skin cancer, or previous cervical carcinoma in situ 
treated curatively;
11. Patients who have not recovered from prior surgery
12. Treatment with other investigational agents within 30 days of Day 1
13. Patients actively receiving therapy with strong CYP3A4 inhibitors (see link for complete 
list of these medications: medicine.iupui.edu/flockhart/table.htm or Appendix 14.1) 
and/or inducers or medications that have the potential to prolong the QT interval (see
http://crediblemeds.org/everyone/composite-list-all-qtdrugs/?rf=All) that cannot be either 
discontinued or switched to a different medication prior to starting study drug
14. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of study drug
15. 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)
16. Women of childbearing 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 or imatinib. 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 6 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):
a. Use of oral, injected, or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate <
1%), e.g. 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
17. Patients not able to understand and comply with study instructions and requirements
For those patients consenting to participate in the optional Stem cells ENESTPath substudy or 
in the ‘CML patient’s voice’ Italian substudy, the same exclusion criteria as for the 
ENESTPath study will apply.

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6
Treatment
6.1
Investigational treatment, other study treatment, supportive 
treatment
Study treatment: nilotinib (AMN107, Tasigna®)
Nilotinib will be supplied as 150 mg hard gelatin capsule. Nilotinib will not be dosed by 
weight or body surface area.
For detailed safety information, refer to the latest [AMN107 Investigator Brochure] and the 
approved product labeling.
6.1.1
Dosing regimen
This is an open-label study; therefore, all patients will receive a daily oral nilotinib dose of 
300 mg BID, given as two 150 mg capsules BID.
Patients eligible for randomization will either enter the TFR phase immediately or continue 
nilotinib for an additional 12 months (on a 1:1 basis).
Patients relapsing during the TFR phase will enter the nilotinib re-treatment phase of the study, 
and will be re-treated with the same dose of nilotinib as they were on before the TFR (i.e., the 
re-treatment dose will be nilotinib 300 mg BID or a lower dose of nilotinib if the dose was 
reduced in the consolidation phase before entering the TFR phase). The patient will 
subsequently remain on study until the patient completes the 5-year study period.
Nilotinib doses should be taken approximately 12 hours apart and must not be taken with food. 
The capsules should be swallowed whole with water. No food should be consumed for 
2 hours before the dose is taken and for at least 1 hour after.
For patients who are unable to swallow capsules, the content of each capsule may be 
dispersed in one teaspoon of apple sauce (puréed apple) and should be taken immediately. No 
more than one teaspoon of applesauce and no other food substance must be used.
The dose regimen can be decreased to 450 mg QD in the case of study drug-related 
non-hematologic and hematologic toxicities. Refer to Section 6.3.2 and Section 6.3.3 for 
further details.
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
regimen
Nilotinib
Capsule for oral use
300 mg BID
Daily
6.1.2
Ancillary treatments
Not applicable.
6.1.3
Rescue medication
Not applicable.

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6.1.4
Guidelines for continuation of treatment
In the 12-month induction phase and the subsequent 12- or 24-month consolidation phase of 
the study, patients may continue treatment until they progress, withdraw consent, experience 
unacceptable toxicity or start new therapy, or it is believed by the investigator to be in the best 
interest of the patient to exit the study.
Patients not achieving a sustained molecular response at 24 months from treatment start (and 
subsequently at 36 months from treatment start dependent of the randomization arm) will exit 
the study and will be treated at the discretion of the investigator according to standard practice. 
Survival information, stem cell transplantation, and information on the status of the patient’s 
disease (i.e., disease progression to AP/BP according to protocol definition, TKI treatment) 
will be collected until death, progression, or until 5 years from study entry, whichever comes 
first.
Patients relapsing during the TFR phase will enter the nilotinib re-treatment phase of the study, 
and will be re-treated with the same dose of nilotinib as they were on before the TFR phase 
(i.e. the re-treatment dose will be nilotinib 300 mg BID or a lower dose of nilotinib if this was 
reduced in the consolidation phase before entering the TFR phase). The patient will 
subsequently remain on study until the completion of the 5-year study period.
If a patient does not tolerate the nilotinib dose, dose modification guidelines specified in 
Table 6-2 and Table 6-3 should be followed.
6.1.5
Treatment duration
All patients will initially receive 24 months of nilotinib treatment unless they experience 
unacceptable toxicity, disease progression or withdrawal of consent, and/or treatment is 
discontinued at the discretion of the investigator.
Following these 24 months of treatment, patients in sustained ≥MR4.0 (as defined in Table 3-1)
for at least the last 12 months will be randomized to either suspend treatment immediately or 
receive a further 12 months of nilotinib therapy.
Patients not achieving a sustained molecular response at 24 months from treatment start (and 
subsequently at 36 months from treatment start depending on the randomization arm) will exit 
the study and will be treated at the discretion of the investigator according to standard practice. 
Survival information, stem cell transplantation, and information on the status of the patient’s 
disease (i.e., disease progression to AP/BC according to protocol definition, TKI treatment) 
will be collected until death, progression, or 5 years from study entry, whichever comes first.
Patients relapsing during the TFR phase will enter the nilotinib re-treatment phase of the study, 
and will be re-treated with the same dose of nilotinib as they were on before the TFR phase 
(i.e., the re-treatment dose will be nilotinib 300 mg BID or a lower dose of nilotinib if the 
dose was reduced in the consolidation phase before entering the TFR phase). The patient will 
subsequently remain on study until the patient completes the 5-year study period.
6.2
Dose escalation guidelines
Not applicable.

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6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. Please refer to the dose 
modification guideline in Table 6-2 and Table 6-3 for details.
For the purpose of these dose-reduction guidelines, toxicity is defined as any AE that is, with 
reasonable likelihood according to investigator’s judgment, caused by the 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 AEs, 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 above the study dose of 300 mg BID (total 600 mg) nilotinib is not allowed. 
Dose 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 a dose reduction to 450 mg daily is required, the dose should be taken as 300 mg in the 
evening and 150 mg in the morning. If a dose reduction to 300 mg daily is required, the dose 
should be taken as 300 mg in the evening.
If multiple toxicities that require dose reduction are present, the greatest dose reduction 
schedule should be applied.
6.3.2
Dose-reduction guidelines for study drug-related non-hematologic 
toxicity
A summary of dose-reduction guidelines for study drug-related clinically significant 
non-hematologic toxicity is presented in Table 6-2.
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 6-2, 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 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

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
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 from the study unless the reason for QTcF prolongation can be 
corrected (such as discontinuing or replacing QT-prolonging concomitant drugs)
Patients who experience Grade 2/3/4 ischemic vascular or cardiovascular events should be 
referred for a cardiac or cardiovascular 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 Scientific Study Management Committee (SSMC) and DMC will be informed on a 
regular basis about the Grade 2/3/4 ischemic vascular or cardiovascular events occurring in
patients enrolled in the CAMN107AIC05 trial.

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Table 6-2
Summary of dose reduction guidelines for study drug-related 
clinically significant non-hematologic toxicity
Study drug and dose
Nilotinib 600 mg daily (as 300 mg BID)
General non-hematologic toxicity
Grade 2
(persisting > 7 days with 
optimal supportive care)
The dose of nilotinib may be reduced to 450 mg daily at the discretion of the 
investigator if clinically appropriate and in the best overall interest of the patient
≥ Grade 3
Hold therapy and resume nilotinib at next lower dose level after recovery to ≤ grade 2 
is seen
l→ 450 mg daily.
If recovery to ≤ grade 2 takes longer than 28 days, the patient must be discontinued 
from the study.
If grade 4 toxicity recurs despite dose reduction to 450 mg daily
l→ discontinue from the study.
Serum hypophosphatemia
Grade 2/3
Continue nilotinib at 300 mg BID and start phosphate supplementation.
Grade 4
Hold therapy and consult Novartis.
Serum creatinine
Grade 2
> 1.5-3.0 x ULN
The dose of nilotinib may be reduced to 450 mg daily 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 daily.
If recovery to ≤ grade 2 takes longer than 28 days, the patient must be 
discontinued from the study.
If grade 4 toxicity recurs despite dose reduction to 450 mg daily
l→ discontinue from the study.
Hepatobiliary [bilirubin, SGPT(AST), SGOT (ALT)]
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, alkaline phosphatase ALP ≤ grade 1, and hemolysis has 
been ruled out per institutional guidelines (e.g. by determination of haptoglobin), 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 daily 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 daily.
If recovery to ≤ grade 2 takes longer than 28 days, the patient must be discontinued 
from the study
If grade 4 toxicity recurs despite dose reduction to 450 mg daily
l→ discontinue from the study.

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Study drug and dose
Nilotinib 600 mg daily (as 300 mg BID)
Pancreatitis (with abdominal symptoms plus lipase elevation)
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 daily after recovery to ≤ grade 1 is seen.
If recovery to ≤ grade 1 take longer than 28 days, the patient must be discontinued 
from the study.
If toxicity recurs
l→ discontinue from the study.
Grade 3
Hold therapy 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 daily after recovery to ≤ grade 2 is seen.
If recovery to ≤ grade 2 takes longer 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 daily based on investigator’s discretion.
Diarrhea
Note: Antidiarrheal medication is recommended at the first sign of loose stools or overt diarrhea. If diarrhea 
cannot be controlled with optimal antidiarrheal 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 daily.
If recovery to ≤ grade 2 takes longer 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 interval, 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 daily.
If recovery to ≤ grade 2 takes longer than 28 days, the patient must be discontinued 
from the study.

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Study drug and dose
Nilotinib 600 mg daily (as 300 mg BID)
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 daily 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 daily.
If recovery to ≤ grade 2 takes longer than 28 days, the patient must be discontinued 
from the study.
If grade 4 toxicity recurs despite dose reduction to 450mg daily
l→ discontinue.
Cardiac QTc prolongation
QTcF > 480 msec
Hold study drug when an ECG shows 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 1 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 re-started, 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 
daily
If QTcF of > 480 msec recurs or QTcF > 500 msec or prolongation of 60 msec to 
baseline value occurs, the patient is to be discontinued.
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 beats per minute, decisions are always 
based on QTcF because QTcB underestimates QT interval prolongation at heart 
rates below 60 beats per minute.

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Study drug and dose
Nilotinib 600 mg daily (as 300 mg BID)
Ischemic vascular or cardiovascular events
Grade 2*
Hold study drug and refer patient for assessment by a vascular or cardiovascular 
specialist.
Resume nilotinib next lower dose level after recovery to ≤ grade 1 is seen
l→ 450 mg daily.
If another recurrence
l→ discontinue.
If recovery to ≤ grade 1 takes longer 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. Patients have to be discontinued whenever in the opinion of the 
investigator the AE is related to the study drug and other treatments could have a 
more favorable benefit/risk profile
* 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 daily.
If recovery to ≤ grade 1 takes longer than 28 days, the patient must be discontinued 
from the study.
If grade 3 toxicity recurs despite dose reduction to 450mg daily
l→ discontinue.
Grade 4
Stop therapy. The patient must be discontinued from study.
6.3.3
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 6-3.
No dose adjustments should be made for grade 1 or 2 hematologic toxicities. Any 
hematologic toxicity must be resolved to < grade 3 within 28 days in order to resume study 
drug. These guidelines provide some general principles as well as recommendations that are 
intended to support the investigator’s judgment and decision about the appropriate 
management of toxicity in the individual patient. However, if a hematologic toxicity does not 
resolve to ≤grade 2 within 28 days, the investigator should consult with the SSMC. Grade 1
or 2 hematologic AEs should not automatically be reported as serious AEs (SAEs) unless the 
event meets the criteria of a SAE as per the protocol.
In the case of any SAEs with a suspected causal relationship to study treatment, it should be 
reported as a SAE, nilotinib treatment may be discontinued, and the SSMC should be 
contacted for advice on patient management.

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Table 6-3
Summary of dose reduction guidelines for study drug-related 
hematologic toxicity
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
ANC or platelets
●
No dose 
reduction
●
No dose 
reduction
●
Grade 3/4 first and second time: Stop nilotinib, 
check at least weekly, resume 600 mg daily dose 
when < grade 3 (ANC > 1.0 x 109/L; platelets > 50 x
109/L)
●
Grade 3/4 third 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 fourth 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 fifth or subsequent time: Stop nilotinib 
until < grade 3, then contact Novartis. It will be 
discussed with the SSMC whether nilotinib can be 
resumed or should be discontinued permanently
6.3.4
Suggested management of selected adverse events
The dose-reduction guidelines listed in Table 6-2 and Table 6-3 should be followed. 
Additional guidelines for management of patients are listed below.
Management of skin rash/pruritus
In most cases, rash is mild, self-limiting, and manageable with antihistamines or topical 
steroids. A short course of oral systemic corticosteroids may be initiated for the management 
of more severe cases, and may be continued until rash has resolved.
Management of edema
Patients should be monitored closely for peripheral edema and rapid weight gain. The use of 
diuretics may be initiated for the management of edema. Patients who develop ≥grade 3 
edema associated with cardiorespiratory symptoms should receive medical evaluations for the 
development of concomitant cardiac or respiratory diagnoses as indicated, such as an ECG
and a chest X-ray. Other medical tests may also be necessary to best manage the medical 
condition.
Management of liver toxicity
Routine liver function tests should be performed throughout the study as indicated in the visit 
schedule. Dose reduction may be warranted, and the decision to continue nilotinib needs to be 
made in light of the clinical situation (see dose-reduction Table 6-2).

