Conditions: Leukemia
Keywords: Nilotinib AMN107 Tasigna Imatinib STI571 Gleevec/Glivec BCR-ABL Positive Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP) Chronic myelogenous leukemia Chronic myeloid leukemia Chronic myelocytic leukemia Acute Lymphoblastic Leukemia (ALL) Philadelphia chromosome positive Acute Lymphoid Leukemia suboptimal molecular response
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 225
Healthy volunteers: no

Brief summary:
The extension study followed the core study CAMN107ECN02 (NCT01275196). which is an open-label, two armed study. All patients enrolled in this extension study were able to benefit from the treatment given in CAMN107ECN02 per investigator's evaluation. Therefore, in this extension study patient continued treatment of the drug (imatinib or nilotinib) which they were taking at the end of CAMN107ECN02. Treatment arms in CAMN107ECN02 were retained. As long as EC approval and agreement from investigators were obtained, the selected sites for CAMN107ECN02 were applied in this extension study.

Detailed description:
Up to 230 patients who benefited from the core study treatment (imatinib or nilotinib), at Investigator's discretion, were enrolled into this extension study. The patients continued receiving the open-label drugs that they were taken by the end of core study. Treatment arms in the core study were retained. No crossover between the arms was allowed.

The extension study started from the first patient last dose date in the core study and ends at the time of nilotinib was commercially available in China as a first line treatment. Eligibility evaluations were given for each patient before the enrollment. Follow-up visits at a frequency of 6 months were required to report AE, SAE and pregnancy only. No efficacy data were collected in the extension study since full efficacy had already been analyzed in the core study.

Arms:
arm 1: Eligible patients from imatinib arm in core study CAMN107ECN02 were enrolled into imatinib arm in this study. Patients in imatinib 400 mg daily arm received imatinib daily dose of 300 mg, 400 mg or 600 mg all at once every day. arm 2: Eligible patients from nilotinib arm in core study CAMN107ECN02 were enrolled into imatinib arm in this study. Patients in nilotinib arm received 300 mg BID by mouth each morning and evening approximately 12 hours apart, or 400 mg QD.

Interventions: intervention 1: Imatinib intervention 2: Nilotinib
Intervention descriptions: intervention 1: Imatinib 400mg QD，300mg QD or 600mg QD intervention 2: Nilotinib 300mg BID or 400mg QD

Protocol document:
Prot_001.pdf: 
Clinical Development 
AMN107 (Nilotinib, Tasigna) 
Protocol Synopsis CAMN107ECN02E1 / NCT02272777
An open-label multi-center study of imatinib and nilotinib in 
CAMN107ECN02 on-treatment patients with Philadelphia 
chromosome positive chronic myelogenous leukemia in 
chronic phase after the end of CAMN107ECN02 core study 
（ENESTChina extension study） 
Authors 
 
 
Document type 
Oncology Amended Protocol 
EUDRACT number 
Not applicable 
Version number 
01 (Protocol amendment) 
Development phase 
IIIb 
Document status 
Final 
Release date 
27-May-2014
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Template version 02-Dec-2013 


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Table of contents 
Table of contents ............................................................................................................. 2 
List of appendices ........................................................................................................... 6 
List of tables ................................................................................................................... 6 
List of abbreviations ........................................................................................................ 7 
Amendment 1 ...................................................................................................................... 11 
1 
Background ................................................................................................................... 13 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment ............. 14 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............ 14 
1.2.1 
Overview of nilotinib ......................................................................... 14 
1.2.2 
Over view of imatinib ........................................................................ 20 
2 
Rationale ....................................................................................................................... 23 
2.1 
Study rationale and purpose ............................................................................... 23 
2.2 
Rationale for the study design ............................................................................ 24 
2.3 
Rationale for dose and regimen selection ........................................................... 24 
2.4 
Rationale for choice of combination drugs ......................................................... 24 
2.5 
Rationale for choice of comparators drugs ......................................................... 24 
3 
Objectives and endpoints ............................................................................................... 24 
4 
Study design ................................................................................................................. 25 
4.1 
Description of study design ................................................................................ 25 
4.2 
Timing of interim analyses and design adaptations ............................................. 25 
4.3 
Definition of end of the study............................................................................. 25 
4.4 
Early study termination ...................................................................................... 26 
5 
Population ..................................................................................................................... 26 
5.1 
Patient population .............................................................................................. 26 
5.2 
Inclusion criteria ................................................................................................ 26 
5.3 
Exclusion criteria ............................................................................................... 26 
6 
Treatment ...................................................................................................................... 27 
6.1 
Study treatment .................................................................................................. 27 
6.1.1 
Dosing regimen.................................................................................. 27 
6.1.2 
Ancillary treatments ........................................................................... 28 
6.1.3 
Rescue medication ............................................................................. 29 
6.1.4 
Guidelines for continuation of treatment ............................................ 29 
6.1.5 
Treatment duration ............................................................................. 29 
6.2 
Dose escalation guidelines ................................................................................. 29 
6.3 
Dose modifications ............................................................................................ 29 


