Conditions: CML
Keywords: CML, chronic myeloid leukemia, stop, niotinib, discontinue, imatinib, switch, MR4.5, undetectable, bcr-abl
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 59
Healthy volunteers: no

Brief summary:
To evaluate molecular relapse free rates 6 months after stopping nilotinib therapy in patients who achieve MR4.5

Detailed description:
Study protocol included criteria for study termination that was met when \> 2 patients lost CCyR during TFR phase (\> 1% BCR-ABL); This study was terminated early as \> 2 cases of confirmed loss of complete cytogenetic response were reported despite BCR-ABL monitoring during the TFR Phase. All cases achieved MR4.5 after Nilotinib treatment re-initiation and maintained until end of study; trial did not mandate re-initiation within 4 weeks after loss of MMR\_ that was a requirement in other Nilotinib TFR trials Initial sample size was 300 patients with CML-CP; Amendment #2 in June 2015 reduced sample size to 59 due to recruitment challenges; Study endpoint analysis and interpretations of data were challenging due to small sample size for early study closure..

Arms:
arm 1: Patients entered a monitoring phase for 2 years and received 300 mg nilotinib mg bid. Patients who achieved MR4.5 entered a Consolidation Phase and were treated with nilotinib for 2 years. If MR4.5 was sustained during the Consolidation phase, patients were eligible to stop taking niltoinib during the treatment-free remission (TFR) phase.

Interventions: intervention 1: nilotinib
Intervention descriptions: intervention 1: Nilotinib will be provided as 150 mg capsules. Patients will take nilotinib 300mg twice daily on study and dose modifications to 450mg once daily is permitted per protocol.

Protocol document:
Prot_001.pdf: 
U.S. Medical Affairs
AMN107, Nilotinib, Tasigna
Protocol CAMN107A US37 / NCT01744665
A phase II randomized, multicenter study of treatment-free 
remission in chronic myeloid leukemia in chronic phase 
(CML-CP) patients who achieve and sustain MR4.5 after 
switching to nilotinib
Authors
Document type
Amended Protocol Version
EUDRACT number
Not applicable
Version number
04 (Clean)
Development phase
II
Document status
Final
Release date
05-Jul-2016
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
Amendment 4 ....................................................................................................................11
Protocol summary:.............................................................................................................18
1
Background........................................................................................................................22
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............22
1.2
Introduction to investigational treatment...............................................................22
1.2.1
Overview of nilotinib............................................................................22
1.2.2
Non-clinical experience ........................................................................22
2
Rationale............................................................................................................................25
2.1
Study rationale and purpose...................................................................................25
2.2
Rationale for the study design ...............................................................................26
2.3
Rationale for dose and regimen selection..............................................................27
3
Objectives and endpoints...................................................................................................27
4
Study design ......................................................................................................................30
4.1
Description of study design ...................................................................................30
4.1.1
Screening (Day -28-0)...........................................................................30
4.1.2
Monitoring Phase (Years 1 and 2) ........................................................30
4.1.3
Consolidation Phase..............................................................................31
4.1.4
Treatment-Free Remission (TFR) Phase...............................................31
4.1.5
Nilotinib Treatment Reinitiation (NTRI) Phase....................................31
4.2
Timing of data cuts ................................................................................................31
4.3
Definition of end of the study................................................................................31
4.4
Early study termination..........................................................................................32
5
Population..........................................................................................................................32
5.1
Patient population..................................................................................................32
5.2
Inclusion criteria ....................................................................................................32
5.3
Exclusion criteria...................................................................................................33
6
Treatment...........................................................................................................................35
6.1
Study treatment......................................................................................................35
6.1.1
Dosing regimen .....................................................................................35
6.1.2
Treatment duration................................................................................36
6.2
Dose escalation ......................................................................................................36


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6.3
Dose modifications ................................................................................................36
6.3.1
Dose modification and dose delay ........................................................36
6.3.2
Suggested management of selected adverse events for nilotinib..........42
6.3.3
Follow-up for toxicities.........................................................................44
6.3.4
Anticipated risks and safety concerns of the study drug.......................44
6.4
Concomitant medications ......................................................................................44
6.4.1
Permitted concomitant therapy .............................................................44
6.4.2
Permitted concomitant therapy requiring caution and/or action...........45
6.4.3
Prohibited concomitant therapy ............................................................45
6.5
Patient numbering, treatment assignment or randomization .................................46
6.5.1
Patient numbering .................................................................................46
6.5.2
Treatment assignment or randomization...............................................47
6.6
Study drug preparation and dispensation...............................................................47
6.6.1
Study drug packaging and labeling.......................................................47
6.6.2
Drug supply and storage........................................................................47
6.6.3
Study drug compliance and accountability ...........................................47
7
Visit schedule and assessments .........................................................................................48
7.1
Study flow and visit schedule................................................................................48
7.1.1
Screening (Day -28 to 0).......................................................................59
7.1.2
Treatment period ...................................................................................60
7.1.3
Study completion and early termination from study.............................61
7.1.4
Safety follow up ....................................................................................63
7.2
Assessment types...................................................................................................63
63
7.2.2
Safety and tolerability assessments.......................................................65
.69
7.2.4
Patient reported outcomes.....................................................................70
8
Safety monitoring and reporting........................................................................................72
8.1
Adverse events.......................................................................................................72
8.1.1
Definitions and reporting ......................................................................72
8.1.2
Laboratory test abnormalities................................................................73
8.1.3
Adverse events of special interest.........................................................74
8.2
Serious adverse events...........................................................................................74
8.2.1
Definitions.............................................................................................74
8.2.2
Reporting...............................................................................................75
8.3
Emergency unblinding of treatment assignment ...................................................76


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8.4
Pregnancies............................................................................................................76
8.5
Warnings and precautions......................................................................................76
8.6
Data Monitoring Committee..................................................................................76
8.7
Study Management Committee (SMC) .................................................................76
9
Data collection and management.......................................................................................76
9.1
Data confidentiality ...............................................................................................76
9.2
Site monitoring ......................................................................................................77
9.3
Data collection.......................................................................................................77
9.4
Database management and quality control............................................................78
10 Statistical methods and data analysis ................................................................................78
10.1
Analysis sets ..........................................................................................................79
10.1.1
Full Analysis Set ...................................................................................79
10.1.2
Safety set ...............................................................................................79
10.1.3
Per-protocol set .....................................................................................79
10.2
Patient demographics/other baseline characteristics .............................................79
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................79
10.4
Primary objective...................................................................................................80
10.4.1
Molecular relapse is defined as having a confirmed BCR-ABL 
ratio above MMR (2 consecutive BCR-ABL levels >0.1%IS taken 
approximately 4 weeks apart) variable .................................................80
10.4.2
Statistical hypothesis, model, and method of analysis..........................80
10.4.3
Handling of missing values/censoring/discontinuations.......................80
10.4.4
Supportive analyses...............................................................................80
10.5
Secondary objectives .............................................................................................80
10.5.1
Key secondary objective(s)...................................................................80
10.5.2
Other secondary efficacy objectives .....................................................80
10.5.3
Safety objectives ...................................................................................81
.82
10.6
Interim analysis......................................................................................................83
10.7
Sample size calculation..........................................................................................83
11 Ethical considerations and administrative procedures ......................................................83
11.1
Regulatory and ethical compliance........................................................................83
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................83
11.3
Informed consent procedures.................................................................................83
11.4
Discontinuation of the study..................................................................................84
11.5
Publication of study protocol and results...............................................................84
11.6
Study documentation, record keeping and retention of documents.......................84


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11.7
Confidentiality of study documents and patient records .......................................85
11.8
Audits and inspections...........................................................................................85
11.9
Financial disclosures..............................................................................................85
12 Protocol adherence ............................................................................................................85
12.1
Amendments to the protocol..................................................................................86
13 References (available upon request)..................................................................................87
List of tables
Table 3-1
Objectives and related endpoints ..........................................................28
Table 6-1
Dose and treatment schedule.................................................................35
Table 6-2
Nilotinib dose adjustments for hematologic AE (WBC or PLT)..........37
Table 6-3
Summary of nilotinib dose reduction guidelines for study drug-
related non-hematologic toxicity and for ischemic vascular and 
cardiovascular events regardless of study drug relationship.................38
Table 7-1
Visit evaluation schedule – Monitoring Phase......................................50
Table 7-2
Visit evaluation schedule – Consolidation Phase..................................53
Table 7-3
Visit evaluation schedule – Treatment-free Remission Phase ..............55
Table 7-4
Visit evaluation schedule – Nilotinib Treatment Re-initiation .............57
Table 7-5
Sokal formulation..................................................................................60
Table 7-6
Loss of efficacy milestones requiring early termination.......................62
Table 7-7
ECOG performance status.....................................................................66
Table 7-8
Clinical laboratory parameters collection plan .....................................67
Table 7-9
Local ECG collection plan....................................................................68
70


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List of abbreviations
ABL
Abelson proto-oncogene
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute Neutrophil Count
AP
Accelerated Phase
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
b.i.d
bis in diem/twice a day
BC
Blast crisis
BCR
Breakpoint Cluster Region gene/BCR gene product
BCR-ABL
Fusion gene from BCR and ABL
CCG
Case Report Form Completion Guidelines
CCyR
Complete cytogenetic Response
CD
Consolidation Day
CHR
Complete hematologic response
CML
Chronic myeloid leukemia
CP
Chronic phase
CRO
Contract Research Organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DNA
Deoxyribonucleic acid
DS&E
Drug Safety and Epidemiology
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report/Record Form
EDC
Electronic Data Capture
EMA
European Medicines Agency
ENESTcmr
Evaluation nilotinib efficacy and safety in clinical trials complete molecular 
response study
ENESTnd
Evaluating nilotinib efficacy and safety in clinical trials newly diagnosed study
EOC
End of Cycle
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
Colony Stimulating Growth Factors
GI
Gastrointestinal
GIMEMA
Gruppo Italiano Malattie EMatologiche dell'Adulto (Italian Group for Hematological 
Diseases in Adults
GM-CSF
Granulocyte-macrophage colony-stimulating factor
H2
Histamine receptor H2


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HBV
Hepatitis B Virus
HBcAb
Hepatitis B Core Antibody
HBsAb
Antibodies to Hepatitis B Surface Antigen
HBsAg
Hepatitis B Surface Antigen
HDL
High Density Lipoprotein
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IN
Investigator Notification
IRB
Institutional Review Board
IRIS
International Randomized Interferon versus STI571 study
IRT
Interactive Response Technology
IS
International Scale
LDH
Lactate dehydrogenase
LDL
Low Density Lipoprotein
LLN
Lower limit of normal
MD
Monitoring Day
MDASI-CML
M.D. Anderson Symptom Inventory – Chronic Myeloid Leukemia
MMR
Major molecular response
NCI
National Cancer Institute
NTRI
Nilotinib Treatment Re-Initiation
OS
Overall Survival
p.o.
per os/by mouth/orally
PCR
Polymerase Chain Reaction
Ph+
Philadelphia chromosome positive
PHI
Protected Health Information
PI-3
Phosphoinositide-3
PK
pharmacokinetics
PLT
Platelets
pt/pts
Patient / Patients
q.d.
Quaque die/ once a day
QoL
Quality of Life
QTcF
Frederica corrected QT interval
RD
Re-Initiation Day
REB
Research Ethics Board
RFR
Relapse-free rate
RNA
Ribonucleic acid
RQ-PCR
Quantitative real-time polymerase chain reaction
RR
Relative Risk (Sokal score)
RR
Respiratory Rate
SAE
Serious Adverse Event
SGOT
Serum Glutamic Oxaloacetic Transaminase


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SGPT
Serum Glutamate Pyruvate Transaminase
SI
International System of Units
SMC
Study Management Committee
SmPC
Summary of Product Characteristics
SOC
Standard of Care
SOP
Standard Operating Procedure
STAT5
Signal Transducer and Activator of Transcription 5
TC
Total Cholesterol
TFR
Treatment Free Remission
TG
Triglycerides
TKI
Tyrosine kinase inhibitor
ULN
Upper Limit of Normal
VAS
Visual analogue scale
VES
Visit Evaluation Schedule
WBC
White Blood Cell
WHO
World Health Organization
WNL
Within Normal Limits


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Accelerated Phase (AP)
Accelerated Phase is defined as any of the following:

≥ 15% blasts in the peripheral blood or bone marrow, but < 30% 
blasts in both the peripheral blood and bone marrow

≥ 30% blasts plus promyelocytes in peripheral blood or bone 
marrow

≥ 20% basophils in the peripheral blood

Thrombocytopenia (<100 x 10^9/L) that is unrelated to therapy
Blast Crisis (BC)
Blast crisis as defined by any of the following:

≥ 30% blasts in peripheral blood or bone marrow

Appearance of extramedullary involvement other than 
hepatosplenomegaly proven by biopsy
Confirmed loss of MR4.0
Two consecutive BCR-ABL results taken 4-8 weeks apart that are 
greater than 0.01%IS
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days. In this study, one cycle = 30 days
Cytogenetic response

Complete (CCyR) - 0% Ph+ metaphases

Partial (PCyR) - 1 to 35% Ph+ metaphases

Minor (mCyR) - 36 to 65% Ph+ metaphases

Minimal - 66 to 95% Ph+ metaphases

None - 96 to 100% Ph+ metaphases
Disease Progression
The following events are considered disease progression:

Accelerated phase

Blast crisis

CML-related death
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 treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). 
This also includes approved drugs used outside of their 
indication/approved dosage, or that are tested in a fixed combination. 
Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required 
or allowed by the protocol when used in within approved 
indication/dosage.
Loss of CCyR
Loss of complete cytogenetic response is defined as any increase 
from 0% in the Ph+ bone marrow cells.


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Loss of CHR
Loss of CHR is defined as the appearance of any of the following, 
confirmed by a second evaluation ≥4 weeks later (unless associated 
with progression to AP/BC or CML-related death):

WBC count >20 x 10^9/L

Platelet count ≥600 x10^9/L

Progressing hepatosplenomegaly to a size ≥5 cm below the left 
intercostal margin

Appearance of ≥ 5% myelocytes + metamyelocytes in the 
peripheral blood

Appearance of blasts or promyelocytes in the peripheral blood
Molecular Response
MMR (major molecular response, MR3.0) = BCR-ABL ≤ 0.1%IS
MR4.0 = BCR-ABL ≤ 0.01%IS
MR4.5 = BCR-ABL ≤0.0032%IS
Subject Number
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study.
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; 
at this time all study treatment administration is discontinued and no 
further assessments are planned, unless the patient will be followed 
for progression and/or survival.
Study treatment
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; 
study treatment in this case refers to the investigational and non-
investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for 
any reason; may or may not also be the point/time of premature 
patient withdrawal.
Treatment-free Remission 
Phase
The phase of the study where patients stop nilotinib treatment.
Variable
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points


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Amendment 4
Primary purpose for this amendment is the following:

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 underlined for insertions.
The following changes were implemented in the protocol synopsis as well as within the 
protocol sections below as applicable:

Added Section 6.3.2.11 Hepatitis B reactivation language

Section 7.1 added language on HBV testing

Table 7-4 corrected the HbA1 and lipid panel visit schedule.

Table 7-8 added language on HBV testing, addition to the collection plan

Added Section 7.2.2.5.5 on Hepatitis B testing

Correct minor discrepancies and add clarifications within the protocol.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs) 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.
Amendment 3
Primary purposes for the amendment are the following:

Redefine Molecular Relapse as confirmed loss of MMR (2 consecutive BCR-ABL 
levels > 0.1% IS taken approximately 4 weeks apart). Molecular relapse was defined as 
having a confirmed BCR-ABL ratio above MR4.0 (2 consecutive BCR-ABL 
levels >0.01%IS) in the original protocol, however per amendment 2 the criterion was 
changed to confirmed BCR-ABL level above MR 3.0, to be consistent with the other TFR 
ongoing trials. The definition of relapse will be changed to be consistent throughout the 
protocol and to align with the definition of relapse.

In the TFR phase, a confirmed loss of MMR rather than an unconfirmed loss of MMR
(BCR-ABL>0.1%IS) will trigger restarting nilotinib due to the variability of the testing.


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
As per the original protocol, any loss of cytogenetic response would lead to early 
termination from the study. During the conduct of the study, the SMC has suggested that it 
would be important to maintain these patients on study so that their subsequent course 
could be monitored. The patients will resume nilotinib at a dose of 300 mg b.i.d. If a 
patient re-starts nilotinib and does not achieve CCyR within 3 months, then the patient 
should come off study. Re-achievement of CCyR must be confirmed through PCR testing 
(PCR<1%IS); repeat bone marrow aspirate is not mandated.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The following changes were implemented in the protocol synopsis as well as within the 
protocol sections below as applicable.

Table 3-1 – Updated the molecular relapse definition for 
 primary 
 
. Molecular relapse free rate at 6 months after discontinuation from nilotinib 
therapy in patients with MR4.5. Molecular relapse is defined as having a confirmed BCR-
ABL ratio above MMR (2 consecutive BCR-ABL levels >0.1%IS taken approximately 4 
weeks apart).

Section 4.1.4 Treatment Free Remission (TFR) Phase. Added confirmation of loss of 
MMR prior to re-starting nilotinib.

Section 4.1.5 Nilotinib Treatment Reinitiation (NTRI) Phase updated the language on 
patients in TFR who lose any cytogenetic response; the patient will start nilotinib at an 
unscheduled visit. If the patient does not achieve CCyR after restarting nilotinib within 3 
months, then the patient must come off of the study. Once a patient enters the re-initiation 
phase, the patient will not be eligible to re-enter the TFR phase again.

Section 6.1.2 Treatment duration. Added re-confirmation of loss of MMR

Table 7-6 for the TFR phase section added loss of CCyR will re-trigger nilotinib re-
initiation.
 
 
 
 

Section 10.4 Updated the molecular relapse definition on the Primary Objective section

Section 10.5.2 Updated the molecular relapse definition for the secondary efficacy 
objectives

Correct discrepancies and add clarifications within the protocol.
Amendment 2
Amendment rationale
Due to low enrollment, the sample size of the study has been reduced to a total of 59 patients, 
all of which were enrolled by January 9, 2015. Of these 59 patients, approximately 20 are 


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expected to enroll into the Treatment Free Remission (TFR) Phase. Based on this small 
sample size the decision was made to no longer have two Consolidation arms (1 year vs. 2 
year), and instead have all patients enter into one Consolidation arm (2 years). The 2 year 
Consolidation Arm was chosen as the more conservative approach. Patients who were 
randomized to Arm A, a total of 1 year Consolidation, and entered into the TFR Phase prior to 
protocol Amendment 2 will continue in the TFR Phase. Patients who were randomized to 
Arm A and are the in Consolidation Phase at the time protocol Amendment 2 was finalized 
will remain in the Consolidation Phase for two years.
Primary purpose for the amendment is:

Reduce the sample size

Change the trial design to a 2 year Consolidation Phase for all patients

Reduce the TFR Phase from 3 years to 2 years in duration

To clarify how patients that are randomized prior to Amendment 2 will be handled

To clarify that the loss of MR3.0, within the variability of the testing used, during 
Monitoring Phase must be confirmed by a subsequent PCR sample before the patient is 
discontinued.

To update the criterion for coming off study during the Consolidation Phase to a 
confirmed loss of MR4.0, rather than a confirmed loss of MR4.5 due to the ±0.5 log 
variability in PCR testing.

To update the criterion for Nilotinib Treatment Re-initiation to a loss of MR3.0 rather than 
a loss of MR3.0 or a confirmed loss of MR4.0 in an effort to align with other ongoing 
Novartis TFR studies.

To update endpoints and statistics in alignment with the aforementioned changes

To update clinical efficacy parameters in the background section to be consistent with the 
label update for nilotinib.

Correct discrepancies and add clarifications within the protocol.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The following changes were implemented in the protocol synopsis as well as within the 
protocol sections below as applicable.

Section 1.2.2.1 Updated to be consistent with the 60-month label update for nilotinib.

Addition of Clinical Pharmacokinetics information on the moderate inhibitory effects 
of nilotinib on CYP3A4.

Addition of 60-month Clinical Efficacy and safety information

Section 2.1, Section 2.2, Section 4.1.3, Section 6.1.2 and Section 6.5.2 Removed 1 year 
consolidation phase arm, randomization and stratification. Reduced the TFR Phase from 3 
years to 2 years.

Table 3-1Revised other secondary endpoint to evaluate molecular relapse free rates at 12 
and 24 months after treatment discontinuation and removed the 36 month time point.


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
Section 4.1 Added figure of new study design, with a 2 years consolidation phase. 
Removed 1 year consolidation phase arm.

Section 4.1.2 Updated the total number of patients enrolled. Clarified that the loss of MR 
3.0, within the variability of the testing used, during monitoring phase must be confirmed 
by a subsequent PCR sample.

Section 4.1.5 Added new section header for Nilotinib Treatment Re-initiation (NTRI) 
Phase and reduced the TFR Phase from 3 years to 2 years.

Section 4.2 Clarification in timing of data cuts for annual abstracts.

Section 4.3 Updated the length of the study was updated from 7 years to 6 years

Section 4.4 Clarification of the early stopping rules to reinforce that they are related to the 
48 weeks following the start of the TFR Phase. Updated the stopping rule number of cases 
of failure to achieve MR3.0 after 12 months of re-initiating nilotinib to 5 from 7 due to the 
overall smaller sample size expected to reach the TFR Phase.

Section 5 the total number of patients enrolled.

Section 6.1 Updated to include dose reduction administration instructions.

Section 6.4 Removed in-vitro data stating that nilotinib is a competitive inhibitor of 
CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 and instructions regarding the co-
administration when co-administering nilotinib with substrates of these enzymes to be 
consistent with the 60-month label update for nilotnib.

Section 6.6 Updated to specify 200mg nilotinib for dose reductions.

Table 7-2 Visit Evaluation Schedule-Consolidation Phase was updated to Removed 1 year 
consolidation phase arm, randomization and stratification.

Table 7-3 Visit Evaluation Schedule-Treatment-free Remission Phase was updated to 
reduce the TFR Phase from 3 years to 2 years.

Table 7-4 Visit Evaluation Schedule-Treatment Re-initiation was updated to reduce the 
TFR Phase from 3 years to 2 years.

Section 7.1.2 Removed 1 year consolidation phase arm, randomization and stratification 
and clarified how patients that are randomized prior to Amendment 2 will be handled.

Table 7-6 clarification in the variability of the PCR testing done by the central lab, 
Genoptix, as ± .5log. and to limit the Efficacy Milestone Lost during the Consolidation 
Phase to a confirmed loss of MR4.0, resulting in patient terminating from the study early.

Section 9.4 Removed reference to randomization and stratification. Updated the 
authorization terms of database changes to locked data.

Section 10 and Section 10.1.1 Removed 1 year consolidation phase arm, randomization 
and clarified how patients that are randomized prior to Amendment 2 will be handled.

Section 10.2, Section 10.3, Section 10.5.2, Section 10.5.3.1, Section 10.5.3.3 and 10.5.3.5 
Removed reference to treatment two arms

Section 10.4.2 Clarify that statistical hypothesis will not be tested on the primary efficacy 
variable.

Section 10.4.4. Removed reference to randomization and stratification from supportive 
analysis.


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
Section 10.7 Removed sample size calculation by statistical methods. Update the number 
of patients enrolled, and the number expected to reach the TFR Phase.

Other minor corrections and clarifications were also made in the protocol.
Amendment 1
Amendment rationale
Primary purposes for the amendment are:

To include additional safety monitoring parameters as recommended by the Investigator 
Brochure version 9.0, version 10, and the 48-month label update for nilotinib.

To address feedback from investigators received during the study startup.

To include cholesterol testing in the assessment schedule. Elevations in total serum 
cholesterol and low density lipoprotein cholesterol have been observed very commonly
(more than 10%) in patients treated with nilotinib and commonly (between 1 to 10%) in 
patients treated with 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 due to the moderate inhibitory 
effect of nilotinib on CYP3A4 isoenzyme that is involved in the metabolic pathway of
some statins (HMG-CoA reductase inhibitors).

To include glucose testing in the assessment schedule. Elevations of blood glucose levels 
have been observed very commonly (more than 10%) 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. Hence the dose reduction guidelines for the non-hematologic 
toxicities have been updated.

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 incorporate precaution of use for antacid drugs to be aligned with Tasigna® FDA 
Prescribing Information and EMA SmPC.

To define ischemic vascular and ischemic cardiovascular events as Adverse Events of 
special interest, and their reporting.


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The main points addressed are:

According to the Novartis “Guideline on Prevention of Pregnancies in Clinical Trials” for 
highly effective contraception, monthly urine pregnancy testing was included in the
assessments schedule. The requirement of using highly effective contraception was
clarified to include 14 days after the final study visit. Additionally the acceptable method
of highly effective contraception was corrected for periodic abstinence

Dose reduction guidelines for study-drug related non-hematologic toxicity and suggested 
management of selected adverse events have been updated to reflect the latest version of
the nilotinib [Investigator Brochure] on Management of Ischemic vascular or
Cardiovascular Events.

