Conditions: Chronic Myelogenous Leukemia (CML) Metastatic Gastrointestinal Stromal Tumors (GIST) Acute Lymphoblastic Leukemia (ALL) Receptor Tyrosine Kinase (KIT) Mutated Melanoma
Keywords: metastatic gastrointestinal stromal tumors (GIST) Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP), adult Chronic myelogenous leukemia (CML) chronic myeloid leukemia (CML) chronic myelocytic leukemia (CML) Acute Lymphoblastic Leukemia (ALL) Philadelphia chromosome positive Acute Lymphoid Leukemia suboptimal molecular response Tasigna CML GIST nilotinib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 57
Healthy volunteers: no

Brief summary:
The purpose of this study was to allow continued use of nilotinib in patients who were on nilotinib treatment in a Novartis-sponsored, Oncology Clinical Development \& Medical Affairs (CD\&MA) study and were benefiting from the treatment as judged by the investigator

Detailed description:
This was a multi-center, open label, single-arm, phase IV study to better characterize the long-term safety of nilotinib in patients treated in Novartis-sponsored studies and who benefited from treatment with nilotinib.

Patients who were enrolled in Novartis-sponsored nilotinib studies, had benefitted from treatment with nilotinib and fulfilled all requirements in the parent study could be enrolled into the current roll-over study.

There was no sample size estimation carried out for this study.

Patients returned to the study center on a quarterly basis (12 weeks ± 1 week) for scheduled visit. Adverse Events (AEs) (non-serious and serious AEs), clinical benefit assessment by investigator and study medication dispensing information were collected.

The original protocol of the current roll-over study was designed to provide continuation of treatment with nilotinib for patients enrolled in nilotinib studies. Therefore, the original protocol did not require AEs (non-serious and serious AEs) to be collected into the clinical database and only required serious adverse events (SAEs) to be collected in the Novartis safety database throughout the study duration.

The scheduled visit frequency was annually.

However, feedback from health authorities stated that all AEs should be collected. To account for this, the protocol was amended in 2016 (Protocol amendment 3 (PA 3)), with the primary objective changed to assess long-term safety of nilotinib. Consequently, PA 3 started to require all AEs (non-serious and serious AEs) to be entered into the clinical database, in addition to the continued SAE collection into the Novartis safety database. At the same time, the scheduled visit frequency was increased from annually to quarterly, and the protocol was also amended to require an investigator assessment of clinical benefit for patients.

Arms:
arm 1: Patients who were on nilotinib treatment in a Novartis-sponsored study (parent study) and were benefiting from nilotinib treatment met the criteria for enrolment into the CAMN107A2409 study and to receive continued nilotinib treatment. The starting dose of nilotinib in the CAMN107A2409 study should have been the same as the last dose administered in the parent study. After the starting dose, the dose of nilotinib was based on the investigator's judgement. The dose of nilotinib should have been ≤ 800 mg/day for adult patients, 230mg/m2 body surface area (BSA) and ≤ 800 mg/day for pediatric patients.

Interventions: intervention 1: Nilotinib
Intervention descriptions: intervention 1: Patients who were on nilotinib treatment in a Novartis-sponsored study (parent study) and were benefiting from nilotinib treatment met the criteria for enrolment into the CAMN107A2409 study and to receive continued nilotinib treatment. The starting dose of nilotinib in the CAMN107A2409 study should have been the same as the last dose administered in the parent study. After the starting dose, the dose of nilotinib was based on the investigator's judgement. The dose of nilotinib should have been ≤ 800 mg/day for adult patients, 230mg/m2 body surface area (BSA) and ≤ 800 mg/day for pediatric patients.

Protocol document:
Prot_000.pdf: 
Clinical Development
AMN107 (NILOTINIB) 
TASIGNA
Oncology Clinical Protocol CAMN107A2409 / NCT01735955
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
Authors
Document type
Amended Protocol Version
EUDRACT number
2012-003902-28
Version number
05 (Clean)
Development phase
IV
Document status
Final
Release date
30-Aug-2018
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 19-Nov-2015


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Amendment 05 (30-Aug-2018).........................................................................................10
Amendment 04 (27-Jul-2016) ...........................................................................................12
Summary of previous amendments ...................................................................................13
Protocol Summary.............................................................................................................20
1
Background........................................................................................................................22
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............22
1.1.1
Overview of chronic myeloid leukemia (CML)....................................22
1.1.2
Overview of gastrointestinal stromal tumors (GIST)............................22
1.2
Introduction to investigational treatment(s) and other study treatment(s).............23
1.2.1
Overview of nilotinib............................................................................23
2
Rationale............................................................................................................................27
2.1
Study rationale and purpose...................................................................................27
2.2
Rationale for the study design ...............................................................................27
2.3
Rationale for dose and regimen selection..............................................................27
2.4
Rationale for choice of combination drugs............................................................27
2.5
Rationale for choice of comparators drugs............................................................27
2.6
Risks and benefits..................................................................................................27
3
Objectives and endpoints...................................................................................................28
4
Study design ......................................................................................................................30
4.1
Description of study design ...................................................................................30
4.2
Timing of interim analyses and design adaptations...............................................31
4.3
Definition of end of study......................................................................................31
4.4
Early study termination..........................................................................................31
5
Population..........................................................................................................................31
5.1
Patient population..................................................................................................31
5.2
Inclusion criteria ....................................................................................................31
5.3
Exclusion criteria...................................................................................................32
6
Treatment...........................................................................................................................33
6.1
Study treatment......................................................................................................33
6.1.1
Dosing regimen.....................................................................................33


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6.1.2
Ancillary treatments..............................................................................34
6.1.3
Rescue medication ................................................................................34
6.1.4
Guidelines for continuation of treatment ..............................................34
6.1.5
Treatment duration................................................................................34
6.2
Dose escalation guidelines.....................................................................................34
6.2.1
Starting dose rationale...........................................................................34
6.3
Dose modifications................................................................................................34
6.3.1
Dose modification and dose delay ........................................................34
6.3.2
Dose reduction guidelines for study drug-related toxicity for 
pediatric patients ...................................................................................40
6.3.3
Management of cholesterol increases ...................................................47
6.3.4
Management of glucose increases.........................................................47
6.3.5
Management of other cardiac risk factors.............................................47
6.3.6
Management of ischemic vascular or cardiovascular events ................47
6.3.7
Hepatitis B reactivation.........................................................................48
6.3.8
Follow up on potential drug-induced liver injury (DILI) cases ............48
6.4
Concomitant medications ......................................................................................49
6.4.1
Prohibited concomitant therapy ............................................................49
6.4.2
Use of Bisphosphonates (or other concomitant agents)........................50
6.5
Patient numbering, treatment assignment or randomization .................................50
6.5.1
Patient numbering .................................................................................50
6.5.2
Treatment assignment or randomization...............................................51
6.5.3
Treatment blinding................................................................................51
6.6
Study drug preparation and dispensation...............................................................51
6.6.1
Study treatment packaging and labeling ...............................................51
6.6.2
Drug supply and storage........................................................................52
6.6.3
Study drug compliance and accountability ...........................................52
6.6.4
Disposal and destruction .......................................................................52
7
Visit schedule and assessments .........................................................................................53
7.1
Study flow and visit schedule................................................................................53
7.1.1
Molecular pre-screening........................................................................55
7.1.2
Screening...............................................................................................55
7.1.3
Treatment period...................................................................................55
7.1.4
Pregnancy and assessment of fertility...................................................55
7.1.5
Discontinuation of study treatment .......................................................56
7.1.6
Withdrawal of consent ..........................................................................57


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7.1.7
Follow up for safety evaluations...........................................................58
7.1.8
Lost to follow-up...................................................................................58
7.2
Assessment types...................................................................................................58
7.2.1
Efficacy assessments.............................................................................58
7.2.2
Safety and tolerability assessments.......................................................59
7.2.3
Pharmacokinetics ..................................................................................59
7.2.4
Resource utilization...............................................................................59
7.2.5
Patient reported outcomes.....................................................................59
8
Safety monitoring and reporting........................................................................................59
8.1
Adverse events.......................................................................................................59
8.1.1
Definitions and reporting ......................................................................59
8.1.2
Laboratory test abnormalities................................................................61
8.1.3
Adverse events of special interest.........................................................61
8.2
Serious adverse events...........................................................................................62
8.2.1
Definitions.............................................................................................62
8.2.2
Reporting...............................................................................................62
8.3
Emergency unblinding of treatment assignment ...................................................63
8.4
Pregnancies............................................................................................................63
8.5
Warnings and precautions......................................................................................64
8.6
Data Monitoring Committee..................................................................................64
8.7
Steering Committee ...............................................................................................64
9
Data collection and management.......................................................................................64
9.1
Data confidentiality ...............................................................................................64
9.2
Site monitoring ......................................................................................................64
9.3
Data collection.......................................................................................................65
9.4
Database management and quality control............................................................65
10 Statistical methods and data analysis ................................................................................66
10.1
Analysis sets ..........................................................................................................66
10.1.1
Full Analysis Set ...................................................................................66
10.1.2
Safety Set ..............................................................................................66
10.1.3
Dose-determining analysis set...............................................................66
10.2
Patient demographics/other baseline characteristics .............................................66
10.3
Treatments (study treatment, compliance) ............................................................66
10.4
Primary objective...................................................................................................66
10.4.1
Variable.................................................................................................66
10.4.2
Statistical hypothesis, model, and method of analysis..........................66


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10.4.3
Handling of missing values/censoring/discontinuations.......................66
10.4.4
Supportive analyses...............................................................................66
10.5
Secondary objectives .............................................................................................67
10.5.1
Key secondary objective(s)...................................................................67
10.5.2
Other secondary efficacy objectives .....................................................67
10.5.3
Safety objectives ...................................................................................68
10.6
Interim analysis......................................................................................................68
10.7
Sample size calculation..........................................................................................68
10.8
Power for analysis of key secondary variables......................................................68
11 Ethical considerations and administrative procedures ......................................................69
11.1
Regulatory and ethical compliance........................................................................69
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................69
11.3
Informed consent procedures.................................................................................69
11.4
Discontinuation of the study..................................................................................69
11.5
Publication of study protocol and results...............................................................70
11.6
Study documentation, record keeping and retention of documents.......................70
11.7
Confidentiality of study documents and patient records .......................................71
11.8
Audits and inspections...........................................................................................71
11.9
Financial disclosures..............................................................................................71
12 Protocol adherence ............................................................................................................71
12.1
Amendments to the protocol..................................................................................71
13 References (available upon request)..................................................................................72
14 Appendices ........................................................................................................................74
14.1
Appendix I: Guidance on concomitant medications with CYP3A and QTc 
prolongation potential interactions ........................................................................74


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List of figures
Figure 4-1
Study design..........................................................................................30
List of tables
Table 3-1
Objectives and related endpoints ..........................................................29
Table 6-1
Dose and treatment schedule.................................................................33
Table 6-2
Summary of nilotinib dose reduction guidelines for study drug-
related non-hematologic toxicity and for ischemic vascular and 
cardiovascular events regardless of study drug relationship (adult 
patients).................................................................................................36
Table 6-3
Summary of dose reduction guidelines for study drug-related 
hematological toxicity...........................................................................40
Table 6-4
Recommended criteria for interruption and re-initiation of nilotinib 
for drug-related toxicities and for ischemic vascular and 
cardiovascular events regardless of study drug relationship.................41
Table 6-5
Preparation and dispensing ...................................................................51
Table 6-6
Packaging and labeling .........................................................................52
Table 6-7
Supply and storage of study treatments ................................................52
Table 7-1
Visit evaluation schedule ......................................................................54
Table 14-1
Medications that can induce CYP3A4..................................................74
Table 14-2
Medications that can inhibit CYP3A4 ..................................................75
Table 14-3 
CYP3A4 substrates: Narrow therapeutic index, sensitive, and 
others.....................................................................................................76


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List of abbreviations
AE
Adverse event
AMN107
Nilotinib /Tasigna
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
BC
Blast crisis (of CML)
BCRP
Breast cancer resistance protein
BID
bis in diem, twice daily
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
CMR
Complete molecular response
CP
Chronic phase (of CML)
CRF
Case report/record form
CRO
Contract research organization
CSR
Clinical Study Report
CYP3A4
Cytochrome 3A4
DDI
Drug –drug interactions
EC
European Commission
ECG
Electrocardiogram
eCRF
Electronic Case report/record form
EDC
Electronic data capture
EMA
European Medicines Agency
EoT
End of treatment
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
GIST
Gastrointestinal stromal tumors
h
Hour
H2
Histamine receptor 
HBc Ab
Hepatitis B Core Antibody
HBs Ag
Hepatitis B Surface Antigen
HGC
hard gelatin capsules
HMG-CoA
Hydroxy-Methyl-Glutaryl-Coenzyme A
IB
Investigator brochure
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
IUD
Intrauterine device
IUS
Intrauterine system


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MCyR
Major cytogenetic response
MRP2
Multi-resistance protein 2
o.d.
Omnia die/once a day
OC
Oral contraceptive
OCRDC
Oracle Clinical Remote Data Capture
OGD&GMA
Oncology Global Development & Global Medical Affairs
OS
Overall survival
p.o.
Per os/by mouth/orally
PAOD
Peripheral Artery Occlusive Disease 
PDGRD- α
Platelet-derived growth factor receptors α
PFS
Progression-free survival
P-gp
P-glycoprotein
Ph
Philadelphia (chromosome)
PHI
Protected Health Information
PK
Pharmacokinetics
q.d.
quaque die/ once daily
QT
Q to T interval (ECG)
SAE
Serious adverse event
SCT
Stem cell transplantation
SmPC
Summary of Product Characteristics
SOC
system organ class
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)
US PI
United States Prescribing Information


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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.
Medication number
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study.
Other study treatment
Any drug administered to the patient as part of the required study 
procedures that 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.
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
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.
Withdrawal of consent
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data.


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Amendment 05 (30-Aug-2018)
Amendment rationale
The primary purpose of the amendment is to provide further clarity to the end of study definition 
and trial timelines:

End of study is defined as the date when all patients have completed their last assessment 
per protocol thirty days after end of treatment visit 

Patients may continue on study treatment until need for a premature discontinuation 
criteria happened, 10 years after First Patient First Visit into this clinical trial or when 
study treatment becomes commercially available and reimbursed in the respective 
indication whichever comes first.
The First Patient First Visit occurred on 29-Mar-2013. 45 total patients’ have been enrolled and 
17 patients are ongoing.
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:

Updated author list of protocol to reflect the team currently working on/managing the 
protocol.