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6.3.1 
Dose modification and dose delay ...................................................... 29 
6.3.2 
Follow-up for toxicities ...................................................................... 46 
6.3.3 
Anticipated risks and safety concerns of the study drug ...................... 46 
6.4 
Concomitant medications ................................................................................... 47 
6.4.1 
Permitted concomitant therapy ........................................................... 47 
6.4.2 
Permitted concomitant therapy requiring caution and/or action .......... 47 
6.4.3 
Prohibited concomitant therapy .......................................................... 47 
6.5 
Patient numbering, treatment assignment or randomization ................................ 48 
6.5.1 
Patient numbering .............................................................................. 48 
6.5.2 
Treatment assignment or randomization ............................................. 48 
6.6 
Study drug preparation and dispensation ............................................................ 48 
6.6.1 
Study drug packaging and labeling ..................................................... 49 
6.6.2 
Drug supply and storage..................................................................... 49 
6.6.3 
Study drug compliance and accountability ......................................... 49 
6.6.4 
Disposal and destruction .................................................................... 49 
7 
Visit schedule and assessments...................................................................................... 50 
7.1 
Study flow and visit schedule ............................................................................. 50 
7.1.1 
Molecular pre-screening..................................................................... 50 
7.1.2 
Screening ........................................................................................... 50 
7.1.3 
Run-in period ..................................................................................... 51 
7.1.4 
Treatment period ................................................................................ 51 
7.1.5 
End of treatment visit including study completion and premature 
withdrawal ......................................................................................... 51 
7.1.6 
Follow up period ................................................................................ 52 
7.2 
Assessment types ............................................................................................... 52 
7.2.1 
Efficacy assessments .......................................................................... 52 
7.2.2 
Safety and tolerability assessments..................................................... 52 
8 
Safety monitoring and reporting .................................................................................... 52 
8.1 
Adverse events................................................................................................... 52 
8.1.1 
Definitions and reporting ................................................................... 52 
8.1.2 
Laboratory test abnormalities ............................................................. 54 
8.2 
Serious adverse events ....................................................................................... 54 
8.2.1 
Definitions ......................................................................................... 54 
8.2.2 
Reporting ........................................................................................... 55 
8.3 
Emergency unblinding of treatment assignment ................................................. 56 
8.4 
Pregnancies........................................................................................................ 56 


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8.5 
Warnings and precautions .................................................................................. 56 
8.6 
Data Monitoring Committee .............................................................................. 56 
8.7 
Steering Committee ........................................................................................... 57 
9 
Data collection and management ................................................................................... 57 
9.1 
Data confidentiality............................................................................................ 57 
9.2 
Site monitoring .................................................................................................. 57 
9.3 
Data collection ................................................................................................... 58 
9.4 
Database management and quality control ......................................................... 58 
10 Statistical methods and data analysis ............................................................................. 58 
10.1 
Analysis sets ...................................................................................................... 59 
10.1.1 
Safety Set........................................................................................... 59 
10.2 
Patient demographics/other baseline characteristics ........................................... 59 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ...................... 59 
10.4 
Primary objective ............................................................................................... 59 
10.4.1 
Variable ............................................................................................. 59 
10.4.2 
Statistical hypothesis, model, and method of analysis ......................... 59 
10.4.3 
Handling of missing values/censoring/discontinuations ...................... 59 
10.4.4 
Supportive analyses ........................................................................... 59 
10.5 
Secondary objectives ......................................................................................... 59 
10.6 
Exploratory objectives ....................................................................................... 59 
10.7 
Interim analysis ................................................................................................. 60 
10.8 
Sample size calculation ...................................................................................... 60 
10.9 
Power for analysis of key secondary variables ................................................... 60 
11 Ethical considerations and administrative procedures .................................................... 60 
11.1 
Regulatory and ethical compliance ..................................................................... 60 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 60 
11.3 
Informed consent procedures ............................................................................. 60 
11.4 
Discontinuation of the study .............................................................................. 61 
11.5 
Publication of study protocol and results ............................................................ 61 
11.6 
Study documentation, record keeping and retention of documents...................... 61 
11.7 
Confidentiality of study documents and patient records ...................................... 62 
11.8 
Audits and inspections ....................................................................................... 62 
11.9 
Financial disclosures .......................................................................................... 62 
12 Protocol adherence ........................................................................................................ 62 
12.1 
Amendments to the protocol .............................................................................. 62 
13 References (available upon request) .............................................................................. 63 


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14 Appendix ...................................................................................................................... 65 
14.1 
Appendix 1 List of CYP3A4 inducers and inhibitors .......................................... 65 
 


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List of appendices 
14.1Appendix 1         List of CYP3A4 inducers and inhibitors Error! Bookmark not defined. 
 