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Dose modification for patients on anticoagulants
For patients on treatment with anticoagulants, the following guidelines will apply for 
thrombocytopenia:

If platelets ≤50 x 109/L, withhold treatment with study drug until recovery to at least 
> 75 x 109/L and resume treatment at same dose

If recurrence of platelets ≤50 x 109/L, then withhold treatment until recovery to at least 
> 75 x 109/L and resume treatment to a minimum of 300 mg/day

If the platelet count remains below 75 x 109/L, then nilotinib should be discontinued or 
management with anticoagulation therapy re-evaluated at the discretion of the investigator.
Every time TKI treatment has to be changed, international normalized ratio (INR) should be
checked at least twice weekly until stable INR values are established.
Management of cholesterol increases
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, which may recommend treatment even for grade 
1 cholesterol elevation. Before prescribing a lipid-lowering medication, the possibility of 
drug-drug interactions should be considered as some HMG-CoA reductase inhibitors are also 
metabolized via the CYP3A4 pathway.
Management of glucose increases
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.
Management of other cardiac risk factors
Patients should be assessed or monitored for any other cardiac risk factors, such as family 
history, cardiovascular events in the past medical history, smoking, hypertension, and obesity. 
If the assessment for presence of any other cardiovascular risk factors warrants intervention, 
investigators should follow their local standards of practice or treatment guidelines.
Management of ischemic vascular or cardiovascular 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 AE, 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 in Table 6-2.

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Hepatitis B reactivation
Hepatitis B virus testing should be performed during the study as indicated in Section 7.1 to 
identify patients who may be at risk for Hepatitis B reactivation. Experts in liver disease and 
in the treatment of hepatitis B should be consulted for patients who test positive for hepatitis 
B virus during nilotinib treatment or for TFR patients who test positive for hepatitis B virus 
before treatment is re-initiated. Carriers of hepatitis B virus 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.
Follow-up for toxicities
Patients whose treatment is permanently discontinued 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 adverse events (SAEs) for 30 days following 
premature discontinuation from any phases of the study or following end of participation as 
per protocol.
6.3.5
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. This applies to either dose reductions due to hematological or non-hematological
toxicities if the following criterion is met at least 28 days on treatment on the reduced dose.

All ≥ Grade 3 toxicities have resolved to ≤ Grade 2
6.4
Concomitant medications
6.4.1
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 patient must be told to notify the investigational 
site about any new medications he/she takes after the start of the study drug. All medications 
(other than study drug) and significant non-drug therapies (including physical therapy and 
blood transfusions) administered during the study must be listed on the Prior and Concomitant 
Medications/Significant Non-Drug Therapies eCRF section.
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 when 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).

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The use of hormonal contraception is permitted.
6.4.2
Permitted concomitant therapy requiring caution and/or action
The use of therapeutic coumarin derivatives (i.e. warfarin, acenocoumarol, phenprocoumon) 
is permitted; however, these should be given with caution. Low molecular weight heparin and 
heparin may be substituted for coumarin, and other medications for anticoagulation should be 
considered.
Patients on anticonvulsants should have regular monitoring of plasma concentration of these 
agents.
Cytochrome P450 3A4 substrates
Nilotinib is a moderate CYP3A4 inhibitor in vivo. Because of the thepotential 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 14.1.1.
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.
6.4.3
Prohibited concomitant therapy
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 anticancer 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 TKIs 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 the medication 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 Appendix 14.1.1; however, this list 
may not be comprehensive.

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Every effort should be made NOT to administer a QT interval-prolonging agent during 
the study. If when 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 
http://crediblemeds.org/everyone/composite-list-all-qtdrugs/?rf=All for a list of agents that 
prolong the QT interval (this list may not be comprehensive).
Cardiac monitoring is required upon re-initiation of nilotinib therapy at any point.
Triplicate ECGs must be obtained before treatment re-initiation and 4 weeks after re-initiation 
of nilotinib therapy.
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.
6.5
Patient numbering, treatment assignment and randomization
6.5.1
Patient numbering
Each patient is identified in the study by a patient number (Patient No.) that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Patient No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
patient number suffixed to it, so that each subject is numbered uniquely across the entire 
database. Upon signing the informed consent form (ICF), the patient is assigned to the next 
sequential Patient No. available to the investigator through the Oracle Clinical RDC interface. 
Once assigned, the Patient No. must not be reused for any other subject, and the Patient No. 
for that individual must not be changed, even if the patient is re-screened.
If the patient fails to be randomized for any reason, the reason will be entered into the End of 
Consolidation Phase page.
6.5.2
Treatment assignment and randomization
All patients will initially receive 24 months of open-label nilotinib treatment. Following this, 
eligible patients (i.e., those deemed to have achieved sustained ≥MR4.0) will be randomized to 
one of the two study arms (see Section 4.1 and Section 6.1) in a ratio of 1:1 on a continued 
open-label basis.
A randomization list will be produced by or under the responsibility of Novartis using a 
validated system that automates the random assignment of treatment groups to randomization 
numbers in the specified ratio.
6.5.3
Treatment blinding
This is an open-label trial and blinding is not applicable.

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6.6
Study drug supply
6.6.1
Study drug preparation and dispensation
No specific preparation instructions are applicable to nilotinib. The investigational agent will 
be dispensed by site study personnel on an outpatient basis (see Table 6-4 for details). Patients 
will be instructed on how to take study medication, and will be provided with an adequate 
supply of study drug for self-administration at home until at least their next scheduled study 
visit. Records of drug formulation, batch number, and number of capsules dispensed, received, 
and returned must be recorded.
The study medication is to be stored at room temperature (< 30oC) in a secure, locked area 
while under the responsibility of the investigator. Receipt and dispensing of study medication 
must be recorded by an authorized person at the investigator’s site. The storage temperature 
should be checked weekly, and recorded on a Temperature Log.
Medication labels will be in the local language and will comply with the legal requirements of 
each country.
Table 6-4
Preparation and dispensing
Study treatment
Dispensing
Preparation
Nilotinib
Capsules and instructions for administration are dispensed by study 
personnel on an outpatient basis.
Patients will be provided with an adequate supply of nilotinib for 
self-administration at home until at least their next scheduled study visit.
Not applicable
6.6.2
Study drug packaging and labeling
Nilotinib will be supplied by Novartis as 150 mg hard gelatin capsules. Medication labels will 
be in the local language and will comply with the legal requirements of each country.
6.6.3
Drug supply and storage
Study medication must be received by a designated person at the study site and be kept in a 
secured location to which only the investigator and designated assistants have access.
Table 6-5
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
AMN107 (nilotinib)
Capsules in bottles
Labeled as “AMN107”
AMN107 (nilotinib)
Capsules in blister
Labeled as Tasigna® “nilotinib”
6.6.4
Study drug compliance and accountability
6.6.4.1
Study drug compliance
All dosages prescribed to the patient and all dose changes during the study must be recorded 
on the Dosage Administration Record eCRF.

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6.6.4.2
Study drug accountability
The Investigator or designee must maintain an accurate record of the prescribing of study 
treatment in a drug accountability ledger. Patients will be asked to return all unused study 
drug at each visit in order to allow the investigator and/or study personnel to complete a drug 
accountability check.
At study close-out and as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability ledger to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site.
6.6.5
Disposal and destruction
The drug supply can be destroyed at the local Novartis facility, Drug Supply group, or third 
party, as appropriate, and according to local regulations and Novartis procedure.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1, Table 7-2, Table 7-3, and Table 7-4 list all of the assessments applicable to each 
phase of the study and indicate with an “X”, when visits are to be performed.
All data obtained from these assessments must be supported in the patient’s source 
documentation. The table indicates which assessments produce data to be entered into the 
database (D) or remain in source documents only (S) (“Category” column).
All assessments should be performed within ± 7 days of the time points specified.
For patients consenting to participate to the ‘CML patient’s voice’ Italian substudy please 
refer to [Post Text Supplement 1].
Hepatitis B testing will be performed once and only once, at the next possible visit when 
patient is on treatment or before treatment is re-initiated (see Section 7.2.2.4.5 for details).

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Table 7-1
Visit evaluation schedule 1: screening and induction/consolidation phase
Category
Screening
Re-Screening
Nilotinib Induction/Consolidation Phase
End of Phase 
(EOP) Visit a,b,c
Safety 
Follow-up 
/Study 
Evaluation 
Completion
Follow-up 
I,j
Visit number
Screening
Re-
Screening
Baseline
VD15
VM1
V1
V2
V3
V4-V8
V9-
Randomi
zation
V201-V204
(Only 
applicable to 
Arm 2)
a: End of Phase
(EOP = V400)
EOS
V501-V520
(if 
applicable)
Day/week/
month of 
study
D −28 to 0
D1
D15
m,g
M1
m,g
M3g
M6g
M9g
M12, 
then 
every 3
months 
until 
M24b,g
Within 
15 
working 
days 
from 
M24 visit
M27, then 
every 
3 months until 
M36b,d,g
If patient 
withdraws 
during
induction/conso
lidation phase 
(at any visits 
from baseline to 
V8 for Arm 1 or 
to V204 for Arm 
2).
30 days 
following the 
EOP visit
Every 3 
months ± 
21 days 
until 
5 years 
from study 
entry
Obtain 
informed 
consent
D
x
X
Inclusion/excl
usion criteria
D
x
X
Demographic
s
D
x
X
Relevant 
medical 
history/current 
medical 
conditionso
D
x
X

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Confidential
Page 63
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Category
Screening
Re-Screening
Nilotinib Induction/Consolidation Phase
End of Phase 
(EOP) Visit a,b,c
Safety 
Follow-up 
/Study 
Evaluation 
Completion
Follow-up 
I,j
Visit number
Screening
Re-
Screening
Baseline
VD15
VM1
V1
V2
V3
V4-V8
V9-
Randomi
zation
V201-V204
(Only 
applicable to 
Arm 2)
a: End of Phase
(EOP = V400)
EOS
V501-V520
(if 
applicable)
Day/week/
month of 
study
D −28 to 0
D1
D15
m,g
M1
m,g
M3g
M6g
M9g
M12, 
then 
every 3
months 
until 
M24b,g
Within 
15 
working 
days 
from 
M24 visit
M27, then 
every 
3 months until 
M36b,d,g
If patient 
withdraws 
during
induction/conso
lidation phase 
(at any visits 
from baseline to 
V8 for Arm 1 or 
to V204 for Arm 
2).
30 days 
following the 
EOP visit
Every 3 
months ± 
21 days 
until 
5 years 
from study 
entry
Disease 
history 
(diagnosis of 
CML)p
D
x
Prior/current 
antineoplastic 
therapy
D
x
X
Echocardiogr
am
D
x
X
ECG
D
x
X
xm
xm
x
x
Edinburgh 
Claudication 
Questionnaire
D
x
X
x
xn
xn

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Confidential
Page 64
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Category
Screening
Re-Screening
Nilotinib Induction/Consolidation Phase
End of Phase 
(EOP) Visit a,b,c
Safety 
Follow-up 
/Study 
Evaluation 
Completion
Follow-up 
I,j
Visit number
Screening
Re-
Screening
Baseline
VD15
VM1
V1
V2
V3
V4-V8
V9-
Randomi
zation
V201-V204
(Only 
applicable to 
Arm 2)
a: End of Phase
(EOP = V400)
EOS
V501-V520
(if 
applicable)
Day/week/
month of 
study
D −28 to 0
D1
D15
m,g
M1
m,g
M3g
M6g
M9g
M12, 
then 
every 3
months 
until 
M24b,g
Within 
15 
working 
days 
from 
M24 visit
M27, then 
every 
3 months until 
M36b,d,g
If patient 
withdraws 
during
induction/conso
lidation phase 
(at any visits 
from baseline to 
V8 for Arm 1 or 
to V204 for Arm 
2).
30 days 
following the 
EOP visit
Every 3 
months ± 
21 days 
until 
5 years 
from study 
entry
Physical 
examination
D
x
X
x*
x
x
x
x
x
x
x
Vital signs
D
x
X
x*
x
x
x
x
x
x
x
ECOG 
performance 
status
D
x
X
x*
x
x
x
x
x
x
Hematology
D
x
X
x*
xm
xm
x
x
x
x
x
x
X
Clinical 
chemistry
D
x
X
x*
xm
xm
x
x
x
x
x
x
X
Serum 
pregnancy 
test (if 
applicable)
D
x
X
x*
x
X