Glossary of terms updated with personal data term and revised definition of withdrawal of 
consent.
Protocol Summary Section updated to match the body of the protocol.
Section 2.6, Risks and benefits: number of countries in which nilotinib is approved was updated.
Clarification that latest Investigator Brochure should be consulted was updated. Has been 
updated to clarify that the 10 years study duration is meant based on First Patient First Visit in 
the study and clarify study duration.
Section 4.1, Description of Study Design.was updated to clarify that trial is planned to be open 
for treatment for 10 years from First Patient First Visit on 29Mar2013 and clarify study duration.
Section 4.3, Definition of End of Study was updated to clarify the end of study definition. The 
end of study is defined as the date when all patients have completed their last assessment per 
protocol thirty days after end of treatment visit. Patients will continue study treatment until a 
discontinuation criteria is met, study treatment becomes commercially available for that 
indication, or 10 years after First Patient First Visit in this trial which occurred on 29-Mar-2013, 
whichever comes first.
Section 4.4, Early study termination: section has been updated per latest Novartis standard.  
Definition of end of study is defined in Section 4.3.
Section 6.1.5 has been updated to clarify that the 10 years study duration is meant based on 
First Patient First Visit in the study.


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Section 6.3.1.1, Dose reduction guidelines for study drug-related non hematological toxicity: 
editorial update with reference to Table –2.
Table 6-2: updated to clarify that dose modification applies to 600 or 800mg total daily dose. 
Guidance for combined elevation of AST or ALT and total bilirubin was added per latest 
Novartis guidance.
Section 6-3-1-2: dose reduction guidelines for study drug-related hematological toxicity have 
been added to harmonize guidance across Novartis-sponsored Tasigna trials.
Table 6-3 summary of dose reduction guidelines for study drug-related hematological toxicity 
was added to harmonize guidance across Novartis-sponsored Tasigna trials.
Section 6.3.2 Dose reduction guidelines for study drug-related toxicity for pediatric patients: 
editorial update with reference to table 6-4.
Table 6-3: Hepato-biliary/Pancreas recommendation updated as guidance as to pancreas 
abnormality are handled in a separate section of Table 6-4.
Section 6.4.1, Prohibited concomitant therapy: additionnal guidance have been added as to 
CYP3A4 substrates and Drug with risk of Torsades de Pointe to hamonize with Novartis 
sponsored Tasigna trials. Cardiac monitoring updated: Documentation will be kept in source 
document.
Section 6.6, Study drug preparation and dispensation: editorial update, Table 6-5 reference was 
updated.
Section 6.6.1, Study treatment packaging and labelling: editorial update, Table 6-6 and table 6-
7 reference were updated.
Section 7.1.3 has been updated to clarify that the 10 year study duration is based on First Patient 
First Visit in the study and to clarify study duration.
Section 7.1.5 has been updated to clarify that the 10 years study duration is meant based on 
First Patient First Visit in the study and to clarify study duration.
Section 7.1.5.1, Criteria for premature patient withdrawal has been updated to clarify that 
adverse event and disease progression based on physician assessment are captured as reason for 
premature patient withdrawal.
Section 7.1.6, Withdrawal of consent has been updated to align with revised standard Novartis 
template language.
Table 14-1, 14-2 and 14-3: the lists of CY3A4 inducers, inhibitors and substrates have been 
updated according to the Novartis Oncology Clinical Pharmacology Internal Memorandum, 
Drug-drug interactions (DDI) Database (last updated 2018). Reference to website where list of 
drug prolonging QT interval was updated.
Editorial modifications to correct typographical errors have been implemented as needed.


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Amendment 04 (27-Jul-2016)
Amendment rationale
The main purpose of 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.
This roll-over study has been opened since 29-Mar-2013 with 45 total patients enrolled and 27 
patients ongoing.
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:
Section 6.3: Updated to clarify that investigators should refer to the approved local label for 
additional details regarding dose modifications and recommendations. If no approved local 
label is available, the SmPC or USPI for Tasigna should be used.
Section 8.4: Section has been updated. Pregnancy outcomes from female partners of any males 
who took study treatment will not be collected in this study.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


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Summary of previous amendments
Amendment 03 (07-Apr-2016)
Amendment rationale
The main purpose of the amendment is:

To change the primary endpoint to safety in order to better characterize the long-term 
safety of nilotinib

To include hepatitis B virus testing as one of the study procedures, to identify study 
patients who may be at risk of hepatitis B reactivation. Reactivation of hepatitis B virus 
can occur in patients who are chronic carriers of this virus and are receiving a drug of the 
BCR-ABL TKI class such as nilotinib. Some cases involving BCR-ABL TKI resulted in 
acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal 
outcome.

To include the collection of all AEs (including non-serious AEs) and an investigator 
attestation of continued clinical benefit.
This roll-over study has been opened since 29-Mar-2013 with 45 total patients enrolled and 28
patients ongoing.
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:
Section 2.1: The purpose of the study has been updated to better characterize the long-term 
safety of nilotinib in patients who are on nilotinib treatment in a Novartis-sponsored study and 
are benefitting from the treatment as judged by the investigator.
Section 2.2: The rationale for the study design has been updated to better characterize the long-
term safety of nilotinib in patients being treated in a current Novartis-sponsored study and who 
are benefitting from treatment with nilotinib.
Section 2.6: Risks and Benefits section added per the new protocol template.
Table 3-1: Updated with revised study objectives. The primary objective is to evaluate long 
term safety data. The secondary objective is to evaluate clinical benefit as assessed by the 
investigator.
Section 4.1: Updated to clarify that study is to better characterize the long-term safety and that 
all adverse events and serious adverse events will be collected continuously throughout the 
study. Additionally at every quarterly visit, the investigator is required to confirm that the 
patient continues to have clinical benefit and may continue receiving study treatment.
Section 5.3 Exclusion criteria #5 updated to clarify highly effective contraception methods and 
to exclude sexually active males unless they use a condom during intercourse while taking study 
drug and for 30 days after stopping treatment.


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Section 6.1.5: Updated to specify that at every quarterly visit, the investigator is required to 
confirm that the patient continues to have clinical benefit and may continue receiving study 
treatment
Section 6.2 and 6.2.1 added per the new protocol template.
Section 6.3 added to include dose modifications for both adult and pediatric patients. 
Subsequent section numbers have been updated as a result.
Section 6.3.6 Hepatitis B reactivation was added to provide information on next steps for 
patients testing positive for hepatitis B virus.
Section 6.3.7 was added to provide follow-up information for drug-induced liver injury.
Section 6.4 added per the new protocol template. Subsequent section numbers were updated as 
a result.
Section 6.4.2 (Use of bisphosphonates) added per new protocol template; however, the section 
has been marked as “Not applicable” for this study.
Section 7.1: Updated to include Hepatitis B testing at the next possible visit.
Table 7-1: Updated to include investigator attestation of clinical benefit at every quarterly visit 
(12 weeks +/- 1 week), collection of relevant medical history, hepatitis B testing, all adverse 
events, and study evaluation completion page.
Section 7.1.2.3: Updated to include collection of relevant medical history.
Section 7.1.3: Updated to specify that the investigator is required to confirm that the patient 
continues to have clinical benefit at every quarterly visit and may continue receiving study 
treatment.
Section 7.1.4: Highly effective contraception definitions have been updated.
Previous section 7.1.4 updated to Section 7.1.5 (Discontinuation of study treatment).
Section 7.1.5 Updated to include the Study Evaluation Completion eCRF page to be completed 
for all patients at the end of the 30 day safety follow up.
Section 7.1.6 (Withdrawal of consent) and 7.1.8 (Lost to follow up) added per the new protocol 
template.
Section 7.1.7: Updated to include adverse events in safety follow up period.
Section 7.2.1: Updated to include investigator attestation of clinical benefit at every quarterly 
visit.
Section 7.2.2: Updated to clarify that safety will be monitored by collecting of the adverse 
events at every visit. For details on AE collection and reporting, refer to Section 8.
Section 7.2.2.1 was added to provide information on hepatitis B testing.
Section 7.2.3 (Pharmacokinetics) and 7.2.3.1 (Analytical methods) added per the new template 
but both sections are “not applicable” for this study.
Section 8: Updated with new AE/SAE reporting process.


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Section 10: Updated statistical analysis section based on revised study objectives.
The protocol summary and list of abbreviations has also been updated based on the changes 
specified above.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


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Amendment 02
Amendment rationale
As of the release date of this amendment 41 patients have enrolled into the study.
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:
Section 1.2.1.2.1: 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 (Sections 6.2.1- 6.2.5).
Sections 6.2.1 to 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 8.1.1: Updated to clarify that medical monitoring as clinically indicated at the 
physician’s discretion should include cardiovascular risk factors such as serum cholesterol and 
glucose levels amongst others. Update also includes the education of patient’s on the reporting 
of clinical conditions of special interest.
Section 8.1.3: Updated to include 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.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes 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
As of the release date of this amendment, 6 patients have been enrolled into the study and started 
on treatment.
This amendment is a global amendment and 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 be 
required, it is recommended that therapy with nilotinib be interrupted if possible.

To add language clarifying the strengths of nilotinib allowed in the study to ensure 
patients can have access to the same strengths as specified in the parent protocol.

To clarify that patients who are pregnant, withdrawn consent or have died must be 
withdrawn from the study.

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 summary as well as within the 
protocol sections below:
Section 2.3: Updated to clarify additional strengths of nilotinib can be provided if specified in 
the parent protocol.
Section 6.1.1: Updated to clarify additional strengths of nilotinib can be provided if specified 
in the parent protocol.
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 be 
required, it is recommended that therapy with nilotinib be interrupted if possible.
Table 6-2: Additional strengths of nilotinib can be provided if specified in the parent protocol.
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 7.1.4.1: Updated to clarify that patients who are pregnant, withdraw consent or have 
died must be withdrawn from the study.


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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes 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.
Data analysis
The assessment of safety will be based mainly on the
frequency of AEs and SAEs. Proportion of patients 
with clinical benefit as assessed by the investigator 
will be summarized at scheduled visits. As needed, 
safety information on patients from this protocol will 
link to the patient identifiers from the parent protocol.
Efficacy assessments
At every quarterly visit, the investigator is required to 
confirm that the patient continues to have clinical 
benefit and may continue receiving study treatment
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, 
Oncology Global Development & Global Medical 
Affairs (OGD&GMA) 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
Tasigna roll-over study for continued use of nilotinib to 
patients receiving nilotinib in a Novartis-sponsored 
Oncology OGD&GMA study which has reached its 
objectives and who are benefiting from treatment with 
nilotinib.
Other assessments
Not applicable.
Population
Male and female patients, who are currently enrolled 
in a Novartis-sponsored, Oncology OGD&GMA 
nilotinib study, are benefiting from treatment with 
nilotinib and have fulfilled all their 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. 
Approximately 100 patients may enroll into this study.
Primary Objective(s) and Key Secondary Objective
Key Secondary Objective
To evaluate long term safety data (SAEs and AEs). 


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Protocol number
CAMN107A2409
Purpose and rationale
The purpose of this study is to better characterize long-term safety data nilotinib
in patients who are on nilotinib treatment in a Novartis-sponsored, Oncology
Global Development & Global Medical Affairs (OGD&GMA) study and are 
benefiting from the treatment as judged by the investigator.
Safety assessments
All adverse events and serious adverse events will be collected continuously 
throughout the study. 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).
For the safe and effective use of Tasigna, medical monitoring should be 
performed as clinically indicated at the physician’s discretion; this should also 
include monitoring of cardiovascular risk factors such as serum cholesterol and 
glucose levels amongst others.
Secondary Objectives
To evaluate clinical benefit as assessed by the investigator
Sponsor and
Clinical Phase
Novartis, 
IV.
Study design
This is a multi-center, open label, phase IV study to better characterize the long-
term safety of nilotinib to patients being treated in current Novartis-sponsored, 
Oncology OGD&GMA 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. At this time, a 3 month supply of nilotinib will be dispensed to the 
patient/or as per local practice.
Patients must return to the study center on a quarterly basis (every 12 weeks +/-
1 week) for resupply of study medication at which time drug dispensing and 
adverse event information will be collected. The patient may return to the clinic at 
any given time as per standard of care, however, only data from the quarterly 
visits will be recorded. All adverse events and serious adverse events will be 
collected continuously throughout the study. 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). For the safe and 
effective use of Tasigna, medical monitoring should be performed as clinically 
indicated at the physician’s discretion, 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 treatment for 10 years from First 
Patient First Visit, which occurred on 29-Mar-2013, until study treatment 
becomes commercially available and is reimbursed in the respective indication or 
until such time that enrolled patients no longer need treatment with nilotinib, 
whichever comes earlier. Should nilotinib not be commercially available to 
patients at end of study due to local regulations, Novartis will make every effort to 
ensure that patients benefiting from treatment continue to have access to 
nilotinib without interruption of treatment in accordance with local regulation.
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 1960, Rowley 1973). The molecular consequence of the translocation is the 
fusion of the ABL proto-oncogene to the BCR gene resulting in the production of an activated 
form of the Abl protein-tyrosine kinase (Bartram 1983, Heisterkamp 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 2006,
Frazer 2007). Tyrosine kinase inhibitors that inhibit BCR-ABL (TKIs) 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 
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 2010, Saglio 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 overall 
survival of 57 months (Verweij 2004, Blanke 2008a, Blanke 2008b, Bertucci 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 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 Philadelphia 
chromosome positive (Ph+) chronic myeloid leukemia in chronic phase and accelerated phase 
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 
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 responses. A 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. Overall survival 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 
chronic phase CML 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 median average daily dose of nilotinib for CML-CP patients was 788.5 mg. The most 
frequently reported (>10%) drug-related adverse events (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 severe adverse events (SAEs) were thrombocytopenia (3.4%), neutropenia 
(2.2%), angina pectoris (2.8%) and pyrexia (2.5%).
Adverse events 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 
thrombocytemia (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 Newly diagnosed 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.
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 


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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.
A detailed description of efficacy and safety data can be found in the current nilotinib 
[Investigator 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 C max
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 C max
by 60% and AUC0-∞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). 
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.


