Clinical trial NCT01863745
Conditions: Gastrointestinal Stromal Tumors
Keywords: gastrointestinal stromal tumors gastrointestinal, stromal, tumors, GIST, AMN107, nilotinib
Sponsor: Novartis Pharmaceuticals
Start date: 2013-06-25; Completion date: 2023-10-02
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to collect and assess long-term safety of nilotinib in patients who are on nilotinib treatment in a Novartis-sponsored, Oncology Clinical Development \& Medical Affairs study and are benefiting from the treatment as judged by the investigator.

Detailed description:
This was an open label, multi-center, phase II study to collect and assess long-term safety of nilotinib to patients treated in Novartis sponsored clinical studies (NCT00785785 and NCT00718562) and who were benefiting from treatment with nilotinib.

There was no screening period for this study. At the enrolment visit the patient was consented to the study and eligible patients started their treatment with nilotinib.

Arms: arm 1: The starting dose of nilotinib was same as the last dose given in the parent nilotinib study. After this, the dose of nilotinib was based on the investigator's judgment. The total daily dose was up to 800 mg.
Interventions: intervention 1: nilotinib
Intervention descriptions: intervention 1: Nilotinib was administered daily as hard gelatin capsules for oral use. The starting dose of nilotinib was same as the last dose given in the parent nilotinib study. After this, the dose of nilotinib was based on the investigator's judgment. The total daily dose was up to 800 mg.

Protocol documents:
Prot_000.pdf: 
Clinical Development
AMN107 (NILOTINIB)
TASIGNA
Protocol CAMN107A1201 / NCT01863745
An open label, multi-center nilotinib roll-over protocol for 
patients who have completed a previous Novartis-
sponsored nilotinib study and are judged by the 
investigator to benefit from continued nilotinib treatment
Author(s):
Document type:
Amended Protocol Version
EUDRACT number
Not applicable
Version number
04 Clean
Development phase
II
Document status:
Final
Release date:
05-Apr-2018
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 appendices................................................................................................................5
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 04 (05-Apr-2018)............................................................................................9
Amendment 03 ..................................................................................................................11
Amendment 02 ..................................................................................................................12
Amendment 01 ..................................................................................................................14
Protocol summary..............................................................................................................15
1
Background........................................................................................................................17
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............17
1.1.1
Overview of chronic myeloid leukemia (CML)....................................17
1.1.2
Overview of gastrointestinal stromal tumors (GIST)............................17
1.2
Introduction to investigational treatment(s) and other study treatment(s).............18
1.2.1
Overview of Nilotinib ...........................................................................18
2
Rationale............................................................................................................................22
2.1
Study rationale and purpose...................................................................................22
2.2
Rationale for the study design ...............................................................................22
2.3
Rationale for dose and regimen selection..............................................................22
3
Objectives and endpoints...................................................................................................23
4
Study design ......................................................................................................................23
4.1
Description of study design ...................................................................................23
4.2
Timing of interim analyses and design adaptations...............................................24
4.3
Definition of end of the study................................................................................24
4.4
Early study termination..........................................................................................24
5
Population..........................................................................................................................24
5.1
Patient population..................................................................................................24
5.2
Inclusion criteria ....................................................................................................24
5.3
Exclusion criteria...................................................................................................25
6
Treatment...........................................................................................................................26
6.1
Study treatment......................................................................................................26
6.1.1
Dosing regimen.....................................................................................26
6.1.2
Ancillary treatments..............................................................................27
6.1.3
Rescue medication ................................................................................27


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6.1.4
Guidelines for continuation of treatment ..............................................27
6.1.5
Treatment duration................................................................................27
6.2
Dose modifications................................................................................................27
6.2.1
Management of cholesterol increases ...................................................27
6.2.2
Management of glucose increases.........................................................28
6.2.3
Management of other cardiac risk factors.............................................28
6.2.4
Management of ischemic vascular or cardiovascular events ................28
6.2.5
Hepatitis B reactivation.........................................................................28
6.2.6
Follow up on potential drug-induced liver injury (DILI) cases ............28
6.2.7
Prohibited concomitant therapy ............................................................29
6.3
Patient numbering, treatment assignment or randomization .................................30
6.3.1
Patient numbering .................................................................................30
6.3.2
Treatment assignment or randomization...............................................30
6.3.3
Treatment blinding................................................................................30
6.4
Study drug preparation and dispensation...............................................................30
6.4.1
Study drug packaging and labeling.......................................................31
6.4.2
Drug supply and storage........................................................................31
6.4.3
Study drug compliance and accountability ...........................................31
6.4.4
Disposal and destruction .......................................................................32
7
Visit schedule and assessments .........................................................................................32
7.1
Study flow and visit schedule................................................................................32
7.1.1
Screening...............................................................................................34
7.1.2
Treatment period...................................................................................34
7.1.3
Pregnancy and assessment of fertility...................................................34
7.1.4
Hepatitis B testing.................................................................................35
7.1.5
End of treatment visit including study completion and premature 
withdrawal.............................................................................................35
7.1.6
Safety follow-up period.........................................................................36
7.2
Assessment types...................................................................................................37
7.2.1
Efficacy assessments.............................................................................37
7.2.2
Resource utilization...............................................................................37
7.2.3
Patient reported outcomes.....................................................................37
8
Safety monitoring and reporting........................................................................................37
8.1
Adverse events.......................................................................................................37
8.1.1
Definitions and reporting ......................................................................37
8.1.2
Adverse events of special interest.........................................................38
8.2
Serious adverse events...........................................................................................38


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8.2.1
Definitions.............................................................................................38
8.2.2
Reporting...............................................................................................39
8.3
Emergency unblinding of treatment assignment ...................................................40
8.4
Pregnancies............................................................................................................40
8.5
Warnings and precautions......................................................................................40
8.6
Data Monitoring Committee..................................................................................40
8.7
Steering Committee ...............................................................................................40
9
Data collection and management.......................................................................................41
9.1
Data confidentiality ...............................................................................................41
9.2
Site monitoring ......................................................................................................41
9.3
Data collection.......................................................................................................42
9.4
Database management and quality control............................................................42
10 Statistical methods and data analysis ................................................................................42
10.1
Analysis sets ..........................................................................................................42
10.1.1
Full Analysis Set ...................................................................................42
10.1.2
Safety Set ..............................................................................................42
10.1.3
Per-Protocol Set ....................................................................................42
10.2
Patient demographics/other baseline characteristics .............................................43
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................43
10.4
Primary objective...................................................................................................43
10.4.1
Analysis set and grouping for the analyses...........................................43
10.4.2
Adverse events (AEs)............................................................................43
10.4.3
Other safety data ...................................................................................43
10.4.4
Pharmacokinetics and biomarkers.........................................................43
10.5
Interim analysis......................................................................................................43
10.6
Sample size calculation..........................................................................................44
11 Ethical considerations and administrative procedures ......................................................44
11.1
Regulatory and ethical compliance........................................................................44
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................44
11.3
Informed consent procedures.................................................................................44
11.4
Discontinuation of the study..................................................................................45
11.5
Publication of study protocol and results...............................................................45
11.6
Study documentation, record keeping and retention of documents.......................45
11.7
Confidentiality of study documents and patient records .......................................46
11.8
Audits and inspections...........................................................................................46
11.9
Financial disclosures..............................................................................................46
12 Protocol adherence ............................................................................................................46


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12.1
Amendments to the protocol..................................................................................47
13 References (available upon request)..................................................................................48
14 Appendices ........................................................................................................................50
14.1
Appendix 1: Guidance on concomitant medications with CYP3A and QTc 
prolongation potential interactions. .......................................................................50
List of appendices
Appendix 1: Guidance on concomitant medications with CYP3A and QTc prolongation 
potential interactions.
List of tables
Table 3-1
Objectives and related endpoints ..........................................................23
Table 6-1
Dose and treatment schedule.................................................................26
Table 6-2
Preparation and dispensing ...................................................................30
Table 6-3
Packaging and labeling .........................................................................31
Table 6-4
Supply and storage of study treatments ................................................31
Table 7-1
Visit evaluation schedule ......................................................................33
Table 14-1
Medications that can induce CYP3A4 ..................................................50
Table 14-2
Medications that can inhibit CYP3A4 ..................................................51
List of figures
Figure 4-1
Study schema ........................................................................................24


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List of abbreviations
AE
Adverse event
AMN107
Nilotinib /Tasigna
Anti HBc
Hepatitis B Core Antibody
AP
Accelerated phase (of CML)
AUC
Area under the plasma concentration-time curve
AUC (0-∞)
Area under the plasma concentration-time curve extrapolated to infinity
b.i.d.
bis in diem, twice daily
BC
Blast crisis (of CML)
BCRP
Breast cancer resistance protein
CCyR
complete cytogenetic response
CHR
Complete hematological response
Cmax
The maximum (peak) observed plasma drug concentration after oral dose 
administration (mass X volume-1)
CML
Chronic myeloid /myelogenous leukemia
CP
Chronic phase (of CML)
CRF
Case report/record form
CRO
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse Event
CYP3A4
Cytochrome P450 3A4
DDI
Drug –drug interactions
DS&E
Drug Safety and Epidemiology
EC
Ethical Committee
ECG
Electrocardiogram
EDC
Electronic data capture
EoT
End of treatment
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
GIST
Gastrointestinal stromal tumors
H2
Histamine receptor 
HBc Ab
Hepatitis B Core Antibody
HBs Ag
Heptitis B Surface Antigen 
HGC
hard gelatin capsules
HMG-CoA
Hydroxy-Methyl-Glutaryl-Coenzyme A
ICH
International Conference on Harmonization
ICVE
Ischemic Cerebrovascular Events
IEC
Independent Ethics Committee
IHD
Ischemic Heart Disease
IIT
Investigator initiated trial
IN
Investigator Notification
IRB
Institutional Review Board


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IUD
Intrauterine device
IUS
Intrauterine system
MCyR
Major cytogenetic response
MRP2
Multi-resistance protein 2
OS
Overall survival
PAOD
Peripheral Artery Occlusive Disease 
PDGFR
Platelet-derived growth factor receptors
PFS
Progression-free survival
P-gp
P-glycoprotein
Ph
Philadelphia (chromosome)
PHI
Protected Health Information
PPS
Per Protocol Set
q.d.
quaque die/ once daily
QT
Q to T interval (ECG)
REB
Research Ethics Board
SAE
Serious adverse event
SCT
Stem cell transplantation
SmPC
Summary of Product Characteristics
SOC
system organ class
SUSAR
Suspected Unexpected Serious Adverse Reactions
T1/2
The elimination half-life associated with the terminal slope of a semi logarithmic 
concentration-tine curve (time)
TKI
Tyrosine kinase inhibitors
Tmax
The time to reach maximum (Cmax) plasma drug concentration after oral dose 
administration (time)


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Glossary of terms
Dose level
The dose of drug given to the patient (total daily dose).
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 approved indication/dosage.
Other study treatment
Any drug administered to the patient as part of the required study 
procedures that were not included in the investigational treatment.
Parent study
The original Novartis-sponsored, Oncology Clinical Development & 
Medical Affairs study where the patient was first enrolled and received 
nilotinib treatment.
Patient number
A unique identifying number assigned to each patient who enrolls in the 
study.
Roll-over study
A roll-over study allows patients from multiple parent studies spanning 
multiple indications to continue to be treated within one study after the 
completion of the parent study/ies.
Study treatment
Includes any drug or combination of drugs in any study arm administered 
to the patient as part of the required study procedures, including placebo 
and active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination.