List of tables 
Table 3-1 
Objectives and related endpoints ........................................................ 24 
Table 6-1 
Recommended dosing ........................................................................ 28 
Table 6-2 
Summary of dose reduction guidelines for study drug-related non-
hematological toxicity and for ischemic vascular and cardiovascular 
events regardless of study drug relationship – IMATINIB .................. 31 
Table 6-3 
Summary of dose reduction guidelines for study drug-related non-
hematological toxicity and for ischemic vascular and cardiovascular 
events regardless of study drug relationship- NILOTINIB .................. 38 
Table 6-4 
Summary of dose reduction guidelines for study drug-related 
hematological toxicity – IMATINIB .................................................. 43 
Table 6-5 
Summary of dose reduction guidelines for study drug-related 
hematological toxicity – NILOTINIB ................................................. 43 
Table 6-6 
Drug supply ....................................................................................... 48 
Table 7-1 
Visit evaluation schedule ................................................................... 50 
Table 14-1 
List of medications metabolized by CYP3A4, strong, moderate and 
weak inhibitors of CYP3A4 to be used with caution........................... 65 
Table 14-2  Medications that can inhibit CYP3A4 ................................................................ 66 
 


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List of abbreviations 
AE 
Adverse Event 
AP 
Accelerated Phase 
BC 
Blast Crisis 
BID 
Twice a day 
CDS 
Core Data Sheet 
CP 
Chronic Phase 
CRF 
Case Report/Record Form 
CRO 
Contract Research Organization 
DLT 
Dose Limiting Toxicity 
DS&E 
Drug Safety and Epidemiology 
GPP 
Good Pharmacoepidemiology Practices 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
IRB 
Institutional Review Board 
QD 
Once a day 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
WHO 
World Health Organization 


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Protocol number 
CAMN107ECN02E1 
Title 
An open-label multi-center study of imatinib and nilotinib in 
CAMN107ECN02 
on-treatment 
patients 
with 
Philadelphia 
chromosome positive chronic myelogenous leukemia in chronic 
phase after the end of CAMN107ECN02 core study（ENESTChina 
extension study） 
Brief title 
Study of imatinib and nilotinib in CAMN107ECN02 on treatment 
patients with CML-CP (ENESTChina extension study） 
Sponsor and Clinical 
Phase 
Novartis, IIIb 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
In the core study CAMN107ECN02, 267 patients were 1:1 
randomized to receive imatinib or nilotinib treatment. Per protocol 
of CAMN107ECN02, patients can have at least 3 calendar years 
treatment and will complete all the treatment in CAMN107ECN02 
this year.  By 24 months, 86.5% of patients in imatinib arm and 
86.3% in nilotinib arm achieved complete cytogenetic response 
(CCyR).  At 24 month, 48.9% patients in imatinib arm and 61.2% in 
nilotinib arm achieved major molecular response (MMR). Both 
treatments showed good safety profile in CAMN107ECN02.   
Patients in CAMN107ECN02 may need continuous treatment when 
they complete the core study.  Protocol of CAMN107ECN02 
mentioned offering possibility of extended treatment to patients who 
derive benefit from the study treatment, in the opinion of the 
investigator at the end of study CAMN107ECN02.  Therefore, 
extension study of CAMN107ECN02 is necessary.  Nilotinib has 
not yet been approved for treatment of newly diagnosed CML-CP in 
China. The purpose of this extension study is to provide extended 
nilotinib treatment to patients in nilotinib arm of CAMN107ECN02. 
To cover the promise and insure the same right to the patients in 
imatinib arm, extended imatinib treatment will also be provided. 
 