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2
Rationale
2.1
Study rationale and purpose
The purpose of this study is to better characterize the long-term safety of nilotinib in patients 
who are on nilotinib treatment in a Novartis-sponsored, Oncology Global Development & 
Global Medical Affairs (OGD&GMA) 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 
of the parent study 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 a multi-center, open label, phase IV study to better characterize the long-term safety of 
nilotinib in patients being treated in a current Novartis-sponsored, Oncology OGD&GMA 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). Additional 
strengths of nilotinib can be provided if specified in the parent protocol. 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.
2.4
Rationale for choice of combination drugs
Not applicable.
2.5
Rationale for choice of comparators drugs
Not applicable.
2.6
Risks and benefits
Tasigna is a marketed drug since 2007. Tasigna has shown considerable efficacy for the 
indications of newly diagnosed Philadelphia chromosome positive chronic myelogenous 
leukemia (Ph+ CML) in chronic phase (CP) and chronic phase and accelerated phase (AP), Ph+ 
CML in adult patients resistant to or intolerant to previous therapy including imatinib. Tasigna 


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has also shown considerable efficacy for resistant patients who have failed treatment with 
Glivec and in patients with newly diagnosed Ph+ CML (CP). Based on the results of clinical 
trials such as [CAMN107A2101] and [CAMN107A2303], nilotinib is approved worldwide in 
130 countries.
Please refer to the latest nilotinib [Investigators’ Brochure] for the known anticipated safety 
concerns of the study drug; dosage and administration; precautions and potential risks; and use 
in specific populations (including pregnancy, lactation and fertility, elderly, renal and hepatic 
impairment and overdosage). The subjects to be enrolled will be patients currently experiencing 
clinical benefit as attested by investigators to better characterize the long-term safety of the 
compound. These subjects will get the opportunity to continue to derive medical benefit from 
the treatment with nilotinib by participating in this study.
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, regular clinical monitoring and proactive dose modification and toxicity 
management.
In case patients do not tolerate the dosing schedule, dose adjustments are permitted in order to 
keep the patient on study drug. Dosing should always be adjusted/discontinued if the physician 
determines it is in the best interest of the patient.
Patients will continue to be treated in the roll-over protocol until they are no longer benefiting 
from the nilotinib, 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 therapy, 
pregnancy occurs or the patient dies, whichever comes first. The study is expected to remain 
open for treatment for 10 years from First Patient First Visit, which occurred on 29-Mar-2013, 
until study treatment becomes commercially available and is reimbursed in the respective 
indication, or until such time that enrolled patients no longer need treatment with nilotinib, 
whichever comes earlier. Should nilotinib not be commercially available to patients at end of 
study due to local regulations, Novartis will make every effort to ensure that patients benefiting 
from treatment continue to have access to nilotinib without interruption of treatment in 
accordance with local regulation.
It is understood that doses and schedule of nilotinib treatment will be different for each patient 
(depending on the parent study).
There may be unforeseen risks with nilotinib which could be serious. Refer to the latest nilotinib 
[Investigator’s Brochure].
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To evaluate long-term safety data (SAEs and 
AEs)
Frequency and severity of AEs/SAEs
Secondary
Refer to Section 10.5.2
To evaluate clinical benefit as assessed by the 
investigator
Proportion of patients with clinical benefit as 
assessed by the investigator at scheduled visits


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4
Study design
4.1
Description of study design
This is a multi-center, open label, phase IV study to better characterize the long-term safety of 
nilotinib in patients being treated in current Novartis-sponsored, Oncology OGD&GMA 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. At this time, 
a 3 month supply of nilotinib will be dispensed to the patient/or as per local practice.
Patients must return to the study center on a quarterly basis (12 weeks +/- 1 week), for resupply 
of study medication at which time limited drug dispensing information will be collected. The 
patient may return to the clinic at any given time as per standard of care, however, only the 
quarterly visits will be recorded. All adverse events and serious adverse events will be collected 
throughout the study. For the safe and effective use of Tasigna, medical monitoring should be 
performed as clinically indicated at the physician’s discretion; 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. At every quarterly visit (12 weeks +/- 1 week), the 
investigator is required to confirm that the patient continues to have clinical benefit and may 
continue receiving study treatment.
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 from First Patient First Visit, which occurred
on 29-Mar-2013, until study treatment becomes commercially available and is reimbursed in 
the respective indication or until such time that enrolled patients no longer need treatment with 
nilotinib, whichever comes earlier. Should nilotinib not be commercially available to patients 
at end of study due to local regulations, Novartis will make every effort to ensure that patients 
benefiting from treatment continue to have access to nilotinib without interruption of treatment 
in accordance with local regulation.
Figure 4-1
Study design


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4.2
Timing of interim analyses and design adaptations
No interim analyses are planned.
4.3
Definition of end of study
The end of study is defined as the date when all patients have completed their last assessment 
per protocol thirty days after end of treatment visit. The last assessment for each patient is the 
follow-up assessment that occurs 30 days after the patient’s last dose of study treatment. 
Patients may continue on study treatment until one of the following criteria is met, whichever 
comes first:

Discontinuation of study treatment per at least one of the premature patient withdrawal 
criteria are met (see Section 7.1.5 and Section 7.1.5.1)

10 years after the First Patient’s First Visit into this clinical trial

Study treatment becomes commercially available and is reimbursed in the respective
indication.
Should nilotinib not be commercially available to patients at end of study due to local 
regulations, Novartis will make every effort to ensure that patients benefiting from treatment 
continue to have access to nilotinib without interruption of treatment in accordance with local 
regulation.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible 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, Oncology Clinical Development & 
Global Medical Affairs 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 oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception.

In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment.


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
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 (i.e. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal 
ligation at least six weeks ago. 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
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. Additional strengths of 
nilotinib can be provided if specified in the parent protocol. 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 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, the 
patient dies, 10 years after First Patient First Visit into this clinical trial, or until study treatment 
becomes commercially available and reimbursed in the respective indication, whichever comes 
first. At every quarterly visit (12 weeks +/- 1 week), the investigator is required to confirm that 
the patient continues to have clinical benefit and may continue receiving study treatment. A 
patient will reach the end of the roll-over study when nilotinib treatment is permanently 
discontinued.
6.2
Dose escalation guidelines
Not applicable.
6.2.1
Starting dose rationale
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.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For the purpose of these dose reduction guidelines, toxicity is defined as any adverse event (AE) 
which is, with reasonable likelihood according to investigator’s judgment, caused by study drug.


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According to International Conference on Harmonization (ICH) E6 the investigator is 
responsible for all trial-related medical decisions.
During and following a patient’s participation in a trial, the investigator should ensure that 
adequate medical care is provided to a patient for any adverse events, including clinically 
significant laboratory values, related to the study drug.
If multiple dose-reducing toxicities are present, the greatest dose reduction schedule must be 
used.
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.
These changes must be recorded on the Dosage Administration Record CRF.
6.3.1.1
Dose reduction guidelines for study drug-related non-hematological 
toxicity and for ischemic vascular and cardiovascular events 
regardless of study drug relationship
A summary of dose reduction guidelines for study drug-related non-hematological toxicity and 
for ischemic vascular and cardiovascular events regardless of study drug relationship is 
presented in Table 6-2.
These guidelines provide general principles and recommendations intended to support the 
investigator’s judgment and decisions about appropriate management of toxicity in the 
individual patient.
However, for those toxicities detailed in Table 6-2, the following rules (as detailed in the bullet 
points below) must be strictly followed:

Any non-hematological toxicity Grade 3 or 4 must be resolved within 28 days to ≤ Grade 
2 in order to resume study drug at the reduced dose. If a non-hematological toxicity Grade 
3 or 4 does not resolve after 28 days, the patient must be discontinued from the study.

If Grade 4 toxicity of the same type recurs despite nilotinib dose reduction to 400 mg QD 
the patient must be discontinued from the study.

In case of Grade 3 pancreatitis, study drug treatment must be held and Novartis must be 
consulted immediately.

In case of Grade 4 pancreatitis, study drug treatment must be permanently stopped and the 
patient must be discontinued from study.

In case of Grade 4 liver toxicity, study drug treatment must be held and Novartis must be 
consulted immediately.

In case of Grade 4 cardiac toxicity, study drug treatment must be permanently stopped and 
the patient must be discontinued from study.

In case of recurrent QTcF prolongation to > 480 msec despite dose reduction the patient 
must be discontinued unless the reason for QTcF prolongation can be corrected (such as 
discontinuing or replacing of QT-prolonging concomitant drugs)


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Table 6-2
Summary of nilotinib dose reduction guidelines for study drug-related 
non-hematologic toxicity and for ischemic vascular and 
cardiovascular events regardless of study drug relationship (adult 
patients)
Study drug and dose
Nilotinib 600 mg daily (as 300 mg BID) or Nilotinib 800 mg daily (as 400 mg 
BID)
General non-hematological toxicity
Grade 2
(persisting > 7 days with 
optimal supportive care)
The dose of nilotinib may be reduced to 400 mg QD at the discretion of the 
investigator if clinically appropriate and in the best overall interest of the patient
≥ Grade 3
●
Hold study drug and resume nilotinib at next lower dose level after recovery to 
≤ Grade 2 is seen
l→ 400 mg QD.
●
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study.
●
If Grade 4 toxicity recurs despite dose reduction to 400 mg QD
l→ discontinue from the study.
Serum hypophosphatemia
Grade 2-3
Continue nilotinib at 300 mg BID and start phosphate supplementation.
Grade 4
Hold study drug and consult Novartis.
Serum creatinine
Grade 2
> 1.5 -3.0 x ULN
The dose of nilotinib may be reduced to 400 mg QD at the discretion of the 
investigator if clinically appropriate and in the best overall interest of the patient.
≥ Grade 3
≥ 3.0 x ULN
●
Hold study drug and resume nilotinib at next lower dose level after recovery to 
≤ Grade 2 is seen
l→ 400 mg QD.
●
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study.
●
If Grade 4 toxicity recurs despite dose reduction to 400 mg QD
l→ discontinue from the study.
Hepato-biliary [bilirubin, SGPT (AST), SGOT (ALT)] 
Note: If hyperbilirubinemia is primarily due to the indirect bilirubin [with indirect bilirubin > direct bilirubin and 
direct bilirubin ≤ 1.5 x ULN and ALT ≤ Grade 1, AST ≤ Grade 1, ALP ≤ Grade 1, and hemolysis has been ruled 
out as per institutional guidelines (e.g. by determination of hepatoglobin)], nilotinib may be continued at the 
same dose, at the discretion of the investigator.
Grade 2
The dose of nilotinib may be reduced to 400 mg QD at the discretion of the 
investigator if clinically appropriate and in the best overall interest of the patient.
≥ Grade 3
●
Hold study drug and resume nilotinib at next lower dose level after recovery to 
≤ Grade 2 is seen
l→ 400 mg QD.
●
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study.
●
If Grade 4 toxicity recurs despite dose reduction to 400 mg QD
l→ discontinue from the study.


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Study drug and dose
Nilotinib 600 mg daily (as 300 mg BID) or Nilotinib 800 mg daily (as 400 mg 
BID)
Combined elevations of AST or ALT and total bilirubin
For patients with normal 
baseline ALT and AST 
and total) bilirubin value:

AST or 
ALT >3.0xULN 
combined with 
direct or total 
bilirubin >2.0 x 
ULN without 
evidence of 
cholestasis
OR (Note to study team: 
If supported by available 
data)
For patients with 
elevated baseline AST or 
ALT or total bilirubin 
value:

AST or ALT>2x 
baseline AND > 
3.0 x ULN OR 
AST or ALT > 8.0 x ULN, 
combined with total 
bilirubin >2x baseline 
AND >2.0 x ULN
Mandatory: 
- Monitor for hemolysis. 
- If elevations of ALT and/or AST (>3.0 x ULN) and total bilirubin (>2.0 x ULN) 
without evidence of cholestasisd (ALKP < 2 x ULN) are observed 
simultaneously at the same visit: interrupt dose and monitor for hemolysis. If 
abnormality persists without evidence of hemolysis, permanently discontinue 
patient from study drug treatment.
Recommendation: If elevations of direct or total bilirubin precede the elevations of 
ALT and or AST, monitor for hemolysis. 
Repeat as soon as possible, preferably within 48 hours from awareness of the 
abnormal results, then with weekly monitoring of liver function tests, or more 
frequently if clinically indicated, until AST, ALT, or bilirubin have resolved to 
baseline or stabilization over 4 weeks. 
Pancreatitis (with abdominal symptoms plus lipase elevation)
Grade 2
●
Hold study drug and perform abdominal CT with contrast to exclude pancreatic 
pathology.
●
If CT is positive, continue to hold therapy and repeat CT, at investigator’s 
discretion.
●
If CT is negative, re-start nilotinib at 400 mg QD after recovery to ≤ Grade 1 is 
seen.
●
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study.
●
If toxicity recurs
l→ discontinue from the study.
Grade 3
Hold study drug and consult Novartis.
Grade 4
Stop study drug. The patient must be discontinued from study.
Elevated lipase without symptoms
≥ Grade 3
●
Hold study drug.
●
Re-start nilotinib at 400 mg QD after recovery to ≤ Grade 2 is seen.
●
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study.
●
If toxicity recurs without symptoms consider appropriate diagnostic procedures 
such as abdominal CT or ultrasound to exclude pancreatitis. After recovery to ≤ 
Grade 2,
l→ continue dosing at 400 mg QD based on investigator’s discretion.


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Study drug and dose
Nilotinib 600 mg daily (as 300 mg BID) or Nilotinib 800 mg daily (as 400 mg 
BID)
Diarrhea
Note: Anti-diarrheal medication is recommended at the first sign of loose stools or overt diarrhea. If diarrhea 
cannot be controlled with optimal anti-diarrheal treatments, take the following actions:
≥ Grade 3
●
Hold study drug and resume nilotinib at next lower dose level after recovery to 
≤ Grade 2 is seen
l→ 400 mg QD.
●
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study.
Vomiting
Note: Antiemetic medication should be withheld until the patient experiences ≥ grade 1 vomiting then institute 
symptomatic therapy as appropriate. Antiemetics with the potential to prolong QT such as domperidone must 
be avoided. If nausea and vomiting cannot be controlled with optimal antiemetic treatment take the following 
actions: 
≥ Grade 3
●
Hold study drug and resume nilotinib at next lower dose level after recovery to 
≤ Grade 2 is seen
l→ 400 mg QD.
●
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study.
Skin rash
Note: Institute symptomatic therapy as appropriate. If skin rash does not resolve with optimal treatments, take 
the following actions:
Grade 2
●
The dose of nilotinib may be reduced to 400 mg QD at the discretion of the 
investigator if clinically appropriate and in the best overall interest of the patient.
≥ Grade 3
●
Hold study drug and resume nilotinib at next lower dose level after recovery to 
≤ Grade 2 is seen
l→ 400 mg QD.
●
If recovery to ≤ Grade 2 is greater than 28 days, the patient must be 
discontinued from the study.
●
If Grade 4 toxicity recurs despite dose reduction to 400 mg QD
l→ discontinue from the study.


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Study drug and dose
Nilotinib 600 mg daily (as 300 mg BID) or Nilotinib 800 mg daily (as 400 mg 
BID)
Cardiac QTc prolongation
QTcF > 480 msec
●
Hold study drug when an ECG with a QTcF > 480 msec. 
●
In addition to the procedures below, the investigator should follow their local 
standards of practice and treatment guidelines for treating prolonged QT intervals. 
●
Perform an analysis of serum potassium and magnesium, and if below lower 
limit of normal, correct with supplements to within normal limits.
●
Concomitant medication usage must be reviewed for their potential to inhibit 
CYP3A4 and/or to prolong the QT-interval.
●
Perform a repeat ECG within one hour of the first QTcF of > 480 msec.
●
If QTcF remains > 480 msec, repeat ECG as clinically indicated, but at least 
once a day until the QTcF returns to < 480 msec.
●
Study drug may be restarted, at same dose, if reason for elevation of QTcF is 
identified and corrected so that QTcF returns to < 450 msec and to within 20 msec 
of baseline within 2 weeks.
●
ECGs must be repeated 7 days after dose re-start for all patients who had 
therapy held due to QTcF > 480 msec.
●
If the QTcF is repeated and is more than 20 msec greater than baseline or 
between 450 msec and 480 msec, the dose of study drug should be reduced to 
400 mg QD.
●
If QTcF of > 480 msec recurs, the patient is to be discontinued from the study.
●
The investigator should contact Novartis regarding any questions that arise if a 
patient with QTcF prolongation should be maintained on study.
●
Note: QTcB can be used in centers that do not have the ability to automatically 
measure QTcF for QTc prolongation. In patients with a heart rate lower than 60 
per minute decisions are always based on QTcF because QTcB underestimates 
QT prolongation at heart rates below 60 per minute. 
Study drug and dose
Nilotinib 600 mg daily (as 300 mg BID)
Ischemic vascular or cardiovascular events
Grade 2*
●
Hold study drug and refer patient for assessment by a vascular or 
cardiovascular specialist.
●
Resume nilotinib at next lower dose level after recovery to ≤ Grade 1 is seen
l→ 400 mg QD.
●
If another recurrence
l→ discontinue from the study.
●
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study.
Grade 3* or 4*
●
Hold study drug and refer patient for assessment by a vascular or 
cardiovascular specialist. Consideration should be given for discontinuation from 
the study. The patient must be discontinued from the study if recovery to ≤ Grade 
2 is greater than 28 days.
* Patient should be assessed for potential risk factors for the event including causality secondary to CML 
therapy.
Cardiac “other”
Grade 2 or Grade 3
●
Hold study drug and resume nilotinib at next lower dose level after recovery to 
≤ Grade 1 is seen
l→ 400 mg QD.
●
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study.
●
If Grade 3 toxicity recurs despite dose reduction to 400 mg QD
l→ discontinue from the study.
Grade 4
Stop study drug. The patient must be discontinued from the study.