Novartis
Confidential
Page 65
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Category
Screening
Re-Screening
Nilotinib Induction/Consolidation Phase
End of Phase 
(EOP) Visit a,b,c
Safety 
Follow-up 
/Study 
Evaluation 
Completion
Follow-up 
I,j
Visit number
Screening
Re-
Screening
Baseline
VD15
VM1
V1
V2
V3
V4-V8
V9-
Randomi
zation
V201-V204
(Only 
applicable to 
Arm 2)
a: End of Phase
(EOP = V400)
EOS
V501-V520
(if 
applicable)
Day/week/
month of 
study
D −28 to 0
D1
D15
m,g
M1
m,g
M3g
M6g
M9g
M12, 
then 
every 3
months 
until 
M24b,g
Within 
15 
working 
days 
from 
M24 visit
M27, then 
every 
3 months until 
M36b,d,g
If patient 
withdraws 
during
induction/conso
lidation phase 
(at any visits 
from baseline to 
V8 for Arm 1 or 
to V204 for Arm 
2).
30 days 
following the 
EOP visit
Every 3 
months ± 
21 days 
until 
5 years 
from study 
entry
Serology 
(Hepatitis B 
testing)
D
X ONLY once after patient is consented to amendment 04
Urine 
pregnancy 
testk (if 
applicable)
D
xk
xk
xk
xk
xk
xk
Urine 
analysisq
D
x
X
x*
Peripheral 
blood BCR-
ABL RQ-PCR 
result from 
local 
laboratory
D
xe

Novartis
Confidential
Page 66
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Category
Screening
Re-Screening
Nilotinib Induction/Consolidation Phase
End of Phase 
(EOP) Visit a,b,c
Safety 
Follow-up 
/Study 
Evaluation 
Completion
Follow-up 
I,j
Visit number
Screening
Re-
Screening
Baseline
VD15
VM1
V1
V2
V3
V4-V8
V9-
Randomi
zation
V201-V204
(Only 
applicable to 
Arm 2)
a: End of Phase
(EOP = V400)
EOS
V501-V520
(if 
applicable)
Day/week/
month of 
study
D −28 to 0
D1
D15
m,g
M1
m,g
M3g
M6g
M9g
M12, 
then 
every 3
months 
until 
M24b,g
Within 
15 
working 
days 
from 
M24 visit
M27, then 
every 
3 months until 
M36b,d,g
If patient 
withdraws 
during
induction/conso
lidation phase 
(at any visits 
from baseline to 
V8 for Arm 1 or 
to V204 for Arm 
2).
30 days 
following the 
EOP visit
Every 3 
months ± 
21 days 
until 
5 years 
from study 
entry
Peripheral 
blood BCR-
ABL RQ-PCR 
(performed in 
a EUTOS 
standardized 
laboratory)
D
xh
X
xh
xh
xh
xh
xh
xc,h
Bone marrow 
assessments/ 
cytogenetics
D
xf
xf
In case of loss of MMR or in case patient has not achieved MMR and it is 
deemed clinically indicated by the investigator
Mutational 
analysis
D
In case of loss of MMR or in case patient has not achieved MMR and it is 
deemed clinically indicated by the investigator

Novartis
Confidential
Page 67
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Category
Screening
Re-Screening
Nilotinib Induction/Consolidation Phase
End of Phase 
(EOP) Visit a,b,c
Safety 
Follow-up 
/Study 
Evaluation 
Completion
Follow-up 
I,j
Visit number
Screening
Re-
Screening
Baseline
VD15
VM1
V1
V2
V3
V4-V8
V9-
Randomi
zation
V201-V204
(Only 
applicable to 
Arm 2)
a: End of Phase
(EOP = V400)
EOS
V501-V520
(if 
applicable)
Day/week/
month of 
study
D −28 to 0
D1
D15
m,g
M1
m,g
M3g
M6g
M9g
M12, 
then 
every 3
months 
until 
M24b,g
Within 
15 
working 
days 
from 
M24 visit
M27, then 
every 
3 months until 
M36b,d,g
If patient 
withdraws 
during
induction/conso
lidation phase 
(at any visits 
from baseline to 
V8 for Arm 1 or 
to V204 for Arm 
2).
30 days 
following the 
EOP visit
Every 3 
months ± 
21 days 
until 
5 years 
from study 
entry
Determination 
of Ph+ stem 
cells in bone 
marrowl 
D
x
X
At V8
At V204
Adverse 
events
D
Continuous
x
x (SAE)

Novartis
Confidential
Page 68
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Category
Screening
Re-Screening
Nilotinib Induction/Consolidation Phase
End of Phase 
(EOP) Visit a,b,c
Safety 
Follow-up 
/Study 
Evaluation 
Completion
Follow-up 
I,j
Visit number
Screening
Re-
Screening
Baseline
VD15
VM1
V1
V2
V3
V4-V8
V9-
Randomi
zation
V201-V204
(Only 
applicable to 
Arm 2)
a: End of Phase
(EOP = V400)
EOS
V501-V520
(if 
applicable)
Day/week/
month of 
study
D −28 to 0
D1
D15
m,g
M1
m,g
M3g
M6g
M9g
M12, 
then 
every 3
months 
until 
M24b,g
Within 
15 
working 
days 
from 
M24 visit
M27, then 
every 
3 months until 
M36b,d,g
If patient 
withdraws 
during
induction/conso
lidation phase 
(at any visits 
from baseline to 
V8 for Arm 1 or 
to V204 for Arm 
2).
30 days 
following the 
EOP visit
Every 3 
months ± 
21 days 
until 
5 years 
from study 
entry
Concomitant 
medications
D
Continuous
x
x (SAE)
Study Drug 
administration
D
Continuous
TKI treatment
D
x
Progression 
to AP/BC
D
x
Stem cell 
transplant 
information
D
x
Survival 
follow-up
D
x

Novartis
Confidential
Page 69
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Category
Screening
Re-Screening
Nilotinib Induction/Consolidation Phase
End of Phase 
(EOP) Visit a,b,c
Safety 
Follow-up 
/Study 
Evaluation 
Completion
Follow-up 
I,j
Visit number
Screening
Re-
Screening
Baseline
VD15
VM1
V1
V2
V3
V4-V8
V9-
Randomi
zation
V201-V204
(Only 
applicable to 
Arm 2)
a: End of Phase
(EOP = V400)
EOS
V501-V520
(if 
applicable)
Day/week/
month of 
study
D −28 to 0
D1
D15
m,g
M1
m,g
M3g
M6g
M9g
M12, 
then 
every 3
months 
until 
M24b,g
Within 
15 
working 
days 
from 
M24 visit
M27, then 
every 
3 months until 
M36b,d,g
If patient 
withdraws 
during
induction/conso
lidation phase 
(at any visits 
from baseline to 
V8 for Arm 1 or 
to V204 for Arm 
2).
30 days 
following the 
EOP visit
Every 3 
months ± 
21 days 
until 
5 years 
from study 
entry
* These assessments should be performed only if the Day 1 visit occurred > 8 days after the screening visit.
a For patients withdrawing from the induction/consolidation phase, this visit should be performed within 15 working days of stopping study treatment.
b If a patient has already had two results with less than MR4.0 by Month 24/36, the patient is not eligible for randomization, and in this case the 24 or the 36 months visit 
should be performed as the EOP visit, including all the assessments of EOP.
c For all other patients, this visit should be performed within 15 working days of the M24 visit to check and confirm their eligibility for randomization, or within 15 working 
days of the M36 visit for patients randomized to study Arm 2 to check and confirm their eligibility to enter the TFR phase-for these eligibility checks at Visits 9/205, no RQ-
PCR evaluation will be done.
d Assessment schedule for patients randomized to receive 24 months of nilotinib consolidation treatment.
e An RQ-PCR result obtained from local laboratory within 14 weeks of signing the ICF is acceptable.
f To be performed only if the patient to deemed to be in less than MMR, as determined by the local laboratory or EUTOS BCR-ABL RQ-PCR assessment: no need to 
re-perform the bone marrow assessment at screening visit if the cytogenetic assessment result shows CCyR and this bone marrow assessment was obtained within 
14 weeks of signing the ICF.
g A “visit window” of ± 7 days is allowed.
h If patients consent, the remaining blood samples after analysis will be stored for biomarker assessment
i For patients withdrawing from the induction/consolidation phase, this follow-up should be done until patient completes 5 years from study entry (starting 3 months after 
the EOP visit).

Novartis
Confidential
Page 70
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Category
Screening
Re-Screening
Nilotinib Induction/Consolidation Phase
End of Phase 
(EOP) Visit a,b,c
Safety 
Follow-up 
/Study 
Evaluation 
Completion
Follow-up 
I,j
Visit number
Screening
Re-
Screening
Baseline
VD15
VM1
V1
V2
V3
V4-V8
V9-
Randomi
zation
V201-V204
(Only 
applicable to 
Arm 2)
a: End of Phase
(EOP = V400)
EOS
V501-V520
(if 
applicable)
Day/week/
month of 
study
D −28 to 0
D1
D15
m,g
M1
m,g
M3g
M6g
M9g
M12, 
then 
every 3
months 
until 
M24b,g
Within 
15 
working 
days 
from 
M24 visit
M27, then 
every 
3 months until 
M36b,d,g
If patient 
withdraws 
during
induction/conso
lidation phase 
(at any visits 
from baseline to 
V8 for Arm 1 or 
to V204 for Arm 
2).
30 days 
following the 
EOP visit
Every 3 
months ± 
21 days 
until 
5 years 
from study 
entry
j For patients who are not eligible for randomization (have already had two results with less than MR4.0 by Month 24/36), this follow-up period should be done until patient 
completes 5 years from study entry (starting 3 months after the EOP visit).
k Urine pregnancy test will be performed on a monthly basis from Month 1 onwards, and test results will be documented in a diary by the patient.
l This assessment is only applicable to those patients consenting to participate in the optional Stem cells ENESTPath substudy. It will be performed at the screening visit, 
at Visit 8 , and (for patients included in Arm 2) at Visit 204.
m Optional visits at Day 15 and Month 1 based on local requirements or as clinically indicated.
n Edinburgh Claudication Questionnaire to be performed every 6 months during the induction/consolidation phase (at Screening and Months 6, 12, 18, 24, 30, and 36 as 
applicable depending on randomization).
o Includes smoking history and family history of cardiovascular events.
p Including if a previous stopping attempt under imatinib was performed and for how long the patient was in TFR.
q: only in patients with known diabetes mellitus (see Section 7.2.2.4.4)

Novartis
Confidential
Page 71
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Table 7-2
Visit evaluation schedule 2: Nilotinib TFR phase (Arm 1)
Category
Nilotinib TFR phase
End of 
Phase 
(EOP)a
visit
Safety 
Follow-up/ 
Study 
Evaluation 
Completion
Follow-upe
Visit Number
V101-V106
V107-V109
V110-V117
EOP = 
401
EOS
V501-V520
(if applicable)
Day/week/month of study in TFR 
phase
M1, then every 
month until M6c
M8, then every 
2 months until 
M12c
M15, then every 
3 months until
M36c,d
If patient 
withdraw 
during
TFR (at 
any visits 
from 
V101 to 
V117)
30 days 
following 
EOP visit
Every 3 months 
± 21 days until 
5 years from 
study entry
Physical examination
D
Every 6 months
x
Vital signs
D
Every 6 months
x
ECOG performance status
D
Every 6 months
x
ECG
D
As needed
x
Edinburgh Claudication Questionnaire
D
Every 6 months
Hematology
D
X
x
x
x
Clinical chemistry
D
Every 6 months
x
Serum pregnancy test (if applicable)
D
x
Urine pregnancy testf (if applicable)
D
xf
xf
xf
Peripheral blood BCR-ABL RQ-PCRb
D
xb
xb
xb
xb
Bone marrow assessments/cytogenetics
D
In case of loss of MMR
Mutational analysis
D
In case of loss of MMR
Adverse events
D
Continuous
x
x
Determination of Ph+ stem cells in bone 
marrowg
D
If patient relapses, before re-starting treatment with nilotinib

Novartis
Confidential
Page 72
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Category
Nilotinib TFR phase
End of 
Phase 
(EOP)a
visit
Safety 
Follow-up/ 
Study 
Evaluation 
Completion
Follow-upe
Visit Number
V101-V106
V107-V109
V110-V117
EOP = 
401
EOS
V501-V520
(if applicable)
Day/week/month of study in TFR 
phase
M1, then every 
month until M6c
M8, then every 
2 months until 
M12c
M15, then every 
3 months until
M36c,d
If patient 
withdraw 
during
TFR (at 
any visits 
from 
V101 to 
V117)
30 days 
following 
EOP visit
Every 3 months 
± 21 days until 
5 years from 
study entry
Concomitant medications
D
Continuous
x
x
TKI treatment
D
x
Progression to AP/BC
D
x
Stem cell transplant information
D
x
Survival follow-up
D
x
a Applicable to all patients withdrawing from the TFR phase and not starting the nilotinib re-treatment phase as per protocol.
b Performed in a EUTOS standardized laboratory. 
c A “visit window” of ± 7 days is allowed.
d For patients completing the TFR phase per protocol, the last scheduled visit of the TFR phase will be the EOP visit (V117 [M36] of the TFR phase).
e For patients withdrawing from the TFR phase and not starting the nilotinib re-treatment phase as per protocol, this follow-up should be done until patient completes 5 
years from study entry (starting 3 months after EOP phase visit).
f Urine pregnancy test will be performed monthly, and test results will be documented in a diary by the patient.
g This assessment is only applicable to those patients consenting to participate in the optional Stem cells ENESTPath substudy. 