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Amendment 04 (05-Apr-2018)
Amendment rationale
This roll-over study has been opened since 25-Jun-2013 with 15 total patients enrolled and 4 
patients ongoing as of 1st-Apr-2018.
The main purpose for the amendment is:

To correct an error in the language regarding pregnancy outcome collection. Pregnancy 
outcomes from female partners of any males who took study treatment will not be 
collected in this study as nilotinib is not genotoxic and no effects on sperm count, motility, 
or on fertility were noted in animal studies.

To extend the study duration from 5 years to 10 years to collect and assess long-term 
safety of nilotinib in patients who are on nilotinib treatment .

To add the section on follow up on potential drug-induced liver injury (DILI) cases. This 
section was added to be aligned with current protocol template. No new safety signal, 
related to liver function AEs were observed as of 1st-Apr-2018. 
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 have been implemented:
List of abbreviations updated.
Section 2.1, 2.2, Table 3-1, 4.1, 5.2, 10.4 and 10.6: Delete the department name.
Section 4.1, 4.3, 4.4, 7.1.2 and 10: Updated the study opening duration to 10 years. 
Section 6.2: Title is corrected to appropriate one.
Section 6.2.6: Section is added to provide follow-up information for drug-induced liver injury.
Section 8.4: Section is updated. Pregnancy outcomes from female partners of any males who 
took study treatment will not be collected in this study.
Section 10.1.1: The definition of full analysis set was updated.
Section 10.3: The analysis for duration of exposure and dose intensity was updated.
Section 10.4.2: The analysis for adverse events was updated.
Section 11.5: Section is updated to be aligned with current protocol template.
Section 14.1: Appendix 1 is corrected the clerical error. 


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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.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 03
Amendment rationale
The main purpose for the amendment is:

To include hepatitis B virus testing as one of the study procedures, to identify study patients 
who may be at risk of hepatitis B reactivation. Reactivation of hepatitis B virus can occur 
in patients who are chronic carriers of this virus and are receiving a drug of the BCR-ABL 
TKI class such as nilotinib/imatinib. Some cases involving BCR-ABL TKI resulted in acute 
hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.
Changes to the protocol

List of abbreviations updated

Section 6.2.5 Hepatitis B reactivation was added to provide information on next steps for 
patients tested positive for hepatitis B virus.

Section 7 Visit schedule and assessments were updated to include the hepatitis B testing 
once and only once at the next possible visit.

Section 7.1.4 Serology-Hepatitis B testing was added to provide information on hepatitis B 
testing. 
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.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 02
Amendment rationale
The main purpose for the amendment is:

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 update the exclusion criteria relating to male patient’s use highly effective 
contraception to be aligned with the current Investigator Brochure.

To incorporate precaution of use for antacid drugs aligned with Tasigna® Prescribing 
Information and SmPC.

To define ischemic vascular and ischemic cardiovascular events as Clinical conditions of 
special interest, and their reporting to the Investigator.

To update the list of medications that can inhibit CYP3A4.
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 summary as well as within the 
protocol sections below:
Updated to include information on efficacy response rate, ischemic vascular and ischemic 
cardiovascular event reported from the 60-month analysis on the CAMN107A2303 study.
Section 4.1: Updated to clarify that medical monitoring as clinically indicated at the physician’s 
discretion should also include cardiovascular risk factors such as serum cholesterol and glucose 
levels amongst others.
Section 5.3: An exclusion criterion is updated to reflect that male patients are no longer required 
to use highly effective contraception during the study and for 30 days after the final dose of 
nilotinib.
Section 6.2: Updated to include guidelines for the management of patients in sub-section listed 
below (Section 6.2.1 to Section 6.2.5).
Section 6.2.1 to Section 6.2.4: Sub-sections added to share guidance for the management of 
cholesterol increases, glucose increases, other cardiac risk factors and ischemic vascular or 
cardiovascular events.
Section 6.2.1: Updated to Section 6.2.5 to include precaution for the use of antacid drugs and 
CYP3A4 inhibitors.


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Section 7.1.3: Updated to include guidelines for highly effective contraception (as defined in 
exclusion criterion 5).
Section 8.1.2: Added the guidance on clinical conditions of special interest.
Section 14.1: Appendix 1 is updated to add information on CYP3A4 inducer classification and 
the list of CYP3A4 inhibitors.
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.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 01
Amendment rationale
This amendment has been implemented to address the following changes for the study:

To add monthly pregnancy tests for female patients of child bearing potential to reflect the 
requirement of highly effective contraception for patients on nilotinib treatment.

To add language clarifying that dose modifications will be based on guidelines provided in 
the parent protocol, as well as investigator’s judgment.

To add language clarifying that should treatment with strong CYP3A4 inhibitors or 
inducers be required, it is recommended that therapy with nilotinib be interrupted.

To clarify that patients who are pregnant, withdrawn consent or have died must be 
withdrawn from the study.

To add the patients’ ethnicity in patient demographics to collect in eCRFs.

To address other administrative and typographical corrections noted in the original 
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 sections below:
Section 6.2: Updated to clarify that dose modifications will be based on guidelines provided in 
the parent protocol as well as investigator’s judgment.
Section 6.2.1: Updated to clarify that should treatment with strong CYP3A4 inhibitors or 
inducers be required, it is recommended that therapy with nilotinib be interrupted.
Table 7-1: Monthly pregnancy testing added in the Visit evaluation table.
Section 7.1.3: Updated to add a section regarding pregnancy testing for female patients of child 
bearing potential.
Section 7.1.1.3: Updated to add patients’ ethnicity as patient demographics.
Section 7.1.4.1: Updated to clarify that patients who are pregnant, withdraw consent or have 
died must be withdrawn from the study.
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
Brief title
An open label, multi-center nilotinib roll-over protocol for patients who have 
completed a previous Novartis-sponsored nilotinib study and are judged by 
the investigator to benefit from continued nilotinib treatment.
Efficacy assessments
Not applicable.
Exclusion criteria
Patient has been permanently discontinued from nilotinib study treatment in 
the parent study due to unacceptable toxicity, non-compliance to study 
procedures, withdrawal of consent or any other reason.
Patient has participated in a Novartis sponsored combination trial where 
nilotinib was dispensed in combination with another study medication and 
is still receiving combination therapy.
Inclusion criteria
Patient is currently enrolled in a Novartis- sponsored clinical study 
receiving nilotinib and has fulfilled all their requirements in the parent study.
Patient is currently benefiting from the treatment with nilotinib, as 
determined by the investigator.
Patient has demonstrated compliance, as assessed by the investigator, 
with the parent study protocol requirements.
Investigation type
Drug
Investigational and 
reference therapy
Nilotinib≤ 800 mg/day
Key words
Nilotinib, long-term safety, roll-over study
Other assessments
Not applicable
Population
Male and female patients who are currently enrolled in a Novartis-
sponsored clinical study, are benefiting from treatment with nilotinib, and 
have fulfilled all requirements in the parent study. All objectives of the 
parent study must have been reached, and the study must be in the 
process of being completed & reported.
Primary Objective(s) 
and Key Secondary 
Objective
To collect and assess long-term safety of nilotinib to patients receiving 
nilotinib in a Novartis-sponsored clinical study which has reached its 
objectives and who are benefiting from treatment with nilotinib.
Protocol number
CAMN107A1201
Purpose and rationale
The purpose of this study is to collect and assess long-term safety of 
nilotinib in patients who are on nilotinib treatment in a Novartis-sponsored 
clinical study and are benefiting from the treatment as judged by the 
investigator.
Safety assessments
Reported adverse events (AEs) will be collected continuously throughout 
the study .For the safe and effective use of nilotinib, medical monitoring 
should be performed as clinically indicated at the physician’s discretion. 
Medical monitoring should also include monitoring of cardiovascular risk 
factors such as serum cholesterol and glucose levels amongst others.
Sponsor and
Clinical Phase
Novartis,
II.


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Study design
This is an open label, multi-center, phase II study to collect and assess 
long-term safety of nilotinib to patients being treated in current Novartis-
sponsored clinical studies and who are benefiting from treatment with 
nilotinib.
There will be no screening period for this study. At the enrollment visit the 
patient will be consented to the study and eligible patients will start their 
treatment with nilotinib.
Patients must return to the study center on a yearly basis (+/- 3 months) for 
resupply of study medication at which time limited drug dispensing 
information will be collected. The patient may return to the study center at 
any given time as per standard of care, however, only one study visit per 
year will be scheduled and AEs reported at general medical care will be 
collected continuously throughout the study. For the safe and effective use 
of nilotinib, medical monitoring should be performed as clinically indicated 
at the physician’s discretion. Medical monitoring this should also include 
monitoring of cardiovascular risk factors such as serum cholesterol and 
glucose levels amongst others.
Patients will continue to be treated until they are no longer benefiting from 
nilotinib treatment, develop unacceptable toxicities, withdraw consent, are 
non-compliant to the protocol, the investigator feels it is no longer in the 
patient’s best interest to continue nilotinib therapy or the patient dies, 
whichever comes first.
A patient will reach the end of study when nilotinib treatment is 
permanently discontinued and the end of treatment visit has been 
performed.
The study is expected to remain open for 10 years or until such time that 
enrolled patients no longer need treatment with nilotinib, whichever comes 
earlier.
Study type
Interventional.
Title
An open label, multi-center nilotinib roll-over protocol for patients who have 
completed a previous Novartis-sponsored nilotinib study and are judged by 
the investigator to benefit from continued nilotinib treatment.