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6.3.1.2
Dose reduction guidelines for study drug-related hematological 
toxicity
A summary of dose reduction guidelines for ≥ Grade 3 study drug-related hematological 
toxicity for 300 mg BID or 400 mg BID dose is presented in Table 6-3. No dose adjustments 
should be made for Grade 1 or 2 hematologic toxicities. These guidelines provide some general 
principles as well as recommendations which are intended to support the investigator’s 
judgment and decision about the appropriate management of toxicity in the individual patient. 
However, if a hematological toxicity does not resolve to ≤ Grade 2 within 28 days, the Novartis 
Clinical Trial Head must be consulted.
Table 6-3
Summary of dose reduction guidelines for study drug-related 
hematological toxicity
Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) or Nilotinib 800 mg daily (as 400 mg 
BID)
≥ Grade 3
Hold therapy and resume nilotinib at the full dose after recovery to ≤ Grade 2, if 
recovery occurs within 14 days
If ≥ Grade 3 toxicity persists for 15-28 days or recurs, hold therapy and resume at 
next lower dose level after recovery to ≤ Grade 2:
l→400 mg QD
If recovery to ≤ Grade 2 is greater than 28 days, consult Novartis.
If another recurrence is seen
l→discontinue.
Note: Dose of study drug need not be reduced or interrupted for hematological toxicity of Grade 2 or lower.
When a patient on a dosage other than 300 mg BID or 400 mg BID experiences study drug-
related Grade 3 or 4 hematologic toxicity, study dose will be held until the toxicity is resolved. 
If the toxicity does not resolve after 28 days of dose interruption, the patient must be 
discontinued from the study.
6.3.2
Dose reduction guidelines for study drug-related toxicity for pediatric 
patients
A summary of dose reduction guidelines for study drug-related toxicity for 230 mg/m2 BID 
dosage is presented in Table 6-4.


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Table 6-4
Recommended criteria for interruption and re-initiation of nilotinib for drug-related toxicities and for ischemic 
vascular and cardiovascular events regardless of study drug relationship
Worst toxicity
NCI CTCAE grade
During therapy
No toxicity
Maintain dose level
Hematological - includes thrombocytopenia, neutropenia, leukopenia, and/or anemia
Grade 1-2 Hematological
No dose interruptions or reductions
Grade 3-4 Hematological
●
Note(1): No dose reductions will be performed for grade 3/4 
anemia. If the patient develops anemia, s/he may be 
transfused at the discretion of the Investigator.
●
Note(2) : Use of G-CSF and GM-CSF may be initiated with 
recurrent Grade 3 neutropenia after consulting with the 
sponsor. Refer to Section 6.3.2.5 for more details.
First Occurrence:
1. Hold nilotinib until recovery to grade ≤ 1.
●
If recovery occurs within 2 weeks of the last day of dosing, resume nilotinib at the same 
daily dose.
●
If recovery occurs more than 2 weeks but ≤ 4 weeks after the last day of dosing, resume 
nilotinib at:
2. 230 mg/m2 once daily in AM or PM if prior dose was 230 mg/m2 twice daily or contact Novartis if 
prior dose was 230 mg/m2 once daily.
Second Occurrence:
1. Hold nilotinib until recovery to grade ≤1.
2. Resume nilotinib at:
230 mg/m2 once daily in AM or PM if prior dose was 230 mg/m2 twice daily or contact Novartis if prior 
dose was 230 mg/m2 once daily.
If recovery to ≤ Grade 1 greater than 28 days, investigator will consult sponsor to define appropriate 
length of dosing reduction/interruption prior to discontinuation.
The length of dose discontinuation should not exceed more than 2 months
Hepato- biliary
Total bilirubin ≥ Grade 2
Note: If hyperbilirubinemia is due to the indirect component 
only, and hemolysis as the etiology has been ruled out as per 
institutional guidelines (e.g., review of peripheral blood smear 
and haptoglobin determination), , nilotinib may be continued at 
the same dose at the discretion of the Investigator.
First Occurrence:
1. Hold nilotinib until return to ≤ grade 1.
2. Resume nilotinib at:
230 mg/m2 once daily in AM or PM if prior dose was 230 mg/m2 twice daily or discontinue patient 
from the study if prior dose was 230 mg/m2 once daily.
Second Occurrence:
Stop nilotinib and contact Novartis.
If recovery to ≤ Grade 1 greater than 28 days, investigator will consult sponsor to define appropriate 
length of dosing reduction/interruption prior to discontinuation.
The length of dose discontinuation should not exceed more than 2 months


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Worst toxicity
NCI CTCAE grade
During therapy
No toxicity
Maintain dose level
≥Grade 3 AST (SGOT) or ALT (SGPT)
First Occurrence:
1. Hold nilotinib until return to ≤ grade 1 (or baseline if disease related).
2. Resume nilotinib at:
230 mg/m2 once daily in AM or PM if prior dose was 230 mg/m2 twice daily or discontinue patient 
from the study if prior dose was 230 mg/m2 once daily.
Second Occurrence:
Stop nilotinib and contact Novartis.
If recovery to ≤ Grade 1 greater than 28 days, investigator will consult sponsor to define appropriate 
length of dosing reduction/interruption prior to discontinuation.
The length of dose discontinuation should not exceed more than 2 months
Amylase and/or Lipase without symptoms ≥ Grade 3
First Occurrence:
1. Hold nilotinib until return to ≤ grade 1.
2. Abdominal CT with contrast to exclude pancreatic pathology.
3. Resume nilotinib at:
230 mg/m2 once daily in AM or PM if prior dose was 230 mg/m2 twice daily or contact Novartis if prior 
dose was 230 mg/m2 once daily.
Second Occurrence:
Continue dosing, if asymptomatic and CT negative, at Investigator’s discretion.
If recovery to ≤ Grade 1 greater than 28 days, investigator will consult sponsor to define appropriate 
length of dosing reduction/interruption prior to discontinuation.
The length of dose discontinuation should not exceed more than 2 months
Pancreatitis ≥ Grade 2 (abdominal symptoms with amylase 
and/or lipase elevation)
First Occurrence:
1. Hold nilotinib until return to ≤ grade 1 and perform abdominal CT.
2. If abdominal CT is negative, resume nilotinib when symptoms have resolved, with continued 
monitoring for recurrent symptoms at:
230 mg/m2 once daily in AM or PM if prior dose was 230 mg/m2 twice daily or discontinue patient 
from the study if prior dose was 230 mg/m2 once daily.
Second Occurrence:
Stop nilotinib and discontinue patient from the study treatment.
If recovery to ≤ Grade 1 greater than 28 days, investigator will consult sponsor to define appropriate 
length of dosing reduction/interruption prior to discontinuation.
The length of dose discontinuation should not exceed more than 2 months


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Worst toxicity
NCI CTCAE grade
During therapy
No toxicity
Maintain dose level
Cardiac – QTc
ECGs with a QTcF > 480 ms
1. In addition to the procedures below, the investigator should follow their local standards of 
practice and treatment guidelines for treating prolonged QT intervals. 
2. Hold nilotinib when an ECG with a QTcF > 480 ms by automated reading is identified at the site.
3. Call the study’s central ECG review laboratory immediately, request a manual read of ECG result 
and notify Novartis.
4. Perform an analysis of serum potassium and magnesium, and if below lower limit of normal, 
correct with supplements to within normal limits. Concomitant medication usage must be reviewed.
5. Perform a repeat ECG within one hour of the first QTcF of > 480 ms, and forward to the study’s 
central ECG review laboratory for a manual reading.
6. If QTcF remains > 480 ms, repeat ECG as clinically indicated, but at least once a day until the 
QTcF returns to < 480 ms.
7. Nilotinib may be restarted at the same dose, if reason for elevation of QTcF is identified, 
corrected and QTcF returns to < 450 ms and to within 20 ms of baseline within 2 weeks. If QTcF is 
repeated and is more than 20 ms greater than baseline or between 450 ms and 480 ms the dose of 
nilotinib is to be reduced by half:
●
230 mg/m2 once daily if prior dose was 230 mg/m2 twice daily OR
●
discontinue patient from treatment if prior dose was 230 mg/m2 once daily.
With resumption of nilotinib at the same or at a reduced dose after interruption of therapy due to 
QTcF > 480 ms, ECGs must be obtained on days 2, 3, and 8.
8. If QTcF > 480 ms recurs, stop nilotinib and contact Novartis.
Forward all ECGs to the study’s central ECG review laboratory. Any ECG with a QTcF >480 ms, not 
obtained by study provided ECG machine, must be forwarded by overnight delivery to the study’s 
central ECG review laboratory.
No dose re-escalation is allowed after dose reduction due to QTcF prolongation suspected to be 
related to nilotinib


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Worst toxicity
NCI CTCAE grade
During therapy
No toxicity
Maintain dose level
Ischemic cardiovascular events
Grade 2* 
First Occurrence:
1. Hold nilotinib and refer patient for assessment by a vascular or cardiovascular specialist.
2. Resume nilotinib at:
230 mg/m2 once daily in AM or PM if prior dose was 230 mg/m2 twice daily after recovery to ≤ Grade 
1 is seen
Second Occurrence:
Stop nilotinib and contact Novartis
If recovery to ≤ Grade 1 takes more than 28 days, the patient must be discontinued from the study.
Grade 3* or 4*
1. Hold therapy and refer patient for assessment by a vascular or cardiovascular specialist.
2. Consideration should be given for discontinuation from the study. 
3. The patient must be discontinued from the study if recovery to ≤ Grade 2 takes more than 28 
days
* Patient should be assessed for potential risk factors for the event including causality secondary to CML therapy
Gastrointestinal
Diarrhea
Grade 3 or 4
First Occurrence:
1. Institute symptomatic therapy as appropriate.
2. If diarrhea cannot be controlled with optimal anti-diarrheal treatments, hold nilotinib until resolved 
to ≤ grade 1, then resume nilotinib at:
230 mg/m2 once daily in AM or PM if prior dose was 230 mg/m2 twice daily or discontinue patient 
from the treatment if prior dose was 230 mg/m2 once daily.
Anti-diarrheal medication is recommended at the first sign of abdominal cramping, loose stools or 
overt diarrhea.
Second Occurrence:
If diarrhea cannot be controlled with optimal anti-diarrheal treatments, stop nilotinib and contact 
Novartis.
If recovery to ≤ Grade 1 greater than 28 days, investigator will consult sponsor to define appropriate 
length of dosing reduction/interruption prior to discontinuation.
The length of dose discontinuation should not exceed more than 2 months


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Worst toxicity
NCI CTCAE grade
During therapy
No toxicity
Maintain dose level
Vomiting
Grade 3 or 4
First Occurrence:
1. Institute symptomatic therapy as appropriate.
2. If vomiting or nausea cannot be controlled with optimal antiemetic treatments, hold nilotinib until 
resolved to ≤ grade 1 then resume nilotinib at:
230 mg/m2 once daily in AM or PM if prior dose was 230 mg/m2 twice daily or discontinue patient 
from the treatment if prior dose was 230 mg/m2 once daily.
Second Occurrence:
If vomiting or nausea cannot be controlled with optimal antiemetic treatments, stop nilotinib and 
contact Novartis.
If recovery to ≤ Grade 1 greater than 28 days, investigator will consult sponsor to define appropriate 
length of dosing reduction/interruption prior to discontinuation.
The length of dose discontinuation should not exceed more than 2 months
Dermatologic
Skin rash
Grade 2
First Occurrence:
1. Institute symptomatic therapy as appropriate.
2. If skin rash does not resolve with optimal treatments, hold nilotinib until resolved to ≤ grade 1, 
then resume nilotinib at the same daily dose.
Second Occurrence:
1. Hold nilotinib instituting symptomatic therapy until recovery to grade ≤1.
2. Resume nilotinib at:
230 mg/m2 once daily in AM or PM if prior dose was 230 mg/m2 twice daily.
If further recurrence, stop nilotinib and contact Novartis.
If recovery to ≤ Grade 1 greater than 28 days, investigator will consult sponsor to define appropriate 
length of dosing reduction/interruption prior to discontinuation.
The length of dose discontinuation should not exceed more than 2 months
Skin rash
Grade 3 or 4
First Occurrence:
1. Hold nilotinib instituting symptomatic therapy as appropriate, until recovery to grade ≤ 1.
2. Resume nilotinib at:
230 mg/m2 once daily in AM or PM if prior dose was 230 mg/m2 twice daily.
Second Occurrence:
Stop nilotinib and contact Novartis.
If recovery to ≤ Grade 1 greater than 28 days, investigator will consult sponsor to define appropriate 
length of dosing reduction/interruption prior to discontinuation.
The length of dose discontinuation should not exceed more than 2 months


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Worst toxicity
NCI CTCAE grade
During therapy
No toxicity
Maintain dose level
Other clinically significant potentially treatment related adverse events
Grade 3 or 4
First Occurrence:
1. Hold nilotinib instituting symptomatic therapy as appropriate, until recovery to grade ≤ 1.
2. Resume nilotinib at:
230 mg/m2 once daily in AM or PM if prior dose was 230 mg/m2 twice daily.
Second Occurrence:
Stop nilotinib and contact Novartis.
If recovery to ≤ Grade 1 greater than 28 days, investigator will consult sponsor to define appropriate 
length of dosing reduction/interruption prior to discontinuation.
The length of dose discontinuation should not exceed more than 2 months


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Every attempt to re-escalate the dose of study treatment to the initial dose level should be made. 
This applies to dose reductions due to both hematological and non-hematological toxicities with 
the exception of dose reductions due to prolongation of QT interval. The dose should be re-
escalated if the following criteria are met at least one month after dose reduction:

All ≥ Grade 2 non-hematological toxicities have resolved to ≤ Grade 1

All ≥ Grade 3 hematological toxicities have resolved to ≤ Grade 1

Or alternatively, all ≥ Grade 3 hematological and non-hematological toxicities have 
resolved to ≤ Grade 2 and are manageable with supportive therapy
No dose re-escalations are allowed after dose reductions due to QTcF prolongation 
suspected to be related to nilotinib.
Investigators should refer to the approved local label for Tasigna as an additional resource. If 
no approved local label is available, the SmPC or USPI for Tasigna should be used.
All dosage changes must be recorded on the “Dosage Administration Record” CRF.
6.3.3
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.
6.3.4
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.
6.3.5
Management of other cardiac risk factors
Patients should be assessed or monitored for any other cardiac risk factors such as family history, 
cardiovascular events in the past medical history, smoking, hypertension, and obesity. If the 
assessment for presence of any other cardiovascular risk factors warrants intervention, 
investigators should follow their local standards of practice or treatment guidelines.
6.3.6
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 Table 6-2 and Table 6-4 and the 
current nilotinib [Investigator’s Brochure].