Novartis
Confidential
Page 73
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Table 7-3
Visit evaluation schedule 3: Nilotinib TFR phase (Arm 2)
Category
Nilotinib TFR phase
End of 
Phase 
(EOP)a
visit
Safety 
Follow-up/ 
Study 
Evaluation 
Completion
Follow-upe
Visit Number
V205
V206-V211
V212-V214
V215-V218
EOP = 
401
EOS
V501-V520
(if 
applicable)
Day/week/month of study 
in TFR phase
Eligibility
M1, then every month until M6c
M8, then 
every 
2 months 
until M12c
M15, then 
every 
3 months 
until
M24c,d
If patient 
withdraw 
during
TFR (at 
any 
visits 
from 
V101 to 
V117) 
30 days 
following 
EOP visit
Every 3 
months ± 
21 days 
until 
5 years 
from study 
entry
Physical examination
D
x
Every 6 months
x
Vital signs
D
x
Every 6 months
x
ECOG performance status
D
Every 6 months
x
ECG
D
As needed
x
Edinburgh Claudication 
Questionnaire
D
Every 6 months
Hematology
D
x
X
x
x
x
Clinical chemistry
D
x
Every 6 months
x
Serum pregnancy test
(if applicable)
D
x
x
Urine pregnancy testf
(if applicable)
D
xf
xf
xf
Peripheral blood BCR-ABL 
RQ-PCRb
D
xb
xb
xb
xb

Novartis
Confidential
Page 74
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Category
Nilotinib TFR phase
End of 
Phase 
(EOP)a
visit
Safety 
Follow-up/ 
Study 
Evaluation 
Completion
Follow-upe
Visit Number
V205
V206-V211
V212-V214
V215-V218
EOP = 
401
EOS
V501-V520
(if 
applicable)
Day/week/month of study 
in TFR phase
Eligibility
M1, then every month until M6c
M8, then 
every 
2 months 
until M12c
M15, then 
every 
3 months 
until
M24c,d
If patient 
withdraw 
during
TFR (at 
any 
visits 
from 
V101 to 
V117) 
30 days 
following 
EOP visit
Every 3 
months ± 
21 days 
until 
5 years 
from study 
entry
Bone marrow 
assessments/ cytogenetics
D
In case of loss of MMR
Mutational analysis
D
In case of loss of MMR
Adverse events
D
Continuous
x
x
Determination of Ph+ stem 
cells in bone marrowg
D
If patient relapses, before re-starting treatment with nilotinib
Concomitant medications
D
Continuous
x
x
TKI treatment
D
x
Progression to AP/BC
D
x
Stem cell transplant 
information
D
x
Survival follow-up
D
x

Novartis
Confidential
Page 75
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Category
Nilotinib TFR phase
End of 
Phase 
(EOP)a
visit
Safety 
Follow-up/ 
Study 
Evaluation 
Completion
Follow-upe
Visit Number
V205
V206-V211
V212-V214
V215-V218
EOP = 
401
EOS
V501-V520
(if 
applicable)
Day/week/month of study 
in TFR phase
Eligibility
M1, then every month until M6c
M8, then 
every 
2 months 
until M12c
M15, then 
every 
3 months 
until
M24c,d
If patient 
withdraw 
during
TFR (at 
any 
visits 
from 
V101 to 
V117) 
30 days 
following 
EOP visit
Every 3 
months ± 
21 days 
until 
5 years 
from study 
entry
a Applicable to patients withdrawing from the TFR phase and not starting the nilotinib re-treatment phase as per protocol.
b Performed in a EUTOS standardized laboratory
.
c A “visit window” of ± 7 days is allowed.
d For patients completing the TFR phase per protocol the last scheduled visit of the TFR phase will be the EOP visit (V117 [M36] of the TFR phase).
e For patients withdrawing from the TFR phase and not starting the nilotinib re-treatment phase as per protocol, this follow-up should be done until patient completes 5 
years from study entry (starting 3 months after EOP phase visit).
f Urine pregnancy test will be performed monthly, and test results will be documented in a diary by the patient.
g This assessment is only applicable to those patients consenting to participate in the optional Stem cells ENESTPath substudy.

Novartis
Confidential
Page 76
Amended Protocol Version 04 (Clean)
Protocol No. CAMN107AIC05
Table 7-4
Visit evaluation schedule 4: Nilotinib re-treatment phase (if applicable)
Category
Nilotinib Re-treatment
End of Phase 
(EOP) visita,e
Safety 
Followup/Study 
Evaluation 
Completion
Follow-upf
Visit number
V301
V302
V303
V304-314 
(as 
applicable)
a: EOP = V402
EOS
V501-V520 
(as 
applicable)
Day/week/month of study in 
re-treatment phase
Day 1
W6d
M3d
M6, then 
every 
3 months 
until 5 years 
from study 
entryd,e
Within 15 
working days 
of last dose
30 days 
following the 
EOP visit
Every 3 
months ± 21 
days until 5 
years from 
study entry
Physical examination
S
x c
x
x
x
Vital signs
D
x c
x
x
x
ECOG performance status
D
x c
x
x
x
Peripheral blood BCR-ABL RQ-PCRb
D
xb
xb
xb
xb
ECG
D
x c
x
x
Edinburgh Claudication Questionnaire
S
x c,h
xh
Hematology
D
x c
x
x
x
Clinical chemistry
D
x c
x
x
x
Mutational analysis
D
In case of 
loss of MMR
As needed
Serum pregnancy test (if applicable)
D
x c
x
Serology (Hepatitis B testing)
D
X ONLY once after patient is consented to amendment 04
Urine pregnancy testg (if applicable)
D
xg
xg
Adverse events/SAE
D
Continuous
x
x (SAE)
Concomitant medications
D
Continuous
x
x (SAE)

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Category
Nilotinib Re-treatment
End of Phase 
(EOP) visita,e
Safety 
Followup/Study 
Evaluation 
Completion
Follow-upf
Visit number
V301
V302
V303
V304-314 
(as 
applicable)
a: EOP = V402
EOS
V501-V520 
(as 
applicable)
Day/week/month of study in 
re-treatment phase
Day 1
W6d
M3d
M6, then 
every 
3 months 
until 5 years 
from study 
entryd,e
Within 15 
working days 
of last dose
30 days 
following the 
EOP visit
Every 3 
months ± 21 
days until 5 
years from 
study entry
TKI treatment information
D
x
Progression to AP/BC
D
x
Stem cell transplant information
D
x
Survival follow-up
D
x
a Applicable to patients withdrawing from the nilotinib re treatment phase before completing the 5-year study period.
b Performed in a EUTOS standardized laboratory. 
.
c The assessment schedule for Day 1 should be completed for those tests that were not performed on the day of confirmed loss of MR4 0, or loss of MMR.
d A “visit window” of ± 7 days is allowed.
e For patients completing the nilotinib re-treatment phase per protocol, the last scheduled visit of the nilotinib re-treatment phase in order to complete the 5 years from 
study entry will be the EOP visit (V314).
f For patients withdrawing from the nilotinib re-treatment phase before completing the 5-year study period, this follow-up should be done until patient completes 5 years 
from study entry (starting 3 months after EOP phase visit).
g Urine pregnancy test will be performed monthly and test results will be documented in a diary by the patient.
h Edinburgh Claudication Questionnaire to be performed every 6 months during the nilotinib re-treatment phase (Day 1 until patient completes 5 years from study entry as 
applicable).

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7.1.1
Pre-screening assessment
Not applicable.
7.1.2
Screening
Written informed consent must be obtained before any study specific medical procedures are 
performed. A screening visit should occur between study days -28 and 0.
During the screening visit, inclusion and exclusion criteria will be assessed. For details of
assessments required during screening, please refer to Table 7-1.
A recent RQ-PCR result must be available to demonstrate a BCR-ABL level of <MR4.0.
If a RQ-PCR was performed by a local laboratory within 14 weeks of signing the informed
consent (ICF), a RQ-PCR peripheral blood sample should be sent to a EUTOS standardized 
laboratory for confirmation of the baseline BCR-ABL levels.
If a RQ-PCR result from a local laboratory is not available within 14 weeks of signing the 
informed consent (ICF), RQ-PCR peripheral blood samples (two separate vials) for the local 
and the EUTOS standardized laboratory assessment should be collected at the same time.
The decision tree for protocol entry based on the molecular response assessment is as follows:

Patients with <MR4.0 as measured in the local laboratory and confirmed in the EUTOS 
standardized laboratory are eligible

Patients with <MR4.0 as measured in the local laboratory, but with ≥MR4.0 as assessed by a 
EUTOS standardized laboratory, are not eligible, and will be considered as screening 
failures

Patients with ≥MR4.0 as measured in the local laboratory, but with <MR4.0 as assessed by a
EUTOS standardized laboratory, are eligible

Patients with ≥MR4.0 as measured in the local laboratory and confirmed by a EUTOS 
standardized laboratory, are not eligible, and will be considered as screening failures.
If BCR-ABL transcript level at screening is <MMR (less than MR3.0) as assessed at a local 
and/or EUTOS standardized laboratory, a bone marrow biopsy/aspirate needs to be performed 
to assess the patient’s cytogenetic response, unless a bone marrow assessment confirming 
CCyR was obtained within 14 weeks of signing the ICF.
Only patients who are shown to be in CCyR are eligible for ENESTPath. Patients without 
CCyR are considered screening failures.
Every effort should be made to collect data on the risk assessment factors at the time of CML 
diagnosis for each patient enrolled in this study (eosinophils, basophils, spleen size, platelets, 
age).
Re-screening of a patient will be allowed for this study. As long as a patient meets all 
inclusion criteria and none of the exclusion criteria, he/she will be enrolled in this study after 
re-screening.

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7.1.2.1
Eligibility screening
Patients must meet all inclusion and none of the exclusion criteria in order to be eligible for 
the study. Patient eligibility will be confirmed by the investigative staff and captured within 
the source documents maintained at the site. This information will be made available during 
planned interim monitoring visits and compared against the clinical database for accuracy.
7.1.2.2
Information to be collected on screening failures
A patient who signs an informed consent form (ICF) but fails to commence treatment for any 
reason will be considered a screening failure. The reason for not being started on treatment 
will be entered on the Screening Log eCRF page. Demographic information, informed 
consent date, and inclusion/exclusion pages must also be completed for screening failure 
patients. No other data will be entered into the clinical database for patients who are screening 
failures, unless the patient experienced a SAE during the screening phase (see Section 8 for 
SAE reporting details).
7.1.2.3
Patient demographics and other screening characteristics
After the patient has signed the ICF, the following assessments will be performed at the 
screening visit:

Demographics (age, gender, race)

Relevant medical history, including current medical conditions, smoking history, and 
family history of cardiovascular events;

Disease history (diagnosis of CML), and whether a previous stopping attempt under 
imatinib was performed and for how long the patient was in TFR

Prior/current antineoplastic therapy

Prior/concomitant medications

Physical examination (see Section 7.2.2.1 for details)

Vital signs (see Section 7.2.2.2 for details)

ECOG performance status

BCR-ABL RQ-PCR result from local laboratory, performed within 14 weeks of signing 
the ICF

Peripheral blood for RQ-PCR to establish a baseline BCR-ABL value will be collected 
and sent to a EUTOS standardized laboratory. If the patient consents, any blood remaining 
after analysis will be stored at a EUTOS standardized laboratory;

Laboratory evaluations:

Hematology (see Section 7.2.2.4.1 for details)

Clinical chemistry (see Section 7.2.2.4.2 for details)

Urine analysis (see Section 7.2.2.4.4 for details)

Serum pregnancy test and discussion of contraception measures to be taken (if 
applicable) (see Section 7.2.2.4.3 for details)

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Potassium, calcium, magnesium, and/or sodium supplements may be given to correct values 
that are < lower limit of normal (LLN). Post-correction values must not be deemed to be a 
clinically significant abnormality prior to patients being dosed.