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1
Overview of chronic myeloid leukemia (CML)
Chronic myeloid leukemia (CML) is a hematologic 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 et al. 1983, 
Heisterkamp et al. 1983). Clinically, CML progresses through three distinct phases of 
increasing refractoriness to therapy: chronic phase (CP), accelerated phase (AP) and blast crisis 
(BC). Most patients however present in the chronic phase at the time of diagnosis, characterized 
by splenomegaly and leukocytosis with generally few symptoms. CML comprises 15% of adult 
leukemias, with an approximate incidence of 1-2 per 100,000 per year and median age of 
presentation of 45 to 55 years of age (Weisberg et al. 2006, Frazer et al. 2007). Tyrosine kinase 
inhibitors (TKIs) that inhibit BCR-ABL are the gold standard treatment for BCR-ABL positive 
CML. Imatinib (Glivec®, Gleevec®; Novartis Pharma AG, Basel, Switzerland) was the first TKI 
approved for this indication and revolutionized the treatment of CML. Imatinib is the TKI with 
the longest follow-up with estimated progression-free survival of 81%, freedom from 
progression to AP/BC of 92% and estimated overall survival (OS) of 85% at 8 yrs for newly 
diagnosed CP-CML patients (93% when only CML-related deaths and those prior to stem cell 
transplantation (SCT) were considered) (Deininger et al. 2009).
Nilotinib (Tasigna®; Novartis Pharma AG, Basel, Switzerland) and dasatinib (Sprycel®; Bristol-
Myers Squibb, Wallingford, CT, USA) are approved for treatment of patients with Ph+ CML 
who have failed prior therapies including imatinib and for newly diagnosed patients. Both 
nilotinib and dasatinib have recently demonstrated superiority over imatinib in head-to-head 
clinical studies in patients newly diagnosed with Ph+ CML (Kantarjian et al. 2010, Saglio et al. 
2010).
1.1.2
Overview of gastrointestinal stromal tumors (GIST)
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the 
gastrointestinal (GI) tract and are thought to originate from the interstitial cells of Cajal. GISTs 
are malignant tumors most commonly resulting from activating mutations in the receptor 
tyrosine kinase KIT (CD117) or the platelet-derived growth factor receptors α (PDGFRα) 
(Demetri et al. 2010). Approximately 85% of KIT (CD117)-positive GISTs harbors an 
activating mutation in the KIT oncogene and 5-8% of GISTs have mutated PDGFRα gene. 
Mutations in KIT exon 11 are the most common (67%) while KIT exon 9 mutations are found 
in 10-12% of GISTs. Mutations in KIT exons 13 and 17 are rare. The remaining cases harbor 
no mutation and are referred to as “Wildtype” GIST (Corless and Heinrich 2008).
GISTs can arise anywhere along the GI tract but are most common in the stomach and small 
intestine (Demetri et al. 2010). The majority of KIT exon 9 mutations arise in small intestinal 
GISTs, while most PDGFRα mutations are found in gastric GISTs. KIT exon 11 mutations are 


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distributed throughout the GI tract. Response to systemic therapies in the metastatic /inoperable 
disease setting is related to the identified activating mutations in GIST and the development of 
subsequent resistance mutations (Corless and Heinrich 2008).
The mainstay of therapy for patients with primary GIST is surgical resection. However, surgery 
alone is generally not curative; the 5-year disease specific survival is reported to be 54%. 
Recurrence rates exceeding 50% within 2 years of resection of primary GIST and 
approximating 90% after re-excision (DeMatteo et al. 2000), underscored the need for effective 
postoperative treatment.
Imatinib is the first-line therapy for metastatic GIST with a median progression free survival 
(PFS) reported between 18 months (Phase III) and 29 months (Phase II) and a median OS of 57 
months (Verweij et al. 2004, Blanke et al. 2008a, Blanke et al. 2008b, Bertucci et al. 2012). For 
patients whose disease has progressed during, or who are intolerant to imatinib therapy, 
sunitinib (Sutent®; Pfizer) is the available second line treatment (Demetri et al. 2006).
Nilotinib also inhibits the tyrosine kinase activity of KIT and PDGFRα which are associated 
with GISTs. However, although nilotinib and imatinib exhibit similar potencies against the KIT 
and PDGFR target enzymes, they exhibit major differences in cell transport. Thus Prenen 
(Prenen et al. 2006) has demonstrated that in two GIST cell lines, intracellular levels of nilotinib 
are much higher (7-10 fold) than those of imatinib, at physiologically relevant concentrations 
of the two agents. The ability of nilotinib to achieve higher intracellular concentrations in GIST 
cells might be the reason that nilotinib has shown anti-proliferative activity at physiologically 
relevant concentrations in imatinib-resistant GIST48 and GIST430 cells (Dileo et al. 2006).
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of Nilotinib
Nilotinib (Tasigna®, AMN107) is a highly potent and selective inhibitor of both wild-type and 
imatinib-resistant forms of the tyrosine kinase activity of the BCR-ABL oncoprotein both in 
cell lines and in primary Philadelphia-chromosome positive (Ph+) leukemia cells. BCR-ABL is 
a constitutively active tyrosine kinase and drives the pathology of chronic myelogenous 
leukemia, a myeloproliferative disorder characterized by a clonal expansion of hematopoietic 
stem cells expressing the BCR-ABL gene. The therapeutic concept of BCR-ABL tyrosine 
kinase inhibition is an effective treatment modality for Ph+ CML as inhibition of BCR-ABL 
kinase activity with nilotinib results in apoptosis of Ph+ CML cells.
Nilotinib is currently approved for the treatment of adult patients with Ph+ chronic myeloid 
leukemia in CP and AP resistant to or intolerant to at least one prior therapy including imatinib 
and for the treatment of adult patients with newly diagnosed Ph+ CML in CP.
Nilotinib also inhibits a small number of receptor tyrosine kinases, including the stem cell factor 
kinase (KIT), platelet-derived growth factor kinases (PDGFRα and PDGFRβ), colony 
stimulating factor receptor kinase (CSF-1R), discoidin domain receptor kinases (DDR1 and 
DDR-2) and ephrin receptor kinase (EphB4). Consequently, the activity of nilotinib has also is 
also being explored in other potential indications.


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1.2.1.1
Non-clinical experience
For information on pre-clinical toxicity please refer to the current nilotinib [Investigator’s
Brochure] (IB).
1.2.1.2
Clinical experience
1.2.1.2.1 Human safety and tolerability data
Imatinib-naïve CML patients:
The efficacy of nilotinib in patients with newly diagnosed Ph+ CML-CP has been evaluated in 
a phase III multi-center open label, randomized study [CAMN107A2303/ENESTnd]
comparing nilotinib to imatinib in adult patients with newly diagnosed CML-CP. This study is 
ongoing and showed continuing superiority of nilotinib vs. imatinib at 12, 24, 36, 48 and 60
months follow-up in terms of cytogenetic and molecular responsesA total of 846 newly 
diagnosed CML-CP patients were randomized into the study of which 484 patients were still 
receiving core treatment as of the 60-month cut-off date (141 patients (49.8%) in the imatinib 
arm, 169 patients (59.9%) in the nilotinib 300 mg BID arm and 174 patients (61.9%) in the 
nilotinib 400 mg BID arm). A total of 362 patients discontinued core study treatment. The study 
met its primary efficacy endpoint at the 12-month analysis time point: the MMR rate was 
significantly higher in the nilotinib arms compared to the imatinib arm. By 60 months, the MMR 
rate remained higher in the nilotinib arms than in the imatinib arm, indicating that the superiority 
of both nilotinib arms over the imatinib arm persists with longer follow-up. Furthermore, the 
proportions of patients achieving molecular response of ≤ 0.01% and ≤ 0.0032% by 60 months 
were higher in the nilotinib arms than in the imatinib arm.
Ischemic Vascular and Ischemic Cardiovascular Events Reported for 
CAMN107A2303 (ENESTnd Study):
Newly-diagnosed or worsened Ischemic Vascular and Ischemic Cardiovascular Events such as 
Ischemic Heart Disease (IHD), Ischemic Cerebrovascular Events (ICVE) or Peripheral Artery 
Occlusive Disease (PAOD) have occurred in a relatively small number of CML-CP patients 
while on study medication. However, such events have been reported with higher frequency on 
the nilotinib treatment arms compared with the imatinib treatment arm. Up to the data cut-off 
for the 60 month analysis (30-Sep-2013), the number of patients reported with these events is 
as follows:

Nilotinib 300 mg BID: IHD, 11 (3.9%); ICVE, 4 (1.4%); PAOD, 7 (2.5%)

Nilotinib 400 mg BID: IHD, 24 (8.7%); ICVE, 9 (3.2%); PAOD, 7 (2.5%)

Imatinib 400 mg QD: IHD, 5 (1.8%); ICVE, 1 (0.4%); PAOD, 0 (0.0%)
The majority of reported ischemic vascular and ischemic cardiovascular events were in patients 
with associated risks (e.g., advanced age, hypertension, hyperlipidemia, hypercholesterolemia, 
smoking, diabetes mellitus, pre-existing peripheral vascular disease). The background 
incidence of these events has not been established for the CML patient population.
A detailed description of efficacy and safety data can be found in the current nilotinib 
[Investigator’s Brochure].


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Imatinib-resistant or -intolerant hematologic diseases:
Data from a Phase I/II [CAMN107A2101]open-label study indicated that nilotinib treatment 
resulted in hematologic and cytogenetic responses in patients who had received prior TKIs 
(including imatinib). In this study a total of 321 CML-CP patients were evaluated for efficacy. 
Of these, 70.4% were imatinib-resistant and 29.6% were imatinib-intolerant. Patients were 
treated with nilotinib 400 mg b.i.d. OS at 24 months was 87%. In terms of efficacy, 165 patients 
(51.4%) achieved a major cytogenetic response (MCyR), which was the primary efficacy 
variable. This study also analyzed the effect of 400 mg b.i.d. nilotinib in a group of 49 CML-
CP patients with prior TKI treatment other than imatinib. At 24 months follow-up, study 
discontinuation rate was 69.4% (38.8% due to disease progression and 12.2% due to AEs). 
Efficacy parameters included 77.1% complete hematological response (CHR) for those not in 
CHR at baseline, 42.9% MCyR, 22.4% complete cytogenetic response (CCyR) and 89% overall 
survival.
The Phase I/II study in imatinib-resistant or -intolerant chronic phase Japanese CML patients
[CAMN107A1101] showed that the efficacy profiles in Japanese patients were similar to those
in non-Japanese patients (Usuki et al. 2012).
The median average daily dose of nilotinib for CML-CP patients in [CAMN107A2101] was 
788.5 mg. The most frequently reported (>10%) drug-related AEs in CML-CP patients, based 
on 24-month data and 321 patients, included rash (30.8%), thrombocytopenia (28.0%), pruritus 
(26.2%), nausea (24.6%), fatigue (20.2%), headache (17.8%), neutropenia (15.0%), 
constipation (13.4%), anemia (13.1%), lipase increased (12.8%), vomiting (12.8%), diarrhea 
(12.1%), alanine aminotransferase increase (10.6%), myalgia (10.3%). In CML-CP patients, the 
most frequent serious adverse events (SAEs) were thrombocytopenia (3.4%), neutropenia 
(2.2%), angina pectoris (2.8%) and pyrexia (2.5%).
AEs that were associated with discontinuation of treatment with nilotinib were reported in 21.2% 
of all patients and 16.8% of these events were of Grade 3 or 4 severity. The most frequent AEs 
associated with discontinuation were neutropenia and thrombocytopenia, which occurred in 10 
(3.1%) patients each.
The most frequent Grade 3 or 4 AEs were neutropenia (3.1%), thrombocytopenia (2.8%) and 
thrombocythemia (1.2%); all other events occurred at a frequency lower than 1%.
A detailed description of efficacy and safety data can be found in the current nilotinib 
[Investigator’s Brochure].
1.2.1.2.2 GISTs:
The in vitro activity of nilotinib in imatinib resistant GIST cell lines has been confirmed in 
[CAMN107A2103] a Phase I study in patients with imatinib-resistant or intolerant GISTs. As 
nilotinib is not subject to the same cellular transport mechanisms as imatinib, it is effective in 
both imatinib-sensitive and imatinib-resistant GIST cells. The median progression free survival 
of nilotinib in imatinib-resistant GIST patients was 168 (5.6 months) days in the 
CAMN107A2103 study.
With the success of the CAMN107A2103 it was reasonable to assume that nilotinib may have 
similar or improved efficacy over imatinib in GIST patients.