Primary Objective(s) 
and Key Secondary 
Objective 
To assess safety of nilotinib and imatinib in newly diagnosed Ph+ 
CML-CP. 
Secondary Objectives 
Not applicable 
Study design 
The extension study follows the core study CAMN107ECN02, 
which is an open-label, two armed study. All patients enrolled in this 


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extension study should be able to benefit from the treatment given in 
CAMN107ECN02 per investigator’s evaluation. Therefore, in this 
extension study patient will continue treatment of the drug (imatinib 
or nilotinib) which they are taking at the end of CAMN107ECN02. 
Treatment arms in CAMN107ECN02 will be retained. As long as 
we get EC approval and agreement from investigators, the selected 
sites for CAMN107ECN02 will be applied in this extension study. 
Patients will be enrolled after eligibility evaluation. During the 
study, follow-up visits at a frequency of 6 months are required 
referring to the core study and recommendation in Chinese CML 
guideline. No data collection plan is included in this extension study 
except safety data. Investigator will be asked to report AE, SAE and 
pregnancy in order to ensure compliance with pharmacovigilance 
requirement. AE&SAE information will be recorded in CRF and 
included in clinical database. In addition, SAE and pregnancy will 
be reported to Novartis safety database.  
The extension study will start from first patient last dose date in 
CAMN107ECN02 and end at the time of nilotinib first line 
treatment commercially available in China. 
Population 
The patients who can continue to derive benefit from the study 
treatment that he/she takes in CAMN107ECN02, in the opinion of 
the investigator, at the end of the core study can be enrolled in this 
extension study. 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. 
Up to 230 patients will be enrolled. 
Inclusion criteria 
Patients eligible for inclusion in this extension phase have to meet 
all of the following criteria: 
1. Patient is currently on treatment in the core study 
CAMN107ECN02  
2. Patient who continues to derive benefit more than risk from the 
study treatment he/she takes in CAMN107ECN02, in the opinion of 
the investigator at the end of the study   
3. Written informed consent must be obtained prior to enrolling in 
the extension study 
Exclusion criteria 
Patients eligible for this extension phase must not meet any of the 
following criteria: 
1. Progression to CML-AP or BC 
2. Patient whose treatment assigned in CAMN107ECN02 is not 
appropriate any longer, per investigator’s assessment.  


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3. History of non-compliance to medical regimens, or patients who 
are considered potentially unreliable and/or not cooperative. 
4. Women who are (a) pregnant and(b) women of child-bearing 
potential, defined as all women physiologically capable of becoming 
pregnant, unless they are using highly effective methods of 
contraception during dosing and at least 14 days after last dose of 
study medication. Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and 
usual lifestyle of the subject. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception 
• Female 
sterilization 
(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 screening). For 
female subjects on the study the vasectomized male partner 
should be the sole partner for that subject. 
• Combination of any two of the following (a+b or a+c, or 
b+c): 
a) Use of oral, injected or implanted hormonal methods of 
contraception 
or 
other
forms of hormonal contraception that have comparable 
efficacy (failure rate <1%), for example hormone vaginal 
ring or transdermal hormone contraception. 
b) Placement of an intrauterine device (IUD) or intrauterine 
system (IUS) 
c) Barrier methods of contraception: Condom or Occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository 
In case of use of oral contraception women should have been stable 
on the same pill for a minimum of 3 months before taking study 
treatment. 
Investigational and 
reference therapy 
Nilotinib (300mg BID，400mg QD) and imatinib（recommended 
on 600mg QD，400mg QD and 300mg QD） 
Efficacy assessments 
Not to be collected  
Safety assessments 
Safety will be monitored by collecting of the adverse events at every 


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visit.  
Other assessments 
 Not applicable 
Data analysis 
In this study, safety data will be descriptively summarized, and all 
data collected will be listed. Categorical data will be presented as 
frequencies and percentages. 
Key words 
ENESTChina extension study, nilotinib, imatinib, Philadelphia 
chromosome positive chronic myelogenous leukemia 
Amendment 1 
This amendment mainly aims to change CAMN107ECN02E1 from a drug supply program to 
a study. Primary objective and endpoint which is related to AE&SAE is added. Requirement 
of collecting AE/SAE data and summary statistics plan is added to serve the objective. 
Exclude criteria is revised to exclude woman who is pregnant or who is with child bearing 
potential without highly effective methods of contraception. Dosage adjustment, patient 
assessment and mandatory criteria of premature discontinuation due to safety are clarified. In 
addition, there are also a lot of changes or reorganization due to change of protocol template. 
Change to the protocol 
Except revision and reorganization due to template change, other changes related to content 
are listed below： 
Section 1 Background 
• Detailed background information of study drug is added including safety and efficacy 
summary 
Section 2 Rationale 
• Clarify that the study is extension study of the core study CAMN107ECN02 
Section 2.2 Rationale for the study design  
• Add the AE&SAE data collection plan 
Section 3 Objectives and endpoint 
• Add objective and endpoint of the study to assess safety. 
Section 4.1 Description of study design 
• Clarify required follow up visit frequency of 6 months 
• Clarify safety data will be collected on CRF besides requirement of reporting 
SAE/pregnancy to Novartis safety database. 
Section 4.4 Early study termination 
• Add process for early study termination 
Section 5 Population 