Cardiac assessments (see Section 7.2.2.6 for details)

Edinburgh Claudication Questionnaire (see Section 7.2.2.7 for details)
All medications and significant non-drug therapies taken within 14 days prior to first dose 
must be recorded on the Concomitant Medication eCRF page and updated on a continuous 
basis if there are any new changes to the medications. Medications include physician 
prescribed and over-the-counter medications, as well as vitamins, herbal, and alternative 
therapies. Information to be collected on concomitant medications/significant non-drug 
therapies will include the following:

Medication/non-drug therapy trade name

Reason for medication

Start date and end date or continuing at time of examination

Dosage regimen
For those patients consenting to participate in the optional Stem cells ENESTPath substudy, a 
determination of Ph+ stem cells in bone marrow will be performed during the screening visit, 
before starting nilotinib 300 mg BID treatment.
7.1.3
Run-in-period
Not applicable.
7.1.4
Induction/consolidation phase
Patients in the induction/consolidation phase will undergo the following assessments on the 
first day of starting study treatment (Day 1 = study entry) and at every subsequent 3-month 
visit until the end of the consolidation phase (either 24 or 36 months, depending on eligibility 
and randomization arm):

Physical examination (see Section 7.2.2.1 for details)

Vital signs (see Section 7.2.2.2 for details)

ECOG performance status (see Section 7.2.2.3 for details)

Hematology (see Section 7.2.2.4.1 for details)

Clinical chemistry (see Section 7.2.2.4.2 for details)

Serum pregnancy test only at Day 1 (see Section 7.2.2.4.3)

Urine analysis only at Day 1 (see Section 7.2.2.4.4)

Serology (Hep B) if not done at an earlier visit (see Section 7.2.2.4.5 for details)
The patient may be required to attend optional visits at Day 15 and Month 1 based on local 
requirements or as clinically indicated.
In the event that Day 1 is performed within 8 days from the screening visit, the following 
evaluations should not be repeated on Day 1:

Physical examination (see Section 7.2.2.1 for details);

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
Vital signs (see Section 7.2.2.2 for details);

ECOG performance status (see Section 7.2.2.3 for details)

Hematology (see Section 7.2.2.4.1 for details)

Clinical chemistry (see Section 7.2.2.4.2 for details)

Serum pregnancy test (see Section 7.2.2.4.3 for details)

Urine analysis (see Section 7.2.2.4.4 for details)
Urine pregnancy tests will be performed monthly from Month 1 (see Section 7.2.2.4.3 for 
details).
Peripheral blood will be taken for BCR-ABL RQ-PCR assessment (performed in a EUTOS 
standardized laboratory) from Month 3 and at each subsequent 3-month visit until the end of 
the consolidation phase in order to assess the effectiveness of the study medication (see 
Section 7.2.1.1 for details).
An ECG will also be performed at Month 3 and at the End of Phase (EOP) visit (and at the 
optional visits of Day 15 and Month 1, if required) (see Section 7.2.2.6.1 for details).
Patients will complete an Edinburgh Claudication Questionnaire at 6-monthly intervals for the 
duration of the study (see Section 7.2.2.7 for details).
Bone marrow assessments/cytogenetics and mutational analysis will be performed if a patient 
demonstrates a loss of MMR or has not achieved MMR and it is deemed clinically indicated 
by the investigator. If the result is positive for a mutation, further analysis will be performed 
as needed at the discretion of the investigator (see Section 7.2.1.3 for details).
The recording of study drug dosing, concomitant medications, and assessment of AEs will be 
performed on a continuous basis throughout the initiation/consolidation phase.
A “visit window” of ± 7 days is allowed during the induction/consolidation phase.
For those patients consenting to participate in the optional Stem cells ENESTPath substudy, a 
determination of Ph+ stem cells in bone marrow will be performed after 24 months of 
nilotinib treatment (at Visit 8).
For those patients consenting to participate to the ‘CML patients voice’ Italian substudy, 
quiestionnaires and expressive writing assessemnts will be conducted at Visit 6 - Month 18. 
[Post Text Supplement 1].
7.1.5
Randomization/Eligibility visit
After completion of the Month 24 visit, the patient will continue nilotinib treatment until Visit 
9-Randomization, which should occur within 15 working days from the last visit.
If the patient has been in sustained ≥MR4.0 for the previous 12 months as evaluated and 
confirmed on Visit 9, randomization to one of the two treatment arms will be done by using 
an interactive voice response system (IVRS). Detailed instruction on the use of the IVRS will 
be given in a manual.

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Patients will be deemed to be in sustained molecular response if:

Four out of the preceding five quarterly RQ-PCR assessments were ≥MR4.0 (equal or more 
than MR4.0), and

The last assessment was ≥MR4.0 (equal or more than MR4.0).
If the patient is randomized to Arm 1, the study treatment will be immediately interrupted and 
the patient will be instructed to follow the schedule of the Arm 1 TFR phase.
At Visit 9 - Randomization, patients will be asked to return their remaining supply of study 
drug to site.
If the patient is randomized to Arm 2, the study treatment will continue for an additional 12 
months with the same visit schedule as in the first 2 year of consolidation treatment and study 
drug will be dispensed.
After completion of the Month 36 visit, the patient will continue nilotinib treatment until Visit 
205-Eligibility, which should occur within 15 working days from the last visit. If the patient is 
still eligible to enter the TFR phase, the patient will be instructed by the investigator to follow 
the visit schedule of the Arm 2 TFR phase.
At Visit 205 - Eligibility, patients will be asked to return any remaining supply of study drug.
For those patients consenting to participate in the optional Stem cells ENEST substudy, and 
randomized to Arm 2, a determination of Ph+ stem cells in bone marrow will be performed 
after 36 months of nilotinib treatment (Visit 204).
For those patients consenting to participate to the ‘CML patient’s voice’ Italian substudy, 
quiestionnaires and expressive writing assessemnts will be conducted at Visit 9 -
Randomization. [Post Text Supplement 1]
Patients not having confirmed sustained molecular response at 24 months (or at 36 months 
depending on eligibility for randomization) will exit the study and will be treated at the 
discretion of the investigator according to standard practice. Information on survival, stem cell 
transplant and the status of the patient’s disease (i.e. disease progression to AP/BC according 
to protocol definition, TKI treatment) will be collected until death, progression, or 5 years 
from study entry, whichever comes first.
For those patients consenting to participate to the ‘CML patient’s voice’ Italian substudy, 
quality of life quiestionnaires and in-depth qualitative interviews will be conducted at Visit 9 -
Randomization. [Post Text Supplement 1]
The following assessments will be performed at the Randomization-Eligibility visits:

Physical examination (see Section 7.2.2.1 for details);

Vital signs (see Section 7.2.2.2 for details);

Hematology (see Section 7.2.2.4.1 for details);

Clinical chemistry (see Section 7.2.2.4.2 for details);

Serology (Hep B) if not done at an earlier visit (see Section 7.2.2.4.5 for details);

Serum pregnancy test (if patient withdrawn from the study).
At this visit, no peripheral blood BCR-ABL RQ-PCR will be done.

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If the Randomization/Eligibility visit is done within 15 days from Visit 8 or Visit 204 
(depending on randomization arm), the above assessments should not be repeated, except for 
the serum pregnancy test.
7.1.6
Treatment-free remission phase
Following the cessation of study therapy (at either 24 or 36 months, depending on 
randomization), patients will attend visits at the following time frames:

Every month for the first 6 months of the TFR phase (both Arms)

Every 2 months between Months 8 and 12 of the TFR phase (both Arms)

Every 3 months between Months 15 and 24 of the TFR phase (both Arms)

Every 3 months between Months 27 and 36 of the TFR phase for patients enrolled into 
Arm 1 of the study
At the TFR Month 1 visit, patients will be asked to return their remaining supply of study 
drug to site if not done at Visit 9 - Randomization or Visit 205 - Eligibility depending on the 
randomization arm.
At each of the visit times stated above, peripheral blood will be taken for BCR-ABL RQ-PCR 
assessment (performed in a EUTOS standardized laboratory) and hematologic assessments 
(see Section 7.2.2.4.1 for details).
In addition, the following assessments will be performed at 6-month intervals:

Physical examination (see Section 7.2.2.1 for details)

Vital signs (see Section 7.2.2.2 for details)

ECOG performance status; clinical chemistry (see Section 7.2.2.4.2 for details)

ECG if needed (see Section 7.2.2.6.1)

Edinburgh Claudication Questionnaire (see Section 7.2.2.7 for details)

Clinical chemistry (see Section 7.2.2.4.2 for details);
A urine pregnancy test will also be performed monthly, and test results will be documented in 
a diary by the patient (see Section 7.2.2.4.3);
Bone marrow assessments/cytogenetics and mutational analysis will be performed if a patient 
demonstrates a loss of MMR. If the result is positive for a mutation, further analysis will be 
performed as needed at the discretion of the investigator.
Patients who need to re-start the treatment with Nilotinib due to a relapse in the TFR phase 
need to be assessed for Hepatitis B if not done at an earlier visit to identify chronic carriers of 
the virus (see Section 7.2.2.4.5 for details).
For those patients consenting to participate to the ‘CML patient’s voice’ Italian substudy, 
quality of life quiestionnaires and in-depth qualitative interviews will be conducted in this 
phase. [Post Text Supplement 1]
The recording of concomitant medications and assessment of AEs will be performed on a 
continuous basis throughout the TFR phase.
A “visit window” of ± 7 days is allowed during the TFR phase.

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7.1.7
Nilotinib re-treatment phase (if applicable)
If according to the EUTOS standardized laboratory result, the definition of relapse (loss of 
MMR/confirmed loss of MR4.0) is met, the investigator should contact the patient for 
immediate start of the nilotinib re-treatment phase. Treatment with nilotinib should re-start at 
the same dose taken before the TFR phase (i.e., the re-treatment dose will be nilotinib 300 mg 
BID or a lower dose of nilotinib if the dose was reduced in the consolidation phase 
before entering the TFR phase).
The following assessments should be performed on Day 1 of the re-treatment phase if not 
already performed on the day of confirmed loss of MR4.0, or loss of MMR:

Physical examination (see Section 7.2.2.1 for details)

Vital signs (see Section 7.2.2.2 for details)

ECOG performance status (see Section 7.2.2.4.2 for details)

ECG (see Section 7.2.2.6.1 for details)

Hematology (see Section 7.2.2.4.1 for details)

Clinical chemistry (see Section 7.2.2.4.2 for details)

Serum pregnancy test (see Section 7.2.2.4.3 for details)

Serology (Hep B) if not done at an earlier visit (see Section 7.2.2.4.5 for details)

Edinburgh Claudication Questionnaire (see Section 7.2.2.7 for details)
Peripheral blood for BCR ABL RQ PCR (done in a EUTOS standardized laboratory) and 
mutational analysis should not be repeated On Day 1 of the re-treatment phase.
Subsequently, patients will attend study visits every 3 months until they complete 5 years 
from study entry, and will undergo the assessments as per Table 7-4:
Bone marrow assessments/cytogenetics and mutational analysis will be performed if a patient 
demonstrates a loss of MMR. If the result is positive for a mutation, further analysis will be 
performed as needed at the discretion of the investigator.
Patients will complete an Edinburgh Claudication Questionnaire at 6-month intervals for the 
duration of the study (see Section 7.2.2.7 for details).
A “visit window” of ± 7 days is allowed during the re-treatment phase.
The recording of study drug dosing, concomitant medications and assessment of AEs will be 
performed on a continuous basis throughout the re-treatment phase.
7.1.8
End of Phase visit, including premature withdrawal and study 
discontinuation visit
Patients will attend the following EOP visits depending on the time points they will interrupt 
the study:

Visit 400: end of induction/consolidation phase if the patient withdraws at any time from 
baseline to Visit 8 for Arm 1 or to Visit 204 for Arm 2 or if the patient does not achieve
stable ≥MR4.0 during the second year of the induction/consolidation phase

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
Visit 401: end of the TFR phase if the patient withdraws during the TFR phase at any time
from Visit 101 to Visit 117 for Arm 1 or from Visit 206 to Visit 218 for Arm 2 and patient 
doesn’t start re-treatment phase

Visit 402: end of re-treatment phase for patients withdrawn from the nilotinib re-treatment 
phase at any time from Visit 301 to Visit 314
The following assessments will be performed at the above-mentioned EOP visits:

Physical examination (see Section 7.2.2.1 for details)

Vital signs (see Section 7.2.2.2 for details)

ECOG performance status (see Section 7.2.2.4.2 for details)

ECG (see Section 7.2.2.6.1 for details)

Hematology (see Section 7.2.2.4.1 for details)

Clinical chemistry (see Section 7.2.2.4.2 for details)

Serology (Hep B) if not done at an earlier visit (see Section 7.2.2.4.5 for details)

Peripheral blood BCR-ABL RQ-PCR

Serum pregnancy test (if patient is withdrawn from the study)
The recording of concomitant medications and assessment of AEs will also be performed.
An EOP eCRF page should be completed, giving the date and reason for stopping the study 
period prematurely (if applicable).
If a patient refuses to return for the EOP visit or is unable to do so, every effort should be 
made to contact them or a knowledgeable informant by telephone to obtain information. The 
investigator should show “due diligence” by documenting in the source documents the steps 
taken to contact the patient, e.g. dates of telephone calls, registered letters, etc. An EOP eCRF 
page should be completed.
All patients who discontinue the study (whether due to successful completion of any of the 
study phases, or premature withdrawal) should be contacted for safety evaluations 30 days 
from the EOP visit in order to follow any safety issues and record/update concomitant 
medications. This information may be collected by a telephone call or a clinic visit, if 
conducted by a telephone call this may trigger a safety follow-up visit if a medical 
intervention is necessary.
For patients returning to the site for a safety follow-up visit a Hepatitis B testing will be 
performed once if not performed at an earlier visit to identify chronic carriers of the virus (see 
Section 7.2.2.4.5 for details). The patient should then be informed about the outcome of the 
serology test and the potential risk for Hepatitis B reactivation if the test result was positive.
For patients who discontinue earlier in any phase and don’t accept to be followed for survival, 
an EOS eCRF page should be completed.
For patients who accept to be followed for survival see Section 7.1.9.