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In the phase III study [CAMN107G2301] patients with unresectable and/or metastatic GIST 
who have either not received prior therapy with a TKI or who have recurrent GIST after 
stopping adjuvant therapy, were randomized to either nilotinib or imatinib therapy. The primary 
objective of this study is to compare PFS of nilotinib and imatinib when used as initial therapy 
in this patient population.
However the study had to be closed to further recruitment at the request of the Data Monitoring 
Committee since the futility boundary was exceeded in an interim futility analysis (e.g. this 
means that there was an extremely low likelihood that continuing with the study would have 
resulted in a significantly positive outcome in favor of nilotinib). There are no plans to initiate 
new studies of nilotinib in the GIST patient population.
In general, the safety profile in GIST patients was similar to that in CML patients, with the 
exception of a lower incidence of hematologic toxicity.
The global phase III study[CAMN107A2201] and Japan phase II study [CAMN107D1201] in 
patients with GIST who have progressed on or are intolerant to both imatinib and sunitinib 
showed that nilotinib has generally been well tolerated in this disease setting and the safety 
profiles are similar between Japanese and non-Japanese in this disease setting.
A detailed description of efficacy and safety data can be found in the current nilotinib 
[Investigator’s Brochure].
1.2.1.2.3 Clinical pharmacokinetics and pharmacodynamics
The relationship of systemic exposure (Cmax, AUC) over the range of 50 to 1200 mg nilotinib 
given once a day was assessed in patients with imatinib resistant or intolerant CML. With once 
daily dosing steady-state nilotinib Cmax and AUC increased with increasing dose from 50 mg 
to 400 mg in a generally dose-proportional manner, but appeared to plateau at dose levels of 
400 mg and higher. Using a twice daily dosing regimen partially overcame the dose-limiting 
exposure, with daily steady-state serum nilotinib exposure at 400 mg twice daily dose (b.i.d.) 
being approximately 35% greater than with 800 mg once daily dose (q.d.). However, there was 
no further relevant increase in nilotinib exposure observed with the administration of 600 mg 
b.i.d. With multiple oral doses of nilotinib, steady-state conditions were achieved by day 8 after 
initiating nilotinib treatment. There was a 2-fold or 3.8-fold accumulation with q.d. or b.i.d. 
dosing, respectively. The median time to reach Cmax of nilotinib (Tmax) was 3 hours. Terminal 
elimination half-life of nilotinib was estimated to be approximately 17 hours.
The bioavailability of nilotinib is increased when the drug is given with a meal. Compared to 
the fasted state, nilotinib AUC is increased by 15% (administered 2 hours after a light meal), 
29% (30 minutes after a light meal), or 82% (30 minutes after high fat meal), and the Cmax
increased by 33% (2 hours after a light meal), 55% (30 minutes after a light meal), or 112% 
(30 minutes after high fat meal). Concurrent intake of grapefruit juice increased the nilotinib 
Cmax by 60% and AUCinf by 29%, but the Tmax and T1/2 were not altered.
Nilotinib is metabolized by the liver, primarily via CYP3A4. Metabolism of nilotinib leads to 
the formation of several minor metabolites, none of which contributes significantly to the 
pharmacological activity of the drug. Unchanged nilotinib represents the predominant 
circulating component in serum (approximately 88% of the total drug-related serum exposure). 


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Strong inhibitors or inducers of CYP3A4 can significantly alter the pharmacokinetics and 
systemic exposure of nilotinib in humans.
Nilotinib is a substrate of P-gp, but is neither a Multi-resistance protein 2 (MRP2) nor a Breast 
Cancer Resistance Protein (BCRP) substrate.
2
Rationale
2.1
Study rationale and purpose
The purpose of this study is to collect and assess long-term safety of nilotinib in patients who 
are on nilotinib treatment in a Novartis-sponsored clinical study and are benefiting from the 
treatment as judged by the investigator. Which parent studies are eligible to participate in the 
roll-over study will be decided by Novartis, Investigator initiated trials (IITs) will not be 
included. All objectives prescribed in the parent study protocol must have been reached, and 
the parent study must be in the process of being completed and reported.
Patients will continue to receive nilotinib until one of the following occurs: the patient is no 
longer benefiting from the treatment, unacceptable toxicity develops, consent is withdrawn, 
there is non-compliance with the protocol, the investigator feels it is no longer in the patient’s 
best interest to continue therapy, or the patient’s death.
2.2
Rationale for the study design
This is an open label, multi-center, phase II study to collect and assess long-term safety of 
nilotinib to patients being treated in a current Novartis-sponsored clinical study and who are 
benefiting from treatment with nilotinib.
The study will not include a screening phase as patients will transfer directly from parent studies 
and will commence treatment with nilotinib as soon as they are consented and meet the 
inclusion criteria of the roll-over protocol.
2.3
Rationale for dose and regimen selection
Nilotinib can be provided as 200 mg and 150 mg hard gelatin capsules (HGC). The starting 
dose of nilotinib should be the same dose which was given in the parent nilotinib study. After 
the starting dose, the dose of nilotinib is based on the investigator’s judgment.
Nilotinib in different formulations and strengths can be used in the roll-over study once they 
are approved and marketed.


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3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To collect and assess long-term safety of 
nilotinib to patients receiving nilotinib in a 
Novartis-sponsored clinical study which 
has reached its objectives and who are 
benefiting from treatment with nilotinib.
Frequency and nature of AEs.
Refer to 
Section 10
4
Study design
4.1
Description of study design
This is an open label, multi-center, phase II study to collect and assess long-term safety of 
nilotinib to patients being treated in current Novartis-sponsored clinical studies and who are 
benefiting from treatment with nilotinib.
There will be no screening period for this study. At the enrollment visit the patient will be 
consented to the study and eligible patients will start their treatment with nilotinib.
Patients must return to the study center on a yearly basis (+/- 3 months) for resupply of study 
medication at which time limited drug dispensing information will be collected. The patient 
may return to the study center at any given time as per standard of care, however, only one 
study visit per year will be scheduled and AEs reported at general medical care will be collected 
continuously throughout the study. For the safe and effective use of nilotinib, medical 
monitoring should be performed as clinically indicated at the physician’s discretion. Medical 
monitoring should also include monitoring of cardiovascular risk factors such as serum 
cholesterol and glucose levels amongst others.
Patients will continue to be treated until they are no longer benefiting from nilotinib treatment, 
develop unacceptable toxicities, withdraw consent, are non-compliant to the protocol, the 
investigator feels it is no longer in the patient’s best interest to continue nilotinib therapy or the 
patient dies, whichever comes first.
A patient will reach the end of study when nilotinib treatment is permanently discontinued and 
the end of treatment visit has been performed.
The study is expected to remain open for 10 years or until such time that enrolled patients no 
longer need treatment with nilotinib, whichever comes earlier.


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Figure 4-1
Study schema
*Note: The starting nilotinib dose will be the same as the last dose in the parent study.
4.2
Timing of interim analyses and design adaptations
No interim analyses are planned.
4.3
Definition of end of the study
End of study is defined as either 10 years duration or when all patients on this study have 
permanently discontinued nilotinib treatment and the end of treatment visit has been performed 
for each patient, whichever comes earlier.
4.4
Early study termination
The study is expected to remain open for 10 years or until such time that enrolled patients no 
longer need treatment with nilotinib, whichever comes earlier.
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 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 health interests. The investigator will be responsible 
for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
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. Patient is currently enrolled in a Novartis-sponsored clinical study receiving nilotinib and 
has fulfilled all their requirements in the parent study.
2. Patient is currently benefiting from the treatment with nilotinib, as determined by the 
investigator.


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3. Patient has demonstrated compliance, as assessed by the investigator, with the parent 
study protocol requirements.
4. Willingness and ability to comply with scheduled visits, treatment plans and any other 
study procedures.
5. Written informed consent obtained prior to enrolling in roll-over study.

If consent cannot be expressed in writing, it must be formally documented and 
witnessed, ideally via an independent trusted witness.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patient has been permanently discontinued from nilotinib treatment in the parent study due 
to unacceptable toxicity, non-compliance to study procedures, withdrawal of consent or 
any other reason.
2. Patient has participated in a Novartis sponsored combination trial where nilotinib was 
dispensed in combination with another study medication and patient is still receiving 
combination therapy.
3. Patients who are currently receiving treatment with any medications that have the potential 
to prolong the QT interval or inducing Torsade de Pointes and the treatment cannot be 
either safely discontinued at least one week prior to nilotinib treatment or switched to a 
different medication prior to start of nilotinib treatment and for the duration of the study 
(Please see Appendix 1 for link to list of agents that prolong the QT interval).
4. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test.
5. 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 30 days after the final dose of nilotinib. Highly effective 
contraception is defined as either:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to enrolling). For female patients on the 
study the vasectomized male partner should be the sole partner for that patient.

Use of a combination of any two of the following (a+b or a+c or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS).


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c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
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.
If a study patient becomes pregnant or suspects being pregnant during the study or within 30 
days after the final dose of nilotinib, the Investigator/Study Doctor needs to be informed 
immediately and ongoing study treatment with nilotinib has to be stopped immediately.
6
Treatment
6.1
Study treatment
Terms related to study treatment are defined below:

Study treatment and investigational treatment refer to nilotinib.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Total daily dose
Frequency and/or 
Regimen
Nilotinib /AMN107
*Hard Gelatin Capsule for oral 
use
≤800 mg
**Daily
* Different formulations and strengths can be used once they are approved and marketed.
**If total daily dose is 600 mg it is taken as 300 mg b.i.d. If total daily dose is 800 mg it is taken as 
400 mg b.i.d.
Nilotinib can be provided as 200 mg and 150 mg hard gelatin capsules. The investigational 
treatment is to be stored in a secure locked area while under the responsibility of the investigator. 
Receipt and dispensing of investigational treatment must be recorded by an authorized person 
at the investigator’s site.
The starting dose of nilotinib should be the same as the last dose that was given in the parent 
nilotinib study. After this, the dose of nilotinib is based on the investigator’s judgment.
Nilotinib must NOT be taken with food. No food should be consumed for at least 2 hours 
before the dose is taken and no additional oral intake other than water should be consumed for 
at least one hour after the dose is taken. This instruction should be followed if patient is to take 
nilotinib once or twice a day. If nilotinib is taken twice a day (when 300-400 mg b.i.d.) patients 
should be instructed to take nilotinib each morning and evening approximately 12 hours apart.
Each dose of nilotinib should be taken with a glass of water. If the morning or the evening dose 
is delayed for more than 4 hours, the patient should skip this dose and resume dosing with the 
next dose as per the original schedule in order to prevent overdosing.