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6.3.7
Hepatitis B reactivation
Hepatitis B virus testing should be performed during the study as indicated in Section 7.1 to 
identify patients who may be at risk for Hepatitis B reactivation. Experts in liver disease and in 
the treatment of hepatitis B should be consulted for patients who test positive for hepatitis B 
virus during nilotinib treatment. Carriers of hepatitis B virus who require treatment with 
nilotinib should be closely monitored for signs and symptoms of active hepatitis B infection 
throughout therapy and for several months following termination of therapy.
6.3.8
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 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.
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 testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.
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.


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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.
6.4
Concomitant medications
6.4.1
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 I in
Section 14.1). Should treatment with strong CYP3A4 inhibitors be required, it is recommended 
that therapy with nilotinib be interrupted if possible. Close monitoring of prolongation of the 
QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. 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 I in Section 14.1.
Every effort should be made NOT to administer strong CYP3A4 inhibitors CYP3A4 
inhibitors may decrease the metabolism of nilotinib and thereby increase serum concentrations 
and increase exposure. If administration of a strong CYP3A4 inhibitor cannot be avoided during 
the study and cannot be switched to an alternative therapy, study treatment must be STOPPED. 
Furthermore, increased awareness should be exercised when administering moderate inhibitors 
and/or multiple weak inhibitors. A list of these medications and inhibitor classifications can be 
found in Appendix 1; however, this list may not be comprehensive.
Every effort should be made NOT to administer strong CYP3A4 inducers however, if
administration of a CYP3A4 inducer cannot be avoided during the study, temporary 
discontinuation of study treatment is NOT required. A list of these medications and inducer 
classifications can be found in Appendix 1, however, this list may not be comprehensive.
Antacid drugs:
Nilotinib has a pH-dependent solubility; therefore, in order not to impact nilotinib 
pharmacokinetics, administration of the following antacid drugs (if necessary) should be as 
follows:

H2 blocker (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


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Drug with “Known risk of Torsades do Pointes,” “Possible risk of Torsades de 
Pointes,” or “Conditional risk of Torsades de Pointes”:
Every effort should be made to avoid co-administering the study drug and drugs with a “Known 
risk of Torsades do Pointes,” “Possible risk of Torsades de Pointes,” or “Conditional risk of 
Torsades de Pointes” (as per https://crediblemeds.org/) during the course of the study:

If concomitant administration of drugs with a “Known risk of Torsades de Pointes” is 
required and cannot be avoided, study drug must be interrupted. If, based on the 
investigator assessment and clinical need, study treatment is resumed, close ECG 
monitoring is advised.

If during the course of the study, concomitant administration of a drug with “Possible 
risk” or “Conditional risk of Torsades de Pointes” is required, based on the investigator 
assessment and clinical need, study drug may be continued under close ECG monitoring 
to ensure patient safety.
A list of drugs associated with QT prolongation and/or Torsades de Pointes is available online
at https://crediblemeds.org/  
All patients must avoid grapefruit, star fruit, pomegranate and Seville oranges during the study.  
The juices and products containing these fruits must also be avoided.
Cardiac Monitoring.
Cardiac monitoring is required upon re-initiation of nilotinib therapy at any point. An 
ECG must be obtained before the treatment re-initiation, 4 weeks after reinitiation and annually 
thereafter during nilotinib therapy. A minimum washout period of 72 hours or longer is 
required (depending on the half-life of the CYP3A4 inhibitor or QT interval prolonging 
agent) prior to study drug re-initiation. Documentation will be kept in source document.
6.4.2
Use of Bisphosphonates (or other concomitant agents)
Not applicable
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled 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 through the Oracle Clinical RDC interface (OCRDC). 
Additionally an eCRF will be completed that identifies the patient by gender and date of birth 
and previous study, site/center and subject number.


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6.5.2
Treatment assignment or randomization
All consented patients who meet all the inclusion criteria and none of the exclusion criteria are 
eligible to receive nilotinib.
6.5.3
Treatment blinding
Not applicable
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
Table 6-5
Preparation and dispensing
Study treatments
Dispensing
Preparation
Nilotinib
*Hard Gelatin Capsules (150mg and 200mg, additional strengths 
can be provided if specified in the parent protocol) 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.
Not applicable
* Different formulations and strengths can be used once they are approved and marketed.
6.6.1
Study treatment packaging and labeling
Nilotinib can be provided as local commercial material or global supply where appropriate and 
as per local regulations. Global supply will be as open label supply, packed and labeled under 
the responsibility of Novartis, Drug supply management. Study treatment labels will be in the 
local language and comply with the legal requirements of each country. They will include 
storage conditions for the drug but no information about the patient.
If nilotinib is sourced and labeled in-country, the locally-approved form and packaging of 
nilotinib will be used.
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 Brochure] for nilotinib dosing instructions and storage 
conditions.


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Table 6-6
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
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.
6.6.2
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 6-7
Supply and storage of study treatments
Study treatments
Supply
Storage
Nilotinib
Centrally Or locally supplied by 
Novartis
Refer to study treatment label or local 
product information
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
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.


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7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. A visit window of +/- 1 week is allowed. All data obtained from these assessments 
must be supported in the patient’s source documentation.
The table indicates which assessments produce data to be entered into the database (D) or 
remain in source documents only (S) (“Category” column).
Hepatitis B testing will be performed once and only once, at the next possible visit.


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Table 7-1
Visit evaluation schedule
Category
Protocol 
Reference 
Section
Enrollment
Quarterly (12 weeks +/- 1 week) visits during 
treatment phase
End of study 
treatment 
(EoT)
Safety 
Follow-
up/End of 
study
Visit Number
1
Visit 2,3,4 etc.
777
778
Informed consent
D
7.1.2
x
Patients’ previous study, site and subject 
number
D
7.1.2.3
x
Demography
D
7.1.2.3
x
Relevant medical history/current medical 
conditions
D
7.1.2.3
Inclusion/exclusion criteria
D
5.2 / 5.3.
x
Nilotinib dosing
D
6.1.
x
X
Pregnancy testing
D,S
7.1.4
x
Monthly (home)
x
Hepatitis screen
D
7.2.2.1
to be performed once and only once, at the next 
possible visit
Confirmation of Clinical Benefit from 
Study Treatment 
D
6.1.5
x
X
x
Adverse events and serious adverse 
events 
D
8.1 / 8.2.
Continuous
x
End of study treatment
D
7.1.5
x
Study Evaluation Completion
D
7.1.5
x


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7.1.1
Molecular pre-screening
Not applicable.
7.1.2
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.
7.1.2.1
Eligibility screening
Not applicable.
7.1.2.2
Information to be collected on screening failures
Not applicable.
7.1.2.3
Patient demographics and other baseline characteristics
For patients that are eligible to participate in this roll-over study, the patients’ gender, date of 
birth and previous study, site/center and subject number and relevant medical history will be 
collected.
7.1.3
Treatment period
The starting dose of nilotinib should be the same as the last dose that was given in the parent 
nilotinib study. A 3 month supply of nilotinib will be dispensed to the patient/or as per local 
practice.
Patients must return to the study center on a quarterly basis (12 weeks +/- 1 week), for 
resupply of study medication at which time limited drug dispensing and adverse event
information will be collected. At every quarterly visit (12 weeks +/- 1 week), the investigator 
is required to confirm that the patient continues to have clinical benefit and may continue 
receiving study treatment. At this time the dose of nilotinib is based on the investigator’s 
judgment. The study is expected to remain open for 10 years from the First Patient First Visit 
in this clinical study, until study treatment becomes commercially available and is reimbursed 
in the respective indication or until such time that enrolled patients no longer need treatment 
with nilotinib, whichever comes earlier. Should nilotinib not be commercially available to 
patients at end of study due to local regulations, Novartis will make every effort to ensure that 
patients benefiting from treatment continue to have access to nilotinib without interruption of 
treatment in accordance with local regulation.
7.1.4
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/locally available or urine pregnancy test) before enrolling into the study.


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Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, unless they are using highly effective methods of contraception during 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 oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception.
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/locally 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.)
7.1.5
Discontinuation of study treatment
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,the 
patient dies, 10 years after First Patient First Visit into this clinical trial or when study treatment 
becomes commercially available and reimbursed in the respective indication, whichever comes 
first. Should nilotinib not be commercially available to patients at end of study due to local 
regulations, Novartis will make every effort to ensure that patients benefiting from treatment 
continue to have access to nilotinib without interruption of treatment in accordance with local 
regulation. At the time the patient 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 


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reason for stopping the study treatment (Section 7.1.5.1), e.g., physician decision, disease 
progression, cause of death, lost to follow-up, withdrawal of consent, etc.
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. The completion of the Study Evaluation Completion eCRF page 
will be required any time a patient discontinues from the study and must be completed 30 days 
after the end of 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 eCRF 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. Adverse event,
5. Disease progression,
6. Patient/guardian decision*,
7. Physician decision,
8. Patient is non-compliant to protocol requirements,
9. Protocol deviation,
10. Patient becomes pregnant*,
11. 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
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient


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
Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
7.1.7
Follow up for safety evaluations
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 adverse events or serious adverse events (SAEs) 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.
Data collected should be added to the Adverse Events eCRF.
7.1.8
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
At every quarterly visit, the investigator is required to confirm that the patient continues to have 
clinical benefit and may continue receiving study treatment.


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7.2.2
Safety and tolerability assessments
Safety will be monitored by collecting of the adverse events at every visit. For details on AE 
collection and reporting, refer to Section 8.
7.2.2.1
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 should have testing performed at the next possible visit in order 
to identify chronic carriers.
7.2.3
Pharmacokinetics
Not applicable.
7.2.3.1
Analytical method
Not applicable.
7.2.3.2
Additional biomarker assessments
Not applicable.
7.2.4
Resource utilization
Not applicable.
7.2.5
Patient reported outcomes
Not applicable.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Any ongoing adverse events from the parent study will be captured as medical history in the 
roll-over database. Any AE that begins (or worsens) after signing of the informed consent for 
the roll-over and during the 30-day (or 28-day) safety follow up period defined in the parent 
protocol should be reported in both clinical databases.


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Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.
Adverse events will be assessed according to the current version of Common Terminology 
Criteria for Adverse Events (CTCAE).
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected through the EOT 
eCRF page.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (start and end dates)
3. Its relationship to the study treatment (reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 


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be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 events (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.1.3
Adverse events of special interest
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them.
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the [Investigator Brochure].
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].


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The Investigator should ensure that the patient is assessed by a vascular or cardiovascular 
specialist.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, 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 serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAE that begins or worsens after signing of the informed consent for the roll-over and 
during the 30-day (or 28-day) safety follow up period defined in the parent protocol should be 
reported as an adverse event in both clinical databases; however, only one SAE report will be 
sent to Novartis.

Any SAE that begins or worsens during the 30-day (or 28-day) safety follow up period 
specified in the parent study should have an SAE report submitted to Novartis with the 
parent protocol study number.

Any SAE that begins or worsens after the 30-day (or 28-day) safety follow up period 
specified in the parent study should have an SAE report submitted to Novartis with the 
roll-over protocol study number.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes 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 


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interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.
It is important to use the right SAE form with the correct protocol number for these two 
scenarios, to avoid confusion in SAE processing. For a patient already on the roll-over protocol 
but follow up information is reported for the previous SAEs in the parent protocol, it must be 
clearly labeled that this is for the parent protocol number.
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.
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 submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated and whether the patient 
continued or withdrew from study participation.
If the SAE is not previously documented in the [Investigator’s Brochure] or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (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 Drug Safety and Epidemiology (DS&E). Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 


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possible relationship to the study treatment 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 Brochure]. Additional safety information collected between [Investigator 
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.
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 AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 


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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.
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 staff is
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.


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10
Statistical methods and data analysis
10.1
Analysis sets
The following analysis sets will be used for statistical analysis and data reporting.
10.1.1
Full Analysis Set
Not applicable.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study medication after 
enrolling into the roll-over protocol.
10.1.3
Dose-determining analysis set
Not applicable.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data characteristics will be summarized descriptively for the 
Safety Set.
10.3
Treatments (study treatment, compliance)
Dose administration data will be summarized using the Safety Set.
10.4
Primary objective
The primary objective is to evaluate long term safety as assessed by the occurrence of 
AEs/SAEs.
10.4.1
Variable
See Section 10.5.3.
10.4.2
Statistical hypothesis, model, and method of analysis
No hypothesis will be tested.
10.4.3
Handling of missing values/censoring/discontinuations
Not applicable.
10.4.4
Supportive analyses
No supportive analysis will be performed.


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10.5
Secondary objectives
10.5.1
Key secondary objective(s)
Not applicable.
10.5.2
Other secondary efficacy objectives
The secondary objective of the study was to evaluate clinical benefit as assessed by the 
investigator. Proportion of patients with clinical benefit as assessed by the investigator will be 
summarized at scheduled visits.


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10.5.3
Safety objectives
The assessment of safety will be based mainly on the frequency of AEs and SAEs.
10.5.3.1 Analysis set and grouping for the analyses
The overall observation period will be divided into two mutually exclusive segments:
1. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
2. post-treatment period: starting at day 30+1 after last dose of study medication.
10.5.3.2 Adverse events (AEs)
Summary tables of adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the post-treatment periods) will be listed and those collected during the 
post treatment period are to be flagged.
The incidence of treatment emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and/or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event.
10.5.3.3 Other safety data
Not applicable.
10.5.3.4 Tolerability
Not applicable.
10.6
Interim analysis
Not applicable.
10.7
Sample size calculation
Not applicable.
10.8
Power for analysis of key secondary variables
Not applicable.


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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 CRFs.
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.
Additional consent form
Not applicable.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.


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11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.


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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.
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.
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).
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.
Corless C, 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 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.
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, 13291338.
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.
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.