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7.1.8.1
Criteria for premature patient withdrawal
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time. Patients may be withdrawn from the study if any of the following 
occur:

AEs

Abnormal laboratory value(s), if deemed necessary by the investigator

Abnormal test procedure result(s), if deemed necessary by the investigator

Pregnancy (patients must be withdrawn if pregnancy occurs during the nilotinib 
induction/consolidation phase or the nilotinib re-treatment phase. In case of a pregnancy 
during the TFR phase, the pregnant woman can stay in the TFR phase as long as no 
nilotinib treatment is needed, but she must be withdrawn from the study when/if she meets 
the definition of relapse [loss of MMR/confirmed loss of MR4.0])

Protocol violation

Subject withdrew consent

Lost to follow-up

Administrative issues

Death
In addition, patients should be withdrawn from the study in the event of disease progression, 
defined as:

Progression to CML-AP, i.e.:

≥ 15% blasts in peripheral blood or bone marrow aspirate, but < 30% blasts in both 
peripheral blood and bone marrow aspirate

≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow aspirate

≥ 20% basophils in peripheral blood

Thrombocytopenia (< 100 x 109/L) that is unrelated to therapy

Progression to BC, as defined by any of the following:

≥30% blasts in peripheral blood or bone marrow aspirate

Appearance of extramedullary involvement other than hepato- and/or splenomegaly 
proven by biopsy (i.e. chloroma)
7.1.9
Follow-up period
Patients who terminate the study early in any phase for any reason and accept to be followed
(see Section 7.1.8.1 for details) will be contacted every 3 months ± 21 days until 5 years from 
study entry. Information on survival, stem cell transplant, and the status of the patient’s 
disease (i.e. disease progression to AP/BC according to protocol definition, TKI treatment) 
will be collected. Patients lost to follow-up during this time 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 the steps taken to contact the patient, e.g., dates of 
telephone calls, registered letters, etc.

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The EOS page should be completed when the patient completes/interrupts the follow-up
period.
7.2
Assessment types
7.2.1
Efficacy assessments
Efficacy assessments will be performed at the time points indicated Table 7-1, Table 7-2, and 
Table 7-3.
7.2.1.1
Molecular response
Molecular response will be assessed in all patients. Levels of BCR-ABL transcripts will be 
determined by RQ-PCR testing of peripheral blood and analyzed at a EUTOS standardized 
laboratory according to the methodology described in the EUTOS guidelines (version 
published in Feb 2015).
The percent ratio of BCR-ABL transcripts versus control gene transcripts converted to IS will 
be calculated for each sample.
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. Examples for deeming a sample unsuitable include:

A sample becoming lost during transit to the PCR laboratory in the consolidation/TFR and 
re-treatment phases

Insufficient sample quality (degraded/insufficient RNA)
Molecular response and related variables are defined as the following (see detailed definition 
in Glossary of terms):

MMR (MR3.0): BCR-ABL ≤ 0.1% (IS)

MR4.0: BCR-ABL ≤ 0.01% (IS)

MR4.5: BCR-ABL ≤0.0032% (IS)

MR 5 : BCR-ABL ≤0.001% (IS)
7.2.1.2
Mutational analysis
Mutational analysis will be performed at a EUTOS standardized laboratories.
During the study, in a patient with loss of MMR, mutational analyses will be performed on the 
cDNA available from the RQ-PCR at this time point. Continued mutational analyses may be 
performed as clinically indicated.
Sites will use standard materials for sample collection and shipment. Collection, storage, and 
shipment of samples for mutational analysis will follow the standard practice of the 
designated EUTOS standardized laboratory, as described in the Study Site Laboratory Manual. 
Samples will be refrigerated (2oC to 8oC) after preparation, and shipped to the designated 
EUTOS standardized laboratory at room temperature as described in the [Laboratory Manual].

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7.2.1.3
Bone marrow analysis and cytogenetics
If a patient is deemed to be in less than MMR, as assessed by a EUTOS standardized 
laboratory, CgR assessment must be performed as soon as possible. Cytogenetics must be 
performed by chromosome banding analysis (CBA) of marrow cell metaphases. If marrow 
cells cannot be obtained, CBA can be substituted with interphase FISH of blood cells, using 
dual color dual fusion probes that allow the detection of BCRABL+ nuclei. However, based 
on interphase FISH, one cannot assess the degree of CgR, (minimal, minor, partial) but can 
establish only if the CgR is complete (< 1% BCR-ABL+ nuclei out of at least 200 nuclei).
Bone marrow assessments/cytogenetics will be performed if a patient demonstrates a loss of 
MMR during the study.
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):

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 minimum of 20 metaphases must be examined in each bone marrow sample. Quantification 
of the percentage of Ph+ chromosome metaphases, number of metaphases, number positive 
for the Ph chromosome, additional chromosomal abnormalities as well as data from cytologic 
evaluation (microscopic analysis) of percentage of blasts and promyelocytes will be recorded 
on the Bone Marrow eCRF. These examinations will be performed and analyzed locally.
7.2.2
Safety and tolerability assessments
Safety and tolerability assessments will be performed at the time points indicated in Table 7-1, 
Table 7-2, and Table 7-3.
Safety will be monitored by performing the assessments described below, in addition to 
collecting AE data at every visit. For details on AE collection and reporting, please refer to 
Section 8.
Significant findings that were present prior to the signing of informed consent must be 
included in the Relevant Medical History/Current Medical Conditions page on the patient’s 
eCRF. Significant new findings that begin or worsen after signing of informed consent must 
be recorded on the AE page of the patient’s eCRF.

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7.2.2.1
Physical examination
Physical examination will include an assessment of height (measured in cm at screening only), 
body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) and an 
examination of the general appearance of the patient, including skin, neck (including thyroid), 
eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, and 
neurological.
Patients are encouraged to measure their body weight regularly and to report to the study 
investigator any body-weight change of more than 2 kg as compared to their pre-study body 
weight to detect early signs of fluid retention. Rapid weight gain of ≥ 2 kg should be carefully 
investigated and other measures considered as appropriate.
Information about the physical examination must be present in the source documentation at 
the study site.
Significant findings that were present prior to the signing of informed consent must be 
included in the Relevant Medical History/Current Medical Conditions page on the patient’s 
eCRF. Significant new findings that begin or worsen after signing of informed consent must 
be recorded on the AE page of the patient’s eCRF.
Presence of extramedullary leukemic involvement will be checked at 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, palpable lymph nodes should be considered to be CML 
related only if leukemic blast infiltration has been confirmed via biopsy/histology or by
technically adequate (not contaminated with peripheral blood) aspiration cytology.
When extramedullary 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.
7.2.2.2
Vital signs
Vital signs (blood pressure, heart rate, and body temperature) will be assessed with the patient 
in the sitting position after 2 minutes of rest. Body temperature may be measured orally or via 
ear.
7.2.2.3
Performance status
The patient’s performance status will be assessed according to the ECOG performance status 
scale (see Table 7-5).

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Table 7-5
ECOG performance criteria
ECOG Grade
Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g. light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Source: Oken MM, Creech RH, Tormey DC, et al (1982). Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol; 5:649-55. 
7.2.2.4
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.
Abnormal laboratory values or test results constitute an AE only if they induce clinical signs 
or symptoms, and are considered clinically significant (i.e. requires dose modification and/or 
interruption of study drug, leads to clinical symptoms, causes study discontinuation, or itself 
constitutes a SAE) or require therapy. These events should be recorded on the AE eCRF, as 
well as the appropriate laboratory eCRF and/or comment eCRF page. If the administration of 
nilotinib is delayed/modified due to unacceptable toxicities (see Section 6.3), re-evaluation 
should be performed prior to the next study treatment at a minimum.
All available laboratory evaluations should be performed and results reviewed prior to 
administration of study drug. More frequent examinations may be performed at the 
investigator’s discretion if medically indicated; results should be recorded on the Unscheduled 
Visit eCRF.
7.2.2.4.1 Hematology
Hematology includes assessment of hemoglobin, platelet count, total (absolute) white blood 
cell (WBC) count and an automated and/or manual full differential count, including absolute 
values and percentages of neutrophils, lymphocytes, eosinophils, basophils, monocytes,
promyelocytes, myelocytes, meta myelocytes, and blast cells.
7.2.2.4.2 Clinical chemistry
Clinical chemistry tests will include AST (SGOT), ALT (SGPT), direct bilirubin, indirect 
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, serum creatinine, potassium, magnesium, 
calcium, inorganic phosphorus, and sodium. Potassium, calcium, magnesium, and/or sodium 
supplements may be given to correct values that are < LLN. Post-correction values must not 
be deemed to be a clinically significant abnormality prior to patients being dosed.

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HDL, LDL, total cholesterol, and triglycerides should be assessed under fasting conditions. 
Thus, those parameters in addition to the evaluation of fasting glucose may be conducted in 
the external laboratory within 7 days prior to scheduled visits. If HDL, LDL, total cholesterol,
and triglycerides assessments are not performed under fasting conditions, an unscheduled 
assessment should be performed within 15 days in order to collect these parameters under 
fasting conditions. If the assessment of fasting glucose was not performed at either the 
external laboratory or at site visit, the HbA1C assessment will replace the missing fasting 
glucose test, but every effort should be made to collect the fasting glucose result.
HbA1C will be included in the clinical chemistry assessment for every patient during the 
duration of the trial (screening, every 3 months while under nilotinib treatment, and every 
6 months during the TFR phase).
7.2.2.4.3 Pregnancy assessment
All women of childbearing potential (WOCBP) should undergo serum and urine pregnancy 
testing at the time points stated in Table 7-1, Table 7-2, Table 7-3, and Table 7-4.
Urine pregnancy testing will be performed by the patient on a monthly basis during the 
induction/consolidation phase, the TFR phase, and the re-treatment phase. The results of these 
tests should be recorded in the patient diary, which should be shown to the investigator at 
each visit to confirm that any WOCBP is not pregnant. If a test result indicates a pregnancy, 
the patient must contact the investigator immediately.
If a patient becomes pregnant or suspects being pregnant during the study or within 30 days
after last dose of nilotinib, the Study Doctor needs to be informed immediately, and study 
treatment with nilotinib must be stopped immediately.
Pregnancy testing is not required for patients who are determined to be post-menopausal.
Women are considered post-menopausal and not of childbearing 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.
7.2.2.4.4 Urine analysis
At the screening and Baseline visits, a urine test will be performed to assess the presence of 
microalbuminuria in patients with known diabetes mellitus.
7.2.2.4.5 Serology (Hepatitis B testing)
Patients will be tested once for the following hepatitis B serologic markers: hepatitis B surface 
antigen (HBs Ag) and antibodies to hepatitis B core antigen (HBc Ab / anti HBc).
Patients currently on nilotinib in the induction and consolidation phases of the study should 
have testing performed at the next possible visit in order to identify chronic carriers.
Patients in the TFR phases of the study should be tested for hepatitis B virus before re-
initiating treatment with nilotinib.

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7.2.2.5
Radiological examinations
No radiological examinations will be performed for the assessment of safety.
7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram
A 12-lead ECG should be obtained at screening and at the time points indicated in Table 7-1, 
Table 7-2, Table 7-3, and Table 7-4.
Interpretation of the standard 12-lead ECG tracing must be made by a qualified physician and 
documented on the ECG eCRF page. QTc will be calculated according to Fridericia’s formula. 
Each ECG tracing should be labeled with the study number, patient initials (where regulations 
permit), patient number and date, and kept in the source documents at the study site. 
Clinically significant abnormalities present when the patient signed informed consent should 
be reported on the Medical History eCRF page. New or worsened clinically significant 
findings occurring after informed consent must be recorded on the Adverse Events eCRF page.
At Day 1 of nilotinib re-treatment, QTcF must be < 450 msec prior to re-starting nilotinib. For 
patients with QTcF prolongation above 450 msec, an analysis of serum potassium and 
magnesium should be performed, and if below normal, corrected with supplements to within 
normal limits. Concomitant medications must be reviewed for their potential to inhibit 
CYP3A4 and/or to prolong QT interval. A repeat ECG should be performed within 1 hour of 
the first QTcF of > 450 msec. If QTcF remains > 450 msec, then repeat ECG as clinically 
indicated, but at least once a day until the QTcF returns to < 450 msec.
In case of a grade 3 QT interval prolongation, a cardiologist’s opinion should be requested,
and an appropriate and closer cardiac monitoring of the patient must be put in place until the 
QTcF decreases to < 500 msec.
Additional ECGs can be performed at any time at the investigator’s discretion.
7.2.2.6.2 Echocardiogram
Echocardiography will be performed at screening to assess left ventricular ejection fraction
and may be repeated at the investigator’s discretion if there are signs or symptoms of 
cardiotoxicity.
7.2.2.7
Edinburgh Claudication Questionnaire
Patients will complete an Edinburgh Claudication Questionnaire at screening and at 6-month 
intervals thereafter for the duration of the study (provided in Appendix 14.2).
The questionnaire will be used to see whether it may predict a higher chance of developing 
PAOD/ICVE in patients treated with nilotinib. The rate of specific AEs of interest will be 
calculated in the two groups of patients with either positive or negative tests. The test however 
will not be used as a selection criterion to include or exclude patients.
In case the questionnaire results positive at any visits, please refer to a cardiovascular expert 
for further assessments.