Correct discrepancies and add clarifications within the protocol.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
Modifications were implemented in Protocol summary, Section 5.2 Exclusion criteria #18,
Section 7.1 Visit Evaluation Schedule (VES) and Section 7.2.2.5.3 Pregnancy and
assessments of fertility to update the pregnancy language in the protocol according to the
Novartis “Guideline on Prevention of Pregnancies in Clinical Trials” for highly effective
contraception.
Table 6-2 Summary of dose reduction guidelines for study-drug related non-hematologic
toxicity and Section 6.3.2 Suggested management of selected adverse events have been
amended to reflect the changes done in the latest version of the nilotinib [Investigator
Brochure] on Ischemic vascular or cardiovascular events.
Other key changes were implemented for correction of discrepancies and clarifications and 
are listed in the sections of the protocol below:

Section 4.1.1. Clarification that it is under the investigator’s discretion how many times a 
patient can be re-screened

Section 4.1.2. Addition of a 4-6 week window for the confirmatory PCR after MR4.5 is 
reached in the Monitoring Phase

Section 4.1.3. Deletion of PCR window of variability language

Section 4.3. Clarification of the approximate length of the study

Section 4.4. Addition of study stopping rules

Section 5.1 Correction and clarification of molecular milestones: MMR (MR3.0), MR4.5

Section 5.2 Clarification for inclusion criteria 6, updated website links for inclusion 
criteria 12 and 13, clarified inclusion criteria 13, and updated pregnancy/contraception 
language in inclusion criteria 15

Section 6.3.1. Clarification of version of the CTCAE that is being used for the study

Table 6-3 Updated guidelines for nilotinib dose adjustments for non-hematologic adverse 
events


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
Section 6.3.2.1 – 6.3.2.4. Addition of Management of cholesterol increases, glucose 
increases, other cardiac risk factors, and ischemic vascular or cardiovascular events
recommendations.

Section 6.3.2.7. Addition of Management of ischemic vascular or cardiovascular events

Section 6.4.1. Updated CRF page name and addition of language for blood glucose 
management

Section 6.4.2. Added permitted concomitant therapy requiring caution and/or action and 
antacid precaution

Section 6.4.3. Updated website links

Section 6.5.1. and Section 6.5.2. Clarification of IRT usage

Section 6.6.3.1. Addition of option for sites to implement a pill diary

Section 7.1. Clarification of visit windows

Table 7-1 Visit Evaluation Schedule updated to include new evaluations, corrected visit 
numbers, and clarified visit schedule

Section 7.1.1.1. Deletion of screen failure information that will not be collected via eCRF 
but instead through IRT.

Section 7.1.1.2.3. Addition of history of tobacco use will be collected on a eCRF

Section 7.1.3. Clarification of Early Termination and End of Study visit definitions

Table 7-5 Updated Sokal score calculator website link

Table 7-8 Clarification of lab parameters, including addition of HbA1c, total cholesterol, 
triglycerides, LDL, and HDL

Section 7.2.2.5.3. Addition of monthly home urine pregnancy test and pregnancy test diary
requirement

Table 7-9 Correction of ECG timing for Cycle 1 Day 8

Section 7.2.4. Correction of typo for patient reported outcome tool, should be EQ-5D-3L

Section 8.2.2. Clarification of SAE reporting during TFR Phase and addition of language 
for SAE causality assessment

Section 8.4.Clarified that pregnancies that occur during the TFR Phase must also be 
reported

Section 8.7 Clarification of Study Management Committee description

Section 9.3. Deletion of coagulation since this field is not a required assessment
Other minor corrections and clarifications were also made in the protocol.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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Protocol summary:
Protocol number
CAMN107AUS37
Title
A phase II randomized, multicenter study of treatment-free remission in 
chronic myeloid leukemia in chronic phase (CML-CP) patients who 
achieve a MR4.5 after switching to nilotinib
Brief title
A study switching patients from imatinib to nilotinib then followed by 
treatment cessation.
Sponsor and Clinical 
Phase
II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The current clinical practice for CML drug therapy is to treat patients 
indefinitely with tyrosine kinase inhibitors (TKIs). With the finding that a 
number of patients treated with imatinib achieved deep responses with TKI 
therapy, investigators have explored the possibility of discontinuing TKI 
treatment once an undetectable BCR-ABL level is achieved and sustained 
over a period of time.
Based on these findings, the Stop Imatinib (STIM) study evaluated imatinib 
discontinuation in 100 CML patients who achieved undetectable BCR-ABL
levels for at least 2 years. Patients must have had 5 undetectable data 
points of BCR-ABL analyses by RT-PCR over 2 consecutive years and the 
6th data point was confirmed by a central PCR lab which assay had a 5 log 
reduction sensitivity. After discontinuation, approximately 60% of patients 
had a molecular relapse in 4-6 months. All relapsed patients were re-
started on imatinib and responded to treatment. Although only a minority of 
patients were able to sustain MR4.5 after discontinuation (~40% at 24 and 
36 months), this study demonstrates that there is a population that may be 
considered “cured” from TKI therapy. Although sustaining MR4.5 is a key 
factor in becoming a candidate for TKI discontinuation, the STIM study 
revealed there may be other factors (i.e. Sokal score and TKI treatment 
duration) which may affect the outcomes (Mahon 2010).
With the development of second generation TKIs, molecular responses 
have been shown to occur at earlier time points and deeper in quality 
compared to imatinib. Limited data is available regarding discontinuation of 
TKI therapy after treatment with 2nd generation TKIs, however, the French 
CML Group has reported on discontinuation data for second generation 
TKIs. Twenty-five patients were enrolled in the study and data for 16 
patients were presented at American Society of Hematology meeting in 
2011, 9 were treated with dasatinib and 7 with nilotinib. After discontinuing 
the TKI for a median of 4 months, 31% (5/16) patients lost MMR (MR3.0). 
Molecular response was regained once the TKI was restarted. (Rea 2012). 
Current discontinuation study designs typically begin discontinuation 
strategies after patients have achieved at least 2 years of sustained 
MR4.5.
Primary Objective(s) 
and Key Secondary 
Objective
Primary Objective: To evaluate molecular relapse free rates 6 months 
after discontinuation from nilotinib therapy in patients who have achieved a
MR4.5
Key Secondary Objective: Estimated Relapse-Free Survival


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Secondary Objectives

To evaluate molecular relapse free rates at 12 and 24 months after 
nilotinib treatment discontinuation

To evaluate the proportion of patients who regain MR4.5 after 
restarting nilotinib following molecular relapse

To describe the impact of nilotinib treatment discontinuation on 
progression to AP/BC and CML-related deaths

Overall survival
Study design
This is an open-label study of imatinib treated patients who are switched to 
nilotinib and their ability to discontinue TKI treatment once MR4.5 is 
achieved and sustained MR4.0 or better for 2 years.
Screening (Day -28 to 0)

Patients who have had at least one year of imatinib therapy and 
achieved MMR (MR3.0) but not MR4.5 are eligible for screening. 
Written informed consent must be obtained prior to any screening 
evaluations. If a patient is unable to read, an impartial witness should 
be present during the entire informed consent discussion.

During screening, a peripheral blood sample for RQ-PCR must be 
drawn and sent to the Novartis designated central lab. Eligible patients 
must have achieved MMR (MR3.0) (BCR-ABL level ≤0.1%IS), but still 
have detectable disease defined as not having achieved MR4.5 (or 
having a BCR-ABL level >0.0032%IS). All other inclusion and 
exclusion criteria should be assessed and screening evaluations 
performed.

Re-screening of a patient will be permitted for this study. As long as 
the patient meets all inclusion and none of the exclusion criteria, the 
patient may be enrolled after re-screening. Patients who did not meet 
the molecular BCR-ABL criteria may be re-screened at least 4 weeks 
from the most recent BCR-ABL assessment.
Monitoring Phase (Years 1 and 2)

Fifty-nine patients were enrolled and switched from imatinib to nilotinib 
300 mg b.i.d. upon study entry. Patients will be monitored every 3 
months for molecular response for up to 2 years.

If during the Monitoring Phase, a patient has a PCR result 
demonstrating a confirmed loss of MR3.0 the patient will not be eligible 
for subsequent phases and will early terminate from the study.

Patients who achieve MR4.5 will have the result confirmed by another 
sample drawn 4 weeks later. Once MR4.5 is confirmed, patients will 
enter the Consolidation Phase.
Consolidation Phase

Patients can enter the Consolidation Phase anytime during and up to 
the first 2 years on study, as soon as MR4.5 is confirmed. After 
confirmation of MR4.5, the date of the initial MR4.5 results will be 
counted as the start of the Consolidation Phase. Patients will continue 
to be treated with nilotinib during the Consolidation Phase.

If MR4.0 or better is sustained during the 2 year the Consolidation 
Phase, patients will be eligible for discontinuing nilotinib therapy in the 
TFR Phase.

If during the Consolidation Phase, a patient has one PCR result above 
MR4.0, within the variability of the testing used or a sample is missing, 
a subsequent unscheduled visit peripheral blood sample for PCR must 
be collected within 4 weeks of the most recent sample. If loss of 


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MR4.0 is confirmed in the subsequent sample, this patient will not be 
eligible for nilotinib discontinuation and will early terminate from the 
study.

Patients who were randomized to Arm A and entered into TFR prior to 
protocol Amendment 2 will follow the TFR visit schedule. Patients who 
were randomized to Arm A and are the in Consolidation Phase at the 
time protocol Amendment 2 was finalized will remain in the 
Consolidation Phase for two years.
Treatment-Free Remission (TFR) Phase

Once nilotinib treatment is stopped in the TFR Phase, patients will be 
followed by PCR every month for the first 6 months, then every 2 
months for the next 18 months. Confirmed loss of MMR (MR3.0)
(BCR-ABL >0.1%IS) will trigger restarting nilotinib.
Nilotinib Treatment Reinitiation (NTRI) Phase

Patients who re-initiate nilotinib during the TFR Phase will be 
monitored by PCR once a month for the first 3 months, and then every 
3 months until they reach 2 years from the start date of their TFR 
Phase. For patients who need to re-initiate nilotinib with less than a 
year left of their TFR Phase, they will be followed for one year in the 
Nilotinib Treatment Re-initiation Phase.
Population

The study has enrolled 59 adult patients who have been treated with at 
least 1 year of imatinib, and have achieved MMR (MR3.0) but not 
MR4.5.

Patients treated with up to 2 weeks of nilotinib may enter the study. 
With sponsor approval, patients may have been treated with other 
FDA approved TKIs for up to 4 weeks prior to study entry. Other 
previous CML non-TKI treatment (e.g. hydrea, ara-C, interferon) are 
permitted.
Key Inclusion criteria

Male or female patients ≥ 18 years of age

ECOG Performance Status of 0, 1, or 2

Diagnosis of Ph+ CML

At least 1 year of imatinib treatment prior to study entry. Dose 
interruptions due to adverse events while on imatinib are permitted. 
Patients must have an imatinib washout of at least 1 day prior to the 
first dose of nilotinib. Patients may have been switched and treated 
with other FDA approved TKIs for up to 4 weeks prior to study entry. 
Other previous CML non-TKI treatment (e.g. Hydrea, Ara-C, interferon) 
are permitted.

BCR-ABL level will be assessed by a central lab at screening and 
must be less than or equal to 0.1% IS and greater than 0.0032% IS.

Adequate end organ function
Key Exclusion criteria

Prior imatinib failure, AP, BC or allo-transplant

Previously documented T315I mutation

Patient ever attempted to permanently discontinue imatinib or nilotinib 
treatment

Known impaired cardiac function

Pregnant or lactating women
Investigational therapy
AMN107, nilotinib


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Efficacy assessments
RQ-PCR, 
 
Safety assessments
Physical Exam, Vital Signs, Height and Weight, Hematology and Clinical 
chemistry labs, Electrocardiogram, ECOG Performance status, Hepatitis B 
serology
Other assessments

An assessment of patient reported outcomes is planned in this trial 
using the MDASI-CML, EQ-5D-3L, and SF-8.
Data analysis

No statistical testing of the relapse-free rate will be performed due to 
the small number of patients that are anticipated to enter into the TFR 
Phase.

The primary efficacy variable molecular relapse free rate at 6 months 
after stopping nilotinib will be summarized descriptively by frequencies 
and percentages. The relapse free rate will also be summarized at 
Months 12 and 24 of stopping nilotinib as a secondary objective. An 
exact 95% confidence interval for the relapse free rate at 6, 12, and 24 
months will also be provided.

The FAS will be used for the analysis.
Key words
CML, nilotinib, discontinuation, imatinib, tyrosine kinase inhibitor (TKI), 
MR4.5, treatment-free remission


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Chronic myeloid leukemia (CML) is a hematological stem cell disorder associated with a 
specific chromosomal translocation known as the Philadelphia (Ph) chromosome detected in 
95% of patients (Nowell and Hungerford 1960, Rowley 1973). The molecular consequence of 
the translocation is the fusion of the ABL proto-oncogene to the BCR gene resulting in the 
production of an activated form of the ABL protein-tyrosine kinase (Bartram 1983, Bartram 
1983, Heisterkamp 1983). Expression of the BCR-ABL protein is capable of inducing 
leukemia in mice, implicating the protein as the cause of these diseases (Daley 1990, Kelliher 
1990).
Clinically, prior to the availability of tyrosine kinase inhibition (TKI) therapy, CML typically 
progressed through three distinct phases of increasing refractoriness to therapy: chronic phase 
(CP) (median duration 3-4 years; median survival up to 10 years with allogeneic bone marrow 
transplant and 5-6 years with interferon), accelerated phase (AP) (median duration 3-9 months; 
median survival 8-18 months), and blast crisis (BC) (median survival 3-6 months) (Enright 
and McGlave 2000). Most patients however present in the chronic phase, characterized by 
splenomegaly and leukocytosis with generally few symptoms.
The National Comprehensive Cancer Network (NCCN) guideline on CML [NCCN guidelines 
v 2.2013] recommends TKI treatment in all responding patients. The guidelines also 
summarize data available from TKI discontinuation trials and TKI discontinuation is not 
recommended outside of a clinical trial.
1.2
Introduction to investigational treatment
1.2.1
Overview of nilotinib
Nilotinib is a novel aminopyrimidine, available as an oral formulation that is an Adenosine 
triphosphate (ATP)-competitive inhibitor of the protein tyrosine kinase activity of BCR-ABL. 
It prevents the activation of BCR-ABL dependent mitogenic and anti-apoptotic pathways (e.g. 
PI-3 kinase and STAT5), leading to the death of the BCR-ABLBCR-ABL phenotype. 
Following oral administration to animals, nilotinib is moderately absorbed with approximately 
30% bioavailability, and is well tolerated.
1.2.2
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 2004, White 2005). 
Therefore, based on the preclinical data, and observed efficacy of nilotinib in imatinib-
resistant and intolerant patients, nilotinib is predicted to have significant efficacy in newly 
diagnosed chronic phase CML patients. For more details on non-clinical experience, please 
refer to [AMN107 Investigator’s Brochure].


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1.2.2.1
Clinical experience
Clinical safety and tolerability
Overall, nilotinib has been found to be effective and well tolerated in patients with Ph+ CML-
CP, and AP who were resistant to imatinib or intolerant of imatinib as well as in patients with 
newly diagnosed Ph+ CML-CP.
For detailed nilotinib clinical safety and tolerability, please refer to [AMN107 Investigator’s 
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 on the nilotinib treatment arms compared with the imatinib treatment arm. Up to 
the data cut-off for the 60 Month analysis (30-Sep-2013), the number of patients reported with 
these events is as follows:

Nilotinib 300 mg b.i.d.: IHD, 11 (3.9%); ICVE, 4 (1.4%); PAOD, 7 (2.5%)

Nilotinib 400 mg b.i.d.: IHD, 24 (8.7%); ICVE, 9 (3.2%); PAOD, 7 (2.5%)

Imatinib 400 mg q.d.: 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.
TKI withdrawal
Some patients who have discontinued imatinib in a clinical trial have experienced 
musculoskeletal pain. This may represent a tyrosine kinase withdrawal syndrome. To date 
there is no published TKI withdrawal syndrome data reported with nilotinib.
In the multinational trial of TKI discontinuation, Europe Stop Tyrosine Kinase Inhibitors 
(EURO-SKI, NCT01596114), fifteen out of fifty (15/50) patients treated with imatinib 
subsequently reported musculoskeletal pain that began or worsened within weeks after 
stopping therapy. The pain occurred to various parts of the body, including the shoulder and 
hip regions, extremities, and/or hands and feet. The 15 patients consisted of nine women and 
six men with a median age at TKI discontinuation of 62 years (range, 49 to 74 years). In eight 
patients the symptoms were graded as 2 on the Common Terminology Criteria for Adverse 
Events scale (version 4.0), and in seven patients as grade 1. Four had a previous medical 
history that included musculoskeletal system symptoms. Although these adverse events were 
mild in seven individuals, only leading to use of nonprescription drugs (paracetamol or 
nonsteroidal anti-inflammatory drugs), eight patients were more severely afflicted, with 
manifestations that interfered with everyday activities. In five of these patients, corticosteroids 


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were given (10 to 20 mg prednisolone per day), with tapering within weeks. All five patients 
demonstrated clear improvement within days, but in one patient, prednisolone could not be 
tapered without the reappearance of symptoms (Richter et al 2014).
The information above is intended to inform you of the possibility that the patients in TFR 
may experience a TKI withdrawal syndrome.
Clinical pharmacokinetics
Nilotinib is metabolized by the liver, primarily via CYP3A4. Therefore strong inhibitors or 
inducers of CYP3A4 can significantly alter the pharmacokinetics and systemic exposure of 
nilotinib in humans. In addition, nilotinib exhibits moderate inhibitory effect on CYP3A4 
substrates. Unchanged nilotinib represents the predominant systemic circulating component 
(approximately 88% of the total drug-related serum exposure). The terminal elimination half-
life of nilotinib was estimated to be approximately 17 hours.
Exposure-response analysis in study ENESTnd [CAMN107A2303], suggested a weakly 
positive, but statistically insignificant association between the degree of exposure and BCR-
ABL transcript reduction at 12 months. There was no clear association between the degree of 
exposure and major molecular response (MMR (MR3.0)) at 12 months.
Patient demographics are not a clinically significant factor contributing to the inter-patient 
variability of nilotinib PK. Race was assessed as a covariate on the bioavailability or 
clearance of nilotinib in the population pharmacokinetic analysis which included a total of 
550 patients. No significant differences were observed in nilotinib PK across various race 
groups, e.g. Caucasian (n=348 patients), Black (n=23 patients), Asian (n=138 patients) and 
other races (n=41 patients) [Modeling report CAMN107A2303]. These findings are consistent 
with the previous observations in patients with imatinib resistant or intolerant CML [Study 
CAMN107A2101 PopPK] and the ethnic insensitivity analysis conducted for the original 
Tasigna submission. Other demographic variables, such as age, body weight, and gender, do 
not significantly affect nilotinib PK.
For additional nilotinib clinical PK information, please refer to [AMN107 Investigator’s 
Brochure].
Clinical efficacy
Nilotinib is approved by US Food and Drug Administration and European Commission to 
treat newly diagnosed adult patients with Ph+ CML-CP, or to treat Ph+ CML-CP and CML-
AP in adult patients resistant to or intolerant to prior therapy that included imatinib. The 
recommended adult dosage of nilotinib is 300 mg orally twice daily for newly diagnosed Ph+ 
CML-CP and 400 mg orally twice daily for resistant or intolerant Ph+ CML-CP and CML-AP.
The results of study ENESTnd [CAMN107A2303] demonstrated superiority of nilotinib vs. 
imatinib in the CML-CP frontline 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 major molecular 
response (MMR (MR3.0)) at 12 months was 43% in the nilotinib 400 mg b.i.d. treatment arm, 
44% in the nilotinib 300 mg b.i.d. treatment arm, and 22% in the imatinib treatment arm 
p<0.001 (primary endpoint). The cumulative incidence of molecular response 4.5 log 


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reduction from standardized baseline (MR4.5) was 7%, 19%, 28%, 39.7% and 52.5% by 12, 
24, 36, 48 and 60 months in the nilotinib 400 mg b.i.d. arm, and was 11%, 25%, 32%, 37% 
and 53.5% in the nilotinib 300 mg b.i.d. arm. In the imatinib arm the rates were 1%, 9%, 15%, 
22.6% and 31.4% at the same time points. The differences between the rates of MR4.5 in 
nilotinib and imatinib arms increased over time (6%, 10%, 13%, 17.1% and 21.1% difference 
by month 12, 24, 36, 48 and 60 for the 400 mg b.i.d. arm and 10%, 16%, 17%, 14.4% and 
22.1% difference for the 300 mg b.i.d. arm by the same time points respectively). These 
results demonstrated that more patients starting CML-CP therapy with nilotinib vs. imatinib 
can achieve levels of molecular response (MR) necessary to allow for a future treatment 
discontinuation.
In ENESTcmr study [CAMN107A2405] patients with persistent residual disease after two or 
more years on imatinib were randomized to either continuing imatinib or switching to 
nilotinib 400 mg b.i.d. This study showed by 12 months that a higher proportion of patients 
treated with nilotinib achieved undetectable BCR-ABL levels (23.1% vs. 10.7%; p=0.02) and 
confirmed undetectable BCR-ABL levels - primary endpoint (12.5% vs. 5.8%; p=0.108). 
Among patients with no MR4.5 at study entry, 33% of patients randomized to nilotinib 
achieved MR4.5 vs. 16.5% of patients who remained on imatinib; p=0.008 (Lipton et al 2012; 
Cervantes et al 2012). This study demonstrated that patients on chronic imatinib therapy after 
switching to nilotinib can also achieve molecular response necessary to allow for a future 
treatment discontinuation.
For additional nilotinib clinical efficacy information, please refer to [AMN107 Investigator’s 
Brochure].
2
Rationale
2.1
Study rationale and purpose
The current clinical practice for CML drug therapy is to treat patients indefinitely with 
tyrosine kinase inhibitors (TKIs). With the finding that a number of patients treated with 
imatinib achieved deep responses with TKI therapy, investigators have explored the 
possibility of discontinuing TKI treatment once an undetectable BCR-ABL level is achieved 
and sustained over a period of time.
A pilot discontinuation study was conducted at five centers in France which evaluated 
discontinuing imatinib treatment in patients with CML who were in complete cytogenetic 
remission (CCyR) and had undetectable BCR-ABL transcripts for longer than 2 years on 
imatinib therapy. Twelve patients were enrolled with the median duration of prior imatinib 
therapy of 45 months. Six patients developed a molecular relapse, all within the first five 
months of discontinuing therapy.
The remaining six patients (50%) maintained an 
undetectable level of BCR-ABL transcript after a median follow-up of 18 months (Rousselot 
2007).
Based on these findings, the Stop Imatinib (STIM) study evaluated imatinib discontinuation in 
100 CML patients who achieved undetectable BCR-ABL levels for at least 2 years. Patients 
must have had 5 undetectable data points of BCR-ABL analyses by RT-PCR over 2 
consecutive years and the 6th data point was confirmed by a central PCR lab which assay had 


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a 5 log reduction sensitivity. After discontinuation, approximately 60% of patients had a 
molecular relapse in 4-6 months. All relapsed patients were re-started on imatinib and 
responded to treatment. Although only a minority of patients were able to sustain MR4.5 after 
discontinuation (~40% at 24 and 36 months), this study demonstrates that there is a population 
that may be considered “cured” from TKI therapy. Although sustaining MR4.5 is a key factor 
in becoming a candidate for TKI discontinuation, the STIM study revealed there may be other 
factors (i.e. Sokal score and TKI treatment duration) which may affect the outcomes (Mahon 
2010).
With the development of second generation TKIs, molecular responses have been shown to 
occur at earlier time points and deeper in quality compared to imatinib. Limited data is 
available regarding discontinuation of TKI therapy after treatment with the newer and more 
potent TKIs (nilotinib or dasatinib), however, the French CML Group has reported on 
discontinuation data for both of these TKIs. Twenty-five patients were enrolled in the study 
and data for 16 patients were presented at American Society of Hematology meeting in 2011, 
9 were treated with dasatinib and 7 with nilotinib. After discontinuing the TKI for a median of 
4 months, 31% (5/16) patients lost MMR (MR3.0). Molecular response was regained once the 
TKI was restarted (Rea 2012).
Current TKI treatment discontinuation study designs typically begin discontinuation strategies 
after patients have achieved at least 2 years of sustained MR4.5.
2.2
Rationale for the study design
The rates of molecular recurrence following discontinuation of imatinib therapy in patients 
who had achieved and maintained deep molecular responses on imatinib have been described 
in previous clinical trials (Mahon 2010; Ross 2012). In contrast, patients who did not achieve 
deep molecular responses after two or more years on imatinib and required a switch to 
nilotinib to achieve MR4.5 may have a disease with distinct biological characteristics. 
Feasibility of TKI treatment discontinuation in this group of patients has not been evaluated in 
any of the previous clinical trials.
This is an open label study with the goal of establishing the rate of successful discontinuation 
of TKI therapy in patients who were previously treated with at least 1 year of imatinib and 
subsequently treated with nilotinib. Patients must have achieved MMR (MR3.0), but still have 
detectable disease and not yet achieved MR4.5 prior to study entry. Eligible patients will be 
enrolled, switched from imatinib to nilotinib and then monitored every 3 months to see if they 
can achieve a deeper response of MR4.5 within 2 years of starting nilotinib therapy 
(Monitoring Phase). Those who achieve a confirmed MR4.5 will enter into the Consolidation 
Phase. Those who sustain MR4.0 or better for 2 years during the Consolidation Phase will be 
eligible for discontinuing nilotinib in the Treatment Free Remission Phase (TFR). Patients in 
the TFR Phase will be followed every month for the first 6 months and then every 2 months 
for the next 18 months, and then every 3 months until the end of the study. In the STIM trial, 
it was observed that that relapses occurred mainly in the first 6 months of the study; therefore 
more frequent monitoring is required during the first six months following nilotinib treatment 
discontinuation. 
 