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Nowell PC, 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.
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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Appendices
14.1
Appendix I: Guidance on concomitant medications with CYP3A 
and QTc prolongation potential interactions
A list of drugs that are inducers and inhibitors and substrates of CYP3A4 is provided below.
Patients should be instructed not to take grapefruit, star fruit, pomegranate, 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, inducers 
and substrates may be found at http://medicine.iupui.edu/flockhart.
Table 14-1
Medications that can induce CYP3A4
Category
Drug Names
Strong inducers 
of CYP3A41
avasimibe, carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, rifabutin, 
rifampicin, mitotane, St. John’s wort (Hypericum perforatum)4
Moderate 
inducers of 
CYP3A42
bosentan, dabrafenib, efavirenz, etravirine, genistein5, lersivirine , lopinavir, modafinil, nafcillin,
semagacestat6, talviraline6, telotristat, thioridazine, tipranavir/ritonavir
Weak inducers 
of CYP3A43
amprenavir, aprepitant, armodafinil, artesunate/mefloquine, bexarotene, boceprevir, 
brivacetam, clobazam, danshen (Salvia miltiorrhiza)4, dexamethasone, echinacea (Echinacea 
purpurea)1, elvitegravir-cobicistat-emtricitabine-tenofovir (Stribild), eslicarbazepine, ginkgo 
(Ginkgo biloba)4, ginseng4, glycyrrhizin5, isavuconazole, lesinurad, methylprednisolone, 
nevirapine, ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak), oritavancin, 
oxcarbazepine, pioglitazone, pleconaril, prednisone, pretomanib, primidone, quercetin5, 
raltegravir, ritonavir, rufinamide, sarilumab, sirukumab, sorafenib, sulfinpyrazone, telaprevir, 
terbinafine, ticagrelor, ticlopidine, topiramate, troglitazone6, vemurafenib, vicriviroc/ritonavir, 
vinblastine, yin zhi huang4
1 A strong inducer for a specific CYP is defined as an inducer that decreases the AUC of a sensitive substrate for 
that CYP by equal or more than 80%.
2 A moderate inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that 
CYP by 50-80%.
3 A weak inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that CYP 
by 20-50%.
4 Herbal product
5 Food product
6 Drugs not available on US market
This list was based on information from the FDA’s “Guidance for Industry, Drug Interaction 
Studies”, from the Indiana University School of Medicine’s “Clinically Relevant” Table, from 
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 January 2018) for update 
or more details.


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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.
Category
Drug Names
Strong inhibitors 
of CYP3A41
atazanavir/ritonavir7, boceprevir, cobicistat,  conivaptan,  clarithromycin,
danoprevir/ritonavir7,  darunavir/ritonavir7, elvitegravir/ritonavir7,  grapefruit juice6,   
idelalisib, indinavir,  indinavir/ritonavir7,  itraconazole,  ketoconazole, lopinavir/ritonavir7,   
mibefradil, nefazodone, nelfinavir,  ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak)7,  
posaconazole,  ritonavir,  saquinavir/ritonavir7,, saquinavir, telaprevir,  telithromycin, 
tipranavir/ritonavir7, troleandomycin, , voriconazol
Moderate 
inhibitors of 
CYP3A42
aprepitant, amprenavir,  asafoetida resin (Ferula asafoetida)4, atazanavir, cimetidine, 
casopitant, ciprofloxacin, crizotinib, cyclosporine, darunavir, diltiazem, dronedarone, 
erythromycin, faldaprevir, fluconazole, grapefruit juice6, imatinib, isavuconazole, netupitant, 
nilotinib, Schisandra sphenanthera (nan wu wei zi)4, tofisopam, verapamil
Weak inhibitors 
of CYP3A43
almorexant, alprazolam, amiodarone, amlodipine, atorvastatin, azithromycin, berberine4, 
bicalutamide, blueberry juice8, brodalumab, chlorzoxazone, cilostazol, clotrimazole, 
cranberry juice8, daclatasvir, delavirdine, evacetrapib, everolimus, flibanserin, fluvoxamine, 
fosaprepitant (IV), fostamatinib, garden cress seeds (Lepidium sativum)5, ginkgo (Ginkgo 
biloba)4, goldenseal (Hydrastis canadensis)4, grazoprevir, guan mai ning4, isoniazid, 
ivacaftor, lacidipine, linagliptin, lomitapide, obeticholic acid, oral contraceptives, palbociclib, 
pazopanib, peppermint oil5, piperine5, pomelo (Citrus grandis)5, propiverine, ranitidine, 
ranolazine, resveratrol4, roxithromycin, Seville orange juice5, simeprevir, sitaxentan, 
suvorexant, tabimorelin, tacrolimus, teriflunomide, ticagrelor, tolvaptan, tong xin luo4
1 A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by equal or more than 5-fold. 
2 A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by less than 5-fold but equal to or more than 2-fold. 
3 A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by less than 2-foldbut equal to or more than 1.25-fold.
4 Herbal product
5 Food product
6 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). 
7 Combination ritonavir-boosted regimens are listed here in the DDI memo as strong CYP3A inhibitors (to avoid 
potential confusion), even though some are considered moderate CYP3A inhibitors in the UW DDI Database.
8 The effect of certain fruit juices varies widely among brands and is concentration-, dose-, and preparation-
dependent.
This list is based on information from the FDA’s “Guidance for Industry, Drug Interaction 
Studies”, from the Indiana University School of Medicine’s “Clinically Relevant” Table and 
from the University of Washington’s Drug Interaction Database. Please note that this is not an
exhaustive list. Please refer to footnotes. Refer to Novartis Oncology Clinical Pharmacology 
Internal Memorandum, Drug-drug interactions (DDI) Database (last updated January 2018) for 
update or more details.


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Table 14-3 
CYP3A4 substrates: Narrow therapeutic index, sensitive, and others.
Category
Drug Names
Narrow 
Therapeutic 
index substrates 
of CYP3A41
alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus, terfanadine, thioridazine
Sensitive 
substrates of 
CYP3A42
alfentanil, alpha-dihydroergocryptine, almorexant , alisoporivir, aplaviroc, aprepitant, 
atazanavir, atorvastatin, avanafil, bosutinib, brecanavir, brotizolam, budesonide, buspirone, 
capravirine, casopitant, cobimetinib, conivaptan, danoprevir, darifenacin, darunavir, 
dasatinib, dronedarone, ebastine, eletriptan, elvitegravir, eplerenone, everolimus, 
felodipine, fluticasone, grazoprevir, ibrutinib, indinavir, isavuconazole, ivabradine, ivacaftor, 
levomethadyl (LAAM), lomitapide, lopinavir, lovastatin, lumefantrine, lurasidone, maraviroc, 
midazolam, midostaurin, naloxegol, neratinib, nisoldipine, paritaprevir, perospirone, 
quetiapine, ridaforolimus, saquinavir, sildenafil, simeprevir, simvastatin, tacrolimus, 
terfenadine, ticagrelor, tilidine, tipranavir, tolvaptan, triazolam, ulipristal, vardenafil, 
venetoclax, vicriviroc, voclosporin
Other 
Substrates of 
CYP3A43
alprazolam, ambrisentan, amlodipine, antipyrine, aripiprazole, artemether, avosentan, 
boceprevir, bosentan, buprenorphine, Cannabis sativa4, carbamazepine, dexloxiglumide, 
dextromethorphan, diazepam, docetaxel, enzalutamide, gemigliptin, halofantrine, 
imipramine, lansoprazole, lidocaine, linagliptin, loperamide, loratadine, losartan, lurasidone, 
macitentan, methadone, mirodenafil, montelukast, morphine, nelfinavir, netupitant, 
nevirapine, nifedipine, nilotinib, nitrendipine, omeprazole, ospemifene, oxycodone, 
paclitaxel, pazopanib, pioglitazone, quinine, ranolazine, repaglinide, rifabutin, ritonavir, 
roflumilast, saxagliptin, selegiline, sertraline, sibutramine, sotrastaurin, telaprevir, 
theophylline, tirilazad, tolterodine, udenafil, vincristine, voriconazole
1 Narrow therapeutic index substrates are drugs whose exposure-response relationship indicates that increases 
in their exposure levels by the concomitant use of an inhibitor may lead to serious safety concerns or drugs 
which have <2-fold difference in the minimum toxic concentrations and minimum effective concentrations in the 
blood (thus safe and effective use requires careful dosage titration and patient monitoring).
2 Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors of 
a given metabolic pathway in clinical DDI studies.
3Other substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors of 
a given metabolic pathway in clinical DDI studies.
4Tetrahydrocannabinol (9THC) and cannabidiol (CBD) are major constituents. 9THC is primarily metabolized 
by CYP2C9 to an active metabolite 11-hydroxy-9-THC (11-OH-THC). CBD is extensively metabolized by 
CYP2C19 and CYP3A4 to eight monohydroxylated metabolites. The effects of multiple daily doses of rifampicin 
600 mg for 10 days, ketoconazole 400 mg for 6 days and omeprazole 40 mg for 6 days on the PK of 9THC, 
11-OH-THC and CBD after a single dose (4 sprays) of an oromucosal spray were determined in a randomized, 
crossover, parallel study in three groups of 12 male subjects. Ketoconazole increased the Cmax and AUC0-24 
of 9THC by 1.2- and 1.8-fold, respectively, increased the Cmax and AUC0-24 of 11-OH-THC by 3.0- and 2.6-
fold, respectively, and increased the Cmax and AUC0-24 of CBD by 2- and 2-fold, respectively. Rifampicin 
decreased the Cmax and AUC24 of 9THC by 40 and 20%, respectively, decreased the Cmax and AUC0-24 
of 11-OH-THC by 85 and 87%, respectively, and decreased the Cmax and AUC24 of CBD by 50 and 60%, 
respectively. There were no effects of omeprazole on the plasma concentrations of all three cannabis 
constituents.
This list of CYP substrates was compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table; from the FDA’s “Guidance for Industry, Drug Interaction Studies” 
and from 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 
January 2018) for update or more details.


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Guidance on QT prolongation agents
A list of drugs associated with QT prolongation and/or Torsades de Pointes is available online
at https://crediblemeds.org/  

SAP_001.pdf: 
Clinical Development
AMN107/Nilotinib/Tasigna®
AMN107A2409 / NCT01735955
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)-Amendment 2
Document type:
SAP Documentation
Document status:
Final Amendment 2
Release date:
29-Jun-2023
Number of pages:
19
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP Amendment 2
AMN107A2409
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
Oct 
1, 
2018
Prior 
to DB 
lock
AMN107A2409 
Protocol 
Amendment v5
AEs and Investigator assessed clinical benefit are 
collected per the new process of Rollover protocol, 
which are collected in the study following Protocol 
Amendment version 3.0. SAP is amended to include 
these new endpoints. Prior to Protocol Amendment 
version 3.0 only SAEs were being collected.
The 
entire 
SAP 
template 
has 
been 
changed 
in 
accordance with the 
new SAP template as 
compared to the SAP 
template in 2012. As 
all the sections have 
been changed, ‘Section 
and title impacted’ are 
not filled up here.
29-Jun-
2023
Prior 
to DB 
lock
Creation 
of 
Amendment 2
Section 2.1 and 2.8.1: added the statement that AEs 
were not collected before Protocol Amendment 
version 3.0. Based on the original protocol only 
information if SAE (yes/no) occurred since previous 
visit was collected, further information related to the 
SAEs were collected only in the safety database.
Section 2.1.: clarified which data is to be included in 
the analysis
Section 2.7 and 5.6: time-windows for analysis of 
clinical benefit were added. 
Section 2.3.2: added COVID-19 related PDs listing.
Section 2.3.2: The relevant medical history and 
current medical conditions listing were added to align 
with the protocol, TFLs and CRF.
Section 2.4.1: removed reporting average daily dose 
and number of dosing days
Section 2.8.1.1: to align with current process 
statement that AESIs will be obtained from SAS 
dataset eCRS in the Novartis computing environment 
not from Excel spreadsheet in CREDI was added
Section 2.8.1.1: AESI listing and listing of Case 
Retrieval Strategy was added.
Section 2.8.1.2: the section on AE posting 
requirements was added
Section 2.8.3: Pregnancy and hepatitis B data listings 
were added to align with the protocol, TFLs and CRF.
Section 5.1.1: added one scenario to cover the 
imputation of the case when both last exposure end 
date and EOT date are partial
2.1, 2.8.1, 2.7, 5.6, 
2.3.2, 2.8.1.1, 2.8.1.2, 
2.8.3, 2.4.1 and, 5.1.1


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SAP Amendment 2
AMN107A2409
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.1.1
Description of study design.....................................................................6
1.1.2
Planned number of patients.....................................................................7
1.1.3
Primary analysis time point.....................................................................7
1.1.4
Timing of interim analyses......................................................................7
1.1.5
Definition of end of the study .................................................................7
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods...............................................................................................................8
2.1
Data analysis general information ...........................................................................8
2.1.1
General definitions..................................................................................9
2.2
Analysis sets ..........................................................................................................10
2.2.1
Full Analysis Set ...................................................................................10
2.2.2
Safety Set ..............................................................................................10
2.2.3
Dose-determining analysis set...............................................................10
2.3
Patient disposition, demographics and other baseline characteristics ...................10
2.3.1
Patient disposition.................................................................................10
2.3.2
Demographics and other baseline characteristics .................................11
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................12
2.4.1
Study treatment / compliance................................................................12
2.4.2
Prior, concomitant and post therapies...................................................12
2.5
Analysis of the primary objective..........................................................................12
2.5.1
Primary endpoint...................................................................................12
2.5.2
Statistical hypothesis, model, and method of analysis..........................12
2.5.3
Handling of missing values/censoring/discontinuations.......................12
2.5.4
Supportive analyses...............................................................................12
2.6
Analysis of the key secondary objective ...............................................................12
2.6.1
Key secondary endpoint........................................................................13
2.6.2
Statistical hypothesis, model, and method of analysis..........................13
2.6.3
Handling of missing values/censoring/discontinuations.......................13
2.7
Analysis of secondary efficacy objective(s)..........................................................13
2.7.1
Secondary endpoints .............................................................................13
2.7.2
Statistical hypothesis, model, and method of analysis..........................13


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2.7.3
Handling of missing values/censoring/discontinuations.......................13
2.8
Safety analyses.......................................................................................................13
2.8.1
Adverse events (AEs)............................................................................13
2.8.2
Deaths....................................................................................................15
2.8.3
Laboratory data .....................................................................................15
2.8.4
Other safety data ...................................................................................15
2.9
Pharmacokinetic endpoints....................................................................................15
2.10
PD and PK/PD analyses.........................................................................................15
2.11
Patient-reported outcomes .....................................................................................15
2.12
Biomarkers.............................................................................................................16
2.13
Other Exploratory analyses....................................................................................16
2.14
Interim analysis......................................................................................................16
3
Sample size calculation .....................................................................................................16
4
Change to protocol specified analyses ..............................................................................16
5
Appendix ...........................................................................................................................16
5.1
Imputation rules.....................................................................................................16
5.1.1
Study drug.............................................................................................16
5.1.2
AE date imputation ...............................................................................17
5.1.3
Concomitant medication date imputation .............................................18
5.1.4
Incomplete date for death......................................................................18
5.2
AEs coding/grading ...............................................................................................18
5.3
Laboratory parameters derivations ........................................................................19
5.4
Statistical models...................................................................................................19
5.4.1
Primary analysis....................................................................................19
5.4.2
Key secondary analysis.........................................................................19
5.5
Rule of exclusion criteria of analysis sets..............................................................19
5.6
Definition of time-windows for analysis of clinical benefit..................................19
6
Reference...........................................................................................................................19


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
bid
bis in diem/twice a day
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
MedDRA
Medical Dictionary for Drug Regulatory Affairs
o.d.
Once Daily
PK
Pharmacokinetics
qd
Qua’que di’e / once a day
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report 
(CSR) of study CAMN107A2409,  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.
The content of this SAP is based on protocol CAMN107A2409 Amendment 5.0. 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
1.1.1
Description of study design
This is a multi-center, open label, phase IV study to better characterize the long-term safety of 
nilotinib in patients being treated in current Novartis-sponsored, Oncology OGD&GMA 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. At this time, 
a 3-month supply of nilotinib will be dispensed to the patient/or as per local practice.
Patients must return to the study center on a quarterly basis (12 weeks +/- 1 week), for resupply 
of study medication at which time limited drug dispensing information will be collected. The 
patient may return to the clinic at any given time as per standard of care, however, only the 
quarterly visits will be recorded. All adverse events and serious adverse events will be collected 
throughout the study. For the safe and effective use of Tasigna, medical monitoring should be 
performed as clinically indicated at the physician’s discretion; 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,
the patient dies, 10 years after First Patient First Visit into this clinical trial, or until study 
treatment becomes commercially available and reimbursed in the respective indication,
whichever comes first. At every quarterly visit (12 weeks +/- 1 week), the investigator is 
required to confirm that the patient continues to have clinical benefit and may continue 
receiving study treatment.
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 from First Patient First Visit, which 
occurred on 29-Mar-2013, until study treatment becomes commercially available and is 
reimbursed in the respective indication or until such time that enrolled patients no longer need 
treatment with nilotinib, whichever comes earlier.