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Nilotinib can be provided as local commercial material or global supply where appropriate and 
as per local regulations. As per Novartis procedures, investigational treatment will only be 
shipped directly to the investigational sites.
Nilotinib in different formulations and strengths can be used once they are approved and 
marketed.
Refer to the latest [Investigator’s Brochure] for nilotinib dosing instructions and storage 
conditions.
6.1.2
Ancillary treatments
Not applicable.
6.1.3
Rescue medication
Not applicable.
6.1.4
Guidelines for continuation of treatment
The starting dose of nilotinib should be the same as the last dose that was given in the parent 
nilotinib study. After this, the dose of nilotinib is based on the investigator’s judgment.
6.1.5
Treatment duration
Patients will continue to be treated until they are no longer benefiting from nilotinib treatment, 
develop unacceptable toxicities, withdraw consent, are non-compliant with the protocol, the 
investigator feels it is no longer in the patient’s best interest to continue nilotinib therapy or the 
patient dies, whichever comes first. A patient will reach the end of the roll-over study when 
nilotinib treatment is permanently discontinued.
6.2
Dose modifications
Dose modifications will be based on guidelines provided in the parent protocol as well as on 
investigator’s judgment. Additional guidelines for the management of patients including 
recommendations for the clinical management of cardiovascular risk factors and related events 
are listed in the sub-sections below.
6.2.1
Management of cholesterol increases
Blood lipid panel tests should be performed as clinically indicated throughout the 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). A list of 
these drugs is listed in Appendix 1 in Section 14.1.


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6.2.2
Management of glucose increases
Blood glucose tests should be performed as clinically indicated throughout the study. If blood 
glucose results warrant intervention, investigators should follow their local standards of practice 
and treatment guidelines in order to normalize blood glucose levels.
6.2.3
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.
6.2.4
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. For further recommendations regarding the management of 
ischemic vascular or cardiovascular-related events refer to the current nilotinib [Investigator’s 
Brochure].
6.2.5
Hepatitis B reactivation
Hepatitis B virus testing should be performed during the study as indicated in Section 7.1.4 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/imatinib treatment. Carriers of hepatitis B virus who require treatment 
with nilotinib/imatinib should be closely monitored for signs and symptoms of active hepatitis 
B infection throughout therapy and for several months following termination of therapy.
6.2.6
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as alkaline phosphatase (ALP) elevation > 2.0 x ULN with R value < 2 in patients without bone 
metastasis, or elevation of ALP liver fraction in patients with bone metastasis.


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Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury).
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and ALP.
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted.
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study.
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented. In this study, result of laboratory test is not collected on the eCRF but these events 
should be reported as AEs/SAEs on the eCRF, and should be monitored and verified with source 
data on site by the field monitor.
6.2.7
Prohibited concomitant therapy
In general, concomitant medications/therapies deemed necessary for the supportive care of the 
patient is permitted.
Avoid the concomitant use of strong CYP3A4 inhibitors and inducers (refer to Appendix 1 in 
Section 14.1). Should treatment with strong CYP3A4 inhibitors or inducers be required, it is 
recommended that therapy with nilotinib be interrupted. Close monitoring of prolongation of 
the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors or inducers. 
For further details refer to the current nilotinib [Investigator’s Brochure].
Cytochrome P450 3A4 substrates:
Nilotinib is a moderate CYP3A4 inhibitor in vivo. Because of the potential risk for drug-drug 
interactions, the systemic exposure of other drugs known to be sensitive substrates of CYP3A4 
and also to have a narrow therapeutic index should be used with caution. A list of these drugs 
is listed in Appendix 1 in Section 14.1.


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Antacid drugs:
Nilotinib has a pH-dependent solubility, therefore, in order not to impact nilotinib 
pharmacokinetics, administration of the following antiacid drugs (if necessary) should be as 
follows:

H2 blocker (e.g. famotidine) may be administered approximately 10 hours before or 
approximately 2 hours after the dose of nilotinib,

Antacids (e.g. magnesium hydroxide, simethicone) may be administered approximately 2 
hours before or approximately 2 hours after the dose of nilotinib.
6.3
Patient numbering, treatment assignment or randomization
6.3.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled in the roll-over study 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.
6.3.2
Treatment assignment or randomization
All consented patients who meet all the inclusion criteria and none of the exclusion criteria are 
eligible to receive nilotinib.
6.3.3
Treatment blinding
Not applicable.
6.4
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 CRF.
Table 6-2
Preparation and dispensing
Study treatments
Dispensing
Preparation
Nilotinib
*Hard Gelatin Capsules (150 mg and 200 mg) including 
instructions for administration will be dispensed by study 
personnel on an outpatient basis.
Patients will be provided with an adequate supply of study 
treatment for self-administration at home until at least their 
next scheduled annual (+/- 3 months) study visit. Or, 
patients can be provided with supply of study treatment 
needed until the next visit if the visit is scheduled within a 
year.
Not applicable
* Different formulations and strengths can be used once they are approved and marketed.


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6.4.1
Study drug packaging and labeling
Study treatment labels will be in Japanese and comply with the legal requirements of Japan. 
They will include storage conditions for the drug but no information about the patient.
Nilotinib in different formulations and strengths can be used once they are approved and 
marketed.
Refer to the latest [Investigator’s Brochure] for nilotinib dosing instructions and storage 
conditions.
Table 6-3
Packaging and labeling
Study treatment
Packaging
Labeling
Nilotinib
Capsules in bottles*
As per local requirements
* For centrally supplied medication. If nilotinib is sourced and labeled in-country/locally, the locally-
approved form, packaging and labeling of nilotinib will be used.
6.4.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the nilotinib should be stored according to the 
instructions specified on the drug labels and in the current [Investigator’s Brochure].
Table 6-4
Supply and storage of study treatments
Study treatment
Supply
Storage
Nilotinib
Centrally or locally supplied by 
Novartis
Refer to study treatment label 
or local product information
6.4.3
Study drug compliance and accountability
6.4.3.1
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.
6.4.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation.
At study close-out, and as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.


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6.4.3.3
Handling of other study treatment
Not applicable.
6.4.4
Disposal and destruction
The drug supply can only be destroyed once the study drug accountability check has been 
performed by the monitor. The study drug supply can be destroyed at the local Novartis facility, 
by Drug Supply group or by a third party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. A visit window of +/-3 months is allowed. All data obtained from these assessments 
must be supported in the patient’s source documentation.
Hepatitis B testing will be performed once and only once, at the next possible visit.
The table indicates which assessments produce data to be entered into the database (D) or 
remain in source documents only (S) (“Category” column).


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Table 7-1
Visit evaluation schedule
Category
Protocol 
Reference 
Section
Enrollment
Annual (+/- 3 months ) visits during treatment 
phase
End of study 
treatment (EoT)
Safety
Follow-up
Visit Number
1
Visit 2,3,4 etc.
777
Informed consent
D
7.1.1
x
Patients’ previous study, site 
and subject number
D
6.3
x
Demography
D
7.1.1.3
x
Inclusion/exclusion criteria
D
5.2 / 5.3
x
Nilotinib dosing
D
6.1
x
x
Pregnancy testing
D,S
7.1.3
Monthly (at home)
x
x
Serology-Hepatitis B Testing
S
7.1.4
ONLY once after patient is consented to amendment 5
AEs
D
8.1
Continuous
x
End of study treatment
D
7.1.5
x


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7.1.1
Screening
At the enrollment visit the patient will need to complete a written informed consent. There will 
be no screening period for this study. Once consented, patients will be evaluated for eligibility 
via the inclusion and exclusion criteria.
7.1.1.1
Eligibility screening
Not applicable.
7.1.1.2
Information to be collected on screening failures
Not applicable.
7.1.1.3
Patient demographics and other baseline characteristics
For patients that are eligible to participate in this roll-over study, an eCRF will be completed 
that identifies the patients’gender, date of birth, ethnicity and previous study, site/center and 
subject number.
7.1.2
Treatment period
The starting dose of nilotinib should be the same as the last dose that was given in the parent 
nilotinib study. A yearly supply of nilotinib will be dispensed to the patient/or as per local 
practice. Or, patients can be provided with supply of study treatment needed until the next visit 
if the visit is scheduled within a year.
Patients must return to the study center on a yearly basis (+/- 3 months) for resupply of study 
medication at which time limited drug dispensing information will be collected. At this time the 
dose of nilotinib is based on the investigator’s judgment.
The study is expected to remain open for 10 years or until such time that enrolled patients no 
longer need treatment with nilotinib, whichever comes earlier.
7.1.3
Pregnancy and assessment of fertility
Since highly effective contraception is required during the study, female patients of child 
bearing potential are required to test negative for a pregnancy (either with serum testing if 
routinely available or urine pregnancy test) before enrolling into the study.
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 30 days after the final dose of nilotinib.
Highly effective contraception is defined as either:

Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of 


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oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment.

Male sterilization (at least 6 months prior to enrolling). For female patients on the study 
the vasectomized male partner should be the sole partner for that patient.

Use of a combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
If patient has tested negative at the end of study on the parent study, no pregnancy testing is 
required if enrollment into this study is carried out on the same day or within few days 
(maximum 5 days) from each other.
Female patients of child bearing potential are required to perform monthly home urine 
pregnancy tests and complete a simple diary with the dates and the outcome of the home urinary 
test while on study treatment and during safety follow-up (30 days after the final dose of study 
medication).
A pregnancy test (either with serum testing if routinely available or urine pregnancy test) on 
female patients of child bearing potential is required at the final study visit.
Any positive results will be recorded in the database and followed up as per Section 8.4.
(Note: In terms of pregnancy prevention in a pediatric population, the detailed guidance in the 
parent protocol could be followed.)
7.1.4
Hepatitis B testing
Patients will be tested once for the following hepatitis B serologic markers: hepatitis B surface 
antigen (HBs Ag) and antibodies to hepatitis B core antigen (HBc Ab / anti HBc).
Patients currently on nilotinib/imatinib should have testing performed at the next possible visit 
in order to identify chronic carriers. 
7.1.5
End of treatment visit including study completion and premature 
withdrawal
Patients will continue to be treated until they are no longer benefiting from nilotinib treatment, 
develop unacceptable toxicities, withdraw consent, are non-compliant to the protocol, the 
investigator feels it is no longer in the patient’s best interest to continue nilotinib therapy or the 
patient dies, whichever comes first.
At the time the patients discontinues study treatment, a visit should be scheduled as soon as 
possible, at which time the assessments listed for the End of Treatment (EOT) visit will be 
performed. End of Treatment information will be completed in the eCRF giving the date and 
reason for stopping the study treatment (see Section 7.1.5.1). e.g. physician decision, disease 
progression, cause of death, lost to follow up, withdrawal of consent, etc.