 


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2.3
Rationale for dose and regimen selection
As per the approved dosage for CML-CP patients, nilotinib 300 mg b.i.d. will be used on 
study. The results of the study ENESTnd [CAMN107A2303] demonstrated numerically 
higher response rates in nilotinib 300 mg b.i.d. vs. 400 mg b.i.d. at every time point and every 
depth of molecular response. The cumulative incidence of MR4.5 by 12 months is 11% and 
7% and by 36 months 32% and 28% in nilotinib 300 mg b.i.d. and 400 mg b.i.d., respectively. 
Patients treated with nilotinib 300 mg b.i.d. experienced fewer adverse events and fewer 
patients discontinued the study due to adverse events (10% vs. 14% in nilotinib 300 mg b.i.d. 
vs. 400 mg b.i.d., respectively.) It is anticipated that with better tolerability of nilotinib 300 
mg b.i.d. dose, more patients will adhere to therapy which may result in further BCR-ABL 
transcript reduction.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To evaluate molecular relapse free rates 6 
months after discontinuation from nilotinib 
therapy in patients who have achieved a MR4.5
Molecular relapse free rate at 6 months after discontinuation 
from nilotinib therapy in patients with MR4.5. Molecular relapse 
is defined as having a confirmed BCR-ABL ratio above MMR
(2 consecutive BCR-ABL levels >0.1%IS taken at least 4 weeks 
apart).
Refer to Section 10.4.
Key secondary
Estimated Relapse-Free Survival
Relapse-free survival
Refer to Section 10.5.1.
Other secondary
To evaluate molecular relapse free rates at 12
and 24 months after nilotinib treatment 
discontinuation
Molecular relapse free rates at 12, and 24 months after nilotinib 
treatment discontinuation
Refer to Section 10.5.2.
To evaluate proportion of patients who regain 
MR4.5 after restarting nilotinib after molecular 
relapse
Proportion of patients who achieve MR4.5 after restarting 
nilotinib after relapse
Refer to Section 10.5.2.
Describe impact of discontinuation of nilotinib 
attempts on progression to AP/BC and CML-
related deaths
Proportion of patients who progress to CML-AP/BC and number 
of CML-related deaths
Refer to Section 10.5.2.
To estimate overall survival (OS)
Time from date of discontinuation of nilotinib therapy to the date 
of death from any cause
Refer to Section 10.5.2.
To assess the impact of nilotinib discontinuation 
on patient symptom burden
Change in symptom burden from baseline to the time when 
MR4.5 is confirmed, and also from the end of the Consolidation 
Phase to 6 and 12 months into the TFR Phase.
Refer to Section 10.5.3.5.
To assess the impact of nilotinib discontinuation 
on patient health utility
Change in health utility from baseline to the time when MR4.5 is 
confirmed, and also from the end of the Consolidation Phase to 
6 and 12 months into the TFR Phase.
Refer to Section 10.5.3.5.


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Objective
Endpoint
Analysis
To assess the impact of nilotinib discontinuation 
on patient quality of life
Change in patient quality of life from baseline to the time when 
MR4.5 is confirmed, and also from the end of the Consolidation 
Phase to 6 and 12 months into the TFR Phase.
Refer to Section 10.5.3.5.


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4
Study design
4.1
Description of study design
This is an open-label study of imatinib treated patients who are switched to nilotinib and their 
ability to discontinue TKI treatment once a confirmed MR4.5 is achieved and sustained 
MR4.0 or better for 2 years.
4.1.1
Screening (Day -28-0)
Patients who have had at least one year of imatinib therapy and achieved MMR (MR3.0) but 
not MR4.5 are eligible for screening. Written informed consent must be obtained prior to any 
screening evaluations. If a patient is unable to read, an impartial witness should be present 
during the entire informed consent discussion.
During screening, a peripheral blood sample for RQ-PCR must be drawn and sent to the 
Novartis designated central lab. Eligible patients must have achieved MMR (MR3.0)(BCR-
ABL level ≤0.1%IS), but still have detectable disease defined as not having achieved MR4.5 
(or having a BCR-ABL level >0.0032%IS). All other inclusion and exclusion criteria should 
be assessed and screening evaluations performed.
Re-screening of a patient will be permitted for this study. As long as the patient meets all 
inclusion and none of the exclusion criteria, the patient may be enrolled after re-screening. 
Patients who did not meet the molecular BCR-ABL criteria may be re-screened at least 4 
weeks from the most recent BCR-ABL assessment. It is under the discretion of the 
investigator how many times a patient can be re-screened.
4.1.2
Monitoring Phase (Years 1 and 2)
Fifty-nine patients have been enrolled and were switched from imatinib to nilotinib 300 mg 
b.i.d. upon study entry. Patients will be monitored every 3 months for molecular response for 
up to 2 years.
If during the Monitoring Phase, a patient has a PCR result demonstrating a loss of MR3.0, a 
subsequent unscheduled visit peripheral blood sample for PCR must be collected within 4 
weeks of the most recent sample. If loss of MR3.0 is confirmed, the patient will not be 
eligible for subsequent phases and will early terminate from the study.
Patients who achieve a MR4.5 will have the result confirmed by another sample drawn 4-6 
weeks later. Once MR4.5 is confirmed, patients will then enter the Consolidation Phase.


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Refer to Table 7-6 for guidance on reasons for early termination.
4.1.3
Consolidation Phase
Patients can enter the Consolidation Phase anytime during and up to the first 2 years on study, 
as soon as MR4.5 is confirmed. After confirmation of MR4.5, the date of the initial MR4.5 
results will be counted as the start of the Consolidation Phase. Patients will continue to be 
treated with nilotinib for 2 years during the Consolidation Phase.
If during the Consolidation Phase, a patient has one PCR result above MR4.0 or a sample is 
missing, a subsequent unscheduled visit peripheral blood sample for PCR must be collected 
within 4 weeks of the most recent sample. If loss of MR4.0 is confirmed by the subsequent 
sample, the patient will not be eligible for nilotinib discontinuation and will early terminate 
from the study.
Refer to Table 7-6 for guidance on reasons for early termination.
4.1.4
Treatment-Free Remission (TFR) Phase
The Treatment-Free Remission Phase will begin after the last scheduled PCR sample 
collected in the Consolidation Phase confirms the patient remains in MR4.0 or better. During 
the TFR phase patients will be monitored for two years. Once nilotinib treatment is stopped in 
the TFR Phase, patients will be followed by PCR every month for the first 6 months, then 
every 2 months for the next 18 months. Confirmed loss of MMR (BCR-ABL>0.1%IS) will 
trigger restarting nilotinib.
Refer to Table 7-6 for guidance on reasons for early termination.
4.1.5
Nilotinib Treatment Reinitiation (NTRI) Phase
Patients who re-initiate nilotinib during the TFR Phase will be monitored by PCR once a 
month for the first 3 months, and then every 3 months until they reach 2 years from the start 
date of their TFR Phase. For patients who need to re-initiate nilotinib with less than a year left 
of their TFR Phase, they will be followed for one year in the Nilotinib Treatment Re-initiation 
Phase.
Refer to Table 7-6 for guidance on reasons for early termination.
4.2
Timing of data cuts
No formal interim analyses will be performed. Data cuts for abstracts are planned at least
annually once enrollment has commenced.
4.3
Definition of end of the study
The end of study is defined as last patient last visit which occurs when the last patient 
completes the TFR Phase, which includes patients who must be followed into the Nilotinib 
Treatment Re-Initiation Phase. The approximate maximum length of the study for a patient is 
six years. It may be longer if the patient requires re-initiation of nilotinib during the end of 
their TFR Phase. Patients who require re-initiation of nilotinib will be followed for a 
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4.4
Early study termination
Should this study show that a pre-determined number of patients who ceased nilotinib therapy 
do not regain MMR (MR3.0) (among patients who lost MMR (MR3.0) during TFR Phase, 
and within 12 months of resuming treatment), or show confirmed loss of CCyR or progress to 
AP/BC, the study will be stopped.
The stopping rules are based upon the frequency of these events occurring on study ENESTnd 
[CAMN107A2303]. It is considered crucial that patients treated on this study have outcomes 
during the TFR phase at least as good as those patients who were treated on study 
[CAMN107A2303] with continuous nilotinib therapy (300 mg b.i.d. or 400 mg b.i.d.). 
Therefore, the following stopping rules for this study will apply to the first 48 weeks after the 
start of the TFR Phase:
1. More than 2 cases of progression to AP/BC despite BCR-ABL monitoring during the TFR 
Phase according to protocol, or
2. More than 2 cases of confirmed loss of CCyR despite BCR-ABL monitoring during the 
TFR Phase according to protocol, or
3. More than 5 cases of failure to achieve MMR (MR3.0) (among patients who lost MMR
(MR3.0)) after 12 months of reinitiation of nilotinib in the NTRI Phase according to 
protocol.
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible according to the timelines provided and the 
same assessments should be performed as described in Section 7 for a prematurely withdrawn 
patient. The investigator may be informed of additional procedures to be followed in order to 
ensure that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing IRBs of the early termination of the trial.
5
Population
5.1
Patient population
The target population of this study includes adult patients with diagnosis of Ph+ CML-CP. 
Patients must have received at least 1 year of imatinib therapy, and have a RQ-PCR result that 
is between ≤ 0.1% (MMR, MR3.0) and > 0.0032% (MR4.5) by IS standardized testing. The 
study enrolled 59 patients.
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria.
1. Male or female patient ≥ 18 years of age
2. ECOG Performance Status of 0, 1, or 2
3. Diagnosis of Ph+ CML


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4. At least 1 year of imatinib treatment prior to study entry. Dose interruptions due to 
adverse events while on imatinib are permitted. Patients must have an imatinib washout of 
at least 1 day prior to the first dose of nilotinib. With sponsor approval, patients may have 
been treated with other FDA approved TKIs for up to 4 weeks prior to study entry. Other 
previous CML non-TKI treatment (e.g. hydrea, ara-C, interferon) are permitted.
5. BCR-ABL level will be assessed by a central lab at screening and must be less than or 
equal to 0.1% IS and greater than 0.0032% IS.
6. Adequate end organ function as defined by:

Total bilirubin < 1.5 x ULN (upper limit of normal) except for i) patients with 
documented Gilbert’s syndrome for whom any bilirubin value is allowed and ii) for 
patients with asymptomatic hyperbilirubinemia (liver transaminases and alkaline 
phosphatase within normal range)

SGOT(AST) and SGPT(ALT) < 2.5 x ULN

Serum lipase ≤ 1.5 x ULN

Alkaline phosphatase ≤ 2.5 x ULN

Serum creatinine < 1.5 x ULN
7. Patients must have the following electrolyte values ≥ LLN limits or corrected to within 
normal limits with supplements prior to the first dose of study medication:

Potassium

Magnesium

Total calcium (corrected for serum albumin)
8. Patients must have normal marrow function as defined below:

Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L

Platelets ≥ 100 x 10^9/L
9. Written informed consent obtained prior to any screening procedures
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Prior imatinib failure, AP, BC or allo-transplant
2. Previously documented T315I mutation
3. Patient ever attempted to permanently discontinue imatinib or nilotinib treatment
4. Known impaired cardiac function including any one of the following:

Inability to determine the QT interval on ECG

Complete left bundle branch block

Long QT syndrome or a known family history of long QT syndrome

History of or presence of clinically significant ventricular or atrial tachyarrhythmias

Clinically significant resting bradycardia (< 50 beats per minute)

QTcF > 450 msec. If QTcF > 450 msec and electrolytes are not within normal ranges, 
electrolytes should be corrected and then the patient re-screened for QTcF

History or clinical signs of myocardial infarction within 1 year of study entry


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
History of unstable angina within 1 year of study entry

Other clinically significant heart disease (e.g. uncontrolled congestive heart failure or 
uncontrolled hypertension)
5. 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, uncontrolled infection)
6. History of acute pancreatitis within 1 year prior to study entry or past medical history of 
chronic pancreatitis
7. Acute or chronic liver, pancreatic, or severe renal disease considered unrelated to study 
disease
8. History of significant congenital or acquired bleeding disorder unrelated to cancer
9. History of other active malignancy within 2 years prior to study entry with the exception 
of previous or concomitant basal cell skin cancer, previous cervical carcinoma in situ. 
Consult with sponsor prior to screening.
10. Major surgery within 4 weeks prior to Day 1 on study or those who have not recovered 
from prior surgery
11. Treatment with other investigational agents (defined as not used in accordance with the 
approved indication) within 4 weeks of Day 1 on study
12. Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and 
the treatment cannot be either discontinued or switched to a different medication prior to 
study entry. Refer to medicine.iupui.edu/clinpharm/ddis/.aspx for a list of agents.
13. Patients who are currently receiving treatment with any medications that are categorized 
as “Drugs with known Torsades de Pointes risk” and the treatment cannot be either safely 
discontinued or switched to a different medication prior to study entry. Refer to
crediblemeds.org/ for a list of agents. If a patient needs treatment with an agent listed 
under the category of “Possible Risk” or “Conditional Risk”, Novartis must be contacted 
and the decision documented on the eCRF.
14. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of study drug
15. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during the study and for 14 days after the final study visit. Highly effective contraception 
is defined as either:

Total abstinence (when this is in line with the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed and documented by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the
study, study participation assumes the vasectomized male partner is the sole partner 
for that patient


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Use of a combination of any two of the following:
a. Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository
b. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception
c. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
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
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
with or without hysterectomy) or tubal ligation at least six 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 not of child bearing 
potential.
6
Treatment
6.1
Study treatment
Study treatment: nilotinib (AMN107, Tasigna)
Study drugs: nilotinib (AMN107, Tasigna)
Nilotinib will be labeled as AMN107 and supplied as 150mg and 200mg hard gelatin capsules. 
Nilotinib will not be dosed by weight or body surface area.
For detailed safety information refer to the [Investigator’s Brochure] and the approved 
product labeling.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and route of 
administration
Dose
Frequency and/or 
Regimen
AMN107 (nilotinib)
Capsule for oral use
300mg
Twice Daily
Nilotinib will be administered orally at 300 mg twice daily (b.i.d.), at approximately 12 hour 
intervals, and must not be taken with food. In the event of a dose reduction, Nilotinib will be 
administered orally at 400mg once daily, and must not be taken with food. The capsules 
should be swallowed whole with water. No food should be consumed for at least 2 hours 
before the dose is taken and no additional food should be consumed for at least one hour after 
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6.1.2
Treatment duration
Patients will be treated on study in the Monitoring Phase for a maximum duration of 2 years 
and, an additional 2 years in the Consolidation Phase. All patients will be treated with 
nilotinib 300mg b.i.d. during the Monitoring and Consolidation Phase, unless the patient 
experiences unacceptable toxicity, disease progression and/or treatment is discontinued at the 
discretion of the investigator or withdrawal of consent.
Once enrolled, patients will have 2 years during the Monitoring Phase to achieve MR4.5. 
Anytime within these first 2 years on study, when MR4.5 is achieved the patient will enter 
into a Consolidation Phase. Patients will continue to receive nilotinib 300mg b.i.d. during the 
Consolidation Phase. Patients who sustain MR4.0 or better for 2 years during the 
Consolidation Phase will be eligible for discontinuing nilotinib in the TFR Phase. If during 
the TFR Phase, patients have a confirmed loss of MR3.0 they will restart nilotinib 300 mg 
b.i.d. and may stay on study drug up to 2 years from the start date of their TFR Phase. Patients 
who lose confirmed MMR (MR3.0) during the TFR Phase will restart nilotinib 300mg b.i.d. 
and will be followed for a total of 2 years from the start date of their TFR Phase. For patients 
who need to re-initiate nilotinib with less than a year left of their TFR Phase, they will be 
followed for one year in the Nilotinib Treatment Re-initiation Phase.
6.2
Dose escalation
Dose escalation beyond 300mg b.i.d. is not allowed for this study.
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 guidelines in Table 6-2 and Table 6-3 for details.
According to International Conference on Harmonization (ICH) E6 the investigator is 
responsible for all trial-related medical decisions. During and following a patient’s 
participation in a trial, the investigator should ensure that adequate medical care is provided to 
a patient for any adverse events, including clinically significant laboratory values, related to 
the study drug. If multiple dose-reducing toxicities are present, the greatest dose reduction 
schedule must be used.
For the purpose of these dose reduction guidelines, toxicity is defined as any adverse event 
(AE) which is, with reasonable likelihood according to investigator’s judgment, caused by 
study drug. Dose reduction is required in cases of grade 3 or 4 hematologic AEs and in cases 
of grade 2, 3 or 4 non-hematologic AEs. The dose reduction schedule used in this study has 
been successfully pioneered by the GIMEMA study group in a nilotinib trial (Rosti 2008), 
which included similar population of patients (1st line CML-CP). If a nilotinib related toxicity 
does not resolve after 28 days, the patient must be early terminated from the study.
These changes must be recorded on the Dosage Administration Record page.


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This study will use the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
version 4.03 for toxicity and adverse event reporting. CTCAE version 4.03 can be found at the 
following 
website: 
evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf
Table 6-2
Nilotinib dose adjustments for hematologic AE (WBC or PLT)
For patients receiving oral anticoagulants, refer to Section 6.3.2.5
to
manage 
thrombocytopenia.
Note: 400mg q.d. must be taken at one time (two 200mg capsules), do not split the dose
Grade
Occurrence
Dose modification
1 or 2
Any time
No dose reduction
3 or 4
1st and 2nd time

Stop nilotinib

Check labs weekly until Grade 2 or 1.

Resume nilotinib at 300mg b.i.d. if recovery to Grade 1/2 occurs 
within 2 weeks.

Resume nilotinib at 400mg q.d. if recovery to Grade 1/2 takes longer 
than 2 weeks. Dose re-escalation to 300mg b.i.d. is permitted if no 
recurrent Grade 3 or 4 hematological toxicities occur over the 4 
weeks while on the reduced dose.
3rd and 4th time

Stop nilotinib

Check labs weekly until Grade 2 or 1.

Resume nilotinib at 400mg q.d.

Dose re-escalation to 300mg b.i.d. is permitted if no recurrent Grade 
3 or 4 hematological toxicities occur over the 4 weeks while on the 
reduced dose.
5th time
Stop nilotinib. Contact Novartis (for review with the SMC) to discuss if 
nilotinib can be resumed at 400mg q.d. or if the patient should be early 
terminated from the study
If nilotinib is stopped and re-initiated, an ECG should be repeated prior to re-starting nilotinib 
and approximately 7 days after.
If nilotinib is dose escalated (i.e. from 400mg q.d. to 300mg b.i.d.), an ECG should be 
repeated approximately 7 days after the dose adjustment.
Myelosuppression can occur at any time during imatinib or nilotinib therapy. Use of colony-
stimulating growth factors (G-CSF and GM-CSF) such as sargramostim, filgrastim, and 
pegfilgrastim may be initiated with recurrent grade 3 neutropenia. The use of recombinant 
erythropoietin is permitted.
A summary of dose reduction guidelines for study drug-related non-hematological toxicity 
and for ischemic vascular and cardiovascular events regardless of study drug relationship is 
presented in Table 6-3.
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.


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However, for those toxicities detailed in Table 6-3, the following rules (as detailed in the 
bullet points below) must be strictly followed:

Any non-hematological toxicity Grade 3 or 4 must be resolved within 28 days to ≤ Grade 
2 in order to resume study drug at the reduced dose. If a non-hematological toxicity Grade 
3 or 4 does not resolve after 28 days, the patient must be discontinued from the study.

If Grade 4 toxicity of the same type recurs despite nilotinib dose reduction to 400 mg q.d.
the patient must be discontinued from the study.

In case of Grade 3 pancreatitis, study drug treatment must be hold and Novartis must be 
consulted immediately.

In case of Grade 4 pancreatitis, study drug treatment must be permanently stopped and the 
patient must be discontinued from study.

In case of Grade 4 liver toxicity, study drug treatment must be hold and Novartis must be 
consulted immediately.

In case of Grade 4 cardiac toxicity, study drug treatment must be permanently stopped and 
the patient must be discontinued from study.

In case of recurrent QTcF prolongation to > 480 msec despite dose reduction the patient 
must be discontinued unless the reason for QTcF prolongation can be corrected (such as 
discontinuing or replacing of QT-prolonging concomitant drugs)
Table 6-3
Summary of nilotinib dose reduction guidelines for study drug-related 
non-hematologic toxicity and for ischemic vascular and 
cardiovascular events regardless of study drug relationship
Study drug and 
dose
Nilotinib 600 mg daily (as 300 mg b.i.d.) or
Nilotinib 400 mg daily (must be taken as two 200mg caps at one time)
General non-hematological toxicity
Grade 2
(persisting > 7 days 
with optimal 
supportive care)
The dose of nilotinib may be reduced to 400 mg q.d. 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→ 400 mg q.d.
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study.
If Grade 4 toxicity recurs despite dose reduction to 400mg q.d.
l→ discontinue from study.
Serum hypophosphatemia
Grade 2-3
Continue nilotinib at the full dose and start phosphate supplementation.
Grade 4
Hold study drug and consult Novartis.
Serum creatinine
Grade 2
> 1.5 -3.0 x ULN
The dose of nilotinib may be reduced to 400mg q.d. at the discretion of the 
investigator if clinically appropriate and in the best overall interest of the 
patient.


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Study drug and 
dose
Nilotinib 600 mg daily (as 300 mg b.i.d.) or
Nilotinib 400 mg daily (must be taken as two 200mg caps at one time)
≥ 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→ 400mg q.d.
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study.
If Grade 4 toxicity recurs despite dose reduction to 400mg q.d.
l→ discontinue from study
Hepato-biliary [bilirubin, SGPT(AST), SGOT (ALT)]
Note: If hyperbilirubinemia is primarily due to the indirect bilirubin (with indirect bilirubin > direct 
bilirubin and direct bilirubin ≤ 15 μmol/L) and ALT ≤ Grade 1, AST ≤ Grade 1, ALP ≤ Grade 1, and 
hemolysis has been ruled out as per institutional guidelines (e.g. by determination of hepatoglobin), 
nilotinib may be continued at the same dose, at the discretion of the investigator.
Grade 2
The dose of nilotinib may be reduced to 400mg q.d. 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→ 400mg q.d.
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study
If Grade 4 toxicity recurs despite dose reduction to 400mg q.d.
l→ discontinue from study
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 400mg q.d. after recovery to ≤ Grade 1 is 
seen.
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study.
If toxicity recurs
l→ discontinue from study
Grade 3
Hold study drug and consult Novartis
Grade 4
Stop study drug. The patient must be discontinued from study
Elevated lipase without symptoms
≥ Grade 3
Hold study drug
Re-start nilotinib at 400mg q.d. after recovery to ≤ Grade 2 is seen.
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study.
If toxicity recurs without symptoms consider appropriate diagnostic 
procedures such as abdominal CT or ultrasound to exclude pancreatitis. After 
recovery to ≤ Grade 2,
l→ continue dosing at 400mg q.d. based on investigator’s discretion.


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Study drug and 
dose
Nilotinib 600 mg daily (as 300 mg b.i.d.) or
Nilotinib 400 mg daily (must be taken as two 200mg caps at one time)
Diarrhea
Note: Anti-diarrheal medication is recommended at the first sign of loose stools or overt diarrhea. If 
diarrhea cannot be controlled with optimal anti-diarrheal treatments, take the following actions:
≥ Grade 3
Hold study drug and resume nilotinib at next lower dose level after recovery to 
≤ Grade 2 is seen
l→ 400mg q.d.
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study.
Vomiting
Note: Antiemetic medication should be withheld until the patient experiences ≥ grade 1 vomiting then 
institute symptomatic therapy as appropriate. Antiemetics with the potential to prolong QT such as 
domperidone must be avoided. If nausea and vomiting cannot be controlled with optimal antiemetic 
treatment take the following actions:
≥ Grade 3
Hold study drug and resume nilotinib at next lower dose level after recovery to 
≤ Grade 2 is seen
l→ 400mg q.d.
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study.
Skin rash
Note: Institute symptomatic therapy as appropriate. If skin rash does not resolve with optimal 
treatments, take the following actions:
Grade 2
The dose of nilotinib may be reduced to 400mg q.d. 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→ 400mg q.d.
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study.
If Grade 4 toxicity recurs despite dose reduction to 400mg q.d.
l→ discontinue from study


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Study drug and 
dose
Nilotinib 600 mg daily (as 300 mg b.i.d.) or
Nilotinib 400 mg daily (must be taken as two 200mg caps at one time)
Cardiac QTc prolongation
QTcF > 480 msec
Hold study drug when an ECG with a QTcF > 480 msec.