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Figure 1-1
1.1.2
Planned number of patients
The total number of patients enrolled will be dependent on the number of patients who enroll 
in Novartis-sponsored AMN107 studies and meet eligibility for the current study.
1.1.3
Primary analysis time point
This study will only have one analysis, namely final analysis. The analysis cut-off date for the 
final analysis will be established at the end of the study when all patients have been followed 
for 30 days after they have either prematurely discontinued from the treatment or completed
treatment as per protocol. All analyses will be performed using all data collected in the database 
up to the data cut-off date.
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘continuing at the cut-off date’. The same rule will be applied to events starting 
before or on the cut-off date and not having documented end date. This approach applies, in 
particular, to adverse event reports. For these events, the end date will not be imputed and 
therefore will not appear in the listings.
It is planned that the data from all centers that participate in this trial will be pooled and analyzed. 
Unless otherwise specified, qualitative data will be described using frequency and percentages, 
while quantitative data, will be described using descriptive statistics: n, mean, standard 
deviation, median, minimum, and maximum.
1.1.4
Timing of interim analyses
No interim analyses are planned.
1.1.5
Definition of end of the study
The end of study is defined as the date when all patients have completed their last assessment 
per protocol thirty days after end of treatment visit. The last assessment for each patient is the 


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follow-up assessment that occurs 30 days after the patient’s last dose of study treatment. 
Patients may continue on study treatment until one of the following criteria is met, whichever 
comes first:
-
At least one of the premature patient withdrawal criteria are met (See [Protocol Section 
7.1.5 and Section 7.1.5.1])
-
10 years after the First Patient’s First Visit into this clinical trial
-
Study treatment becomes commercially available and is reimbursed in the respective 
indication.
Should nilotinib not be commercially available to patients at end of study due to local 
regulations, Novartis will have a transition plan in place to ensure that patients benefiting from 
treatment continue to have access to nilotinib without any interruption of treatment.
1.2
Study objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below altogether with the planned 
analysis of collected data.
Table 1-1
Objective 
Endpoint
Analysis
Primary
To evaluate long term safety 
data (SAEs and AEs)
Frequency of
AEs/SAEs
Frequency and severity of
adverse events (AEs)
and Frequency of serious 
adverse
events (SAEs)
Secondary
To evaluate clinical benefit as 
assessed by the investigator
Clinical benefit as assessed 
by the investigator at 
scheduled visits.
Proportion of patients
with clinical benefit as
assessed by the
investigator will be
summarized at scheduled
visits.
2
Statistical methods
This section contains information that will be used to draft CSR Section 9.7 on statistical 
analysis.
2.1
Data analysis general information
The statistical analysis of these data will be performed by Novartis personnel or designated 
CRO in accordance with the data analysis section, Section 10, of the study protocol which is
available in [Appendix 16.1.1 of the CSR]. SAS version 9.4 or higher will be used in all analyses.  


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Data included in the analysis
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, 10 
years from First Patient First Visit 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.
All data reported in the database will be included in the analyses.
It is planned that the data from all centers that participate in this trial will be pooled and analyzed. 
Protocol amendment 3 (PA 3) was approved 07-Apr-2016. In this amendment the scheduled 
visits were changed from annually to quarterly and the regular data collection was increased.
Additional eCRFs were added to collect data related to

Study Evaluation Completion

AEs (based on original protocol only SAE yes/no was collected, and all SAEs were only 
collected on safety database)

Relevant medical history/current medical conditions

Hepatitis screen (only once at next possible visit)

Confirmation of Clinical Benefit from Study Treatment
However, at the time the PA 3 was approved, 45 patients were enrolled; 28 out of 45 patients 
were ongoing. Therefore, the additional data is not available for the patients who already 
discontinued when PA 3 was implemented in the countries, and many of the still ongoing 
patients only agreed to PA3 in 2017 at their next scheduled visit. Due to this, the data may be 
underestimated.
Unless otherwise specified, qualitative data will be described using frequency and percentages, 
while quantitative data, will be described using descriptive statistics: n, mean, standard 
deviation, median, minimum, and maximum.
2.1.1
General definitions
2.1.1.1
Study Treatment
Study drug and investigation treatment refers to nilotinib. Patients are to use the study treatment 
based on the parent protocol.
2.1.1.2
Date of first/last administration of study drug
The start date of study drug is defined as the first date when a non-zero dose of study drug was 
administered and recorded on the Dosage Administration Record (DAR) eCRF.
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug was administered and recorded on DAR eCRF.


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2.1.1.3
Treatment period
The overall observation period will be divided into two mutually exclusive segments:
1. on-treatment period: from day of first dose of study medication to 30 days after last dose of 
study medication
2. post-treatment period: starting at day 30+1 after last dose of study medication.
2.1.1.4
Study day
Definitions will be applied for all situations:
-
Study day for post-treatment event = event date – first dose date + 1
-
Study day for pre-treatment event = first dose date - event date
The first day of study drug is study day 1.
If duration is to be reported in weeks, duration in days will be divided by 7, likewise if in months, 
then duration in days will be divided by 30.4375 and if in years, duration in days will be divided 
by 365.25.
2.2
Analysis sets
The following analysis sets will be used for statistical analysis and data reporting.
2.2.1
Full Analysis Set
Not applicable.
2.2.2
Safety Set
The Safety Set includes all patients who received at least one dose of study medication after 
enrolling into the roll-over protocol.
2.2.3
Dose-determining analysis set
Not applicable.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
Patient disposition will be summarized using the Safety Set. The following will be tabulated:
-
Number (%) of patients, who remained in the trial at the time of data cut-off or final 
data base lock;
-
Number (%) of patients who discontinued the treatment;
-
Number (%) of patients by primary reason for end of treatment (based on patient status 
entered in the ‘END OF TREATMENT DISPOSITION’ page).


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Listings will be provided for disposition, protocol deviation using the Safety set. In addition, 
patients with any COVID-19 related protocol deviation will be listed.
2.3.2
Demographics and other baseline characteristics
Demographic (sex, age, previous study number and women of childbearing potential (WOCBP)) 
will be summarized descriptively and listed for the Safety Set. The relevant medical history and 
current medical conditions will be listed. Medical history/current medical conditions are coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The latest 
MedDRA version available at the time of reporting will be used.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Dose administration data will be summarized using the Safety Set.
2.4.1.1
Dose intensity and exposure
Definition of duration of exposure, includes:

Duration of exposure (days):   last date of study drug − first date of study drug + 1
Duration of exposure to study drug will be summarized descriptively. In addition, the duration 
of exposure to study drug will be categorized into time intervals; frequency counts and 
percentages of patients with exposure in each time interval will be presented.
The Dose administration data along with derived parameters will be listed using Safety Set.
2.4.2
Prior, concomitant and post therapies
Not applicable.
2.5
Analysis of the primary objective
The primary objective is to evaluate long term safety as assessed by the occurrence of 
AEs/SAEs.
2.5.1
Primary endpoint
The assessment of safety will be based mainly on the frequency and severity of AEs and SAEs. 
See also Section 2.8.
2.5.2
Statistical hypothesis, model, and method of analysis
The primary endpoint (AEs ans SAEs) will be summarized descriptively, and no formal analysis 
will be performed.
2.5.3
Handling of missing values/censoring/discontinuations
Not applicable.
2.5.4
Supportive analyses
No supportive analysis will be performed.
2.6
Analysis of the key secondary objective
There is no key secondary objective.


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2.6.1
Key secondary endpoint
Not applicable.
2.6.2
Statistical hypothesis, model, and method of analysis
Not applicable.
2.6.3
Handling of missing values/censoring/discontinuations
Not applicable.
2.7
Analysis of secondary efficacy objective(s)
The secondary objective of the study was to evaluate clinical benefit as assessed by the 
investigator. The definition of time windows for the analysis of clinical benefit are provided in 
the Section 5.6.
2.7.1
Secondary endpoints
Proportion of patients with clinical benefit as assessed by the investigator will be summarized 
at scheduled visits by using the Safety Set.
2.7.2
Statistical hypothesis, model, and method of analysis
Not applicable.
2.7.3
Handling of missing values/censoring/discontinuations
Not applicable.
2.8
Safety analyses
Safety analyses will be performed on Safety Set. The assessment of safety will be based mainly 
on the frequency of AEs and SAEs.
2.8.1
Adverse events (AEs)
Treatment emergent AEs are defined as those that started on or after the study medication or 
those that started before study medication but worsened afterwards up to after 30 days post the 
last dose of study medication. AEs starting after 30 days post the last dose of study medication 
are not considered treatment emergent AEs.
Summary tables of adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, i.e. the treatment-emergent AEs. However, all safety data 
(including those from the post-treatment periods) will be listed and those collected during the 
post treatment period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and/or preferred term, severity based on CTCAE grades 
(version 4.03 or higher), type of adverse event, relation to study treatment. The categorical 
summary will include AEs regardless of study-drug relationship. The same analysis will be 
repeated for SAEs.


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Adverse events will be summarized by presenting the number and percentage of patients having 
any adverse event, having an adverse event in each primary system organ class, and having an 
adverse event with a particular preferred term within a system organ class.
However, all AEs and SAEs data including those collected before study day 1 or more than 30 
days after end of study will be listed and flagged.
AEs were not collected before Protocol Amendment version 3.0. Based on the original protocol 
only information on whether SAE  occurred since previous visit (yes/no) was collected.  Further 
information related to the SAEs were collected only in the safety database. All adverse events
ended before Protocol Amendment version 3.0 will be flagged in the listing.
Adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology using the latest available MedDRA version at the time of the analyses and the 
information of MedDRA version will be specified in the footnote of relevant outputs.
The following selection of AEs will be listed and summarized separately. All these AEs will be 
summarized for all grades and for grade 3 or 4 side-by-side for Safety Set.

AEs

AEs suspected to be study drug related

AEs reported as serious AEs (SAEs)

SAEs suspected to be study drug related

AEs associated with discontinuation of study drug
2.8.1.1
Adverse events of special interest / grouping of AEs
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them.
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the [Investigator Brochure].
Specific grouping of AEs (AESI) will be obtained from SAS dataset eCRS in the Novartis 
computing environment. For each specified safety event category, number and percentage of 
patients with at least one event part of the safety event category will be reported by safety subset
and listed. PTs associated with every AESI group will also be listed.
2.8.1.2
Adverse events posting
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-
treatment adverse events which are not serious adverse events with an incidence greater than 5% 
and on on-treatment serious adverse events and SAE suspected to be related to study treatment 
will be provided by system organ class and preferred term on the safety set population.
If, for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:


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
a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. Since the regular 
AE data collection only started with ICF date for PA3, the table related to SAE will be produced 
directly from the safety database. And only the table related to non-serious AEs will be 
programmed using the data from the clinical database.
2.8.2
Deaths
On-treatment deaths which occur within the study or within 30 days after discontinuation from 
the study will be summarized using n (%) for safety set. All deaths due to any cause at any time 
in the study, including the follow-up period, will also be summarized using n (%). All deaths 
will also be listed and post treatment deaths will be flagged.
2.8.3
Laboratory data
All pregnancy monitoring data will be listed. Hepatitis B surface antigen (HBs Ag) and 
antibodies to hepatitis B core antigen (HBc Ab / anti HBc) data will be listed. 
2.8.4
Other safety data
Not applicable.
2.8.4.1
ECG and cardiac imaging data
Not applicable.
2.8.4.2
Vital signs
Not applicable.
2.9
Pharmacokinetic endpoints
Not applicable.
2.10
PD and PK/PD analyses
Not applicable.
2.11
Patient-reported outcomes
Not applicable.