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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 informed consent was signed 
should be recorded in the Medical History eCRF. Adverse event monitoring should be 
continued during TFR phase, and for at least 30 days following the last dose of study 
treatment or the last day of the TFR phase. Adverse events (including laboratory
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate 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. 
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 Section 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 loss of 
response, progression to AP/BC, and death due to disease progression) will be recorded as 
part of the efficacy evaluation and should not be reported as an AE/SAE.
AEs separate from the progression of malignancy (e.g. deep vein thrombosis at the time of 
progression or hemoptysis concurrent with finding of disease progression) will be reported as 
per usual guidelines used for such events with proper attribution regarding relatedness to the 
drug.

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8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an AE in their own right (i.e. are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy, or 
require changes in study treatment) should be recorded on the Adverse Events eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for an AE 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 AE, it is not necessary to separately record the laboratory/test result as an 
additional event.
Laboratory abnormalities that do not meet the definition of an AE should not be reported as 
AEs. A grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a SAE 
unless it meets the definition of serious as defined below and/or as per investigator’s 
discretion. A dose hold or medication for the laboratory abnormality may be required by the 
protocol, in which case the laboratory abnormality should still be reported as an AE.
8.1.3
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 and arterial 
stenosis of a limb
If patients experience ischemic vascular or ischemic cardiovascular events (i.e. ischemic, 
cardiac, cerebrovascular, or peripheral artery-related), carefully consider protocol guidance 
for dose reduction or study drug discontinuation (Protocol Table 6-2).
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. Careful consideration should be given to the 
recommendations outlined in the study protocol (Table 6-2, Table 6-3). Additional laboratory
assessments of lipid profile and glucose should be performed where clinically indicated.
The SSMC and DMC will be informed on regular basis on the grade 2-4 ischemic vascular or 
cardiovascular events occurring to the patients enrolled in the AMN107AIC05 trial.

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8.2
Serious adverse events
8.2.1
Definitions
A SAE is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition
Protocol-exempt SAEs are SAEs specifically defined in the protocol where there has been a 
clear agreement with regulators not to collect these SAEs in the safety database, provided the 
information is collected elsewhere. For example, this may include SAEs that are also a 
primary outcome measure, such as mortality, survival rate, or number of flares of the 
condition being studied.
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has ended the
study (EOS) must be reported to Novartis within 24 hours of learning of its occurrence. Any 
SAEs experienced after this 30-day period (or five half-lives, whichever is longer) should 
only be reported to Novartis if the investigator suspects a causal relationship to the study 
treatment. Recurrent episodes, complications, or progression of the initial SAE must be 
reported as follow-up to the original episode within 24 hours of the investigator receiving the 
follow-up information. An SAE occurring at a different time interval or that is otherwise 
considered completely unrelated to a previously reported one should be reported separately as 
a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess and record the relationship of each SAE to each specific 
study treatment (if there is more than one study treatment), complete the SAE Report Form in 
English, and send the completed, signed form by fax within 24 hours to the oncology Novartis 
Drug Safety and Epidemiology (DS&E) department.

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The telephone and telefax number of the contact persons in the local department of DS&E, 
specific to the site, are listed in the investigator folder provided to each site. The original copy 
of the SAE Report Form and the fax confirmation sheet must be kept with the eCRF 
documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each reoccurrence, 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.
8.3
Emergency unblinding of treatment assignment
Not applicable.
8.4
Pregnancies
To ensure patient safety, each pregnancy in a patient in the induction/consolidation phase, the 
TFR phase, or the re-treatment phase, or within 30 days of the last dose of nilotinib, must be 
reported to Novartis within 24 hours of learning about it. 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. If a study patient becomes pregnant or suspects being pregnant 
during the study or within 30 days of the last dose of nilotinib, the Study Doctor needs to be 
informed immediately, and study treatment with nilotinib has to be stopped immediately.
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the oncology Novartis DS&E department. Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible relationship of 
any pregnancy outcome to the Novartis study treatment. Any SAE experienced during 
pregnancy must be reported on the SAE Report Form.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient ICF
and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee (DMC)
A Data Monitoring Committee (DMC) will be established prior to the randomization of the 
first patient. The DMC will be responsible for reviewing the trial. It is expected that the DMC
will consist of four hematologists, one cardiologist, and one PAG member. There will be a 
DMC charter describing their roles and responsibilities and discussing potential data format
and process issues.

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DMC reports will be provided regularly and specifically:

When at least 200 patients enrolled in the trial have been treated with nilotinib 300 mg
BID for 6 months or discontinued earlier

When 300 patients have been treated for 1 year (expected in March 2015), with objectives 
to assess both efficacy and safety.

When 300 patients have been treated for 2 years (expected in March 2016) with the 
objectives to assess both efficacy and safety.

After 100 patients have had a minimum of 6 months’ follow-up in the TFR phase
DMC reports will include a first assessment of molecular response and early discontinuation 
rate after switching treatment to nilotinib. If the response rates or the attrition rate makes the 
achievement of the target number of patients randomized unlikely, the overall number of 
patients needing to be enrolled into the trial will be reassessed in coordination with the study 
statistician.
In addition to the planned DMC reports, additional safety analyses may also be performed at 
the discretion of the DMC.
The above timing for meetings will be discussed with the DMC and modified if requested 
during the course of the trial.
It is envisioned that the DMC may make four types of recommendations, namely:
1. No safety issues, ethical to continue the study as planned
2. Recommendation to continue the study but proposing an amendment to the protocol (e.g. 
incorporate additional safety assessments)
3. Serious safety concerns precluding further study conduct, regardless of efficacy
4. Other recommendations per DMC decision
8.7
Scientific Study Management Committee
An SSMC will be established comprising investigators participating in the trial who are 
clinical experts in CML.
The SSMC will ensure:

Transparent management of the study according to the protocol through recommending 
and approving modifications as circumstances require

Review of protocol amendments as appropriate
At a minimum, the SSMC will meet once a year. The details of the role of the SSMC are 
defined in the SSMC charter.
9
Data collection and management
9.1
Data confidentiality
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
subject of the following:

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
What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients who have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. whether the patient is 
alive) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
Prior to entering key sensitive personally identifiable information (patient initials and exact 
date of birth), the system will prompt the site to verify that this data is allowed to be collected. 
If the site indicates that country rules or ethics committee standards do not permit collection 
of these items, the system will not solicit patient initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the patient satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated Contract Research Organization [CRO]) will review the protocol and 
eCRFs with the investigators and their staff. During the study, the field monitor will visit the 
site regularly to check the completeness of patient records, the accuracy of entries on the 
eCRFs, the adherence to the protocol and to Good Clinical Practice (GCP), the progress of 
enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information recorded on eCRFs must be traceable to source documents in the patient’s file. 
The investigator must also keep the original signed ICF (a signed copy is given to the patient).
The investigator must give the field monitor access to all relevant source documents to 
confirm their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
and documentation of SAEs. Additional checks of the consistency of the source data with the 
eCRFs are performed according to the study-specific monitoring plan.

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9.3
Data collection
This study will use Electronic Data Capture (EDC). The designated investigator staff will 
enter the data required by the protocol into the eCRF. The eCRFs have been built using fully 
validated secure web-enabled software that conforms to 21 CFR Part 11 requirements, 
investigator site staff will not be given access to the EDC system until they have been trained. 
Automatic validation programs check for data discrepancies in the eCRFs and allow 
modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete and accurate, and that entry and updates are performed in a timely manner.
9.4
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the remote data capture (RDC) system. Designated investigator site 
staff are required to respond promptly to queries and to make any necessary changes to the 
data.
Concomitant treatments entered into the database will be coded using the World Health 
Organization Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and AEs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) terminology.
Randomization codes and data about which arm the patient has been assigned to will be 
tracked using IVRS. The data will be sent electronically to Novartis personnel (or designated 
CRO).
For RDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who complete the consolidation phase 
successfully (i.e. who maintain sustained MR4.0 or better (≥MR4.0) for the last 12 months on 
study) and are randomized.
10.1.2
Patients entering the TFR phase
This population includes all patients who are randomized and enter the TFR phase. For Arm 1,
this population matches the FAS. For Arm 2, it includes all patients entering the TFR phase 
after the additional 12-month treatment period.

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10.1.3
Safety Set
The Safety Set (SS) includes all patients who received at least one dose of study medication. 
Reporting of safety information for these patients will be split into subsets by study phases 
and corresponding time windows.
10.1.4
Per-Protocol Set
The PPS consists of a subset of the patients in the FAS who are compliant with requirements 
of the clinical study protocol.
Protocol deviations leading to exclusion from the PPS will be detailed in the report and 
analysis plan (RAP) and the validation and planning (VAP).
10.1.5
Other analysis sets
Secondary 
 efficacy analyses will be performed in the following analysis 
populations:

All patients enrolled who received at least one dose of study medication;

Patients entering the optional Stem cells substudy who received at least one dose of 
study medication.

Patients entering the ‘CML patient’s voice’ Italian substudy
10.2
Patient demographics/other screening characteristics
Demographic and other data will be summarized descriptively for both the SS and the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, 
summary statistics, such as mean, standard deviation, median, 25th and 75th percentiles, 
minimum, and maximum, will be presented.
10.3
Treatments (study treatment, concomitant therapies, compliance)
All study medication data will be summarized using the safety set (SS).
Time on treatment, duration of exposure, percentage of days on treatment, average dose 
intensity, and actual daily dose will be summarized.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized.
10.4
Primary objective
The primary objective of this trial is to assess the optimal duration of consolidation treatment 
with nilotinib 300 mg BID in order that patients remain in TFR (≥MR4.0) without molecular 
relapse 12 months after entering the TFR phase.
10.4.1
Variable
The primary efficacy variable is the number of patients who remain in TFR (≥MR4.0), without 
molecular relapse and without re-starting nilotinib therapy, at the end of 12 months in the TFR 
phase of the study, in the nilotinib 12 months consolidation treatment arm (total trial time 24 

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months + 36 months) versus the nilotinib 24 months consolidation treatment arm (total trial 
time 36 months + 24 months).
10.4.2
Statistical hypothesis, model, and method of analysis
The optimal duration of a nilotinib 300 mg BID treatment will be evaluated using the null 
hypothesis that the rate of no documented confirmed loss of MR4.0, no loss of MMR in the 
first 12 months after nilotinib cessation is the same in both the arms, with an alternative 
hypothesis that this rate is 40% in Arm 1 versus 60% in Arm 2.