Perform an analysis of serum potassium and magnesium, and if below 
lower limit of normal, correct with supplements to within normal limits.

Concomitant medication usage must be reviewed for their potential to 
inhibit CYP3A4 and/or to prolong the QT-interval.

Perform a repeat ECG within one hour of the first QTcF of > 480 msec

If QTcF remains > 480 msec, repeat ECG as clinically indicated, but at 
least once a day until the QTcF returns to < 480 msec.
Study drug may be restarted, at same dose, if reason for elevation of QTcF is 
identified and corrected so that QTcF returns to < 450 msec and to within 20 
msec of baseline within 2 weeks.
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 400mg q.d.
ECGs must be repeated 7 days after dose re-start for all patients who had 
therapy held due to QTcF > 480 msec.
If QTcF of > 480 msec recurs, the patient is to be discontinued from study
The investigator should contact Novartis regarding any questions that arise if 
a patient with QTcF prolongation should be maintained on study.
Ischemic cardiovascular events
Grade 2*
Hold study drug and refer patient for assessment by a vascular or 
cardiovascular specialist.
Resume nilotinib at next lower dose level after recovery to ≤ Grade 1 is seen
l→ 400mg q.d.
If another recurrence
l→ discontinue from study
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study.
Grade 3* or 4*
Hold study drug and refer patient for assessment by a vascular or 
cardiovascular specialist. Consideration should be given for discontinuation 
from the study.
* 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→ 400mg q.d.
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study.
If Grade 3 toxicity recurs despite dose reduction to 400mg q.d.
l→ discontinue from study
Grade 4
Stop study drug. The patient must be discontinued from study
If nilotinib is stopped and re-initiated, an ECG should be repeated prior to re-starting nilotinib 
and approximately 7 days after.


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If nilotinib is dose escalated (i.e. from 400mg q.d. to 300mg b.i.d.), an ECG should be 
repeated approximately 7 days after the dose adjustment.
6.3.2
Suggested management of selected adverse events for nilotinib
Dose reduction guidelines listed in Table 6-2 and Table 6-3 should be followed. Additional 
guidelines for management of patients are listed below.
6.3.2.1
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 due to the moderate inhibitory effect of nilotinib 
on CYP3A4 isoenzyme that is involved in the metabolic pathway of some statins (HMG-CoA 
reductase inhibitors).
6.3.2.2
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.
6.3.2.3
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.
6.3.2.4
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 adverse event the Investigator should ensure that the patient is assessed 
by a vascular or cardiovascular specialist. Further recommendations for the management of 
ischemic vascular or cardiovascular-related events are outlined in Table 6-3.
6.3.2.5
Management of myelosuppression
Myelosuppression can occur at any time during nilotinib therapy. Use of granulocyte colony 
stimulating growth factors and granulocyte-macrophage colony-stimulating factors (G-CSF 
and GM-CSF) such as sargramostim, filgrastim, and pegfilgrastim may be initiated with 
recurrent grade 3 neutropenia. The use of recombinant erythropoietin is also permitted as per 
local clinical practice. In case of late onset of severe peripheral blood cytopenia underlying 
progression of CML and other alternative etiologies may need to be considered and ruled out.


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6.3.2.6
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 steroids may be initiated for the management of more severe 
cases. Prednisone 25 mg is recommended for one week or until rash has resolved.
6.3.2.7
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 cardio-respiratory symptoms should receive immediate medical 
evaluations for the development of concomitant cardiac or respiratory diagnoses as indicated, 
such as an echocardiogram and a chest X-ray. Other medical tests may also be necessary to 
best manage the medical condition.
6.3.2.8
Management of liver toxicity
Routine Liver Function Tests (LFTs) 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). Alternative 
etiologies for LFT abnormalities such as viral hepatitis should be considered as clinically 
indicated.
6.3.2.9
Dose modification for patients nilotinib and oral anticoagulants other 
than coumarin derivatives
For patients on treatment with oral anticoagulants other than coumarin derivatives, the 
following guidelines will apply for thrombocytopenia: If platelets ≤ 100 x 10^9/L, withhold 
treatment with study drug until recovery to at least > 100 x 10^9/L and resume treatment at 
same dose. If recurrence of platelets ≤ 100 x 10^9/L, then withhold treatment until recovery to 
at least > 100 x 10^9/L and resume treatment at the same dose or may be reduced to a
minimum dose of 400mg/day. If the platelet count remains below 100 x 10^9/L, then nilotinib 
should be ceased or management with anticoagulation therapy re-evaluated at the discretion of 
the Investigator.
See Section 6.4.1 for patient taking coumarin derivatives.
6.3.2.10 Platelet aggregation inhibitors
For patients on treatment with platelet aggregation inhibitors and platelets ≤ 100 x 10^9/L, 
modification of platelet aggregation inhibitor therapy and/or study drug interruption/dose 
reduction should be considered by the investigator as clinically appropriate. Advice from 
SMC may be requested via Novartis.
6.3.2.11 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 


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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
6.3.3
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. All patients must be followed up for adverse events and serious 
adverse events for 30 days following the last dose of nilotinib or the last day in the TFR Phase.
6.3.4
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria, as well as specific dose modification and stopping rules are 
included in this protocol. Recommended guidelines for prophylactic or supportive treatment 
for expected toxicities are provided in Section 6.3.2. Refer to preclinical toxicity and or 
clinical data found in the [Investigator’s Brochure].
6.4
Concomitant medications
In general, 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. These include blood and platelet transfusions for 
patients with anemia and with thrombocytopenia.
Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1 
in vitro, potentially increasing the concentrations of drugs eliminated by these enzymes. In
addition, single-dose administration of nilotinib with midazolam to healthy subjects increased 
midazolam exposure by 30%. Caution should be exercised when co-administering nilotinib 
with substrates of these enzymes having a narrow therapeutic index.
6.4.1
Permitted concomitant therapy
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, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Prior/Concomitant 
Medications/Significant Non-Drug Therapies eCRF.
Note that previously the use of therapeutic coumarin derivatives (i.e. warfarin, acenocoumarol, 
phenprocoumon) was not permitted while taking nilotinib but it is now allowed. There is data 
demonstrating the lack of effect of nilotinib on PK and pharmacodynamics (PD) of warfarin, 
suggesting nilotinib does not inhibit CYP2C9 activity in human subjects. These findings 
suggest that warfarin may be used with nilotinib concurrently if needed (Yin et al 2011). Low 
molecular weight heparin and heparin may be substituted for coumarin and other medications 
for anticoagulation may also be considered at the physicians discretion.


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Patients on anticonvulsants should have regular monitoring of plasma concentration of these 
agents.
The routine use of systemic corticosteroid therapy is permitted. Note glucocorticoids are 
CYP3A4 inducers, please refer to Section 6.4.3.
Anti-emetics may be allowed if the patient has experienced > Grade 1 nausea or vomiting.
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 p.o. x 1, than 2 mg 
p.o. after each loose stool, up to a max of 16mg/day).
Nilotinib is known to be associated with an increase of blood glucose in some patients who 
might need to be optimally managed for hyperglycemia according to current clinical standards. 
However, when a patient enters TFR, management of previously elevated blood glucose 
might need to be adapted.
6.4.2
Permitted concomitant therapy requiring caution and/or action
Cytochrome P450 3A4 substrates
Nilotinib is a moderate CYP3A4 inhibitor in vivo. Because of the potential risk for drug-drug 
interactions, the systemic exposure of other drugs known to be sensitive substrates of
CYP3A4 and also to have a narrow therapeutic index should be used with caution.
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.
All patients must avoid grapefruit, star fruit, and Seville oranges during the study. The juices 
and products containing these fruits must also be avoided.
Cardiac monitoring (ECG) is required upon re-initiation of nilotinib at any point during 
the study. See Section 7.2.2.5.4.
CYP3A4 inhibitors
Every effort should be made NOT to administer strong CYP3A4 inhibitors. CYP3A4 
inhibitors may decrease the metabolism of nilotinib and thereby increase serum 


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concentrations and increase exposure to nilotinib. If administration of a strong CYP3A4 
inhibitor cannot be avoided during the study and cannot be switched to an alternative therapy, 
nilotinib must be STOPPED. If a patient requires long term therapy with a strong CYP3A4 
inhibitor which requires study drug (nilotinib) interruption for > 28 days, then the investigator 
must notify the sponsor to discuss further treatment options.
A comprehensive list of cytochrome P450 isoenzymes and CYP3A4 inhibitors may be found 
at medicine.iupui.edu/clinpharm/ddis/ Novartis must be contacted if a patient needs to be 
started on any of these drugs during study treatment.
QT prolonging agents
Every effort should be made NOT to administer a QT prolonging agent. Please see
crediblemeds.org/ for a comprehensive list of agents that prolong QT interval. If during the 
course of the study, concomitant administration of an agent listed under the category of 
“Drugs with Known Risk of Torsades de Pointes” on the above link is required and cannot be 
switched to an alternative therapy, nilotinib must be STOPPED. If a patient requires long term 
therapy with a QT prolonging agent which requires nilotinib study drug interruption for > 28 
days, the investigator must notify the sponsor to discuss further treatment options
If a patient needs treatment with an agent listed under the category of “Possible Risk” or 
“Conditional Risk”, Novartis must be contacted and the decision documented on the eCRF. In 
such cases an ECG must be obtained both 24 to 48 hours and 7 days after initiating the 
concomitant therapy.
CYP3A4 inducers
Every effort should be made NOT to administer CYP3A4 inducers however, if administration 
of a CYP3A4 inducer cannot be avoided during the study, temporary stopping of study drug is 
NOT required. Please see medicine.iupui.edu/clinpharm/ddis/table.aspx for a list of CYP3A4 
inducers. Novartis must be contacted if a patient needs to be started on any of these drugs 
during study treatment.
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject 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 Subject 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, the patient is assigned to the next 
sequential Subject No. available to the investigator through the Interactive Response 
Technology (IRT) system.
The investigator or designated staff will use IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be 


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changed, even if the patient is re-screened. If the patient fails to enroll or start treatment for 
any reason, the reason will be entered IRT.
6.5.2
Treatment assignment or randomization
Sites will register their patients who sign consent at screening with IRT and subsequently at 
Enrollment (C1D1).
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF.
Patients will be provided with an adequate supply of nilotinib study drug supply until their 
next scheduled visit. Patients will be dispensed 150mg capsules (or 200mg capsules in the 
event of a dose reduction), including instructions for self-administration.
6.6.1
Study drug packaging and labeling
Medication labels will be in English and comply with the legal requirements of the U.S. They 
will include storage conditions for the drug and the medication number but no information 
about the patient.
6.6.2
Drug supply and storage
Nilotinib study drug will be centrally supplied by Novartis. The study drug must be received 
by designated personnel at the study site, handled and stored safely and properly, and kept in a 
secured location to which only the investigator and designated site personnel have access. 
Upon receipt, nilotinib should be stored according to the instructions specified on the drug 
labels and in the [Investigator’s Brochure].
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit. Total daily dose of nilotinib administered with start and end date will be 
collected on the dose administration eCRF. Sites may ask patients to keep a pill diary for 
compliance purposes, but it is not required for the study.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 


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all unused study treatment and packaging on a regular basis, at the end of the study/early 
termination or at the time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the study monitor (or to the Novartis address provided in 
the investigator folder at each site), or destroy study treatment on site if approved by the 
sponsor.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.3.4
Disposal and destruction
The study drug supply can be destroyed by a Novartis contracted third party or on site 
provided that Novartis grants approval after reviewing the site drug destruction SOP.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. No eCRF will be used as a source document. The table indicates which 
assessments produce data to be entered into the clinical database (D) or remain in source 
documents only (S) (“Category” column).
Hepatitis B testing will be performed once and only once, at the next possible visit. The 
hepatitis serology will include: Hepatitis B surface antigen (HbsAG), antibodies to hepatitis B 
surface antigen (HBsAb), antibodies to hepatitis B core antigen (HbcAb).
Visit windows
One cycle is equal to 30 days.
In the event that an evaluation is performed within 2 days of the next study visit, the 
evaluations will not be required to be repeated.
Assessments must be performed within 2 days of the day indicated on the visit schedules for 
the following:

Monitoring Phase Cycle 1

Re-Initiation Phase Cycle 1

First 6 months of the TFR Phase
Screening evaluations may be performed on Monitoring Phase C1D1 as long as all the results 
are reviewed to confirm inclusion/exclusion criteria prior to dosing the patient with study drug.
During the TFR Phase EOC 24 and Re-Initiation Phase EOC 24, assessments must be 
performed within 15 days of the day indicated on the visit schedules.


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The confirmatory MR4.5 PCR blood sample may be drawn 4-6 weeks after the previous draw.
All other assessments during the various phases must be performed within 10 days of the day 
indicated on the visit evaluation schedule.


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Table 7-1
Visit evaluation schedule – Monitoring Phase
Follow this schedule until confirmed MR4.5 is achieved (* MD = Monitoring Day)
Category
Protocol 
Section
Screening
Cycle 1 
Day 1 
(baseline, 
prior to 
dosing)
Cycle 1 
Day 8
End of 
Cycle 
(EOC) 1
EOC 3, 6, 9, 12, 15, 
18, 21, 24
Early 
Termination
30 Day 
Safety 
Follow-up
Visit Number
1
2
3
4
5,6,7,8,9,10,11,12
777
501
Day of cycle
-28 to-0
MD*1
MD8
MD30
MD90,180,270,360, 
450,540, 630, 720, --
--
Obtain Informed Consent
(S)
X
IVRS Registration
(D)
X
X
X
Patient history
Inclusion/exclusion criteria
(S)
7.1.1.2.1.
X
Demography
(D)
7.1.1.2.2.
X
Relevant medical history/current 
medical conditions
(D)
7.1.1.2.3.
X
Disease History/Sokal risk score
(D)
7.1.1.2.4.
7.1.1.2.5.
X
Prior antineoplastic therapy
(D)
7.1.1.2.6.
X
Prior/concomitant medications
(D)
7.1.1.2.7.
X
Prior RQ-PCR, 
 
result
(D)
7.1.1.2.8.
X
Physical examination, Extramedullary 
involvement
(D)
7.2.2.1.
X
X
X
Vital signs
(D)
7.2.2.2.
X
X
X
Height
(D)
7.2.2.3.
X
Weight
(D)
7.2.2.3.
X
X
X
Performance status
(D)
7.2.2.4.
X
X
X


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Category
Protocol 
Section
Screening
Cycle 1 
Day 1 
(baseline, 
prior to 
dosing)
Cycle 1 
Day 8
End of 
Cycle 
(EOC) 1
EOC 3, 6, 9, 12, 15, 
18, 21, 24
Early 
Termination
30 Day 
Safety 
Follow-up
Visit Number
1
2
3
4
5,6,7,8,9,10,11,12
777
501
Day of cycle
-28 to-0
MD*1
MD8
MD30
MD90,180,270,360, 
450,540, 630, 720, --
--
Laboratory assessments
7.2.2.5.
Hematology (local)
(D)
7.2.2.5.1.
X
X
X
Chemistry (local)
(D)
7.2.2.5.2.
X
X
X
HbA1c and Lipid Panel (local) – LDL, 
HDL, TC, TG
(D)
7.2.2.5.
X
X – Visit 5, 6, 8, 12
X
Serum Pregnancy test (local), if 
applicable
(D)
7.2.2.5.3.
X
X
Urine Pregnancy test and diary, if 
applicable
(D)
7.2.2.5.3.
X
X- Monthly (every 30 days)
ECG (local)
(D)
7.2.2.5.4.
X
X
X
Required for dose changes
RQ-PCR (central)
(D)
7.2.1.1.
X
X
X
X
Safety
Adverse events
(D)
8.
Continuous
X
Patient reported Outcomes
MDASI-CML
(D)
7.2.4.
X
EQ-5D-3L
(D)
7.2.4.
X
SF-8
(D)
7.2.4.
X
Study Drug administration
(D)
6.1.1.
Continuous


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Category
Protocol 
Section
Screening
Cycle 1 
Day 1 
(baseline, 
prior to 
dosing)
Cycle 1 
Day 8
End of 
Cycle 
(EOC) 1
EOC 3, 6, 9, 12, 15, 
18, 21, 24
Early 
Termination
30 Day 
Safety 
Follow-up
Visit Number
1
2
3
4
5,6,7,8,9,10,11,12
777
501
Day of cycle
-28 to-0
MD*1
MD8
MD30
MD90,180,270,360, 
450,540, 630, 720, --
--
End of Treatment (eCRF)
(D)
7.1.3.
X – at visit 12 for 
patient ineligible for 
the Consolidation 
Phase
X
Study Evaluation Completion (eCRF)
(D)
7.1.3.
X – only at visit 12
X


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Table 7-2
Visit evaluation schedule – Consolidation Phase
* CD = Consolidation Day
Category
Protocol 
Section
Consolidation 
EOC 3
Consolidation 
EOC 6
Consolidation 
EOC 9
Consolidation 
EOC 12, 15, 18, 
21, 24)
Early 
Termination
30 Day 
Safety 
Follow-up
Visit Number
13
14
15
16,17,18,19,20
778
501
Day of cycle
CD90
CD180
CD270
CD360, 450, 
540, 630, 720
--
--
IVRS Registration
(D)
X
Physical examination, Extramedullary 
involvement
(D)
7.2.2.1.
X
X
X
X
Vital signs
(D)
7.2.2.2.
X
X
X
X
X
Weight
(D)
7.2.2.3.
X
X
X
X
X
Performance status
7.2.2.4.
X
X
X
X
X
Laboratory assessments
7.2.2.5.
Hematology (local)
(D)
7.2.2.5.1.
X
X
X
X
X
Chemistry (local)
(D)
7.2.2.5.2.
X
X
X
X
X
HbA1c and Lipid Panel (local) – LDL, 
HDL, TC, TG
(D)
7.2.2.5.
The lipid panel and HbA1c level must be done at 
the end of every 3 cycles until the patient has been 
on nilotinib for 1 year regardless of phase.
X – only at Visit 
16 and Visit 20
X
Serum Pregnancy test (local), if 
applicable
(D)
7.2.2.5.3.
X
Urine Pregnancy test and diary, if 
applicable
(D)
7.2.2.5.3.
X - Monthly (every 30 days)
ECG (local)
(D)
7.2.2.5.4.
Required for dose changes
PCR (central)
(D)
7.2.1.1.
X
X
X
X
X
Safety


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Category
Protocol 
Section
Consolidation 
EOC 3
Consolidation 
EOC 6
Consolidation 
EOC 9
Consolidation 
EOC 12, 15, 18, 
21, 24)
Early 
Termination
30 Day 
Safety 
Follow-up
Visit Number
13
14
15
16,17,18,19,20
778
501
Day of cycle
CD90
CD180
CD270
CD360, 450, 
540, 630, 720
--
--
Adverse events
(D)
8.
Continuous
X
Patient reported Outcomes
MDASI-CML
(D)
7.2.4.
X
At Visit 16 and 
20
X
EQ-5D-3L
(D)
7.2.4.
X
X
SF-8
(D)
7.2.4.
X
X
Study Drug administration
(D)
6.1.1.
Continuous
End of Treatment (eCRF)
(D)
7.1.3.
X – when last 
dose of study 
drug is taken
X
Study Evaluation Completion (eCRF)
(D)
7.1.3.
X


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Table 7-3
Visit evaluation schedule – Treatment-free Remission Phase
* TFR = TFR Day
Category
Protocol 
Section
TFR EOC 
1,2,3,4,5,6
TFR EOC 8,10, 12, 14, 16, 18, 
20, 22, 24
Early 
Termination
30 Day Safety 
Follow-up
Visit Number
21,22,23,24,25,26
27, 28, 29 30, 31, 32, 33, 34,35
779
501
Day of cycle
TFRD*30, 60, 90, 
120, 150, 180
TFRD240, 300, 360, 420, 480, 
540, 600, 660, 720
--
--
IVRS Registration
(D)
X
Physical examination, Extramedullary 
involvement
(D)
7.2.2.1.
X (Visit 23, 26)
X (Visit 29,32,35)
X
Vital signs
(D)
7.2.2.2.
X (Visit 23,26)
X (Visit 29,32,35)
X
Weight
(D)
7.2.2.3.
X (Visit 23, 26)
X (Visit 29,32,35)
X
Performance status
(D)
7.2.2.4.
X (Visit 23, 26)
X (Visit 29,32,35)
X
Laboratory assessments
7.2.2.5.
Hematology (local)
(D)
7.2.2.5.1.
X (Visit 23, 26)
X (Visit 29,32,35)
X
Chemistry (local)
(D)
7.2.2.5.2.
X (Visit 23, 26)
X (Visit 29, 32,35)
X
HbA1c and Lipid Panel (local) – LDL, HDL, 
TC, TG
(D)
7.2.2.5.
X – at Visit 29 and 35
X
Serum Pregnancy test (local), if applicable
(D)
7.2.2.5.3.
X
Urine Pregnancy test and diary, if applicable
(D)
7.2.2.5.3.
X - Monthly (every 30 days)
ECG (local)
(D)
7.2.2.5.4.
Required for dose changes
PCR (central)
(D)
7.2.1.1.
X
X
X
Safety
Adverse events
(D)
8.
Continuous
X (patients must 
be followed for 
AEs 30 days after 
stopping nilotinib)


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Category
Protocol 
Section
TFR EOC 
1,2,3,4,5,6
TFR EOC 8,10, 12, 14, 16, 18, 
20, 22, 24
Early 
Termination
30 Day Safety 
Follow-up
Visit Number
21,22,23,24,25,26
27, 28, 29 30, 31, 32, 33, 34,35
779
501
Day of cycle
TFRD*30, 60, 90, 
120, 150, 180
TFRD240, 300, 360, 420, 480, 
540, 600, 660, 720
--
--
MDASI-CML
(D)
7.2.4.
At Visit 26, for 
those with MR4.5
At Visit 29, for those with MR4.5
EQ-5D-3L
(D)
7.2.4.
SF-8
(D)
7.2.4.
Study Evaluation Completion (eCRF)
(D)
7.1.3.
X – only at Visit 39
X


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Table 7-4
Visit evaluation schedule – Nilotinib Treatment Re-initiation
Follow this schedule if a patient in TFR phase must be restarted on nilotinib (* RD = Re-initiation Day)
Category
Protocol 
Section
Re-Initiation 
Cycle 1 Day 
1 (baseline, 
prior to 
dosing)
Re-
initiation 
Cycle 1 
Day 8
Re-initiation 
End of Cycle 
(EOC) 1,2,3
End of every 3 cycles until 2 yrs 
from D/C phase start date
Early 
Termination
30 Day 
Safety 
Follow-up
Visit Number
40
41
42,43,44
45,46,47,48,49, 50,51
780
501
Day of cycle
RD*1
RD8
RD30, 60, 90
RD180,270,360,450,540,630,720
--
IVRS Registration
(D)
X
Physical examination, 
Extramedullary involvement
(D)
7.2.2.1.
X
X
X
X
Vital signs
(D)
7.2.2.2.
X
X
X
X
Weight
(D)
7.2.2.3.
X
X
X
X
Performance status
(D)
7.2.2.4.
X
X
X
X
Laboratory assessments
7.2.2.5.
Hematology (local)
(D)
7.2.2.5.1.
X
X
X
X
HbA1c and Lipid Panel (local) 
– LDL, HDL, TC, TG
(D)
7.2.2.5.
X – Visit 44
X – Visit 45, 46, 47, and 51
X
Chemistry (local)
(D)
7.2.2.5.2.
X
X
X
X
Urine Pregnancy test and diary 
(local), if applicable
(D)
7.2.2.5.3.
X
X – Monthly (every 30 days)
Serum Pregnancy test, if 
applicable
(D)
7.2.2.5.3.
X
ECG (local)
(D)
7.2.2.5.4.
X
X
Required for dose changes
RQ-PCR (central)
(D)
7.2.1.1.
X
X
X


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Category
Protocol 
Section
Re-Initiation 
Cycle 1 Day 
1 (baseline, 
prior to 
dosing)
Re-
initiation 
Cycle 1 
Day 8
Re-initiation 
End of Cycle 
(EOC) 1,2,3
End of every 3 cycles until 2 yrs 
from D/C phase start date
Early 
Termination
30 Day 
Safety 
Follow-up
Visit Number
40
41
42,43,44
45,46,47,48,49, 50,51
780
501
Day of cycle
RD*1
RD8
RD30, 60, 90
RD180,270,360,450,540,630,720
--
Safety
Adverse events
(D)
8.
Continuous
X
Study Drug Administration
(D)
6.1.1.
Continuous
End of Treatment (eCRF)
(D)
7.1.3.
X – at the last study visit
X
Study Evaluation Completion 
(eCRF)
(D)
7.1.3.
X


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7.1.1
Screening (Day -28 to 0)
Written informed consent must be obtained prior to having any study evaluations performed. 
It is recommended that the first evaluation to be done as part of screening is the peripheral 
blood draw for RQ-PCR testing. Once the result confirms that the patient meets the molecular 
criteria for entry, the rest of the screening visit evaluations may be performed which are listed 
in Table 7-1.
7.1.1.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure. The reason for not being started on treatment will be entered on
in IRT. No other data will be entered into the clinical database for patients who are screen 
failures, unless the patient experienced a Serious Adverse Event during the Screening Phase 
(see Section 8 for SAE reporting details). If the patient fails to be enrolled, the IRT must be 
notified within 2 days of the screen fail that the patient was not enrolled.
7.1.1.2
Patient demographics and other baseline characteristics
7.1.1.2.1 Inclusion/exclusion criteria
Patient eligibility is to be established by confirming all inclusion/exclusion criteria. A relevant 
record (e.g. checklist) must be stored with the source documentation at the study site. 
Deviation of any entry criterion excludes a subject from enrollment into the study.
7.1.1.2.2 Demographics
The patient’s date of birth, gender, and predominant race will be collected.
7.1.1.2.3 Relevant medical history / current medical conditions
Relevant medical history and current medical conditions, including condition and symptoms 
related to CML will be collected until the start of the study drug. History of tobacco use will 
also be collected on an eCRF.
7.1.1.2.4 Disease history
Date of initial diagnosis of CML and the initial disease classification (CML-CP, CML-AP, 
CML-BC) will be reported on the eCRF. Information on CML disease response will also be 
collected (
).
7.1.1.2.5 Sokal score
Sokal risk score at time of diagnosis will be collected if available. If a Sokal Risk score has 
not been assigned in the medical record, the components required to calculate the Sokal risk 
score will be collected (i.e. Age, spleen size, platelet count and % peripheral blood 
myeloblasts).