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2.12
Biomarkers
Not applicable.
2.13
Other Exploratory analyses
Not applicable.
2.14
Interim analysis
Not applicable.
3
Sample size calculation
Not applicable.
4
Change to protocol specified analyses
Not applicable.
5
Appendix
5.1
Imputation rules
In this section provide necessary details as needed for imputation.
5.1.1
Study drug
Below mentioned imputation rules will be used in case of missing or partial end date of study 
drug.
Scenario 1
If the last date of study drug is after the cut-off date or is completely missing and there is no 
end of treatment eCRF page and no death date the patient should be considered to be ongoing 
and use the cut-off date for the analysis as the last dosing date
Scenario 2
If the last date of study drug is partial and the end of treatment (EOT) eCRF page is available 
but partial then the last dosing date will be imputed with the earliest date among the latest visit 
date, last day of the month of last dose end date, last day of the month of EOT date. 
Scenario 3
If the last date of study drug is completely or partially missing and there is EITHER an end of 
treatment eCRF page OR a death complete date available then imputed last dose date:
= 31DECYYYY, if only Year is available and Year < Year of min (EOT visit date, 
death date) 
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT visit date, death date) and Month < the month of min (EOT visit date, death date)


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= min (EOT visit date, death date), for all other cases
The imputed date will be compared with start date of study drug.
If the imputed date < start date of study drug, then last date of study drug is set to start date of 
study drug; otherwise, use the imputed date.
5.1.2
AE date imputation
Missing date for AE will be handled according to rules specified below. A partial date is simply 
an incomplete date e.g. DDOCT2001: the days are missing from this DDMMMYYYY date.
There will be no attempt to impute the following:
-
Missing AE start dates
-
AE start dates missing the year
-
Partial/missing AE end dates
Table 5-1
AE/Treatment date abbreviations
Day
Month
Year
Partial AE start date
<not used>
AEM
AEY
Treatment start date (TRTSTD)
<not used>
TRTM
TRTY
The following matrix Table 5-2 describes the possible combinations and their associated 
imputations. In the light grey boxes the upper text indicates the imputation and the lower text 
the relationship of the AE start date to the treatment start date (TRTSTD).
Table 5-2
AE partial date imputation algorithm
AEM Missing
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY Missing
NC
NC
NC
NC
AEY < TRTY
Before TRTSTD
(D)
Before TRTSTD
(C)
Before TRTSTD
(C)
Before TRTSTD
(C)
AEY = TRTY
Uncertain
(B)
Before TRTSTD
(C)
Uncertain
(B)
After TRTSTD
(A)
AEY > TRTY
After TRTSTD
(E)
After TRTSTD
(A)
After TRTSTD
(A)
After TRTSTD
(A)
Table 5-3
AE/treatment date relationship and imputation legend
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
NC/Blank 
No convention/imputation
(A) 
01MONYYYY


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Relationship
(B) 
TRTSTD+1
(C)
15MONYYYY
(D) 
01JULYYYY
(E) 
01JANYYYY
The following Table 5-4 gives a few examples.
Table 5-4
AE imputation example scenarios
Partial AE start date
Treatment start date
Relationship 
Imputation 
calculation
Imputed date
12mmyyyy  
20OCT2001
Uncertain
NC
<blank>
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
5.1.3
Concomitant medication date imputation
Not applicable
5.1.3.1
Prior therapies date imputation
Not applicable
5.1.3.2
Post therapies date imputation
Not applicable
5.1.3.3
Other imputations
Not applicable
5.1.4
Incomplete date for death
All dates must be completed with day, month and year. If the day or month is missing, death 
will be imputed to the maximum of the last contact date (excluding the date of death) and the 
following:
-
Missing day: 15th of the month and year of death
-
Missing day and month: July 1st of the year of death
5.2
AEs coding/grading
Not applicable


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5.3
Laboratory parameters derivations
Not applicable.
5.4
Statistical models
5.4.1
Primary analysis
Not applicable.
5.4.2
Key secondary analysis
Not applicable.
5.5
Rule of exclusion criteria of analysis sets 
Not applicable.
5.6
Definition of time-windows for analysis of clinical benefit
For clinical benefit, time windows will be used to identify data to be considered for the specific 
analysis at a specific time point. The time windows are defined so that there are no gaps between 
the planned assessments, i.e. every assessment including additional unscheduled assessments 
would be assigned to one specific time point. If there is more than one assessment within the 
time window, the last available assessment in that time window will be used. Time windows 
are defined based on date of first study drug intake (= Study Day 1). Table 5-5 shows the time 
windows for the analyses of clinical benefit.
Table 5-5
Time windows for analyses of clinical benefit
Planned assessment
Time window
Week 24 (Day 168)
Day 2 to Day 251
Week 48 (Day 336)
Day 252 to Day 419
Week 72 (Day 504)
Day 420 to Day 587
Week 96 (Day 672)
Day 588 to Day 755
Year 3 (Day 1008)
Day 756 to Day 1175
Year xx (Day xx*7*48)
Day ((xx*48 - 24) * 7) to Day ((xx*48 + 24) * 7-
1)
xx = Every year until data is available
6
Reference
None.


Clinical Development
AMN107/Nilotinib/Tasigna®
AMN107A2409 / NCT01735955
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) 
for Novartis Safety database (ARGUS) generated data – Amendment 1
Author:
 
Document type:
SAP Documentation
Document status:
Final – Amendment 1
Release date:
21-July -2023
Number of pages:
10
Property of Novartis Pharma AG
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis Pharma AG


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Amendment 1
Document History - Changes compared to previous final version
Version
Date
Changes
Final 1.0
05-Oct-2022
NA – First version (Prior to DB lock)
Final 1.0 
Amendment 
1
21-July-2023
Amendment 1 was performed to incorporate changes requested by 
CTT:

for all outputs clarified that SAEs are coming from ARGUS

Listing 14.3.2-2.1: columns SAE and Grades were removed. 
Footnote "* More than 30 days after last study treatment." was
replaced with "+ = start date is in the pre and post-treatment 
period."

Table 14.3.1-2.3: replaced title  "On-treatment deaths and 
serious adverse events by system organ class, preferred term 
and risk group” with "On-treatment deaths and serious adverse 
events,  by system organ class, preferred term". Clarified that for 
this output deaths are coming from clinical database while SAEs 
are coming from ARGUS database. 

Section 3.1 was updated to reflect that time of SAE is not 
collected in ARGUS


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Table of contents
Table of contents .................................................................................................................3
List of output shells .............................................................................................................3
1
Introduction .........................................................................................................................4
2
Analysis of serious adverse events from ARGUS database................................................4
3
Novartis safety database (ARGUS).....................................................................................4
3.1
Retrieval of data from ARGUS ...............................................................................4
3.2
Transfer of data from Novartis Safety database to GPS tool...................................6
4
Shells for Outputs................................................................................................................7
List of output shells
Table 3-1
Data field in ARGUS version 8 ..............................................................5
Listing 14.3.2-2.1
Serious adverse events from ARGUS database (Safety set)...................7
Table 14.3.1-2.1
Serious adverse events from ARGUS database, regardless of study 
drug relationship by primary system organ class and preferred term 
(Safety Set)..............................................................................................8
Table 14.3.1-2.2
Serious adverse events from ARGUS database, suspected to be 
study drug related by primary system organ class and preferred 
term (Safety Set) .....................................................................................9
Table 14.3.1-2.3
On-treatment deaths and serious adverse events by system organ 
class, preferred term (Safety Set)..........................................................10


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1
Introduction
This statistical analysis plan (SAP) describes the planned analyses for tables which will be 
generated from Novartis Safety database (ARGUS) reported in the study CAMN107A2409.
The purpose of this roll-over study CAMN107A2409 is to allow continued use of nilotinib to 
patients who are on nilotinib treatment in a Novartis-sponsored, Oncology Clinical 
Development & Medical Affairs (CD&MA) study, have fulfilled all their requirements in the 
parent study and are benefiting from the treatment as judged by the investigator. As per the 
initial study protocol dated 11-Oct-2012, the safety reporting requirement was only limited to 
reporting of all serious adverse events (SAEs) to Novartis Safety database (ARGUS). The 
collection of all adverse events (including serious and non-serious) in the clinical database was 
introduced in the protocol amendment version 03 dated 07-Apr-2016 which was approximately 
3 years after the First Patient First Visit (29-Mar-2013) in this study. Thus, the tables and listings 
reflecting the totality of SAEs reported in the entire study period can be generated only based 
on the data recorded in ARGUS.
This document serves as a complement to the CAMN107A2409 Statistical Analysis Plan for 
the final clinical study report (CSR) and describes the criteria of the line listings to be retrieved 
from ARGUS and used by the statistical programming team to generate the above stated tables 
and listings.
2
Analysis of serious adverse events from ARGUS database
The following SAE summary tables and listing will be generated based on the data from 
ARGUS.

Listing of SAEs from ARGUS

Table of SAEs regardless of study treatment relationship from ARGUS by primary 
system organ class and preferred term

Table of SAEs suspected to be study drug related from ARGUS by primary system 
organ class and preferred term

Table of on-treatment deaths and treatment-emergent SAEs by system organ class and 
preferred term (for legal requirements of ClinicalTrials.gov and EudraCT).
The layout of these tables and listing will be similar to the one produced from the clinical 
database. The corresponding output shells are provided in section 4.
3
Novartis safety database (ARGUS)
3.1
Retrieval of data from ARGUS
A line listing of all SAEs with a case receipt date from First Patient First Visit date (29-Mar-
2013) to Last Patient Last Treatment (LPLT) +30 days for Study ID CAMN107A2409 will be 
generated from the ARGUS by the Novartis Data Science & Analytics team (DS&A).
The line listings will include the following information (column headings). Description of the 
data field is provided wherever necessary in the Table 3-1 below.


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Table 3-1
Data field in ARGUS version 8
Data field in ARGUS version 8
Description
Case Number
Number of the case
Study ID
Trial Number
Center ID
Site ID
Subject number/Patient ID
-
Company Drug code
-
Product Name/Study drug
-
Onset date
Event onset date
Seriousness criteria
Event seriousness criteria
Causality as Reported Source
Causality as Reported by the Investigator or Health Care 
professional
Causality as Determined Source
Causality as Determined by Novartis
Event Preferred Term
Coded term based on MedDRA version at the time of 
event reported in ARGUS
Lower Level Term
MedDRA term
HLT name
MedDRA term
HLGT name
MedDRA term
SOC
MedDRA term
Outcome of Event
-
Death Date
-
Death Cause PT
MedDRA term
Product Indication
-
Daily dose with Units
-
Duration of Regimen
-
Action taken 
-
De-challenge
-
Re-challenge
-
Country
-
Patient date of birth
-
Description of events
Event verbatim


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Data field in ARGUS version 8
Description
End date
Event end date
Lower Level Term Code
MedDRA Code
High Level Term Code
MedDRA Code
High Level Group Term Code
MedDRA Code
Primary System Organ Class Code
MedDRA Code
Preferred Term Code
MedDRA Code
Occurrences
-
Death Flag
-
Deleted/Deactivated case
-
Reason for deletion/deactivation
-
3.2
Transfer of data from Novartis Safety database to GPS tool
The line listings from ARGUS database will be sent via email (Global, Pvdm (Gen) 
) from DS&A to the programming team.
PI


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4
Shells for Outputs 
The below shells are used for the analysis from adverse event data coming from clinical database. For the analysis of SAEs from ARGUS 
database the shells may be updated to incorporate the different data structure in ARGUS.
Listing 14.3.2-2.1
Serious adverse events from ARGUS database (Safety set)
Country/
Center/ 
Patient
Age/ 
Sex
REPORTED /
  Preferred term /
  System organ 
class
Start 
date+/
Study 
day
End 
date/
Study 
day
Dur. 
(day
s)
Relat
.
to 
study
drug
Acti
on
take
n
USA/201/
0001
55/M
/Ca
MILD DIZZINESS /    
  Dizziness (exc 
vertigo) /
  Nervous system 
disorders
1999-
09-16/
9
1999-
09-23/
16
8
Not 
susp 
0
                   
_
        
_
        
_
      
_
USA/201/
0008
71/F
/Ca
GASTRIC DISTRESS /  
  Abdominal pain 
upper /
  Gastrointestinal 
disorders
1999-
09-25/
93*
1999-
09-26/
94*
2
Susp   0
Action taken: 0=Dose reduced, 1=No Change, 2=Not Applicable, 3=Treatment 
Discontinued, 4=Treatment Temporary Interrupted.
+ Start date is in the pre or post-treatment period.
MedDRA version <xx.x>, CTCAE version <x.xx>.
Study day is calculated from treatment start date.
Programming Note:
1.
Please note that the output may be updated to incorporate the different data structure in ARGUS.
2.
Flag those SAEs that occurred more than 30 days after last treatment.
3.
Display ‘Ongoing’ under column ‘End date/Study Day’ if AE is ongoing at final exam / at time of data cut-off.
4.
All dates should be provided in the format ddmmmyyy as they are in the database.


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5.
Oncology standards CSR v3.1 Listing L_AE_303B
Table 14.3.1-2.1 Serious adverse events from ARGUS database, regardless of study drug relationship by primary system organ 
class and preferred term (Safety Set)
Primary system organ class
  Preferred term
All patients
N=xxx
n (%)
Number of patients with
at least one event
xxx (xx.x)
Cardiac disorders
xxx (xx.x)
Angina pectoris
xxx (xx.x)
Oedema NOS
xxx (xx.x)
Oedema lower limb
xxx (xx.x)
Bradycardia NOS
xxx (xx.x)
Oedema peripheral
xxx (xx.x)
Sinus bradycardia
xxx (xx.x)
SOC 2
xxx (xx.x)
PT1
xxx (xx.x)
etc.
xxx (xx.x)
Numbers (n) represent counts of patients.
MedDRA version <xx.x>
Includes only on-treatment events.
Programming Note:
1.
Sort SOC by alphabetical order, PTs by descending frequency.
2.
Include only on-treatment events (as defined in SAP). 
3.
CSR Oncology standard TLF version 3.1 Table T_AE_301X


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Table 14.3.1-2.2 Serious adverse events from ARGUS database, suspected to be study drug related by primary system organ 
class and preferred term (Safety Set)
Primary system organ class
  Preferred term
All patients
N=xxx
n (%)
Number of patients with
at least one event
xxx (xx.x)
Cardiac disorders
xxx (xx.x)
Angina pectoris
xxx (xx.x)
Oedema NOS
xxx (xx.x)
Oedema lower limb
xxx (xx.x)
Bradycardia NOS
xxx (xx.x)
Oedema peripheral
xxx (xx.x)
Sinus bradycardia
xxx (xx.x)
SOC 2
xxx (xx.x)
PT1
xxx (xx.x)
etc.
xxx (xx.x)
Numbers (n) represent counts of patients.
MedDRA version <xx.x>
Includes only on-treatment events.
Programming Note:
1.
Sort SOC by alphabetical order, PTs by descending frequency.
2.
Include only on-treatment events (as defined in SAP) suspected to be study-drug related. 
3.
CSR Oncology standard TLF version 3.1 Table T_AE_301X


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Table 14.3.1-2.3 On-treatment deaths and serious adverse events by system organ class, preferred term (Safety Set)
This is a ClinTrials.gov requirement. This will not be used for the CSR.
Primary system organ class
  Preferred term
All patients
N=xxx
Total number of patients affected
Patients affected by serious adverse events / exposed (%)
xxx/xxx (xx.xx)
Number of deaths (all causes)
xx
Number of deaths resulting from adverse events*
xx
Infections and infestations
Pneumonia
Patients affected / exposed (%)
xxx/xxx (xx.xx)
Occurrences causally related to treatment/all
xx/xx
Deaths causally related to treatment/all
xx/xx
Sepsis
Patients affected / exposed (%)
xxx/xxx (xx.xx)
Occurrences causally related to treatment/all
xx/xx
Deaths causally related to treatment/all
xx/xx
Investigations
Platelet count decreased
Patients affected / exposed (%)
xxx/xxx (xx.xx)
Occurrences causally related to treatment/all
xx/xx
Deaths causally related to treatment/all
xx/xx
etc.
*Number of deaths resulting from adverse events corresponds to deaths resulting from serious AE throughout the study in 
safety database (ARGUS) causally related to treatment.
Occurrences causally related to treatment/all: all occurrences are all SAEs occurrences regardless of causality to 
treatment.
Deaths causally related to treatment/all: all deaths are all SAEs with fatal outcome regardless of causality to treatment.
Includes only on-treatment events.
The on-treatment death data is from the clinical database, and the SAE data is from Argus.
MedDRA version <xx.x>.
Programming Note:
1.
Table used for posting to EudraCT and CT.gov.
2.
Oncology standards CSR v3.1 Table T_AE_320.