H0: p1 = p2, where p1 and p2 are the rates of no documented confirmed loss of MR4.0, no 
loss of MMR in the first 12 months after starting TFR phase in the two arms of the study

H1: p1 ≠ p2, where p1= 0.40 and p2 = 0.60
A two-sided test with = 0.05 will be used to test this hypothesis.
The rate of successful TFR will be presented together with an exact 95% Clopper-Pearson 
confidence interval.
The chi-square test will be carried out to compare the percentage of patients with no 
documented confirmed loss of MR4.0, no loss of MMR in the first 12 months after starting 
TFR phase in the two arms of the study.
A primary efficacy analysis will be performed on the patients entering the TFR phase.
10.4.3
Handling of missing values/censoring/discontinuations
For the primary analysis of the rate of successful TFR, patients dropping out early from the 
study during the TFR phase will be considered as unsuccessful TFR. In case of missing PCR 
assessment at 12 months after starting the TFR phase, the PCR assessments at 10 and 15
months will be taken into account, if available. Details will be provided in the RAP.
10.4.4
Supportive analyses
The primary analysis will be repeated on the FAS and PPS. Patients randomized to Arm 2 not 
entering the TFR phase will be considered as unsuccessful TFR. The same rule described in 
the previous section will be used to deal with any missing PCR assessment at Month 12.
The proportion of patients treatment free (≥MR4.0) after 2 years and after 3 years from 
randomization will also be computed based on the FAS and descriptively summarized by arm.
10.5
Secondary objectives
10.5.1
Key secondary objective(s)
The key secondary objectives for this trial are:

To evaluate the proportion of patients who are eligible to suspend nilotinib therapy by 
achieving and maintaining a sustained ≥MR4.0 for at least 12 months during consolidation 
treatment with nilotinib 300 mg BID:

Determined by the proportion of patients who have achieved a sustained ≥MR4.0
(defined as having four out of five quarterly assessments of ≥MR4.0 by a EUTOS 

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standardized laboratory over the last 12 months and the last assessment before 
randomization is ≥MR4.0) during the consolidation phase of the study

The proportion of patients who are in sustained ≥MR4.0 at 24 months after completing 
the induction/consolidation phase will be calculated by dividing the number of 
patients who have achieved sustained ≥MR4.0 over at least the last 12 months of the 
consolidation phase by the number of patients who entered the study protocol

To assess the achievement of MMR, MR4.0, and MR4.5 during induction/consolidation 
treatment with nilotinib 300 mg BID at the different time points in patients without that 
response at study entry:

Determined by the proportion of patients who achieve MMR, MR4.0, or MR4.5 on the 
study at selected timepoints (every 3 months until Month 24 or 36 depending on the 
randomized arm) during the induction/consolidation phase

The proportion of patients achieving MMR, MR4.0, or MR4.5 at selected timepoints 
will be computed based on the number of patients without that response at baseline

To assess the molecular response in patients during the induction/consolidation phase with 
nilotinib 300 mg BID at the different time points:

Determined by the proportion of patients in MMR, MR4.0, or MR4.5 at selected time 
points (every 3 months until Month 24 or 36 depending on the randomized arm) 
during the induction/consolidation phase of the study

The proportion of patients in MMR, MR4.0 or MR4.5 at selected time points will be 
descriptively analyzed on all patients enrolled

To assess the proportion of patients in TFR at 3, 6, 12, 18, and 24 months after nilotinib 
cessation in the two treatment arms:

Determined by the proportion of patients with no confirmed loss of MR4.0, no loss of 
MMR, and no re-starting of nilotinib therapy within the first 3, 6, 12, 18 and 24 
months following nilotinib cessation

The proportion of patients in TFR will be calculated by dividing the number of 
patients with no confirmed loss of MR4.0, no loss of MMR, and no re-starting of 
nilotinib therapy in the first 3, 6, 12, 18 and 24 months following nilotinib cessation
by the number of patients entering the TFR phase in the two treatment arms

To assess the molecular response in patients after randomization in the two treatment arms:

Determined by the proportion of patients who are in MMR, MR4.0 or MR4.5 at selected 
time points (i.e. Month 3, Month 6, Month 12 and every 3 months thereafter until 
Month 24 or 36 depending on the randomized arm) during the TFR phase in each of 
the two treatment arms

The proportion of patients in MMR, MR4.0 or MR4.5 at selected time points during the 
TFR phase will be descriptively analyzed on the number of patients in the TFR phase 
in each of the two treatment arms

To assess the kinetics of BCR-ABL transcript level during induction/consolidation 
treatment with 300 mg BID nilotinib, during the TFR phase and during the nilotinib re-
treatment phase:

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
Descriptive statistics of BCR-ABL transcript levels (IS) over time separately for the 
induction/consolidation phase, TFR phase, and nilotinib re-treatment phase will be 
provided

To assess the PFS rate after randomization in the two treatment arms:

Failure of PFS is defined as the earliest occurrence of: progression to AP/BC or death 
from any cause

KM estimation of PFS, which is measured from the randomization date to the date of 
the earliest failure event, will be used for this analysis. Patients not known to have 
progressed or died on or before the cut-off date for the KM analysis will have their 
PFS censored at the earlier of the date of their last assessment for patients who are 
still on study and the date of last contact for patients who are in follow-up.

To assess the TFS rate after start of the TFR phase in the two treatment arms:

Failure of TFS is defined as lack of any of the following events: loss of MMR, 
confirmed loss of MR4.0, re-start of nilotinib treatment, progression to AP/BC, or 
death from any cause

KM estimation of TFS, which is measured from the start of TFR phase to the date of 
the earliest failure event, will be used for this analysis. Patients not known to have had 
any of the events on or before the cut-off date for the KM analysis will have their TFS 
censored at the earlier of the date of their last assessment for patients who are still on 
study and the date of last contact for patients who are in follow-up.

To estimate the OS rate after randomization in the two treatment arms:

KM estimation of OS, which is measured from the date of randomization to the date 
of death due to any cause, will be used for this analysis. For patients not known to 
have died on or before the cut-off date, survival time will be censored at the date of 
last contact.

To assess the safety profile of nilotinib during the induction/consolidation phase, the TFR 
phase, and the re-treatment phase (see Section 10.5.3)
10.5.2
Other secondary efficacy objectives
For those patients consenting to participate in the optional Stem cells ENESTPath substudy, 
the following secondary objectives will also be evaluated:

To evaluate the presence and number of LSC and their progenitors in the bone marrow of 
all patients participating in this substudy before and after completing induction and first 
year of consolidation phase (at Visit 8):

The proportion of patients presenting LSC in the bone marrow will be calculated at 
each time point and descriptively analyzed.

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
To evaluate whether a longer treatment period of consolidation with nilotinib (patients in 
Arm 2 versus patients in Arm 1) induces a reduction in the percentage of patients 
presenting LSC and progenitor cells in bone marrow at the end of consolidation phase and 
to quantify this reduction:

The proportion of patients presenting LSC in the bone marrow at the end of the 
consolidation arm (Visit 8 for Arm 1 and Visit 204 for Arm 2) will be descriptively 
analyzed by treatment arm

To perform an exploratory analysis in order to evaluate whether relapse in patients during 
the TFR phase in either arm correlates with the presence of LSC and progenitor cells in 
bone marrow at the end of the consolidation phase and at the time of relapse during TFR.
Please refer to the [Post-Text Supplement 1] to see the objectives of the ‘CML patient’s 
voice’ Italian substudy.
10.5.3
Safety objectives
10.5.3.1
Analysis set and grouping for the analyses
Safety analyses will be based on the SS and presented by study phase. The safety summary 
tables will include only assessments collected no later than 30 days after study treatment 
discontinuation. All safety assessments will be listed, and those collected later than 30 days 
after treatment discontinuation will be flagged.
10.5.3.2 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 and study phase.
Specific safety event categories will be considered. Such categories consist of one or more 
well-defined safety events that are similar in nature and for which there is a specific clinical 
interest in connection with the study treatment.
For each specified safety event category, the number and percentage of patients with at least 
one event that is in the category will be reported.
10.5.3.3 Laboratory abnormalities
For laboratory tests covered by the CTCAE version 4.03, the study’s biostatistician 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 for which grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following summaries, split by treatment and study phase, will be generated separately for 
hematology and clinical chemistry:

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Therefore, it is assumed that the percentage of patients without relapse will be 40% in Arm 1, 
and 60% in Arm 2. Considering this, a sample size of 107 patients per group (a total of 214) is 
needed to detect such difference. These calculations are based on a two-sided chi-square test 
at the 0.05 alpha level and with a power of 80%.
Assuming that 5% of patients will be unevaluable after randomization, a total of 226 patients 
will need to be randomized in order to adequately power the study.
Finally, as explained above, assuming that 40% of the patients switched from imatinib to 
nilotinib will achieve ≥MR4.0 at the end of the 12-month induction phase, and will maintain 
this level of MR by the end of the 12-month consolidation phase prior to randomization, a 
total of 565 patients are required for this study.
10.8
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented, and will be reported in accordance 
with the International Conference on Harmonization (ICH) Harmonised Tripartite Guidelines 
for GCP, with applicable local regulations (including European Directive 2001/20/EC and US 
Code of Federal Regulations Title 21), and with the ethical principles laid down in the 
Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed ICF must be reviewed and approved by a properly constituted 
IRB/IEC/Research Ethics Board (REB) before study start. A signed and dated statement that 
the protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Prior to study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs, and 
regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may be included in the study only after providing written (witnessed, where 
required by law or regulation) and IRB/IEC/REB-approved informed consent. Informed 
consent must be obtained before conducting any study-specific procedures (i.e. all of the 
procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient’s source documents. The date when a patient’s informed consent 
was actually obtained will be captured in their eCRFs.

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Novartis will provide investigators in a separate document with a proposed ICF that is 
considered appropriate for this study and complies with the ICH GCP guideline and 
regulatory requirements. Any changes to this ICF suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the approved 
version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of childbearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered into the study.
Those patients who decide to participate in the optional Stem cells ENESTPath substudy will 
sign a specific ICF, separate from the ICF for the core protocol. Refusal to give consent for 
the stem cells study will not affect eligibility for the main ENESTPath study.
Those patients who decide to participate in the ‘CML patient’s voice’ Italian sub study will 
sign a specific ICF, separate from the ICF for the core protocol. This substudy will be 
conducted in Italy only.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.4.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database, such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report, the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
Together with the clinical trial team, the DMC chair and the SSMC Chair will also develop 
recommendations for publication of study results, including authorship rules.
All authors must have:

Contributed substantially to the concept, design and/or conduct of the (i.e. patient accrual), 
or to the acquisition, analysis, and interpretation of data, AND

Drafted or critically revised the proposed clinical publication for important intellectual 
content, AND

Approved the final proposed clinical publication for submission, AND

Have intimate knowledge of trial implementation/analysis
Authors may be external or internal to Novartis. There is no predetermined ratio of internal to 
external authors but due consideration will be given to balance.
The details of the publication guidelines are summarized in the ENESTPath publication 
charter.

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11.6
Study documentation, record keeping, and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of patients. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits, and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, 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 patient files 
and records kept at the pharmacy, laboratories, and medico-technical departments involved in 
the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study eCRF is the primary data collection instrument for 
the study. The investigator should ensure the accuracy, completeness, legibility, and 
timeliness of the data reported in the eCRFs and all other required reports. Data reported on 
the eCRF derived from source documents should be consistent with the source documents or 
the discrepancies should be explained. All data requested on the eCRF must be recorded. Any 
missing data must be explained. 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 
eCRFs, 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 
15 years from the completion of the clinical trial unless the sponsor provides written 
permission to dispose of them or requires their retention for an additional period of time 
because of applicable laws, regulations, and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed ICFs and the patient enrollment log 
must be kept strictly confidential to enable patient identification at the site.

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11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by the study personnel who is directly involved in 
the treatment or evaluation of patients at the site, prior to study start.
12
Protocol adherence
Investigators must ascertain they will apply due diligence to avoid protocol deviations. Under 
no circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the Clinical Study Report.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC/REB at the 
study site should be informed within 10 working days.

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13
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O’Dwyer ME, Swords RT, Giles F, et al (2009). Nilotinib 300 mg twice daily is effective and 
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For the ‘CML patients' voice' Italian substudy, please refer to the Post text Supplement 1

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Appendices
14.1
Appendix 1 List of CYP3A4 inducers and inhibitors
14.1.1
List of medications metabolized by CYP3A4, strong, moderate and 
weak inhibitors of CYP3A4 to be used with caution
CYP3A4 substrates permitted but 
patients should be carefully monitored 
for drugs indexed 1 and 2
Strong 
inhibitors
Moderate
inhibitors
Weak inhibitors
alfentanil1,2
fentanyl2
clarithromycin
aprepitant
alprazolam
fluticasone1
diergotamine2
conivaptan
atazanavir
AMD070
cyclosporine2
adinazolam
indinavir
cimetidine
amlodipine
maraviroc1
alprazolam
itraconazole
ciprofloxacin
azithromycin
midazolam1
amlodipine
ketoconazole
darunavir
bicalutamide
alpha-
dihydroergocryptine1
aripiprazole
lopinavir
diltiazem
chlorzoxazone
sildenafil1
chlorpheniramine
mibefradil
erythromycin
cilostazol
tipranavir1
diazepam
nefazodone
fluconazole
cyclosporine
triazolam1
estazolam
nelfinavir
grapefruit juice
fluvoxamine
perospirone1
nisoldipine
posaconazole
imatinib
ginkgo
darifenacin1
quinine
ritonavir
tofisopam
goldenseal
ebastine1
trazodone
saquinavir
verapamil
isoniazid
eletriptan1
nitrendipine
telithromycin
lacidipine
eplerenone1
mevastatin
troleandomycin
M100240
everolimus1
lovastatin1
voriconazole
oral contraceptives
felodipine1
atorvastatin1
peppermint oil
brotizolam1
simvastatin1
propiverine
budesonide1
fluvastatin
ranitidine
buspirone1
ranolazine
sirolimus1,2
roxithromycin
ergotamine2
Seville orange juice
tabimorelin
1 Sensitive substrates: drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-
administered with a potent inhibitor of the respective enzyme.
2 Substrates with narrow therapeutic index (NTI): drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades 
de Pointes).
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.

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Weak inhibitors may result in a substrate AUC ≥ 1.25-fold increase and < 2-fold 
increase.
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 Novartis Oncology Clinical Pharmacology Internal 
Memorandum, Drug-drug interactions (DDI) Database (last updated 30 August 2010) for 
update or more details.

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Edinburgh Claudication Questionnaire