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Table 7-5
Sokal formulation
Sokal’s variables
Age (years)
0.0116 (age – 43.4)
*Spleen (cm)
0.0345 (spleen – 7.51)
Platelets (x10^9/L)
0.188[(platelets/700)^2 – 0.563]
^ Myeloblasts (%)
0.0887 (myeloblasts – 2.10)
Relative Risk (RR)
Exponential of the total
* Maximum distance from costal region
^ Percent in peripheral blood
Reference: (Sokal et al 1984)
Sokal score calculator at leukemia-net.org/content/leukemias/cml/cml_score/index_eng.html
In the Sokal formulation, all four variables are continuous. High, intermediate, and low Sokal 
risk scores are defined as the following:

Low risk patients have a Relative Risk (RR) < 0.8

Intermediate risk patients have a RR ≥0.8 and ≤1.2

High risk patients have a RR > 1.2
The Sokal risk score at diagnosis will be recorded on an eCRF page.
7.1.1.2.6 Prior antineoplastic therapy
Prior antineoplastic medications, radiotherapy, and surgeries will be collected on the 
appropriate Prior Antineoplastic Therapy eCRF.
7.1.1.2.7 Prior/concomitant medications
All prescription medications and over-the-counter drugs including vitamins and blood 
transfusions taken within 30 days prior to the start of and throughout the study must be 
recorded on the Concomitant Medications/Significant Non-Drug Therapies eCRFs. 
Medication entries should include the name, start and end dates, and the reason for therapy.
7.1.1.2.8 Prior RQ-PCR results
Prior RQ-PCR and laboratory information will be collected if available. The information to be 
collected will be outlined in the case report form completion guidelines.
7.1.2
Treatment period
Patients will be treated with nilotinib and monitored for MR4.5 for up to 2 years. After Cycle 
1 Day 8, patients will have study visits every 3 months during the Monitoring Phase. Those 
who achieve a confirmed MR4.5 and sustain MR4.0 or better for 2 years during the 
Consolidation Phase will be eligible for discontinuing nilotinib during the Treatment Free 
Remission Phase (TFR). Patients who achieve a confirmed MR4.5 will enter the 
Consolidation Phase and continue to receive nilotinib and be monitored every 3 months for 2 
years. Patients who are able to sustain MR4.0 or better during the 2 years of consolidation 
therapy with nilotinib will be eligible for stopping nilotinib therapy during the TFR Phase. 


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Patients will receive no study drug treatment during the TFR Phase and will have study visits 
every month for the first 6 months, and every other month for the next 18 months.
7.1.2.1
TFR visit schedule. Dose administration record
The Dosage Administration Record eCRF will capture the nilotinib dosing regimen 
information. Reasons for dose changes as well as start and end dates are recorded in the 
entries.
Patients should be reminded to bring in their study drug containers (blister packs/bottles) at 
each study visit. Compliance will be assessed by the investigator and/or study personnel at 
each visit using pill counts.
7.1.2.2
Additional assessments
If it is necessary to perform an additional unscheduled assessment (i.e. laboratory test, ECG, 
RQ-PCR), the results of the evaluation should be entered in the appropriate additional 
assessment eCRF page.
7.1.3
Study completion and early termination from study
At the time patients complete the study, there will be a study visit for either Early Termination
(Visit 777, 778, 779, or 780) or at the end of the study (which is either Visit 12 for those not 
eligible to continue on to the Consolidation Phase or Visit 39 for those who complete the TFR 
Phase). Refer to the visit schedules for evaluations required. An End of Treatment and Study 
Evaluation Completion eCRF pages should be completed according to the visit schedule. At a 
minimum, all patients who stop treatment, including those who refuse to return for a final visit, 
will be contacted for safety evaluations during the 30 days following the last dose of study 
treatment.
Patients who stop study treatment prematurely during the treatment phases should be 
considered withdrawn from the study after the final visit assessments are performed or when it 
is clear that the patient will not return for these assessments. If a study withdrawal occurs, or 
if the patient fails to return for visits, the investigator must determine the primary reason for a 
patient’s premature withdrawal from the study and record this information on the End of 
Treatment eCRF page.
7.1.3.1
Criteria for early termination from study
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
1. Pregnancy
2. Discovery of patient ineligibility/ Protocol deviation
3. Non-compliance
4. Adverse event(s)
5. Abnormal laboratory value(s)
6. Abnormal test procedure result(s)


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7. Lost to follow-up
8. Unsatisfactory therapeutic effect – Refer to Table 7-6.
Table 7-6
Loss of efficacy milestones requiring early termination
Phase
Efficacy Milestone Lost
within the variability of the 
testing used (±.5log)
Action Required
Follow-up Required
Monitoring Phase
Confirmed loss of MMR 
(MR3.0)
Patient terminates 
from study early
AEs 30 days after 
stopping nilotinib
Consolidation Phase
Confirmed loss of MR4.0
Patient terminates 
from study early
AEs 30 days after 
stopping nilotinib
TFR Phase
Confirmed loss of MMR 
(MR3.0)
Loss of CCyR
Patient re-starts 
nilotinib and 
continues on study
See Table 7-4.
Nilotinib Treatment Re-
Initiation (NTRI)
Failure to achieve 
MMR(MR3.0) after 12 
months of re-initiation
Contact Sponsor and the case will be 
reviewed with SMC
Failure to achieve CCyR 
within 3 months of nilotinib 
re-initiation (confirm loss -
PCR<1%IS)
Patient terminates 
from study early
AEs 30 days after 
stopping nilotinib
9. Subject’s condition no longer require study drug (i.e. bone marrow transplantation)
10. Treatment duration completed as per protocol
11. Administrative problems
12. Disease progression
a. Accelerated phase as defined by any of the following (Kantarjian 1993):
i.
≥ 15% blasts in the peripheral blood or bone marrow, but < 30% blasts in both 
the peripheral blood and bone marrow
ii. ≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow
iii. ≥ 20% basophils in the peripheral blood
iv. Thrombocytopenia (<100 x 10^9/L) that is unrelated to therapy
b. Blast crisis as defined by any of the following (Druker 2007):
i.
≥ 30% blasts in peripheral blood or bone marrow
ii. Appearance of extramedullary involvement other than hepatosplenomegaly 
proven by biopsy
c. CML-related death (any death during treatment or follow-up if the principal cause of 
death is marked as “study indication” in the CRF by the investigator, or if the death 
occurred subsequent to documented progression to AP/BC and the cause of death is 
reported as “unknown” or not reported by the investigator)
Refer to the visit schedules for the list of evaluations required at Early Termination/End of 
Study.


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7.1.4
Safety follow up
All patients must have safety evaluations for 30 days after the last dose of study treatment or
the last day of the TFR Phase. This follow-up period for safety does not require a visit and can 
be conducted over the phone.
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc.
7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Molecular response
Levels of BCR-ABL transcripts will be determined by quantitative RQ-PCR testing of 
peripheral blood. Samples will be analyzed at a central testing laboratory and reported on the 
International Scale (IS). Log reduction in BCR-ABL transcripts levels from the standardized 
baseline value will be calculated for each sample from the reported percent ratio of BCR-ABL 
transcripts versus control gene transcripts converted to a reference standard. Samples for RQ-
PCR analysis will be collected according to the visit schedules.
RQ-PCR laboratory and supplies
The BCR-ABL RQ-PCR test quantitatively measures the RNA blood level of BCR-ABL. For 
this test total RNA from whole leukocytes is reverse transcribed with random primers and the 
cDNA product is quantitated by fluorescent real-time RQ-PCR. The BCR-ABL RQ-PCR 
contains primers from bcr exons b2 & b3 and abl exon 2, such that the major (p210) 
translocation breakpoint is detected. Abl cDNA copy numbers are used to control for the 
quality and quantity of sample RNA. Therefore, the result of this test is expressed in % as a 
fraction of BCR-ABL expression to that of the control gene ABL (% BCR-ABL/ABL).
Major Molecular Response (MMR) (MR3.0)) is equivalent to a 3-log reduction from a 
standardized baseline value from the International Randomized Interferon versus STI571 
(IRIS) study or 0.1% per IS. A standardized baseline value was established in the IRIS trial by 
calculating the median BCR-ABL transcript value of 30 patient samples collected from newly 
diagnosed CML-CP patients prior to commencing study drug. The same set of patient samples 
were tested in the three IRIS trial RQ-PCR laboratories. The standardized baseline, instead of 
the baseline transcript level of an individual patient, was then used to calculate subsequent 
molecular response. A correction factor is applied to all BCR-ABL/ABL ratios to obtain the 
International Scale value and MMR (MR3.0) is reported when a patient shows a BCR-
ABL/Abl% less than or equal to 0.1% IS. A result of MR4.5 indicates a greater than or equal 
to 4.5-log reduction of Bcr- Abl copy number from a standardized baseline value on the 
international scale.
The central RQ-PCR laboratory used in this study has a validated assay and values of BCR-
ABL/control gene% will be reported on the International Scale and also calculated as a log 


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reduction from the standardized baseline value. RQ-PCR kits from the central RQ-PCR lab 
will be provided to each site. Each kit will have accession numbers that are specific to each 
patient and to each sample. Peripheral blood samples will be couriered to the central RQ-PCR 
laboratory. The results of the central RQ-PCR laboratory will be communicated to the sites to 
guide patient treatment.
Sample collection for molecular response
In order to monitor molecular response under study treatment, 10 ml of peripheral blood will 
be collected at each sampling time point for RQ-PCR analysis. The blood will be analyzed for 
the presence and quantity of BCR-ABL transcripts by RQ-PCR.
Sample collection kits for RQ-PCR 
 will be provided to each site by 
the central lab. Please refer to the central PCR lab manual for collection and shipping 
instructions. Refer to the visit schedules for PCR evaluation time points.


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7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing hematology and biochemistry laboratory results, 
physical exam results, and ECG monitoring as well as collecting of the adverse events and 
concomitant medications at every visit. For details on AE collection and reporting, refer to 
Section 8.
7.2.2.1
Physical examination and extra-medullary involvement
A physical examination will be performed according to the visit schedules. A complete 
physical examination should include examination of general appearance, eyes, ears, nose, 
throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, and neurological 
systems.
Information about the physical examination must be present in the source documentation at 
the study site. Significant findings that are present prior to the start of study drug must be 
included in the Relevant Medical History/ Current Medical Conditions eCRF. Significant 
findings made after the start of study drug, which meets the definition of an Adverse Event, 
must be recorded on the Adverse Events eCRF. There are no eCRF pages to capture routine 


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normal findings from physical examinations; however these findings must be present in the 
patient’s source documents.
Presence of extra-medullary leukemic involvement will be checked with each physical exam 
as outlined above. Findings on physical examination consistent with extra-medullary 
involvement will be recorded on the eCRF (i.e. lymph nodes, liver, and spleen size).
7.2.2.2
Vital signs
Pulse rate, blood pressure, body temperature data will be collected on the eCRFs at the 
specified visits in the visit schedules must be present in the patient’s chart.
7.2.2.3
Height and weight
Height (in centimeters) will be measured only at baseline and recorded on the eCRF.
Body weight (in kilograms) will be measured. To detect early signs of fluid retention, patients 
should be weighed according to the visit schedules. Patients should be counseled to measure 
their body weight regularly and report to the study investigator any body weight change of 
more than 2 kg as compared to their pre-study body weight. Rapid weight gain of ≥ 2 kg 
should be carefully investigated and managed as appropriate Except for the body weight 
measurements performed during study visits, other body weight measurements will not be 
captured on eCRFs nor entered into the clinical database
7.2.2.4
Performance status
Performance status will be recorded in the eCRF according to the visit schedules and as 
defined by the Eastern Cooperative Oncology Group (ECOG) criteria in Table 7-7.
Table 7-7
ECOG performance status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair
5
Dead
7.2.2.5
Laboratory evaluations
Each institution will perform hematology and clinical chemistry using their local laboratory 
according to the visit schedules. The normal ranges and units for each parameter will be 
collected. If at any time a patient has laboratory parameters obtained from a different 
laboratory, the certification, tabulation of the normal ranges and units for that laboratory must 
be provided.
When abnormal laboratory values or test results constitute an adverse event (i.e. induces 
clinical signs/symptoms or requires therapy) they must be recorded on the Adverse Events 


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eCRF. Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms, are considered clinically significant (e.g. cause study 
discontinuation or constitutes in and of itself a Serious Adverse Event) or require therapy (e.g., 
any hematologic abnormality that requires transfusion or cytokine treatment); and should be 
recorded on the Adverse Events eCRF under the signs, symptoms or diagnosis associated with 
them. Refer to the visit schedule for the collection frequency.
Table 7-8
Clinical laboratory parameters collection plan
Test 
Category
Test Name
Hematology
Hemoglobin, total WBC count, platelet count, and a differential count (neutrophils, 
bands, lymphocytes, monocytes, eosinophils, basophils, promyelocytes, myelocytes, 
metamyelocytes, blasts, atypical cells)
Chemistry
Creatinine, uric acid, albumin, total protein, total bilirubin, direct bilirubin and/or
indirect bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), LDH, sodium, 
chloride, fasting glucose, HbA1c, calcium, lipase, potassium, magnesium, 
phosphorus, total cholesterol, triglycerides, LDL, HDL
Serology
Hepatitis B surface antigen (HBs Ag), hepatitis B core antibodies (HBc Ab), 
antibodies to hepatitis B surface antigen (HBsAb)
7.2.2.5.1 Hematology
Hematology labs are to be done locally at the site. The hematology parameters required to be 
evaluated are listed in Table 7-8.
Automated differential counts are permitted, however manual differential counts are 
mandatory in the following situations:

if loss of CHR is suspected

if progression to accelerated phase/blast crisis is suspected

whenever automated differential counts indicate the presence of blasts, promyelocytes, 
myelocytes, metamyelocytes or atypical cells which cannot be automatically counted
7.2.2.5.2 Clinical chemistry
Blood chemistry labs, including the lipid profile, are to be done locally at the site and the 
parameters required are listed in Table 7-8. Patients should fast for the biochemistry labs. The 
routine biochemistry evaluations identified on the visit schedule will be captured on the eCRF.
In addition to the routine biochemistry assessments identified on the visit schedule, patients 
must have their serum potassium and magnesium levels checked when there is QTcF 
prolongation and also at the investigator’s discretion throughout the study. Additional 
electrolyte results (i.e. potassium and magnesium) will not be captured on eCRFs nor entered 
into the clinical database unless supplementation or replacement is required. If 
supplementation or replacement is required, the lab abnormality should be documented on an 
unscheduled or scheduled lab result eCRF page, and also as an adverse event. If a supplement 
or replacement is given, these are to be identified as a concomitant medication. Otherwise, 
these additional results must be only present in the source documentation at the study site.


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7.2.2.5.3 Pregnancy and assessments of fertility
At screening, a serum pregnancy test is required and a urine pregnancy test is required at 
baseline prior to dosing at Visits 777, 778, 779, and 780. Pregnancy testing is not required for 
patients who are determined to be post-menopausal as defined in the Exclusion criteria. The 
serum pregnancy tests will be performed by the local lab.
In addition, monthly urine pregnancy test is also mandatory for all women of child bearing 
potential throughout the duration of this study. Urine pregnancy tests should be performed at 
home by the patient throughout the duration of this study. All urine pregnancy test results 
should be recorded in patient diaries and brought to each scheduled visit for the site to review. 
Sites are to document the results of the home urine pregnancy test recorded in the diary to an 
eCRF page. If a positive urine pregnancy test result is discovered at home, the patient should 
contact the investigator immediately. All pregnancies should be recorded on a Clinical Trial 
Pregnancy Form and reported by the investigator to the oncology Novartis Drug Safety and 
Epidemiology Department (DS&E).
7.2.2.5.4 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed locally according to the schedule below.
Table 7-9
Local ECG collection plan
Cycle
Day
Time
ECG Type
Screening
D-28 to 0
Anytime
12 Lead
1
1
Pre-dose
12 Lead
1
8
Anytime
12 Lead
Unscheduled sample
Anytime
12 Lead
An ECG must be performed at screening, Day 1, and Day 8. QTcF values must be 
documented in the CRFs. The ECG performed on Day 1 should be done prior to dosing. The 
ECG obtained at screening and Day 8 can be done at any time. The QT interval should be 
corrected using the Fridericia formula which is QTcF = QT/(RR)1/3. If the ECG machine is 
preprogrammed with the Bazett formula, QTcB = QT/(RR)1/2, the value of QTcF can be 
manually 
calculated 
by 
using 
the 
formula 
QTcF 
= 
QT/ 
(RR)1/3, 
or
QTcF = QT/[(QT/QTcB)2]1/3 since RR = (QT/(QTcB)2). A study tool will also be provided to 
help with this conversion. If the QTcB value is converted to QTcF, provide both values on the 
eCRF page. (Bazett 1920) (Fridericia 1920)
After a dose interruption or after any dose changes, additional (unscheduled) ECGs are 
required. For example, if nilotinib is stopped due to administration of any agents known to 
prolong the QT interval or strong CYP3A4 inhibitors, additional ECGs are required prior to 
re-initiation of nilotinib and approximately 7 days after. If a patient is dose reduced to 400mg
q.d. for an adverse event, an ECG is required 7 days after re-escalating the dose to 300mg 
b.i.d.
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG eCRF page. Each ECG tracing should be labeled with the study number, patient number, 
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 


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eCRF page. Clinically significant findings must be discussed with Novartis prior to enrolling 
the patient in the study. New or worsened clinically significant findings occurring after 
informed consent must be recorded on the Adverse Events eCRF page.
7.2.2.5.5 Hepatitis B testing
Patients will be tested once for the following hepatitis B serologic markers: hepatitis B surface 
antigen (HBsAg), antibodies to hepatitis B surface antigen (HBsAb) and antibodies to 
hepatitis B core antigen (HBcAb).


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7.2.4
Patient reported outcomes
Patients will be asked to complete the M.D. Anderson Symptom Inventory – Chronic Myeloid 
Leukemia (MDASI-CML), the EuroQol- Five Dimension Three -level (EQ-5D-3L), and SF-8 
questionnaires. The MDASI-CML is a symptom-burden questionnaire, the EQ-5D-3L and the 
SF-8 are health related quality of life questionnaire.
The patient should be given the questionnaire(s) to be completed at the scheduled visit before 
any clinical assessments are conducted. Patient’s refusal to complete all or any part of a 
questionnaire should be documented in the study data capture system and should not be 
captured as a protocol deviation. Patient questionnaires should be completed in the language 
most familiar to the patient.
The patient should be given sufficient space and time to complete the questionnaire. The site 
personnel should check the questionnaire for completeness and ask the patient to complete 
any missing responses. The original questionnaire will be kept with the patient’s file as the 
source document.
Completed questionnaire(s) and any unsolicited comments written by the patient should be 
reviewed and assessed by the investigator for responses which may indicate potential AEs or 
SAEs before any clinical study examinations. This assessment should be documented in study 
source records. If AEs or SAEs are confirmed, study investigators should not encourage the 
patient to change responses reported in the completed questionnaires. Study investigators 
must follow reporting instructions outlined in Section 8 (e.g. reference “Adverse Events” 
section) of the study protocol.
MDASI-CML
The M.D. Anderson Symptom Inventory (MDASI) tool will be utilized to measure symptom 
burden during the first year on study (Cleeland et al 2000). The 13 core symptom items of the 
MDASI have been tested in a sample of 527 cancer patients that included CML patients and 
were found to have discriminant and construct validity. Principle factor analysis showed two 
underlying constructs of general symptom severity and gastrointestinal symptom severity for 
the MDASI. The reliability, measured by coefficient a values, for the general symptom 


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severity factor, the GI symptom severity factor, and the symptom interference in the 
validation sample were 0.85, 0.82, and 0.91, respectively, and in the cross-validation sample 
were 0.87, 0.87, and 0.94, respectively, which demonstrates a high level of reliability 
(Cleeland et al 2000). The MDASI is scored by calculating a mean symptom severity score of 
symptom ratings and a mean interference score of interference item ratings.
A CML specific MDASI has been developed and patients will be asked to complete this 
questionnaire. The MDASI-CML consists of 13 validated core symptom items and 6 validated 
core interference items. Six additional symptom items specific to patients undergoing 
treatment for CML are being investigated. The items are assessed utilized an 11 point scale. 
Patients will be asked to rate their symptom severity and interference within the last 24 hours.
The MDASI-CML questionnaire will be given to patients to complete upon the patient’s 
arrival at the clinic. This is to ensure that the patients’ recordings are not influenced by any 
discussions with the physicians during the visit. The data collector will remain with the 
patient while the questionnaires are completed to ensure that it is the patient who completes 
the forms and that no one else influences the patient’s answers. Patients should be instructed
to read the instructions before completing the questionnaire. Patients should be encouraged to 
answer every item. Patients should be instructed to indicate the response they think best 
represents how they are feeling. If for whatever reason the patient does not complete the 
questionnaire at the scheduled assessment, time and reason should be recorded. The study 
personnel is responsible for collecting the form from the patient at each of the visits when 
indicated. Translated versions of the MDASI-CML will be available as CRFs. Refer to the 
eCRF Completion Guidelines (CCGs) on how to administer the questionnaire.
EQ-5D-3L
The EQ-5D-3L questionnaire is a standardized measure of health status developed by the
EuroQol Group in order to provide a simple, generic measure of health for clinical and
economic appraisal. The EQ-5D-3L is applicable to a wide range of health conditions and
treatments; it provides a simple descriptive profile and a single index value for health status
that can be used in the clinical and economic evaluation of health care as well as in population
health surveys.
The EQ-5D-3L is designed for self-completion by respondents and is ideally suited for use in
postal surveys, in clinics, and in face-to-face interviews. It is cognitively undemanding, taking
only a few minutes to complete.
Instructions to respondents are included in the questionnaire. The EQ-5D-3L measures 5
items on mobility, self-care, usual activities, pain/discomfort, anxiety/depression, measured 
on 3 levels: no problems, some problems, and extreme problems. The EQ-5D-3L also 
includes a 20 cm vertical, VAS (visual analogue scale) with on a scale of 0-100, with 
endpoints labeled ‘the best health you can imagine’ and ‘the worst health you can imagine’. A 
single index value is analyzed for the EQ-5D-3L and VAS score.
Patients must be asked to complete each questionnaire prior to clinical assessments being
undertaken, and these must be completed in accordance with the schedules listed in the visit 
schedule.