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At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for a safety evaluation during the 30 days following the 
last dose of study treatment.
Patients who discontinue study treatment should be considered withdrawn from the study after 
the final visit assessments are performed or when it is clear that the patient will not return for 
these assessments.
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 withdrawal from the study and record this 
information on the appropriate CRF page.
A patient will reach the end of study when nilotinib treatment is permanently discontinued and 
there will be no further follow-up study visits.
7.1.5.1
Criteria for premature patient withdrawal
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time.
Patients may be withdrawn from the study if any of the following occur:
1. Death*.
2. Lost to follow-up.
3. Staying in the study would be harmful.
4. Patient/guardian decision*.
5. Physician decision.
6. Patient is non-compliant to protocol requirements.
7. Protocol deviation.
8. Patient becomes pregnant*.
9. Study terminated by sponsor.
*Note: Patients who are pregnant, withdrawn consent or have died must be withdrawn from the 
study.
7.1.5.2
Replacement policy
Not applicable.
7.1.6
Safety follow-up period
All patients must be followed up for safety evaluations for 30 days after the last dose of study 
treatment. At the end of this period, the investigator should contact the patient to inquire about 
any AE observed during this period. This could be done via a phone contact. Following this 
there are no further follow-up study visits.
Patients lost to follow up should be recorded as such on the appropriate 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.


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7.2
Assessment types
7.2.1
Efficacy assessments
Not applicable.
7.2.1.1
Additional biomarker assessments
Not applicable.
7.2.2
Resource utilization
Not applicable.
7.2.3
Patient reported outcomes
Not applicable.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s), or medical condition(s) that occur after patient’s signed informed consent has been 
obtained.
Abnormal laboratory values or test results occurring after dosing constitute AEs only if they 
induce clinical signs or symptoms, are considered clinically significant, require therapy (e.g., 
hematologic abnormality that requires transfusion or hematological stem cell support), or 
require changes in study medication(s).
AEs that begin or worsen after dosing should be recorded in the Adverse Events CRF. AE 
monitoring should be continued for at least 30 days following the last dose of study treatment. 
AEs (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 AE.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. If CTCAE grading does not exist for an AE, the severity of mild, 
moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE 
Grade 5 (death) will not be used in this study; rather, information about deaths will be collected 
though End of Treatment.
The occurrence of AEs should be sought by non-directive questioning of the subject after
signing informed consent and at each visit during the study. AEs also may be detected when 
they are volunteered by the subject between visits, or through physical examination, laboratory 
test, or other assessments. As far as possible, each AE 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)


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3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, concomitant medication taken, non-
drug therapy taken, hospitalization/prolonged hospitalization)
5. Whether it is serious, where a SAE is defined as in Section 8.2.1
All AEs should be treated appropriately. If a concomitant medication or non-drug therapy is 
given, this action should be recorded on the Adverse Event CRF.
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it. Laboratory abnormalities that meet the criteria for AEs should be followed 
until they have returned to normal or an adequate explanation of the abnormality is found. When 
an abnormal laboratory or test result corresponds to a sign/symptom of an already reported AE, 
it is not necessary to separately record the lab/test result as an additional event.
8.1.2
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 guidance provided in 
the current nilotinib [Investigator’s Brochure].
The Investigator should ensure that the patient is assessed by a vascular or cardiovascular 
specialist.
8.1.2.1
Definitions and reporting
Not applicable.
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


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
Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization

Note that hospitalizations for the following reasons should not be reported as SAEs:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a SAE
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and for 30 days after the patient has stopped study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
SAEs information will be collected in the Novartis safety database.
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.
The telephone and telefax number of the contact persons in the local department 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 and whether the patient continued or withdrew from study 
participation.


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If the SAE is not previously documented in the [Investigator’s Brochure] or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis DS&E department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug that this 
SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable. This is an open-label study.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis DS&E. Pregnancy follow-up should be recorded on the 
same form and should include an assessment of the possible relationship to the study treatment 
of any 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 nilotinib 
[Investigator’s Brochure]. Additional safety information collected between [Investigator’s
Brochure] updates will be communicated in the form of INs. This information will be included 
in the patient informed consent and should be discussed with the patient during the study as 
needed.
8.6
Data Monitoring Committee
Not applicable.
8.7
Steering Committee
Not applicable.


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9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened SAEs) 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 (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan.


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9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRFs is 
complete, accurate, and that entry and updates are performed in a timely manner.
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staffs are 
required to respond promptly to queries and to make any necessary changes to the data.
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and made available for data analysis. 
Authorization is required prior to making any database changes to locked data, by joint written 
agreement between the Global Head of Biostatistics and Data Management and the Global Head 
of Clinical Development.
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
Statistical analysis will be performed when all patients discontinued the trial or 10-year follow 
up was completed, whichever comes earlier. Those analyses results will be used to document 
the summary of the safety.
10.1
Analysis sets
10.1.1
Full Analysis Set
No Full Analysis Set (FAS) is defined for this trial.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of Nilotinib.
10.1.3
Per-Protocol Set
No Per-Protocol Set (PPS) is defined for this trial.


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10.2
Patient demographics/other baseline characteristics
Patient demographics and baseline characteristics such as age will be listed by patient.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
Study drug administration record will be listed by patient.
The duration of exposure in days to Nilotinib is defined as the time between the date of last 
dosing and the date of first dosing. It includes periods of temporary interruption of Nilotinib. 
The duration of exposure will be calculated for each patient, and will not be summarized. It will 
be used for dose intensity.
The dose intensity defined as the ratio of the cumulative dose to the duration of exposure may 
be calculated and summarized.
10.4
Primary objective
Primary objective of this trial is to collect and assess the long-term safety of Nilotinib to patients 
receiving nilotinib in a Novartis-sponsored clinical study (/ies) which has reached its objectives 
and who are benefiting from treatment with Nilotinib.
10.4.1
Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used.
10.4.2
Adverse events (AEs)
An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s), or medical condition(s) that occur after patient’s signed informed consent has been 
obtained.
All AE data (including those from pre-study and post-treatment period) will be listed by patient 
and those collected during the pre-study is to be flagged. The incidence of AE will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of AE, relation to study drug. Note that AEs from pre-study will not be analyzed.
Deaths reportable as SAEs and non-fatal serious AEs will be listed by patient.
10.4.3
Other safety data
Not applicable.
10.4.4
Pharmacokinetics and biomarkers
No pharmacokinetics and biomarkers will be assessed.
10.5
Interim analysis
No interim analysis is planned.


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10.6
Sample size calculation
No formal sample size calculation is required for this trial since only Japanese patients who are 
still on treatment in Novartis-sponsored clinical study (/ies) will be enrolled in this trial.
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. 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 
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.


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11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www clinicaltrials.gov before study start. 
In addition, results of interventional clinical trials in adult patients are posted on www
novartisclinicaltrials.com, a publicly accessible database of clinical study results within 1 year 
of study completion (i.e., LPLV), those for interventional clinical trials involving pediatric 
patients within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (www icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with [Section 4.9 of the ICH E6 GCP], and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 


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at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, and 
timeliness of the data reported in the eCRFs and all other required reports. Data reported on the 
eCRF, that are derived from source documents, should be consistent with the source documents 
or the discrepancies should be explained. All data requested on the eCRF must be recorded. 
Any missing data must be explained. For electronic CRFs an audit trail will be maintained by 
the system.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial [ICH E6 Section 8] and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
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 Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.


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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, de Klein A, Hagemeijer A, et al. (1983) Translocation of c-ab1 oncogene 
correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. 
Nature; 306(5940):277-80.
Blanke CD, Demetri GD, von Mehren M, et al. (2008a) Long-term results from a randomized 
Phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable 
or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol; 26:620-625.
Blanke CD, Rankin C, Demetri GD, et al. (2008b) Phase III randomized, intergroup trial 
assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic 
gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin 
Oncol; 26:626-632.
Bertucci F et al. (2012) Effect of five years of imatinib on cure for patients with advanced 
GIST: Updated survival results from the prospective randomized phase III BFR14 trial. J Clin 
Oncol 30; 2012 (suppl; abstr 10095).
Corless C and Heinrich M (2008) Molecular pathobiology of gastrointestinal stromal
sarcomas. Annu Rev Pathol; 3:557-86
Deininger M, O'Brien SG, François Guilhot F, et al. (2009) International Randomized Study 
of Interferon Vs STI571 (IRIS) 8-Year Follow up: Sustained Survival and Low Risk for 
Progression or Events in Patients with Newly Diagnosed Chronic Myeloid Leukemia in 
Chronic Phase (CML-CP) Treated with Imatinib. Poster Abstract 1126: 51st ASH Annual 
Meeting; Dec 5-8, New Orleans, LA.
DeMatteo RP, Lewis JJ, Leung D, et al. (2000) Two hundred gastrointestinal stromal tumors: 
recurrence patterns and prognostic factors for survival. Ann Surg; 231:51–8.
Demetri GD, von Mehren M, Blanke CD, et al. (2006) Efficacy and safety of sunitinib in 
patients with advanced gastrointestinal stromal tumors after failure of imatinib: a randomized 
controlled trial. Lancet; 368:1329-1338.
Demetri G, von Mehren M, Antonescu CR, et al. (2010) NCCN Task Force report: update on 
the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw; 8: 
Suppl 2:S1-41.
Dileo P, Bauer S, Van den Abbeele A, et al. (2006) Results with AMN107, a novel kinase 
inhibitor, in gastrointestinal stromal tumor (GIST):Preclinical rationale and early results in a 
patient (Pt) with imatinib (IM)-resistant GIST. 2006 Gastrointestinal Cancer Symposium. 
Abstr n. 53.
Frazer R, Irvine AE, McMullin MF (2007) Chronic Myeloid Leukaemia in The 21st Century. 
Ulster Med J; 76(1):8-17.
Heisterkamp N, Stephenson JR, Groffen J, et al. (1983) Localization of the c-ab1 oncogene 
adjacent to a translocation break point in chronic myelocytic leukaemia. Nature;
306(5940):239-42.