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SF-8
SF-8 is an 8-item questionnaire designed to provide a HRQL profile, developed by 
QualityMetric, Incorporated (QMI). It measures health profile in eight scales (i.e., domains) 
with a single item in each scale: general health (SF8GH), physical functioning (SF8PF), role 
physical (SF8RP), bodily pain (SF8BP), vitality (SF8VT), social functioning (SF8SF), mental 
health (SF8MH), emotional roles (SF8RE). The profile is summarized into physical 
component (PCS) and mental component (MCS) continuous summary scores, with higher 
scores indicating better self-reported HRQL. The PCS and MCS have been normalized in the 
United States population. These norms are useful for comparing the health of participants to 
the general US population. SF-8 is sensitive to change, and can therefore be used to assess 
change in HRQL over time.
SF-8 belongs to short form (SF) family, which also include SF-36 (based on 36 questions) and 
SF-12 (based on 12 questions). SF-8 measures the same eight health domains as the SF-36 
and SF-12. It has the advantage of being brief, while yielding scores that are directly 
comparable to that produced by the standard SF-36 and SF-12 questionnaires.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. This includes any adverse events that occur in the TFR Phase
Conditions that were already present at the time of informed consent should be recorded in the 
Medical History page of the patient’s eCRF. Adverse event monitoring should be continued 
for at least 30 days (or 5 half-lives, whichever is longer) following the last dose of study 
treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 


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not be used in this study; rather, information about deaths will be collected though a Death 
form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates or Ongoing at End of Study)
3. Its relationship to the study treatment
4. Action taken with respect to study or investigational treatment
5. Whether medication or therapy was given
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.


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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, 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 6-3).
The Investigator should ensure that the patient is assessed by a vascular or cardiovascular 
specialist.
8.1.3.1
Reporting of AE of special interest
Ischemic vascular or ischemic cardiovascular events in patients should be documented and 
reported as any other AE (please refer to Section 8.1.1 for further details).
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication (CML), not associated with 
any deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital
admission and involves an event not fulfilling any of the definitions of a SAE given above 
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8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided the main informed consent and until at least 30 days after the patient has 
stopped study treatment or last day in the TFR Phase must be reported to Novartis (using the 
SAE Report Form) within 24 hours of learning of its occurrence. SAEs will be followed until 
resolution or until clinically relevant improvement or stabilization.
Any SAEs experienced after this 30 days period (or 5 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 otherwise considered 
completely unrelated to a previously reported one should be reported separately as a new 
event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department. Causality for each reported 
serious event on the SAE report form must be assessed as either as “Suspected” or “Not 
Suspected” to the study drug. No other term such as “Probable”, “Plausible”, “May be” or 
“Could be” etc. should be used for causality assessment.
The telephone and telefax number of the contact persons in the 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 case report 
form documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation.
If the SAE is not previously documented in the [Investigator’s Brochure] or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
DS&E department associate may urgently require further information from the investigator 
for Health Authority reporting. Novartis may need to issue an Investigator Notification (IN), 
to inform all investigators involved in any study with the same drug that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with 
Directive 2001/20/EC or as per national regulatory requirements in participating countries.


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8.3
Emergency unblinding of treatment assignment
Not applicable
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
and/or in the TFR Phase must be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment and pregnancy outcome. 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 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee
Not applicable
8.7
Study Management Committee (SMC)
A Study Management Committee (SMC) will be established comprising 5 external
investigators who are clinical experts in CML and 3 Novartis team members.
The SMC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require; to interpret/clarify RQ-
PCR and mutation analysis results as appropriate. The SMC will review protocol amendments 
as appropriate. Together with the clinical trial team, the SMC will also develop 
recommendations for abstracts and publications of study results including authorship rules.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study


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
Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel and the designated CRO will review the protocol and Electronic Case Report Forms 
(eCRFs) with the investigators and their staff. During the study, the field monitor will visit the 
site regularly to check the completeness of patient records, the accuracy of entries on the 
eCRFs, the adherence to the protocol to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria 
and documentation of SAEs. Additional checks of the consistency of the source data with the 
eCRFs are performed according to the study-specific monitoring plan. No information in 
source documents about the identity of the patients will be disclosed.
9.3
Data collection
This study will use Electronic Data Capture (EDC) and the designated investigator staff will 
enter the data required by the protocol into the eCRFs using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements. Designated 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.


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The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
PCR 
 will be collected and analyzed by 3rd party vendors. Results will be 
sent to the designated CRO, who will export the data to SAS datasets.
Laboratory assessments for hematology, chemistry, and ECGs will be collected locally and 
entered directly onto the eCRFs.
9.4
Database management and quality control
This study will be using eCRFs and the designated CRO will review the data entered by 
investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing 
values and sent to the investigational site via the EDC system. Designated investigator site 
staff are required to respond promptly to queries and to make any necessary changes to the 
data.
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
 data will be processed centrally and the results will be 
sent electronically to the designated CRO.
PCR samples and/or data will be processed centrally and the results will be sent electronically 
to the designated CRO.
Patient status during the study will be tracked using an Interactive Response Technology. The 
system will be supplied by a vendor(s), who will also manage the database. The data will be
sent electronically to the designated CRO.
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After this action has been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and the data made available for data analysis. 
Authorization is required prior to making any database changes to locked data.
For EDC 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
A designated Clinical Research Organization (CRO) will perform the statistical analysis.
It is planned that the data from all centers that participate in this protocol will be used, so that 
an adequate number of patients will be available for analysis.
The primary analyses of all efficacy and safety variables will be performed when all patients 
enrolled have completed 6 months of the TFR Phase, follow-up or discontinued from the
study. All analyses will include patients who entered the TFR Phase following a 12 month 


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Consolidation Phase (Arm A) prior to protocol amendment 2 and a 24 month Consolidation 
Phase (formerly Arm B).
After all patients enrolled have completed 12 and 24 months of follow-up, analyses of all
efficacy and safety will be performed including the same patients as in the primary analyses. 
These analyses performed after the primary analyses will be considered secondary. No formal 
testing of any kind will be performed at these analyses.
Since the study collects data in 3 phases (monitoring, consolidation and treatment-free 
remission phases), all safety (dosing, AEs, vitals signs and laboratory) and patient reported 
outcomes data will also be summarized overall in the Consolidation Phase.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) for the primary analyses comprises all patients who entered the 
TFR Phase.
The FAS will be the primary set for all efficacy analyses and safety analyses in the TFR Phase 
only.
10.1.2
Safety set
The safety set consists of all patients who received at least one dose of study drug and had at 
least one post-baseline safety assessment after enrollment.
Please note: the statement that a patient had no adverse events (on the Adverse Event eCRF) 
constitutes a safety assessment. Patients who have received at least one dose of study drug but 
who have no post-treatment safety data of any kind would be excluded from the safety set.
The safety set will be used for the summary of all safety and patient reported outcomes in the 
monitoring and Consolidation Phase.
10.1.3
Per-protocol set
No per-protocol set will be defined for this study.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including age, gender, height, weight, ECOG status, 
disease history, medical conditions etc. will be summarized overall for all enrolled patients. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum and maximum will be 
presented.
10.3
Treatments (study treatment, concomitant therapies, compliance)
The actual daily dose and duration of study drug will be summarized overall using descriptive 
statistics in the monitoring and Consolidation Phase respectively.


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Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized overall in both monitoring and Consolidation Phases.
10.4
Primary objective
The primary objective of the study is to evaluate molecular relapse-free rates 6 months after 
discontinuation from nilotinib therapy in patients who have achieved a MR4.5.
10.4.1
Molecular relapse is defined as having a confirmed BCR-ABL ratio 
above MMR (2 consecutive BCR-ABL levels >0.1%IS taken 
approximately 4 weeks apart) variable
Molecular relapse free rate (RFR) at 6 months after discontinuation from nilotinib therapy in 
patients with MR4.5
10.4.2
Statistical hypothesis, model, and method of analysis
No statistical hypothesis will be tested on the primary efficacy variable.
The primary efficacy variable will be summarized by frequencies and percentages overall. An 
exact 95% confidence interval for the relapse free rate at 6 months will also be provided
overall.
The FAS will be used for the summary.
10.4.3
Handling of missing values/censoring/discontinuations
No imputation of missing values will be performed.
10.4.4
Supportive analyses
An exploratory analysis of the relapse free rate will be performed using a logistic regression 
model to evaluate the dependence of relapse (Yes or No) on important prognostic variables 
(e.g., duration on nilotinib, duration of sustained MR4.5, and selected baseline characteristics).
10.5
Secondary objectives
10.5.1
Key secondary objective(s)
The key secondary objective of the study is to evaluate relapse-free survival.
10.5.2
Other secondary efficacy objectives
The other secondary objectives of the study are:

To evaluate molecular relapse free rates at 12 and 24 months after nilotinib treatment 
discontinuation

To evaluate the proportion of patients who regain MR4.5 after restarting nilotinib 
following molecular relapse

To describe the impact of nilotinib treatment discontinuation on progression to AP/BC and 
CML-related deaths

Overall survival


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Relapse free survival is defined as time from the date of nilotinib treatment discontinuation to 
the first documented molecular relapse (confirmed loss of MR4.0, confirmed loss of MMR 
are 2 consecutive BCR-ABL levels > 0.1% IS taken approximately 4 weeks apart).The 
relapse-free survival will be summarized and graphed using the product-limit (Kaplan-Meier)
overall. Patients who drop out without relapse will be treated as censored observations. The 
estimates of the 25th, median, 75th percentiles for the relapse-free survival and its 95% 
confidence intervals will be provided, if applicable.
The molecular relapse free rates at 12 and 24 months and the proportion of patients who 
regain MR4.5 after restarting nilotinib will summarized overall by frequencies and 
percentages. An exact 95% confidence interval for each will also be provided using binomial 
distribution.
Overall survival is defined as the time from the date of nilotinib treatment discontinuation to 
the date of death from any cause.
Overall survival will be summarized and graphed using the product-limit (Kaplan-Meier) 
method as described above. Patients who are alive at the date of last contact will be treated as 
censored observations.
The FAS for the primary analysis as described above will be used for these analyses.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
The assessment of safety will be based primarily on the frequency of adverse events and on 
the number of laboratory values that fall outside of pre-determined ranges. Other safety data 
(e.g., electrocardiogram, vital signs, etc.) will be also be summarized. All safety data will be 
summarized overall in the 3 different phases as appropriate. All safety listings will be done 
overall.
The safety set will be used for all safety summaries.
10.5.3.2 Adverse events (AEs)
All adverse events recorded during the study will be summarized. The incidence of treatment-
emergent adverse events (new or worsening from baseline) will be summarized by system 
organ class, severity (based on CTC grades), type of adverse event, relation to the study drug. 
The adverse events which result in death, early termination of the treatment or are otherwise 
classified as dose limiting will be presented separately.
10.5.3.3 Laboratory abnormalities
All laboratory values will be converted into SI units and the severity grade calculated using
appropriate common toxicity criteria (CTC).
A listing of laboratory values will be provided by laboratory variable, patient, and dose level. 
A separate listing will display notable laboratory abnormalities (i.e., newly occurring CTC 
grade 3 or grade 4 laboratory toxicities). The frequency of laboratory abnormalities will be 
displayed by variable andcycle. Laboratory data will be summarized by presenting shift tables.


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10.5.3.4 Other safety data
Data from other tests (e.g., electrocardiogram or vital signs) will be summarized and listed, 
notable values will be flagged, and any other information collected will be listed as 
appropriate. Any statistical tests performed to explore the data will be used only to highlight 
any interesting comparisons that may warrant further consideration.
10.5.3.5 Supportive analyses for secondary objectives
The M.D. Anderson Symptom Inventory for CML patients (MDASI-CML) will be used to 
assess the nature and impact of symptom burden on life. The MDASI-CML consists of 19 
validated symptom items and 6 validated core interference items. Each item is assessed on an 
11 point scale.
The symptom, interference subscale total scores and the overall total score in MDASI-CML 
with their change from baseline will be summarized descriptively at all post-baseline time 
points by mean, median, standard deviation, 25th and 75th percentiles and the range.
The EQ-5D-3L will be used to assess the impact of nilotinib treatment discontinuation on 
patient utility. The questionnaire comprises 5 items: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression and the EQ visual analog scale. Each item has 3 levels 
(no problems, some problems and extreme problems) and visual analog has a scale 0 to 100 
(0=worst imaginable health state, 100=best imaginable health state).
The percentages of patients at each level of the five items of the EQ-5D-3L will be 
summarized overall as appropriate at baseline and all post-baseline time points.
Mean and standard deviation of the visual analog scale be provided.
The SF-8 Questionnaire consisting of 8 items (general health, physical functioning, role-
physical, bodily pain, vitality, social functioning, role-emotional and mental health) will be 
used to assess the impact of nilotinib treatment discontinuation on the quality of life. Each 
item has a 5 or 6 point response range. Physical and mental component summary measures 
(calculated using a norm-based scoring method given in the instrument guidelines) and each 
item score will be summarized at baseline and all post-baseline time points using mean and 
standard deviation.


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10.6
Interim analysis
No interim analysis will be performed for this study.
10.7
Sample size calculation
The sample size of the study is not based on statistical considerations, it is based on feasibility. 
Due to slow enrollment, the sample size of the study has been reduced to 59 patients, all of 
which were enrolled by January 9, 2015. Of these 59 patients, approximately 20 are expected 
to enter into the TFR Phase. It is assumed that the study will show an improvement of 20% 
RFR rate over the historical control rate of 40% RFR observed in the STIM study.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Prior to study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs and 
regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their eCRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 


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guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.4.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 


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microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (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 CRFs and all other required reports. Data 
reported on the eCRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the eCRF 
must be recorded. Any missing data must be explained. Any change or correction to a paper 
eCRF should be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. For electronic CRFs an audit trail will be maintained by the system. The 
investigator should retain records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 


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Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.


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13
References (available upon request)
Bartram CR, deKlein A, Hagemeijer A, et al (1983) Translocation of c-Abl correlates with the 
presence of a Philadelphia chromosome in chronic myelogenous leukemia. Nature; 306: 277-
80.
Bazett HC (1920) An analysis of the time-relations of electrocardiograms. Heart. 1920;7:353-
370.
Cervantes C, et al (2012) Nilotinib induces deeper molecular responses vs continued imatinib 
in patients with Ph+ chronic myeloid leukemia (CML) with detectable disease after 2 years on 
imatinib: ENESTcmr 12-month results. Haematologica; 97(s1): 239.
Cleeland CS, Mendoza TR, Wang XS, et al (2000) Assessing symptom distress in cancer 
patients: The M. D. Anderson symptom inventory. Cancer, 89, 1634-1646.
Daley GQ, Van Etten RA, Baltimore D (1990) Induction of chronic myelogenous leukemia in 
mice by the p 210 bcr/Abl gene of the Philadelphia chromosome. Science; 247: 824-30.
Druker BJ (2007) Chronic Myelogenous Leukemia In: DeVita VT, Lawrence TS, Rosenburg 
SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. Vol.2 
(ed8): Lippincott, Williams, and Wilkins; 2267-2304.
Enright H, McGlave P (2000) Chronic myelogenous leukemia. In: Hoffman R, Benz EJ, 
Shattil SJ et all, eds. Hematology: Basic Principles and Practice, Third Edition. New 
York:Churchill-Livingstone, Inc., 1155-71.
Fridericia LS (1920) Die Systolendauer im Elektrokardiogramm bei normalen Menschen und 
bei Herzkranken. Acta Med Scand. 1920;53:469-486.
Gugliotta G, et al (2011) Early CP CML, Nilotinib 400 mg Twice Daily Frontline: Beyond 3 
Years, Results Remain Excellent and Stable (A GIMEMA CML Working Party Trial). Blood
(ASH Annual Meeting Abstracts) 2011 118: Abstract 2756.
Heisterkamp N, Stephenson JR, Groffen J, et al (1983) Localization of the c-Abl oncogene 
adjacent to a translocation break point in chronic myelocytic leukemia. Nature; 306: 239-42.
Kantarjian HM, et al (1993) Chronic myelogenous leukemia: A concise update. Blood; 
82:691-703.
Kelliher MA, McLaughlin J, Witte ON, et al (1990) Introduction of a chronic myelogenous 
leukemia-like syndrome in mice with v-Abl and BCR/ABL. Proc Natl Acad Sci USA 
87;6649-53.
Larson RA, et al (2012) Nilotinib vs imatinib in patients with newly diagnosed Philadelphia 
chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. 
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Le Coutre P, Baskaynak G, Tamm I, et al (2004) Activity and induction of apoptosis of the 
specific tyrosine kinase inhibitor nilotinib in BCR-ABL + cell lines and in imatinib resistant 
primary cells from CML patients. Blood; 104(11), abstract #762.
Lipton J, et al (2012) Switch to nilotinib versus continued imatinib in patients (pts) with 
chronic myeloid leukemia in chronic phase (CML-CP) with detectable BCR-ABL after 2 or 


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more years on imatinib: ENESTcmr 12-month (mo) follow-up. J Clin Oncol 30, 2012 (suppl; 
abstr 6505).
Mahon F, et al (2010) Discontinuation of imatinib in patients with chronic myeloid leukaemia 
who have maintained complete molecular remission for at least 2 years: the prospective, 
multicentre Stop Imatinib (STIM) trial. The Lancet Oncology, Volume 11, Issue 11, 
November 2010, Pages 1029–1035.
Nowell PC, Hungerford DA (1960) A minute chromosome in human chronic granulocytic 
leukemia. Science; 132: 1497-1501.
Quintás-Cardama A, et al (2011) Efficacy of Frontline Nilotinib Therapy in Patients (Pts) with 
Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Myeloid Leukemia in 
Early Chronic Phase (CML-CP). Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 
454.
Rea D, et al (2011) Discontinuation of Dasatinib or Nilotinib in Chronic Myeloid Leukemia 
(CML) Patients (pts) with Stable Undetectable BCR-ABL Transcripts: Results From 
theFrench CML Group (FILMC). ASH Annual Meeting Abstracts 2011 118: 604.
Richter J, Söderlund S, Lübking A, et al (2014) Musculoskeletal pain in patients with chronic 
myeloid leukemia after discontinuation of imatinib: A tyrosine kinase inhibitor withdrawal 
syndrome? J Clin Oncol 32:2821–2823.
Ross M, et al (2012) Frequent and sustained drug-free remission in the Australasian CML8 
trial of imatinib withdrawal. Haematologica; 97(s1): 74.
Rosti G, et al (2008) Nilotinib 800 mg daily as first line treatment of chronic myeloid 
leukemia in early chronic phase: results of phase II trial of the GIMEMA CML Working Party. 
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Edition) 26: 7054.
Rousselot P, et al (2007) Imatinib mesylate discontinuation in patients with chronic 
myelogenous leukemia in complete molecular remission for more than 2 years. Blood, Jan 
2007; 109: 58 - 60.
Rowley JD (1973) A new consistent abnormality in chronic myelogenous leukemia identified 
by quinacrine, fluorescence and Giemsa staining. Nature; 243:290-93.
Saglio G, Kim DW, Issaragrisil S, et al (2010) Nilotinib versus Imatinib for Newly 
DiagnosedChronic Myeloid Leukemia. New England Journal of Medicine; 362 (24): 2251-
2259.
Sokal JE, Cox EB, Baccarani M, et al (1984) Prognostic discrimination in “Good-Risk” 
chronic granulocytic leukemia. Blood; 63: 789-99.
White D, Saunders V, Engler J, et al (2005) Low baseline intrinsic sensitivity to imatinib 
(high IC50) in CML patients is due to reduced Oct-1 mediated influx. Intrinsic sensitivity to 
nilotinib does not correlate with that of imatinib and uptake of nilotinib is not Oct-1 mediated. 
Blood; 106(11), abstract #1081.
Yin O, Gallagher N, Fischer D, et al (2011) Effects of Nilotinib on Single-Dose Warfarin 
Pharmacokinetics and Pharmacodynamics: A Randomized, Single-Blind, Two-Period 
Crossover Study in Healthy Subjects. Clin Drug Investig; 31(3):169-79.

SAP_000.pdf: 
Clinical Development 
AMN107 (Nilotinib, Tasigna®) 
Protocol CAMN107AUS37 / NCT01744665 
A phase II randomized, multicenter study of treatment-free 
remission in chronic myeloid leukemia in chronic phase 
(CML-CP) patients who achieve and sustain MR4.5 after 
switching to nilotinib 
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Final Version 1.0 
Release date: 
21-June-2018
Number of pages: 
34 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Template Document History – Changes compared to previous version 
 
Date 
Version 
number 
Summary of changes 
18-May-
2017 
0.1 
First draft version 
05-April-
2018 
0.2 
v0.1 comments updated by 
 
18-Jun-2018 
0.3 
Some text formatting updated in section 1.1 
21-Jun-2018 
1.0 
Final version 
Document History – Changes compared to previous final version of SAP 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
 
 
 
 
 
 
 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study Design ............................................................................................................ 7 
1.2 
Open Study and Blinded Data ................................................................................. 8 
1.3 
Interim and Final Analysis....................................................................................... 8 
1.4 
Study Objectives and Endpoints .............................................................................. 9 
2 
Statistical Methods ............................................................................................................ 10 
2.1 
Data Analysis General Information ....................................................................... 10 
2.1.1 
Data Included in the Analysis ............................................................... 10 
2.1.2 
General Analysis Conventions .............................................................. 10 
2.1.3 
General Definitions ............................................................................... 11 
2.2 
Analysis Sets .......................................................................................................... 14 
2.3 
Patient Disposition, Demographics and Other Baseline Characteristics ............... 14 
2.3.1 
Patient Disposition ................................................................................ 14 
2.3.2 
Protocol Deviations ............................................................................... 15 
2.3.3 
Background and Demographic Characteristics ..................................... 15 
2.3.4 
Medical History ..................................................................................... 16 
2.3.5 
History of Tobacco ................................................................................ 16 
2.4 
Treatments (study treatment, concomitant therapies, compliance) ....................... 16 
2.4.1 
Study Treatment .................................................................................... 16 
2.4.2 
Prior,  Concomitant and Post Therapies ................................................ 18 
2.5 
Efficacy Evaluation ............................................................................................... 19 
2.5.1 
Definition of Efficacy Variables ........................................................... 19 
2.5.2 
Primary Efficacy Endpoint .................................................................... 21 
2.5.3 
Secondary Endpoints ............................................................................. 23 
 
 
 24 
2.6 
Safety Evaluation ................................................................................................... 25 
2.6.1 
Adverse Events ...................................................................................... 25 
2.6.2 
Laboratory Values ................................................................................. 27 
2.6.3 
Serum and urine pregnancy test results will be listed.ECG Analysis ... 31 
2.6.4 
Vital Signs ............................................................................................. 31 
2.6.5 
Physical Examination ............................................................................ 32 
2.6.6 
Extramedullary Involvement ................................................................. 32 
2.6.7 
ECOG Performance Status .................................................................... 32 


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2.6.8 
Patient-reported outcomes ..................................................................... 32 
3 
References ......................................................................................................................... 33 
 
 


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List of Abbreviations 
ABL 
Abelson proto-oncogene 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
BCR 
Breakpoint Cluster Region gene/BCR gene product 
BCR-ABL 
Fusion gene from BCR and ABL 
bid 
bis in diem/twice a day 
 
 
CML 
Chronic myeloid leukemia 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
DMC 
Data Monitoring Committee  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECOG 
Eastern Cooperative Oncology Group 
EOC 
End of cycle 
FAS 
Full Analysis Set 
 
 
HBV 
Hepatitis B Virus 
HBcAb 
Hepatitis B Core Antibody 
HBSAb 
Antibodies to Hepatitis B Surface Antigen 
HBSAg 
Hepatitis B Surface Antigen 
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
MDASI-CML 
M.D. Anderson Symptom Inventory – Chronic Myeloid Leukemia 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMR 
Major molecular response 
NCI 
National Cancer Institute 
NTRI 
Nilotinib Treatment Reinitiation 
o.d. 
Once Daily 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
qd 
Qua’que di’e / once a day 
QoL 
Quality of Life 
QTcF 
Frederica corrected QT interval 
RAP 
Report and Analysis Process 
RECIST 
Response Evaluation Criteria in Solid Tumors  


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RR 
Relative Risk (Sokal score) 
RR 
Respiratory Rate 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 


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1 
Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the statistical methods for all 
safety and efficacy analyses planned to be included for the clinical study report (CSR) of 
study CAMN107AUS37 (A phase II randomized, multicenter study of treatment-free 
remission in chronic myeloid leukemia in chronic phase (CML-CP) patients who achieve and 
sustain MR4.5 after switching to nilotinib). 
The content of this SAP is based on protocol CAMN107AUS37 Amendment Version 04. All 
decisions regarding final analysis, as defined in the SAP document, have been made prior to 
database lock of the study data. 
 
The planned analysis identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, conference submissions or future manuscripts. 
 
 
 
In addition to the study protocol, the following documents were reviewed in preparation of 
this SAP: 
• Electronic case report form (eCRF) for Protocol CAMN107AUS37 
• ICH Guidance on Statistical Principles for Clinical Trials (E9) 
1.1 
Study Design 
This is an open-label study of imatinib treated patients who are switched to nilotinib and their 
ability to discontinue TKI treatment once a confirmed MR4.5 is achieved and sustained 
MR4.0 or better for 2 years. 
 
 
Monitoring Phase (Years 1 and 2) 
Fifty-nine patients have been enrolled and were switched from imatinib to nilotinib 300 mg 
b.i.d. upon study entry. Patients will be monitored every 3 months for molecular response for 
up to 2 years. 
If during the Monitoring Phase, a patient has a PCR result demonstrating a loss of MR3.0, a 
subsequent unscheduled visit peripheral blood sample for PCR must be collected within 4 
weeks of the most recent sample. If loss of MR3.0 is confirmed, the patient will not be 
eligible for subsequent phases and will early terminate from the study. Patients who achieve a 


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MR4.5 will have the result confirmed by another sample drawn 4-6 weeks later. Once MR4.5 
is confirmed, patients will then enter the Consolidation Phase. 
Consolidation Phase 
Patients can enter the Consolidation Phase anytime during and up to the first 2 years on study, 
as soon as MR4.5 is confirmed. After confirmation of MR4.5, the date of the initial MR4.5 
results will be counted as the start of the Consolidation Phase. Patients will continue to be 
treated with nilotinib for 2 years during the Consolidation Phase. 
If during the Consolidation Phase, a patient has one PCR result above MR4.0 or a sample is 
missing, a subsequent unscheduled visit peripheral blood sample for PCR must be collected 
within 4 weeks of the most recent sample. If loss of MR4.0 is confirmed by the subsequent 
sample, the patient will not be eligible for nilotinib discontinuation and will early terminate 
from the study. 
Treatment-Free Remission (TFR) Phase 
The Treatment-Free Remission Phase will begin after the last scheduled PCR sample 
collected in the Consolidation Phase confirms the patient remains in MR4.0 or better.  
During the TFR phase patients will be monitored for two years. Once nilotinib treatment is 
stopped in the TFR Phase, patients will be followed by PCR every month for the first 6 
months, then every 2 months for the next 18 months. Confirmed loss of MMR (BCR-
ABL>0.1%IS) will trigger restarting nilotinib. 
Nilotinib Treatment Reinitiation (NTRI) Phase 
Patients who re-initiate nilotinib during the TFR Phase will be monitored by PCR once a 
month for the first 3 months, and then every 3 months until they reach 2 years from the start 
date of their TFR Phase. For patients who need to re-initiate nilotinib with less than a year left 
of their TFR Phase, they will be followed for one year in the Nilotinib Treatment Re-initiation 
Phase. 
1.2 
Open Study and Blinded Data 
This study is an open label, single arm study where investigators, patients and Novartis 
employees involved in the analyses have full knowledge of the treatment allocation. 
1.3 
Interim and Final Analysis 
No interim analysis will be performed for this study. 
The primary analyses of all efficacy and safety variables will be performed when all patients 
enrolled have completed 6 months of the TFR Phase, follow-up or discontinued from the 
study. All analyses will include patients who entered the TFR Phase following a 12 month 
Consolidation Phase (Arm A) prior to protocol amendment 2 and a 24 month Consolidation 
Phase (formerly Arm B). 
 
After all patients enrolled have completed 12 and 24 months of follow-up, analyses of all 
efficacy and safety will be performed including the same patients as in the primary analyses. 
These analyses performed after the primary analyses will be considered secondary. No formal 


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testing of any kind will be performed at these analyses. 
1.4 
Study Objectives and Endpoints 
Objective 
Endpoint 
Primary 
 
To evaluate molecular relapse free rates 6 
months after discontinuation from nilotinib 
therapy in patients who have achieved a MR4.5 
Molecular relapse free rate at 6 months after discontinuation from 
nilotinib therapy in patients with MR4.5. Molecular relapse is defined as 
having a confirmed BCR-ABL ratio above MMR  
(2 consecutive BCR-ABL levels >0.1%IS taken approximately 4 weeks 
apart) 
 
Key secondary 
 
Estimated Relapse-Free Survival 
Relapse-free survival 
 
Other secondary 
 
To evaluate molecular relapse free rates at 12 
and 24 months after nilotinib treatment 
discontinuation 
Molecular relapse free rates at 12,  and 24 months after nilotinib 
treatment discontinuation 
To evaluate proportion of patients who regain 
MR4.5 after restarting nilotinib after molecular 
relapse 
Proportion of patients who achieve MR4.5 after restarting nilotinib after 
relapse 
Describe impact of discontinuation of nilotinib 
attempts on progression to AP/BC and CML-
related deaths 
Proportion of patients who progress to CML-AP/BC and number of 
CML-related deaths 
To estimate overall survival (OS) 
Time from date of discontinuation of nilotinib therapy to the date of 
death from any cause  
To assess the impact of nilotinib 
discontinuation on patient symptom burden  
Change in symptom burden from baseline to the time when MR4.5 is 
confirmed, and also from the end of the Consolidation Phase to 6 and 12 
months into the TFR Phase. 
To assess the impact of nilotinib 
discontinuation on patient health utility 
Change in health utility from baseline to the time when MR4.5 is 
confirmed, and also from the end of the Consolidation Phase to 6 and 12 
months into the TFR Phase. 
To assess the impact of nilotinib 
discontinuation on patient quality of life 
Change in patient quality of life from baseline to the time when MR4.5 is 
confirmed, and also from the end of the Consolidation Phase to 6 and 12 
months into the TFR Phase. 
 
 


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2 
Statistical Methods 
2.1 
Data Analysis General Information 
The final analysis will be performed 
.  No interim analysis will be 
performed for this study.  SAS version 9.3 or later software will be used to perform all data 
analyses and to generated tables, figures, and listings. 
2.1.1 
Data Included in the Analysis 
The analysis cut-off date for the primary analysis of all study data will be established after all 
enrolled patients have completed 6 months of the TFR Phase, follow-up or discontinued 
from the study. All statistical analyses will be performed using all data collected in the 
database up to the data cutoff date. All data with an assessment date or event start date (e.g. 
vital sign assessment date or start date of an adverse event) prior to or on the cut-off date 
will be included in the analysis. Any data collected beyond the cut-off date will not be 
included in the analysis and will not be used for any derivations. 
All events with start date before or on the cut-off date and end date after the cut-off date will 
be reported as ‘ongoing. The same rule will be applied to events starting before or on the cut-
off date and not having documented end date. This approach applies, in particular, to adverse 
event and concomitant medication reports. For these events, the end date will not be imputed 
and therefore will not appear in the listings. 
The analysis cut-off date for the secondary final analysis will be established after all enrolled 
patients have completed 12 and 24 months of follow-up, all efficacy and safety analyses will 
be performed. All analyses will be performed using all data collected in the database up to the 
data cutoff date for this secondary set of analyses. The same above rules regarding assessment 
dates will apply for this analysis. 
2.1.2 
General Analysis Conventions 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables 
by overall patients; a missing category will be included as applicable. Percentages will be 
calculated using the number of patients in the relevant population or subgroup as the 
denominator. Percentages will be rounded to 1 decimal place 
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate 
descriptive statistics (i.e. mean, standard deviation, median, 25th percentile, 75th percentile, 
minimum, and maximum) by overall patients. The number of decimal places for the minimum 
and maximum will be based on the maximum number of decimal places of the data.  One 
additional decimal place will be used to summarize the mean, median, 25th percentile, and 75th 
percentile.  Two additional decimal places will be used to summarize the standard deviation.  
A maximum of 2 decimal places for the mean and 3 decimal places for the standard deviation 
will be used. 
All data collected on the CRF will be listed.  In general, there will be one listing per CRF 
page, but additional listings could be produced if necessary. 


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2.1.3 
General Definitions  
2.1.3.1 
Investigational Drug and Study Treatment 
Investigational drug, and study treatment will refer to nilotinib (AMN107, Tasigna) only.  
No control treatment is administered in this study. 
2.1.3.2 
Date of First Administration of Investigational Drug 
The date of first administration of investigational drug is defined as the first date when a non-
zero dose of investigational drug is administered and recorded on the Dosage Administration 
Record (DAR) (e)CRF. The date of first administration of study drug will also be referred as 
start of investigational drug. 
2.1.3.3 
Date of Last Administration of Investigational Drug 
The date of last administration of investigational drug is defined as is the last date when a 
nonzero dose of investigational drug is administered and recorded on DAR eCRF. The date of 
last administration of investigational drug will also be referred as end of investigational drug. 
2.1.3.4 
Date of First Administration of Study Treatment  
The date of first administration of study treatment is the same as the date of first 
administration of investigational drug.  
2.1.3.5 
Date of Last Administration of Study Treatment  
The date of last administration of study treatment is the same as the date of last administration 
of investigational drug. 
2.1.3.6 
Study Day 
The study day, describes the day of the event or assessment date, relative to the reference start 
date.  
The study day is defined as: 
 The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date; 
 The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date. 
The reference date for all assessments (safety, efficacy, pk, QoL/PRO, etc) is the start of 
study treatment.  
2.1.3.7 
Time unit 
A year length is defined as 365.25 days. A month length is 30.5 days. If duration is reported in 
months, duration in days will be divided by 30.5.  If duration is  reported in years, duration in 
days will be divided by 365.25. 


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2.1.3.8 
Baseline 
This study has multiple baselines for different phases of the study. 
For safety and efficacy evaluations, the last available assessment on or before the date of start 
of study treatment is defined as “baseline” assessment.  In the rare case that time of 
assessment and time of treatment start is captured, the last available assessment before the 
treatment start date/time is used for baseline. 
In addition to the above baseline for the monitoring phase at the start of the study, three 
additional baselines will be used for analyses regarding reporting a change from baseline in 
phase (e.g. shift tables): 
 Monitoring Phase baseline: is defined above. 
 Consolidation Phase baseline:  last available assessment before the first dose date of 
the consolidation phase. 
 Treatment-Free Remission phase (TFR) baseline:  last available assessment before 
the first day of the TFR phase. 
 Nilotinib Treatment Reinitiation phase (NTRI) baseline:  last available assessment 
before the first dose date of the NTRI phase. 
If patients have no value as defined above for the baseline within a given study phase, the 
baseline result will be missing. 
2.1.3.9 
On-treatment assessment/event and observation periods  
For adverse event (AE) reporting, the overall observation period will be divided into mutually 
exclusive segments:  
 Pre-treatment period: any day prior to a patient’s first dose of study drug during the 
monitoring phase 
 Monitoring phase: from date of first administration of study treatment until the day a 
patient enters the consolidation phase. Patients enter the consolidation phase after two 
consecutive BCR-ABL levels ≤ 0.0032%.  The day of the first measurement is the 
start of the consolidation phase. 
 Consolidation phase: from date of first administration of study treatment during the 
consolidation phase to the date the last scheduled PCR sample collected in the 
consolidation phase confirms the patient remains in MR4.0 or better. 
 Treatment-Free Remission (TFR) phase:  from the day after the date the last 
scheduled PCR sample in the consolidation phase confirms a patient remains in 
MR4.0 or better to one of the following: 
o the day of the last scheduled visit during the TFR phase for patients that 
maintain MMR throughout the TFR phase 
o the day a scheduled PCR sample shows a confirmed loss of MMR for patients 
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 Nilotinib Treatment Reinitiation (NTRI) phase:  from the day after a scheduled 
PCR sample shows a confirmed loss of MMR during the TFR phase until the last 
scheduled  visit during the NTRI phase. 
 Follow-up period:  The follow-up period can have three possible start dates. 
o For patients who maintain MMR throughout the TFR phase, the follow-up 
period begins the day after the last scheduled visit in the TFR phase. 
o For patients who enter into the NTRI phase, the follow-up period begins the 
day after the last scheduled visit in the NTRI phase. 
o For patients who discontinue from the study early, the follow-up period begins 
the day after discontinuation. 
The follow-up period lasts until the last follow-up visit in the study.  If a subject does not 
have any follow-up visits, the follow-up period ends 30 days after the start of the follow-
up period. 
2.1.3.10 Last contact date  
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following: 
 
Table 2-1 
Last contact date data sources  
Source data 
Conditions 
Last contact date/last date patient was known to 
be alive from Survival Follow-up page  
 
Patient status is reported to be alive, lost to 
follow-up or unknown. 
Start/End* dates from drug administration record  
 
Non-missing dose. Doses of 0 are allowed. 
End of treatment date from end of treatment page 
 
No condition. 
Any efficacy assessment date if available 
Evaluation is marked as ‘done’. 
Laboratory/PK collection dates 
 
Sample collection marked as ‘done’.  
Vital signs date 
 
At least one non-missing parameter value 
ECOG Performance Status date 
 
Non-missing performance status 
Start/End dates of AE  
Non-missing verbatim term 
The last contact date is defined as the latest complete date from the above list on or before 
the data cut-off date . The cut-off date will not be used for last contact date, unless the patient 
was seen or contacted on that date. No date post cut-off date will be used. Completely 
imputed dates (e.g. the analysis cut-off date programmatically imputed to replace the 
missing end date of a dose administration record) will not be used to derive the last contact 


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date. Partial date imputation is allowed for event (death)/censoring is coming from ‘Survival 
information’ eCRF.  
The last contact date will be used for censoring of patients in the analysis of overall survival. 
2.1.3.11 Withdrawal of Informed Consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial will not be included in the analysis.  The date on which a 
patient withdraws full consent or completes the study is recorded in the eCRF. 
2.2 
Analysis Sets 
2.2.1.1 
Full Analysis Set (FAS) 
The Full Analysis Set for the primary analysis comprises all patients who entered the TFR 
Phase. 
The FAS will be the primary set for all efficacy analyses and safety analyses in the TFR Phase 
only. 
2.2.1.2 
Safety Set (SS)  
The safety set consists of all patients who receive at least one dose of study drug and had at 
least one post-baseline safety assessment after enrollment. 
The statement that a patient had no adverse events (on the Adverse Event eCRF) constitutes a 
safety assessment.   
Safety analyses will be presented by phase and visit within phase where applicable. 
The safety set will be used for all safety and patient reported outcomes in the monitoring and 
consolidation phase. 
2.2.1.3 
Per-Protocol Set 
No per-protocol set is defined for this study. 
2.3 
Patient Disposition, Demographics and Other Baseline 
Characteristics 
The FAS and SS will be used for these all disposition, demographics, and baseline 
characteristics analyses.  Separate tables will be produced for the two analysis sets. 
All demographic and baseline disease characteristics data will be summarized and listed by 
overall patients.  Categorical data will be summarized by frequency counts and percentages;.  
Continuous data will be summarized by descriptive statistics (N, mean, standard deviation, 
median, 25th percentile, 75th percentile, minimum, and maximum). 
2.3.1 
Patient Disposition 
The number of patients enrolled, randomized,  and in the safety set will be summarized. 


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The number and percentage of patients who entered in the different phases of the study, 
discontinued treatment, discontinued the study, and the study phase in which discontinuation 
occurred will be summarized.   
Patient disposition information will be summarized for the SS and FAS. 
2.3.2 
Protocol Deviations 
The number of patients with major and minor protocol deviations will be summarized using 
frequencies and percentages by type of deviation for the SS and FAS. 
2.3.3 
Background and Demographic Characteristics 
The following demographic and other baseline data will be summarized for the SS and FAS: 
 Age (years) 
 Gender 
 Race 
 Screening ECOG Status 
 Prior therapy types 
Sokal risk score at time of CML diagnosis will be summarized categorically using low, 
intermediate, and high categories.  If a subject does not have a classification collected on the 
Sokal risk score relative risk will be derived using the below formula (Sokal, et al 1984).   
Relative risk = exp{0.0116*(age(yrs) – 43.4) + 0.0345*(spleen(cm) – 7.51) + 
0.188*[(platelets(x10^9L)/700)^2 – 0.563] + 0.0887*(myeloblasts(%) – 2.10) 
 Age is the age in years collected on the demography eCRF page at screening 
 Spleen is the distance in cm between the spleen and costal margin at screening 
 Platelates are collected in the laboratory data at screening 
 Myeloblasts are collected in the laboratory data at screening 
High, intermediate, and low Sokal risk scores are defined as follows: 
 Low risk patients have a relative risk < 0.8 
 Intermediate riks patients have relative risk ≥ 0.8 and ≤ 1.2 
 High risk patients have relative risk > 1.2 
Prior Imatinib Treatment duration will be summarized. Prior Imatinib treatment information 
will be obtained from the prior antineoplastic therapy data collected. Medications identified as 
Imatinib or Gleevac will be used for this summary. Partial date imputation rules will be used 
as specified in section 2.4.2. 
  
 
 
 


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2.3.4 
Medical History 
Relevant medical history and current medical conditions, including condition and symptoms 
related to CML will be collected until the start of the study drug will be listed. 
2.3.5 
History of Tobacco 
Information related to history of tobacco use will be listed. 
2.4 
Treatments (study treatment, concomitant therapies, 
compliance) 
2.4.1 
Study Treatment 
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized. Summaries will be performed for overall study duration and for 
monitoring, consolidation, and NTRI Phases (If Applicable).   
Subject level listing of all doses administered on treatment along with dose change reasons 
will be produced.   
The safety set will be used for all summaries and listings of study treatment.  
2.4.1.1 
Duration of Exposure to Study Treatment 
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the study treatment: 
Duration of exposure to study treatment (months) = (date of last administration to study 
treatment) – (date of first administration of study treatment) + 1/ 30.5.  
Duration of exposure to study treatment (days) = (date of last administration to study 
treatment) – (date of first administration of study treatment) + 1.  
Summary of duration of exposure of study treatment in months will include continuous 
summaries. 
Duration of exposure will also be summarized for Overall study, Monitoring, Consolidation 
and Nilotinib Reinitaition Phases (if applicable). The duration of exposure to study treatment 
for each phase will use the same above formula with the exception of using last date of 
exposure to study treatment within the specified phase and date of first administration of study 
treatment within the specified phase. 
Date of last administration to study treatment is defined as follows within each study phase: 
 For non-last study phases and for patients still ongoing on treatment when entering the 
next phase before the data cut-off date, the date of last administration to study 
treatment is defined as the last date in the study phase. 
 For the last study phase (in database at data cutoff date) and for patients ongoing on 
treatment, the date of last administration to study treatment is defined as the earlier 
date of the following two dates: 


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o Data cut-off date 
o The last date of the last available dates reported on the dose administration 
record.  
o For the last study phase (in database at data cut-off date) and for patients who 
entered post-treatment follow up phase before the data cut-off date, the date of 
last dose is defined as the date of the last non-zero dose of study drug reported 
in the dose administration record CRF page. 
2.4.1.2 
Cumulative Dose 
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for overall study, Monitoring, Consolidation and 
Nilotinib Reinitaition Phases (if applicable). 
The planned cumulative dose for a study treatment component refers to the total planned 
dose as per the protocol up to the last date of drug administration.  
The actual cumulative dose  refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the Dose Administration eCRF.  
For patients who did not take any drug the cumulative dose is by definition equal to zero. 
For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded 
over the dosing period and the planned cumulative dose is the planned starting dose summed 
over the same dosing period. 
2.4.1.3 
Average Daily Dose 
Average daily dose will be summarized for overall study, Monitoring, Consolidation and 
Nilotinib Reinitaition Phases (if applicable). 
Average daily dose = actual cumulative dose/ Duration of exposure to study treatment (days). 
2.4.1.4 
Dose Intensity and Relative Dose Intensity 
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:  
DI (mg / months) = Actual Cumulative dose (mg) / Duration of exposure to study treatment 
(months). 
For patients who did not take any drug the DI is by definition equal to zero.  
Planned dose intensity (PDI) is defined as follows: 
PDI (mg / months) = Planned Cumulative dose (mg) / Duration of exposure (months) 
Relative dose intensity (RDI) is defined as follows: 
RDI = DI (mg / months))  / PDI (mg / months) 
DI and RDI will be summarized for Overall study, Monitoring, Consolidation and Nilotinib 
Reinitaition Phases (if applicable). 


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2.4.1.5 
Dose Reductions, Interruptions or Permanent Discontinuations 
The number of patients who have dose reductions, permanent discontinuations or 
interruptions, and the reasons, will be summarized.  
‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the Dosage 
Administration CRF pages (DAR) will be used to determine the dose reductions, dose 
interruptions, and permanent discontinuations, respectively. 
The corresponding fields ‘Reason for dose changes’ will be used to summarize the reasons. 
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries 
on consecutive days, then it will be counted as one interruption.  
Reduction: A dose change where the prescribed dose level is lower than the previous 
prescribed dose level or where the actual dose administered/total daily dose is lower than the 
planned dose. Only dose change is collected in the CRF, number of reductions will be derived 
programmatically  based on the change and the  direction of the change. 
Missing data: If dose is recorded but regimen is missing or entered as ‘none’, it is assumed 
that the study treatment was taken as per-protocol. 
2.4.2 
Prior,  Concomitant and Post Therapies 
2.4.2.1 
Data Handling 
If partial dates occur, the convention for replacing missing dates for the purposes of 
calculating derived variables is as follows: 
For partial start dates: 
 If the year is unknown, then do not impute the date but assign as missing value. 
 If the year is known, but month or month and day are unknown, then: 
o If the year matches the year of of first administration of study treatment, then 
impute the month and day of the of first administration of study treatment. 
o Otherwise, assign 01 January 
 If the year and month are known, but day is unknown, then: 
o If the month and year match the month and year of the of first administration 
of study treatment, then impute the day of the of first administration of study 
treatment. 
o Otherwise, assign 01 
For end dates: 
 If the year is unknown, then do not impute the date but assign a missing value. 


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 If the month is unknown, then assign the last day of the year, 31 December. If this 
results in a date after the of last administration of study treatment, assign the day and 
month of the last administration of study treatment. 
 If the day is unknown, then assign the last day of the month. 
2.4.2.2 
Prior Antineoplastic Therapy 
The number and percentage of patients who received any prior anti-neoplastic radiotherapy 
will be summarized. Prior anti-neoplastic therapies will be summarized by therapy type (e.g. 
chemotherapy, hormonal therapy etc.), and also by lowest ATC class and preferred term. 
Summaries will also include total number of regimens.  
All prior antineoplastic therapy data will be listed. 
Anti-neoplastictherapies will be coded using the WHO Drug Dictionary (WHO-DD); Details 
regarding WHO-DD version will be included in the footnote in the tables/listings.  
The above analyses will be performed using the safety set. 
2.4.2.3 
Prior and Concomitant Medications 
Prior and concomitant medications/significant non-drug therapies will be listed and 
summarized for the safety set. 
Medications will be classified as prior or concomitant based on the following rules: 
 Prior medications are medications that started before the first dose of study drug 
regardless of whether the medication ended before or after the first dose of study drug 
 Concomitant medications are medications that started on or after the first dose of study 
drug, or started before the first dose of study drug and continued after the first dose of 
study drug. 
o Medications starting on or after the start of study treatment but no later than 30 
days after start of last dose of study treatment and 
o Medications starting prior to start of study treatment and continuing after the 
start of study treatment 
The number and percentage of patients with prior and concomitant medication will be 
presented separately by ATC class and preferred term according to the WHO DRL dictionary. 
Any concomitant medication starting and ending prior to the start of study treatment or 
starting more than 30 days after the last date of study treatment will be flagged in the listing.  
2.5 
Efficacy Evaluation 
2.5.1 
Definition of Efficacy Variables 
2.5.1.1 
Molecular Response 
Molecular response will be assessed in all patients. Levels of BCR-ABL transcripts will be 
determined by real-time quantitative PCR (RQ-PCR) testing of peripheral blood. The samples 


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will be sent to a Novartis designated central laboratory with validated PCR technology that 
has a sensitivity of at least 4.5 logs to evaluate BCR-ABL transcript levels by RQ-PCR. The 
percent ratio of BCR-ABL transcripts versus control gene transcripts converted to IS will be 
calculated for each sample. 
Molecular response and related variables are defined as the following: 
 Major molecular response (MMR) 
Major molecular response is defined as a value of ≤ 0.1% of BCR-ABL ratio on the 
International Scale (IS). For statistical comparison purpose, MMR will be considered 
as a binary variable with patients achieving MMR grouped as ‘responders’ and 
patients not achieving MMR, patients with missing PCR evaluations grouped as ‘non-
responders’. 
 Loss of a major molecular response (MMR) is defined as a BCR-ABL ratio > 0.1%  
 Molecular response 4.0 (MR4.0) 
MR4 is defined as a value of ≤ 0.01% of BCR-ABL ratio on the International Scale 
(IS).  
 Loss of MR4.0 is defined as a BCR-ABL ratio > 0.01% (on international scale). 
 Confirmed Loss of MR4.0 is defined as is two consecutive BCR-ABL > 0.01% IS 
after the achievement of MR4.0. 
 Molecular response 4.5 (MR4.5) 
MR4.5 is defined as a value of ≤ 0.0032% of BCR-ABL ratio on the International 
Scale (IS).  
 Loss of MR4.5 is defined as a BCR-ABL ratio > 0.0032% (on international scale) 
 Confirmed Loss of MR4.5 is defined as two consecutive BCR-ABL > 0.0032% IS 
after the achievement of MR4.5. 
 Molecular Relapse is defined as having two consecutive BCR-ABL levels >0.1%. 
2.5.1.2 
Relapse-Free Survival (RFS) 
Relapse-free survival is defined as time in months from date of cessation of nilotinib therapy 
(date of entering TFR phase) to the first documented molecular relapse.  The duration will be 
calculated by (date of first document molecular relapse – date of nilotinib treatment 
discontinuation + 1)/30.5.  Molecular relapse is defined as having a confirmed BCR-ABL 
ratio above MMR (2 consecutive BCR-ABL levels >0.1%IS taken approximately 4 weeks 
apart) variable 
If a patient does not experience molecular relapse after nilotinib treatment discontinuation the 
relapse-free survival time will be considered censored at the following duration: (date of last 
RQ-PCR sample prior to treatment discontinuation – date of nilotinib treatment 
discontinuation + 1)/30.5. 
This analysis will be performed on the FAS. 