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Kantarjian H, Shah NP, Hochhaus A, et al. (2010) Dasatinib versus imatinib in newly 
diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med; 362(24):2260-70.
Nowell PC and Hungerford DA (1960) Chromosome studies on normal and leukemic human 
leukocytes. J Natl Cancer Inst; 25:85-109.
Prenen H, Guetens G, de Boeck G, et al. (2006) Cellular uptake of the tyrosine kinase 
inhibitors imatinib and AMN107 in Gastrointestinal stromal tumor cell lines. Pharmacology;
77(1):11-16.
Rowley JD (1973) Letter: A new consistent chromosomal abnormality in chronic 
myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature;
243(5405):290-3.
Saglio G, Kim DW, Issaragrisil S, et al. (2010) Nilotinib versus imatinib for newly diagnosed 
chronic myeloid leukemia. N Engl J Med; 362(24):2251-9.
Usuki K, Tojo A, Maeda Y et al. (2012) Efficacy and safety of nilotinib in Japanese patients 
with imatinib-resistant or –intolerant Ph+ CML or relapsed/refractory Ph+ ALL: 36-month 
analysis of a phase I and II study. Int J Hematol; 95:409-419.
Verweij J et al. (2004) Progression-free survival in Gastrointestinal Stromal tumours with 
High-dose Imatinib: Randomised Trial. Lancet; 364:1127-1134.
Weisberg E, Manley P, Mestan J, et al. (2006) AMN107 (nilotinib): a novel and selective 
inhibitor of BCR-ABL. Br J Cancer; 94(12):1765-9.


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14
Appendices
14.1
Appendix 1: Guidance on concomitant medications with CYP3A 
and QTc prolongation potential interactions.
A list of drugs that are inducers and inhibitors of CYP3A4 is provided below.
Patients should be instructed not to take grapefruit, St. John’s Wort or Seville (sour) orange 
juice while receiving study treatment throughout the study due to potential CYP3A4 induction 
or inhibition.
As the information listed below may not be all inclusive, a list of CYP3A4 inhibitors and 
inducers may be found at http://medicine.iupui.edu/flockhart.
Table 14-1
Medications that can induce CYP3A4
Strong inducers
Moderate inducers
Weak inducers
Unclassified inducers
avasimibe
bosentan
amprenavir
topiramate
carbamazepine
efavirenz
aprepitant
dexamethasone*
etravirine
armodafinil (R-modafinil)
phenobarbital
modafinil
echinacea
phenytoin
nafcillin
garlic
rifabutin
ritonavir
gingko
rifampin
talviraline
glycyrrhizin
rifapentin*
tipranavir
methylprednisolone
St. John's wort
nevirapine
oxcarbazepine
pioglitazone
prednisone
pleconaril
rufinamide
troglitazone
* Discrepancies on the level of induction of these drugs exist in the literature, however, they are 
listed in the “strong inducers” group in order to be consistent with the Tasigna  Labeling
Note:

Inducer classification:

Strong inducers may result in a substrate area under curve (AUC) decreased by ≥ 
80%.

Moderate inducers may result in a substrate AUC decreased by 50-80%.

Weak inducers may result in a substrate AUC decreased by 20-50%.

This list is compiled based on the FDA’s “Guidance for Industry, Drug Interaction 
Studies”, the Indiana University School of Medicine’s Drug Interactions Database, and the 
University of Washington’s Drug Interaction Database. This list may not be 
comprehensive and may be updated periodically. Refer to Novartis Oncology Clinical 


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Pharmacology Internal Memorandum, Drug-drug interactions (DDI) Database (last 
updated 30 August 2010) for update or more details.
Table 14-2
Medications that can inhibit CYP3A4
List of medication metabolized by CYP3A4, strong, moderate and weak inhibitors of CYP3A4 
to be used with caution.
CYP3A4 substrates permitted but 
patients should be carefully 
monitored for drugs indexed 1 and 2
Strong 
inhibitors
Moderate
inhibitors
Weak inhibitors
alfentanil1,2
fentanyl2
clarithromycin
aprepitant
alprazolam
fluticasone1
diergotamine2
conivaptan
atazanavir
AMD070
cyclosporine2
adinazolam
indinavir
cimetidine
amlodipine
maraviroc1
alprazolam
itraconazole
ciprofloxacin
azithromycin
midazolam1
amlodipine
ketoconazole
darunavir
bicalutamide
alpha-
dihydroergocryptine1
aripiprazole
lopinavir
diltiazem
chlorzoxazone
sildenafil1
chlorpheniramine
mibefradil
erythromycin
cilostazol
tipranavir1
diazepam
nefazodone
fluconazole
cyclosporine
triazolam1
estazolam
nelfinavir
grapefruit juice
fluvoxamine
perospirone1
nisoldipine
posaconazole
imatinib
ginkgo
darifenacin1
quinine
ritonavir
tofisopam
goldenseal
ebastine1
trazodone
saquinavir
verapamil
isoniazid
eletriptan1
nitrendipine
telithromycin
lacidipine
eplerenone1
mevastatin
troleandomycin
M100240
everolimus1
lovastatin1
voriconazole
oral
contraceptives
felodipine1
atorvastatin1
peppermint oil
brotizolam1
simvastatin1
propiverine
budesonide1
fluvastatin
ranitidine
buspirone1
ranolazine
sirolimus1,2
roxithromycin
ergotamine2
Seville orange
juice
tabimorelin
1 Sensitive substrates: drugs whose plasma AUC values have been shown to increase 5-fold or 
higher when co-administered with a potent inhibitor of the respective enzyme.
2 Substrates with narrow therapeutic index (NTI): drugs whose exposure-response indicates that 
increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious 
safety concerns (e.g., Torsades de Pointes).


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Note:

Inhibitor classification:

Strong inhibitors may result in a substrate AUC > 5-fold increase.

Moderate inhibitors may result in a substrate AUC ≥ 2-fold increase and < 5-fold 
increase.

Weak inhibitors may result in a substrate AUC ≥ 1.25-fold increase and < 2-fold 
increase.
This list is compiled based on the FDA’s “Guidance for Industry, Drug Interaction Studies”, 
the Indiana University School of Medicine’s Drug Interactions Database, and the University of 
Washington’s Drug Interaction Database. This list may not be comprehensive and may be 
updated periodically. Refer to Novartis Oncology Clinical Pharmacology Internal 
Memorandum, Drug-drug interactions (DDI) Database (last updated 30 August 2010) for 
update or more details.
Guidance on QT prolongation agents
Please see http //azcert org/medical-pros/drug-lists/bycategory.cfm (or similar) for a 
comprehensive list of agents that prolong the QT interval.

SAP_001.pdf: 
Clinical Development
AMN107/Nilotinib/Tasigna®
CAMN107A1201 / NCT01863745
An open label, multi-center nilotinib roll-over protocol for 
patients who have completed a previous Novartis 
sponsored nilotinib study and are judged by the 
investigator to benefit from continued nilotinib treatment
Statistical Analysis Plan (SAP)
Document type:
SAP Documentation
Document status:
Amendment 1
Release date:
20-Oct-2023
Number of pages:
15
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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CAMN107A1201
Document History – Changes compared to previous final version of SAP
Time 
point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
Prior 
to 
DB 
lock
Creation of 
final 
version
N/A - First version
NA
Prior 
to 
DB 
lock
Protocol 
amendment
Modified the follow up period from 5 years to 10 years.
Section 1.1 
Study design
Protocol 
amendment
Removed all changes to protocol specified analyses.
Section 4
Use of 
common 
word
Renamed “pre-study period” to “pre-treatment period” 
and “on-study period” to “on-treatment period”
Section 2.1.1
Mandatory 
for CSR
Added analysis to summarize demographics data
Section 2.3
Analysis for 
final CSR
Removed the number of patients who are on-going and 
add the number of patients who completed study 
treatment
Section 2.3.1
Not 
mandatory 
for analysis 
of AESI
Removed analysis for AESI
Section 2.8.1.1
Mandatory 
for the 
study 
registered 
in CT.gov
Added analysis for death, serious AE and non-serious 
AE.
Section 2.8.1


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CAMN107A1201
Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................6
2
Statistical methods...............................................................................................................6
2.1
Data analysis general information ...........................................................................6
2.1.1
General definitions..................................................................................7
2.2
Analysis sets ............................................................................................................8
2.3
Patient disposition, demographics and other baseline characteristics .....................8
2.3.1
Patient disposition...................................................................................9
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)..............................................................................................................9
2.4.1
Study treatment / compliance..................................................................9
2.4.2
Prior, concomitant and post therapies...................................................10
2.5
Analysis of the primary objective..........................................................................10
2.5.1
Primary endpoint...................................................................................10
2.5.2
Statistical hypothesis, model, and method of analysis..........................11
2.5.3
Handling of missing values/censoring/discontinuations.......................11
2.5.4
Supportive analyses...............................................................................11
2.6
Analysis of the key secondary objective ...............................................................11
2.7
Analysis of secondary efficacy objective(s)..........................................................11
2.8
Safety analyses.......................................................................................................11
2.8.1
Adverse events (AEs)............................................................................11
2.8.2
Deaths....................................................................................................12
2.8.3
Laboratory data .....................................................................................12
2.8.4
Other safety data ...................................................................................12
2.9
Pharmacokinetic endpoints....................................................................................12
2.10
PD and PK/PD analyses.........................................................................................12
2.11
Patient-reported outcomes .....................................................................................12
2.12
Biomarkers.............................................................................................................12
2.13
Other Exploratory analyses....................................................................................12
2.14
Interim analysis......................................................................................................12
3
Sample size calculation .....................................................................................................12
4
Change to protocol specified analyses ..............................................................................12
5
Appendix ...........................................................................................................................13


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CAMN107A1201
5.1
Imputation rules.....................................................................................................13
5.1.1
Study drug.............................................................................................13
5.1.2
AE date imputation ...............................................................................13
5.1.3
Concomitant medication date imputation .............................................15
5.2
AEs coding/grading ...............................................................................................15
5.3
Laboratory parameters derivations ........................................................................15
5.4
Statistical models...................................................................................................15
6
Reference...........................................................................................................................15


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CAMN107A1201
List of abbreviations
AE
Adverse event
AESI
Adverse Event of Special Interest
CSR
Clinical Study report
CTCAE
Common Terminology Criteria for Adverse Events
DI
Dose Intensity
EOT
End of Treatment
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NMQ
Novartis MedDRA Queries
PDI
Planned dose intensity
PK
Pharmacokinetics
PPS
Per-Protocol Set
PT
Preferred Term
RDI
Relative Dose Intensity
SAP
Statistical Analysis Plan
SMQ
Standardized MedDRA Queries
SOC
System Organ Class


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report 
(CSR) of study CAMN107A1201, an open label, multi-center nilotinib roll-over protocol for 
Japanese patients who have completed a previous Novartis sponsored nilotinib study and are 
judged by the investigator to benefit from continued nilotinib treatment. 
The content of this SAP is based on protocol CAMN107A1201 Amendment version 3. All 
decisions regarding final analysis, as defined in the SAP document, have been made prior to 
database lock of the study data.
1.1
Study design
This is an open label, multi-center, phase II study to collect and assess long term safety of 
nilotinib in Japanese patients being treated in current Novartis-sponsored, clinical studies and 
who are benefiting from treatment with nilotinib.
Frequency and nature of Adverse Events (AEs) are the primary endpoints in this study.
The final analysis will be performed when all patients discontinued the trial or 10-year follow-
up was completed, whichever comes earlier.
1.2
Study objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below.
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Primary
To collect and assess long-term safety of nilotinib to patients 
receiving nilotinib in a Novartis-sponsored clinical study which 
has reached its objectives and who are benefiting from 
treatment with nilotinib.
Frequency and nature of AEs
2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by Novartis and/or a designated CRO. SAS version 9.4 or 
later software will be used to perform all data analyses and to generate tables, figures and 
listings.
General analysis conventions
Pooling of center: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small size of centers, no center effect will be assessed.
Qualitative data will be summarized by means of contingency tables by treatment group; a 
missing category will be included as applicable. Percentages will be calculated using the 
number of patients in the relevant population or subgroup as the denominator.
Quantitative data will be summarized by appropriate descriptive statistics (i.e. mean, 
standard deviation, median, minimum, and maximum) by treatment group.


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2.1.1
General definitions
Study treatment
Study treatment will refer to Nilotinib in this study.
Date of first administration of study treatment in this study
The date of first administration of study treatment is derived as the first date in this rollover 
study when a nonzero dose of study treatment was administered as per the Dosage 
Administration CRF. The date of first administration of study treatment will also be referred as 
start of study treatment.
Date of last administration of study treatment in this study
The date of last administration of study treatment is defined as the last date in this rollover study 
when a nonzero dose of study treatment was administered as per Dose Administration eCRF. 
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 is the start of treatment in this particular study. 
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.
Baseline
For safety and efficacy evaluations, the last available assessment on or before the date of start 
of study treatment in this particular study is defined as “baseline” assessment.
If patients have no value as defined above, the baseline result will be considered as missing.
On-treatment assessment/event and observation periods
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: before first administration of study treatment in this rollover study
2. on-treatment period: from date of first administration of study treatment in this study
to 30 days after date of last actual administration of any study treatment (including start 
and stop date)
3. post-treatment period: starting at day 30+1 after last administration of study treatment.


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Summary tables for adverse event (AEs) will summarize on-treatment period events as 
described in the point (2) above. However, all safety data (including those from the pre-
treatment and post-treatment period) will be listed and those collected during the pre-treatment
and post-treatment period are to be flagged.
2.2
Analysis sets
Full Analysis Set
No Full Analysis Set (FAS) is defined for this trial.
Per protocol set (PPS) 
No Per-Protocol Set (PPS) is defined for this trial.
Safety Set
The Safety Set includes all patients who received at least one dose of Nilotinib in this study. 
All the analyses will be conducted by Safety Set.
Patient Classification: 
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in Table 
2-2. 
Table 2-1
Subject classification based on protocol deviations and non-protocol 
deviation criteria
Analysis set
Protocol deviations leading 
to exclusion
Non 
protocol 
deviation 
leading to exclusion
Safety set
No written inform consent
No dose of study medication
in this study
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis data sets.  The date on which 
a patient withdraws full consent is recorded in the eCRF.
2.3
Patient disposition, demographics and other baseline 
characteristics
Patient demographics and baseline characteristics at entry in this rollover study, such as age 
will be listed by patient.
Basic demographic and background data
All demographic data will be summarized and listed.


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2.3.1
Patient disposition
The number (%) of patients who are enrolled in this study, who are still on treatment, who 
discontinued the study phases and the reason for discontinuation will be presented. This analysis 
will be presented for enrolled patients.
The following summaries will be provided: % based on the total number of patients in safety 
set:

Number (%) of patients who completed treatment (“Treatment duration completed 
as per protocol" was selected in the ‘End of Treatment’ page) 

Number (%) of patients who discontinued the study treatment phase (any reason 
aside from “Treatment duration completed as per protocol” was selected in the 
‘End of Treatment’ page) 

Primary reason of study treatment phase discontinuation for patients who 
discontinued the study treatment (based on the ‘End of Treatment’ page)
All primary reason for end of treatment will be listed.
Protocol deviations
Since the number of patients will be limited, so all protocol deviations will be provided as 
listings, but no summery will be provided. 
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
The duration of exposure to Nilotinib in the current study will be calculated for each patient, 
and will be summarized. 
The dose intensity defined as the ratio of the cumulative dose to the duration of exposure may 
be calculated and summarized.
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 in this particular study:
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) –
(date of first administration of study treatment in this study) + 1. 
The last date of exposure to study treatment is the latest of the last dates of exposure to study 
treatment. The duration of exposure to study treatment will not be summarized. It will be used 
for dose intensity.


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Cumulative dose
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized. The actual cumulative dose refers to the total actual 
dose administered, over the duration for which the patient 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.
The planned cumulative dose for a study treatment component is the total planned dose as per 
the protocol up to the last date of study treatment administration. The planned cumulative dose 
will not be summarized. It will be used for relative dose intensity calculations. 
For the study treatment which is administered daily the planned cumulative dose is the planned 
starting dose summed over the duration of exposure.
Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows: 
DI (mg / days) = Actual Cumulative dose (mg) / Duration of exposure to study treatment (days).
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 / days) = Planned Cumulative dose (mg) / Duration of exposure (days).
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg / days) / PDI (mg / days).  
DI and RDI will be summarized.
Dose change
The change and the reason will be listed. 
‘Dose change’ fields from the Dosage Administration CRF pages (DAR) will be used to 
determine the dose change.
2.4.2
Prior, concomitant and post therapies
Not applicable.
2.5
Analysis of the primary objective
Primary objective of this trial is to collect and assess the long-term safety of Nilotinib in patients 
receiving nilotinib in  Novartis-sponsored clinical studies which has reached its objectives and 
who are benefiting from treatment with Nilotinib.
2.5.1
Primary endpoint
The primary endpoint of the study is frequency and nature of AEs.


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2.5.2
Statistical hypothesis, model, and method of analysis
No null hypothesis test and statistical modeling are planned. Method of analysis is referred to 
Section 2.8.1.
2.5.3
Handling of missing values/censoring/discontinuations
Not applicable.
2.5.4
Supportive analyses
Not applicable.
2.6
Analysis of the key secondary objective
Not applicable.
2.7
Analysis of secondary efficacy objective(s)
Not applicable.
2.8
Safety analyses
An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s), or medical condition(s) that occur after patient’s signed informed consent has been 
obtained.
All AE data (including those from pre-study and post-treatment period) will be listed by patient 
and those collected during the pre-treatment and post-treatment are to be flagged. The incidence 
of AE will be summarized by system organ class and or preferred term, severity (based on 
CTCAE grades), type of AE, relation to study drug. CTCAE Grade 5 (death) was not used in 
this study; rather, information about deaths will be collected at the End of Treatment.
Note that AEs from pre-treatment will not be analyzed.
Deaths reportable as SAEs and non-fatal serious AEs will be listed by patient.
2.8.1
Adverse events (AEs)
AE summaries will include all AEs occurring during on-treatment period. All AEs collected in 
the AE eCRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs with start date outside of on-treatment period 
will be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending order of AE frequencies.


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The following adverse event summaries will be produced; AEs by SOC and PT, severity, 
relationship, leading to treatment discontinuation, serious AEs and non-serious AEs.
2.8.2
Deaths
On treatment deaths will be summarized. All deaths will be listed.
2.8.3
Laboratory data
Not applicable.
2.8.4
Other safety data
Not applicable.
2.9
Pharmacokinetic endpoints
Not applicable.
2.10
PD and PK/PD analyses
Not applicable.
2.11
Patient-reported outcomes
Not applicable.
2.12
Biomarkers
Not applicable.
2.13
Other Exploratory analyses
Not applicable.
2.14
Interim analysis
Not interim analysis is planned.
3
Sample size calculation
No formal sample size calculation is required for this trial since only Japanese patients who are 
still on treatment in Novartis-sponsored clinical studies will be enrolled in this trial. 
4
Change to protocol specified analyses
Table 4-1 summarizes the changes to protocol-specified analyses and associated rationale for 
inclusion in Appendix 16.1.9 (Documentation of Statistical Methods) of the CSR.


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Table 4-1
Changes to protocol specified analysis or descriptions and rationale
Protocol section
Protocol description
Change
Rationale
10.2 Patient 
demographics/other 
baseline characteristics
Patient demographics 
and baseline 
characteristics such as 
age will be listed by 
patient
Patient demographics 
and baseline 
characteristics such as 
age will be summarized 
and listed by patient
Summary table for 
demographics is 
necessary for CSR.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:
If the dose end date is completely or partially missing and the EOT page is available: 
Case 1: The dose end date is completely missing, and the EOT completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date: 
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the 
year of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.
5.1.2
AE date imputation
The following missing dates will not be imputed

Partial/missing AE end dates
For other type of missing dates, rules specified in Tables 5-1 to 5-3 will be used
Table 5-1
AE/Treatment Date Abbreviations 
Day
Month
Year
Partial Adverse Event Start Date
<not used>
AEM
AEY


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Day
Month
Year
Treatment Start Date (TRTSTD)
<not used>
TRTM
TRTY
Table 5-2 describes the possible combinations and their associated imputations. The upper 
text indicates the imputation (A, B, C etc.) and the lower text the relationship of the AE start 
date to the treatment start date (TRTSTD).
Table 5-2
Imputation algorithm
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY MISSING
( B )
Uncertain
( B )
Uncertain
( B )
Uncertain
( B )
Uncertain
AEY < TRTY
( D )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
AEY = TRTY
( B )
Uncertain
( C )
Before TRTSTD
( B )
Uncertain
( A )
After TRTSTD
AEY > TRTY
( E )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
The legend to the above table is shown in Table 5-3.
Table 5-3
Imputation algorithm legends
Relationship
Before TRTSTD
Indicates AE start date prior to Treatment Start Date
After TRTSTD
Indicates AE start date after Treatment Start Date
Uncertain
Insufficient to determine the relationship of AE start date 
to Treatment Start Date
Imputation calculation
( A )
01MONYYYY
( B )
TRTSTD+1
( C )
15MONYYYY
( D )
01JULYYYY
( E )
01JANYYYY
Few examples are shown in Table 5-4.
Table 5-4
Example scenarios
Partial
AE start date
Treatment
start date
Relationship 
with TRTSTD
Imputation 
Calculation
Imputed Date
ddmmmyyyy
20OCT2001
Uncertain
( B )
21OCT2001
ddmmm2000
20OCT2001
Before
( D )
01JUL2000
ddmmm2002
20OCT2001
After
( E )
01JAN2002
ddmmm2001
20OCT2001
Uncertain
( B )
21OCT2001
ddSEP2001
20OCT2001
Before
( C )
15SEP2001
ddOCT2001
20OCT2001
Uncertain
( B )
21OCT2001
ddNOV2001
20OCT2001
After
( A )
01NOV2001


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5.1.3
Concomitant medication date imputation
Not applicable.
5.2
AEs coding/grading
Adverse events were coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
AEs were assessed by the investigator according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). The CTCAE grade of 5 (death) 
is not used; rather, ‘fatal’ is collected as AE outcome and death information is also collected on 
a separate eCRF page. 
5.3
Laboratory parameters derivations
Not applicable.
5.4
Statistical models
No null hypothesis test and statistical modeling were planned.
6
Reference
No reference.