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2.5.1.3 
Overall Survival (OS) 
Overall survival is defined as the time in months from the date of cessation of nilotinib 
therapy (date of entering TFR phase) to the date of death from any cause at any time during 
the study, including the follow-up period after discontinuation of study up to cut-off date. 
For patients who do not have events on or before the cut-off date, the time will be censored at 
the date of last assessment (from the list of sources specified below) for patients who are still 
in study before the follow-up period and at the date of last contact for patients who are in the 
follow-up period after early discontinuation of study (from the End of Treatment CRF page). 
Specific last assessment date sources for this study are: 
 PCR (RQ-PCR) testing of peripheral blood sample dates  
 Start/End dates from drug administration record with non-missing total daily dose 
 Laboratory/PK collection dates  
 Vital signs date with at least one non-missing measurement 
 ECOG performance status date 
 Start/End dates of AE with non-missing AE name 
This analysis will be performed on the FAS. 
2.5.1.4 
Progression Free Survival (PFS) 
Progression free survival is defined as the time in months from the date of cessation of 
nilotinib therapy (date of entering TFR phase) to the date of progression at any time after the 
start of the TFR phase.  Progression is defined as the first reported progression to accelerated 
phase (AP) or blast crisis (BC) as reported on the disease response eCRF after the start of the 
TFR phase.  The duration will be calculated by (date of first documented progression – date of 
nilotinib treatment discontinuation + 1)/30.5.  If a subject does not experience progression 
after the start of the TFR phase, they will be censored at their last AP or BC assessment. 
2.5.1.5 
Treatment Free Survival (TFS) 
Treatment free survival is defined as the time in months from the cessation of nilotinib 
therapy (date of entering TFR phase) to the date of treatment reinitiation at the start of the 
NTRI phase.  The duration will be calculated by (NTRI start date – TFR start date + 1)/30.5.  
Subjects who do not reinitiate nilotinib will be censored at their study completion date. 
2.5.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the molecular relapse free rate (RFR) at 6 months after 
discontinuation from nilotinib therapy in patients with MR4.5.   
2.5.2.1 
Data Handling 
Patients with confirmed MR4.5 and without confirmed loss of MR4.5 prior to the start of the 
TFR phase will be included in this analysis.  Patients without consecutive confirmed BCR-
ABL >0.1%IS measurements within 6 months after entering the TFR phase will be considered 
responders.   


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Unscheduled visits falling between the start of the TFR phase and the scheduled 6 month TFR 
visit will be considered when determining if a subject is not a responder.  If a subject is 
missing the 6 month TFR visit, any unscheduled visit during the TFR phase occurring ≤ 185 
days after the TFR start date will be considered when determining of a subject is not a 
responder. 
2.5.2.2 
Statistical Hypothesis, Model, and Method of Analysis 
The proportion of patients without molecular relapse within 6 months of starting the TFR 
phase will be summarized using frequencies and percentages.  The demoninator for this 
proportion will be the number of patients who enter the TFR phase with confirmed MR4.5 
and without confirmed loss of MR4.5 prior to the start of the TFR phase.  A 95% confidence 
interval calculated using the exact Clopper-Pearson method will be provided. 
No statistical hypothesis will be tested on the primary efficacy variable. 
The analysis will be performed on the FAS. 
2.5.2.3 
Supportive Analyses 
An exploratory analysis of the relapse free rate after starting the TFR phase will be performed 
using a logistic regression model to evaluate the dependence of relapse (Yes or No) on 
important prognostic variables.  The following parameters will be included in the model as 
covariates: 
 Age 
 Gender 
 Sokal risk score classification (high/medium/low) 
 Duration of nilotinib in months defined as (date of last dose of study drug prior to start 
of consolidation phase – date of first dose of study drug + 1)/30.5. 
 Maintenance of MR4.5 in the TFR phase defined as (date of confirmed loss of MR4.5 
– start date of MR4.5 + 1)/30.5. If a subject loses MR4.5 after the start of the TFR 
phase and regains it, only the longest interval of sustained MR4.5 will be considered.  
The start date of sustained MR4.5 is the date of confirmed MR4.5 at the beginning of a 
sustained MR4.5 interval.  If confirmed MR4.5 for an interval occurs prior to the start 
of the TFR phase, the start of the TFR phase will be considered the start of the 
interval.  Only patients who achieved MR4.5 when entering the TFR phase will be 
included in this anlaysis. 
o If the subject does not have confirmed MR4.5 loss throughout the duration of 
the study, the end date will be taken as the last BCR-ABL assessment 
collected.  This includes patients that early terminate from the study. 
o If the patient has a confirmed loss of MR4.5 after the start of the TFR phase 
the first of the consecutive BCR-ABL > 0.0032%IS measurements will be 
considered the end date of MR4.5 maintenance. 


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Stepwise selection of the covariates will be used.  Signficance level is 0.05 for a covariate to 
remain in the model.  Parameter estimates of the covariates as well as odds ratio estimates and 
95% confidence intervals will be provided. 
This analysis will be performed on the FAS. 
2.5.3 
Secondary Endpoints 
The key secondary objective of the study is to evaluate relapse-free survival. 
The other secondary objectives of the study are: 
 To evaluate molecular relapse free rates at 12 and 24 months after nilotinib treatment 
discontinuation 
 To evaluate the proportion of patients who regain MR4.5 after restarting nilotinib 
following molecular relapse 
 To describe the impact of nilotinib treatment discontinuation on progression to AP/BC 
and CML-related deaths 
 Overall survival 
2.5.3.1 
Statistical Analysis Methods for the Secondary Efficacy Endpoints 
 Relapse-free survival (as described in Section 2.5.1.2) after the start of the TFR phase 
will be summarized and graphed using the product-limit (Kaplan-Meier) estimates of 
the 25th, median, 75th percentiles for the relapse-free survival and its 95% confidence 
intervals will be provided, if applicable.  This analysis will be performed on the FAS. 
 Overall survival (as described in Section 2.5.1.3) after the start of the TFR phase will 
be summarized and graphed using the product-limit (Kaplan-Meier) method as 
described above.  Patients who are alive at the date of last contact will be treated as 
censored observations.  This analysis will be performed on the FAS. 
 Progression free survival (as described in section 2.5.1.4) after the start of the TFR 
phase will be summarized and graphed using the product-limit (Kaplan-Meier) method 
as described above.  Progression is defined as the first reported progression to 
accelerated phase (AP) or blast crisis (BC) as reported on the disease response eCRF 
after the start of the TFR phase.  This analysis will be performed on the FAS. 
 Treatment free survival (as described in section 2.5.1.5) after the start of the TFR 
phase will be summarized and graphed using the product-limit (Kaplan-Meier) method 
as described above.  This analysis will be performed on the FAS. 
 The molecular relapse free rates at 12 and 24 months after the start of the TFR phase  
will be summarized and analyzed using the same multivariate logistic regression 
model as the primary efficacy endpoint. 
 The rate of patients who confirm MR4.5 after restarting nilotinib treatment following a 
molecular relapse will be presented with an exact 95% Clopper-Pearson method.  The 
time to regain MR4.5 (months) will be summarized and graphed using the product-


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limit (Kaplan-Meier) method as described above.  The time to regain MR4.5 is defined 
as (date of confirmed MR4.5 – start date of NTRI phase + 1)/30.5.  If a patient does 
not regain MR4.5 prior to the end of the NTRI phase, the patient will be censored at 
the last BCR-ABL ratio assessment prior to treatment discontinuation.  The time to 
regain MR4.5 will also be graphed with cumulative curves to depict current MR4.5 
rates over time in the NTRI phase by considering censored patients as non-responders.  
In addition, the time by which 50% of retreated patients have regained MR4.5 will be 
calculated. 
 The rate of patients who confirm MR4.0 and MMR after restarting nilotinib will be 
summarized using the same method as described above for the rate of patients who 
confirm MR4.5. 
 The number of patients with stable molecular response (MR4.5, MR4.0, or MMR) 
during the NTRI phase will be summarized using frequencies and percentages.  Each 
response will be summarized separately.  Stable molecular response is defined as 
achievement of confirmed molecular response in the NTRI phase if again the same 
response is confirmed after 6 months of the original confirmation irrespective of 
whether there is loss of response in between achievement and 6 months.  This analysis 
will be performed on the FAS only for subjects who have entered the NTRI phase. 
 The number of CML related deaths will be summarized using frequencies and 
percentages. 
The FAS for the primary analysis as described above will be used for these analyses.  
2.5.3.2 
BCR-ABL Ratio (%) 
Tables summarizing BCR-ABL Ratio (%) over time by phase and visit within phase for the 
consolidation and TFR phases will be provided.  The frequency and percentage of subjects 
with BCR-ABL at the following levels will be provided: ≤ 0.1% (MMR), ≤ 0.01% (MR4.0), 
≤ 0.001%, ≤ 0.0032% (MR4.5) 
The BCR-ABL Ratio over time will be summarized using a box-plot. 


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2.6 
Safety Evaluation 
For all safety analyses, the safety set will be used.  Safety analyses will be presented overall, 
by study phase and visit within phase. 
2.6.1 
Adverse Events 
Summary tables for AEs will include only AEs that started or worsened during the on-
treatment period (all 4 study phases including treatment-free remission phases), the 
treatment-emergent AEs (TEAEs). The start day used to define the TEAEs in the entire 
study is the first day of dosing of the Monitoring Phase. 


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The incidence of TEAEs will be summarized by system organ class and preferred term using 
the latest MedDRA version available. Grading will be based on CTCAE Version 4.03. 
Adverse events will be summarized by presenting the number and percentage of patients 
having any adverse event, having an adverse event in each primary system organ class, and 
having an adverse event with a particular preferred term within a system organ class. 
The following selection of AEs will be listed and summarized separately. All summaries will 
be by system organ class (SOC), preferred term (PT), and severity grade unless otherwise 
specified.  Summaries will include a total column. 
 AEs by system organ class (SOC) and preferred term (PT) 
 AEs by PT 
 AEs by relationship to study drug 
 AEs occurring in >= %5 of all patients 
 AEs by severity grade group (Grade 1 or 2 and Grade 3 or 4) 
 AEs that are dose-limiting 
 AEs reported as serious (SAEs) 
 AEs excluding the serious AEs 
 AEs associated with discontinuation of study drug 
 AEs associated with death 
 Adverse events of special interest 
o Ischemic Heart Disease (IHD): angina pectoris, coronary artery disease, acute 
myocardial infarction and coronary artery stenosis 
o Ischemic Cerebrovascular Events (ICVE): ischemic cerebrovascular accident, and 
transient ischemic attack 
o Peripheral Artery Occlusive Disease (PAOD): intermittent claudication, arterial 
stenosis of a limb 
o Musculoskeletal Pain 
All summaries, except for AEs by relationship to study drug will be repeated using only AEs 
suspected to be related to study drug. 
Summaries will be repeated for the safety set, safety set by phase, full analysis set, and full 
analysis set by phase.  Full anlaysis set by phase tables will only include the TFR and NTRI 
phases. 
Figures for incidences of AEs occurring in the consolidation and TFR phases and for 
incidences of AEs occurring in the TFR and NTRI phases will be provided for both the SS 
and FAS. The incidence rate will be calculated by dividing the number of patients with any 
AE at a particular time by the number of patients in the safety set who are continuing in the 
study at that time. 
If partial dates occur, the convention for replacing missing dates for the purposes of 
calculating derived using the same method as described in section 2.4.2. 


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If an AE has a missing severity, it will be imputed as “Grade 4”; any missing relationship to 
study drug of an AE will be imputed as related.  No other missing data will be imputed unless 
otherwise specified. 
2.6.2 
Laboratory Values 
2.6.2.1 
Hematology 
Hematology tests will include hemoglobin, total white blood cell count, platelet count, and a 
differential count (neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils, 
promyelocytes, myelocytes, metamyelocytes, blasts, and atypical cells. 
2.6.2.2 
Blood Chemistry 
Chemistry tests will include creatinine, uric acid, albumin, total protein, total bilirubin, direct 
bilirubin and/or indirect bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine 
aminotransferase, lactate dehydrogenase, sodium chloride, fasting glucose, HbA1c, calcium, 
lipase, potassium, magnesium, phosphorus, total cholesterol, triglycerides, low density 
lipoprotein, and high density lipoprotein. 
2.6.2.3 
Hepatitis B Serology 
Patients will be tested once for the following hepatitis B serologic markers: hepatitis B surface 
antigen (HBsAg), antibodies to hepatitis B surface antigen (HBsAb) and antibodies to 
hepatitis B core antigen (HBcAb).  The results will be listed and summarized by phase. 
2.6.2.4 
Analysis 
Laboratory values will be converted to SI units and analyzed using the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.   For laboratory tests covered by CTCAE, 
a Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 will 
not be used.  A table of CTCAE grades for the parameters of interest in the study is given 
below (U.S. HHS Dept., 2010). 
 
 


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Parameter 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin (g/L) 
Anemia 
<LLN – 100 
<100 – 80 
<80 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Hemoglobin (g/L) 
Hemoglobin increased 
Increase in >0 – 20  above 
ULN or above BL if BL is 
above ULN 
Increase in >20 – 40  
above ULN or above BL 
if BL is above ULN 
Increase in >40 above ULN 
or above baseline if baseline 
is above ULN 
N/A 
White blood cells (10^9/L) 
White blood cell 
decreased 
<LLN – 3x10^9/L 
<3 – 2x10^9/L 
<2 – 1x10^9/L 
<1x10^9/L 
Lymphocytes (10^9/L) 
Lymphocyte count 
decreased 
<LLN – 0.8x10^9/L 
<0.8 – 0.5x10^9/L 
<0.5 – 0.2x10^9/L 
<0.2x10^9/L 
Lymphocytes (10^9/L) 
Lymphocyte count 
increased 
N/A 
>4 - 20 
>20 
N/A 
Neutrophils (10^9/L) 
Neutrophil count 
decreased 
<LLN – 1.5x10^9/L 
<1.5 – 1.0x10^9/L 
<1.0 – 0.5x10^9/L 
<0.5x10^9/L 
Platelets (10^9/L) 
Platelet count 
decreased 
<LLN – 75.0x10^9/L 
<75.0 – 50.0x10^9/L 
<50.0 – 25.0x10^9/L 
<25.0x10^9/L 
Albumin (g/L) 
Hypoalbuminemia 
<LLN – 30 
<30 – 20 
<20 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Alkaline phosphatase (IU/L) 
Alkaline phosphatase 
increased 
>ULN – 2.5xULN 
>2.5 – 5.0xULN 
>5.0 – 20.0xULN 
>20.0xULN 
Alanine aminotransferase 
(IU/L) 
Alanine 
aminotransferase 
increased 
>ULN – 3.0xULN 
>3.0 – 5.0xULN 
>5.0 – 20.0xULN 
>20.0xULN 
Aspartate aminotransferase 
(IU/L) 
Aspartate 
aminotransferase 
increased 
>ULN – 3.0xULN 
>3.0 – 5.0xULN 
>5.0 – 20.0xULN 
>20.0xULN 
Bilirubin (umol/L) 
Blood bilirubin 
increased 
>ULN – 1.5xULN 
>1.5 – 3.0xULN 
>3.0 – 10.0xULN 
>10.0ULN 


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Parameter 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Calcium (mmol/L) 
Hypocalcemia 
Corrected serum calcium 
<LLN – 2.0; Iodized 
calcium <LLN – 1.0 
Corrected serum calcium 
<2.0 - 1.75; Ionized 
calcium <1.0- 0.9 
Corrected serum 
calcium<1.75 - 1.5; Ionized 
calcium <0.9-0.8; 
hospitalization indicated 
Corrected serum 
calcium <1.5; 
Ionized calcium 
<0.8; life-
threatening 
consequences 
Calcium (mmol/L) 
Hypercalcemia 
Corrected serum calcium 
of >ULN -2.9; Ionized 
calcium >ULN - 1.5 
Corrected serum calcium 
of >2.9 - 3.1; Ionized 
calcium >1.5- 1.6; 
symptomatic 
Corrected serum calcium 
of >3.1 - 3.4; Ionized 
calcium >1.6-1.8; 
hospitalization indicated 
Corrected serum 
calcium of >3.4; 
Ionized 
calcium >1.8; 
life-threatening 
consequences 
Cholesterol (mmol/L) 
Cholesterol high 
>ULN – 7.75 
>7.75 – 10.34 
>10.34 – 12.92 
>12.92 
Creatinine 
Creatinine increased 
>1 - 1.5 x baseline; >ULN -
1.5 x ULN 
>1.5 - 3.0 x 
baseline; >1.5 -3.0 x 
ULN 
>3.0 baseline; >3.0 - 6.0 
xULN 
>6.0 x ULN 
Glucose (mmol/L) 
Hypoglycemia 
<LLN – 3.0 
<3.0 – 2.2 
<2.2 – 1.7 
<1.7; life-
threatening 
consequences; 
seizures 
Glucose (mmol/L) 
Hyperglycemia 
>ULN – 8.9 
>8.9 – 13.9 
>13.9 – 27.8; hospitalization 
indicated 
>27.8; life-
threatening 
consequences 
Lipase 
Lipase increased 
>ULN – 1.5xULN 
>1.5 – 2.0xULN 
>2.0 – 5.0xULN 
>5.0xULN 
Magnesium (mmol/L) 
Hypomagnesemia 
<LLN – 0.5 
<0.5 – 0.4 
<0.4 – 0.3 
<0.3; life-
threatning 
consequences 
Magnesium (mmol/L) 
Hypermagnesemia 
>ULN – 1.23 
N/A 
>1.23 – 3.30 
>3.30; life-
threatening 
consequences 
Phosphate (mmol/L) 
Hypophosphatemia 
<LLN – 0.8 
<0.8 – 0.6 
<0.6 – 0.3 
<0.3; life-
threatening 
consequences 
Potassium (mmol/L) 
Hypokalemia 
<LLN – 3.0 
<LLN – 3.0; 
symptomatic; 
<3.0 – 2.5; hospitalization 
indicated 
<2.5; life-
threatening 


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Parameter 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
intervention indicated 
 
consequences 
Potassium (mmol/L) 
Hyperkalemia 
>ULN – 5.5 
>5.5 – 6.0 
>6.0 – 7.0; hospitalization 
indciated 
>7.0; life-
threatening 
consequences 
Sodium (mmol/L) 
Hyponatremia 
<LLN - 130 
N/A 
<130 - 120 
<120; life-
threatening 
consequences 
Sodium (mmol/L) 
Hypernatremia 
>ULN - 150 
>150 - 155 
>155 – 160; hospitalization 
indicated 
>160; life-
threatening 
consequences 
Triglycerides (mmol/L) 
Hypertriglyceridemia 
1.71 – 3.42 
>3.42 – 5.7 
>5.7 – 11.4 
>11.4; life-
threatening 
consequences 
 
 
 


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For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
The following by-safety subset summaries will be generated separately for hematology, and 
biochemistry laboratory tests: 
 Shift tables using CTCAE grades to compare baseline to the worst on-phase value.  Four 
different baseline definitions for the different study phases, as defined in section 2.1.3.8, 
will be used. 
 For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high). Four different baseline definitions for the different study 
phases, as defined in section 2.1.3.8, will be used. 
 Summary statistics of raw values and change from baseline by time point and by study 
phase 
 Listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges. 
2.6.3 
Serum and urine pregnancy test results will be listed.ECG Analysis 
A standard 12 lead ECG will be performed at screening, Day 1, and Day 8.  After a dose 
interruption or after any dose changes, additional (unscheduled) ECGs are required. 
Summary statistics for raw values and change from baseline of heart rate, PR interval, QRS 
duration, QT interval, QTcF, QTcB, and frequencies and percentages of investigator 
interpretation will be presented by phase and visit within phase. 
A shift table for QTinterval and QTc values by phase will be provided using the following 
categories: 
 <= 450 ms 
 >450 to 480 
 >480 to 500 
 >500 
The largest post-baseline result in each phase will be included in the shift table. 
Four different baseline definitions for the different study phases, as defined in section 2.1.3.8, 
will be used. 
2.6.4 
Vital Signs 
Vital signs raw values and change from baseline (weight, pulse rate, systolic blood pressure, 
diastolic blood pressure) will be summarized by phase and visit within phase   
Vital signs data will be summarized by shift table based on notable values by phase. 
The criteria for clinically notable abnormalities are defined as follows: 
Clinically notable values above normal 
 Systolic BP: ≥ 140 mmHg 


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 Diastolic BP: ≥ 90 mmHg 
 Body Temperature (C): ≥ 37.5◦C 
 Weight: Baseline ≥ 110kg; Post-baseline: increase from baseline of ≥ 10% 
 Heart rate: Baseline: ≥ 120 beats per minute (bpm); Post-baseline: ≥ 120 beats per 
minute (bpm) with increase from baseline of ≥ 15 bpm 
Clinically notable values below normal 
 Systolic BP: ≤ 90 mmHg 
 Diastolic BP: ≤ 40 mmHg 
 Body Temperature (C): ≤ 35◦C 
 Weight: Baseline ≤ 60kg; Post-baseline: decrease from baseline of ≥ 10% 
 Heart rate: Baseline: ≤ 50 bpm; Post-baseline: ≤ 50 bpm with decrease from baseline 
of ≥ 15 bpm 
Four different baseline definitions for different study phases, as defined in section 2.1.3.8, will 
be used. 
Vital signs data will be listed. 
2.6.5 
Physical Examination 
Significant physical examination findings that are present prior to the start of study drug must 
be summarized with the medical history data.  Significant findings made after the start of 
study drug, which meets the definition of an adverse event, will be summarized with the 
adverse event data. 
2.6.6 
Extramedullary Involvement 
Extramedullary involvement data such as presence and location will be listed. 
2.6.7 
ECOG Performance Status 
Eastern Cooperative Oncology Group (ECOG) performance status will be summarized using 
frequencies and percentages by phase and visit within phase. 
2.6.8 
Patient-reported outcomes 
2.6.8.1 
MDASI-CML 
The M.D. Anderson Symptom Inventory for CML patients (MDASI-CML) will be used to 
assess the nature and impact of symptom burden on life.  The MDASI-CML consists of 20 
validated symptom items and 6 validated core interference items.  Each item is assessed on an 
11 point scale with responses from 0-10, = being “not present” and 10 being “as bad as you 
can imagine”. 


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The interference score will be calculated when a patient scores at least 4 items out of the 6 
interference items using the formula: (sum of scores for the items answered) / number of 
items answered.  If a subject responds to less than 4 interference items, the interference score 
will be considered missing. 
The symptom score will be calculated when a patient scores at least 8 items out of the 14 
symptom items using the formula: (sum of scores for the items answered) / number of items 
answered.  If a subject responds to less than 8 symptom items, the symptom score will be 
considered missing (Ceeland, 2009). 
The symptom and interference subscale total scores with their change from baseline will be 
summarized descriptively at all post-baseline time points by phase and visit within phase. 
This analysis will be performed on the SS. 
2.6.8.2 
EQ-5D-3L 
The EQ-5D-3L will be used to assess the impact of nilotinib treatment discontinuation in 
patient utility.  The questionnaire comprises 5 items: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression and the EQ visual analog scale.  Each item has 3 
levels (no problems, some problems, and extreme problems) and visual analog has a scale of 0 
to 100 (0=works imaginable health state, 100=best imaginable health state). 
The percentages of patients at each level of the five items of the EQ-5D-3L will be 
summarized overall as appropriate at baseline and all post-baseline time points by phase and 
visit within phase. 
The visual analog scale raw values and change from baseline will be summarized using 
numeric summary statistics by visit and phase. 
This analysis will be performed on the SS. 
2.6.8.3 
SF-8 Questionnaire 
The SF-8 Questionnaire consists of 8 items (general health, physical functioning, role-
physical, bodily pain, vitality, social functioning, role-emotional, and mental health) will be 
used to assess the impact of nilotinib treatment discontinuation on the quality of life.  Each 
item has a 5 or 6 point response range.  Physical and mental component summary measures 
(calculated using Optum’s norm-based scoring method) will be summarized at baseline and 
all post-baseline time points using numeric summary statistics.  Individual item scores will be 
listed. 
This analysis will be performed on the SS. 
3 
References 
Ceeland CS., (2009) The M.D. Anderson Symptom Inventory User Guide, Version 1. 
Retrieved from https://www.mdanderson.org. 
Sokal JE, Cox EB, Baccarani M, et al (1984) Prognostic discrimination in “Good-Risk” 
chronic granulocytic leukemia. Blood: 63: 789-99. 


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U.S. Department of Health and Human Services, (2010) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03. Retrieved from https://evs.nci.nih.gov.