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• Move the criterion about compliance from inclusion criteria to exclusion criteria.  
• Add an exclusion criterion to exclude pregnant women and women of child bearing 
potential. 
Section 6.1 Study treatment 
• Clarified starting dose. 
• Add instruction of nilotinib and imatinib administration 
Section 6.3.1 Dose modification and dose delay 
• Add dose modification guideline 
• Add suggested management of cholesterol increase, glucose increase, other cardiac risk 
factor, ischemic vascular or cardiovascular events. 
• Add guideline for toxicity follow up 
Section 6.4 Concomitant medication 
• Add this section to avoid concomitant medication with risk of drug-drug interaction with 
study drug. 
Section 6.5 Patient numbering, treatment assignment or randomization 
• Add this section to specify how to number patient in this study. 
Section 6.6 Study drug preparation and dispensation 
• Remove the not applicable drug request process. 
• Clarify the requirement of recording of study drug compliance and accountability 
Section 7 visit schedule and assessments 
• Add mandatory scheduled visit and content of every visit 
• Add requirement of monthly urine pregnancy test at home. 
• Clarify enrollment process 
Section 7.1.5 End of the treatment visit including study completion and premature withdrawal 
• Revise reason list of patient withdraw 
Section 7.1.6 Follow up period 
• Clarify that there is only one follow up visit and it can be done via phone. 
Section 8 Safety monitoring and reporting 
• Delete the requirement of non-serious to Novartis DS&E via AE report form, because 
CAMN107ECN02E1 follows safety reporting requirement of interventional study. 
Section 9 Data collection and management 
• Rewrite this section to meet requirement of data management and collection for study. 


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• Add the plan of site monitoring because CAMN107ECN02E1 is study. 
Section 10 Statistical methods and data analysis 
• Add a descriptive summary plan at the end of the study. Some details of analysis plan is 
provided.   
Section 11 Ethical consideration and administrative procedures 
• Add this section to clarify administrative procedures including responsibility of 
investigator and IRB/IEC/REB, informed consent, study documentation, record keeping, 
audit. 
Section 14 Appendix 
• Provide a list of CYP3A4 inducer and inhibitor. 
 
1 
Background 
Imatinib, the first BCR-ABL kinase inhibitor has been approved as treatment of newly 
diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) in 
many countries including China.  
Nilotinib is a second-generation inhibitor of BCR-ABL, with a similar mechanism of action to 
imatinib, but with greater binding affinity for wild-type BCR-ABL kinase and improved 
target selectivity. The efficacy of nilotinib compared to imatinib and its overall positive 
benefit/risk ratio for the treatment of patients with newly diagnosed CML-CP was established 
in the pivotal study CAMN107A2303. Tasigna (nilotinib) has been approved for the treatment 
of patients with newly diagnosed Ph+ CML-CP in 99 countries.  
In 2010, Novartis initiated Chinese registration study CAMN107ECN02 (ENESTChina). In 
the core study, 267 Chinese adult patients with newly diagnosed Ph+ CML in chronic phase 
(CP) were enrolled. This study is extension study of CAMN107ECN02.  


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1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Chronic myelogenous leukemia (CML) is a hematological stem cell disorder associated with a 
specific chromosomal translocation resulting in the Philadelphia (Ph) chromosome detected in 
95% of patients (Nowell and Hungerford 1960, Rowley 1973). The molecular consequence of 
the translocation is the fusion of the Abl proto-oncogene to the Bcr gene resulting in the 
production of an activated form of the Abl protein-tyrosine kinase (Bartram, et al 1983, 
Heisterkamp, et al 1983). Expression of the BCR-ABL protein is capable of inducing 
leukemias in mice, implicating the protein as the cause of these diseases (Daley, et al 1990, 
Kelliher, et al 1990). Clinically, CML progresses through three distinct phases of increasing 
refractoriness to therapy: chronic phase (median duration 3-4 years; median survival up to 10 
years with allogeneic bone marrow transplant and 5-6 years with interferon), accelerated 
phase (median duration 3-9 months; median survival 8-18 months), and blast crisis (median 
survival 3-6 months) (Enright and McGlave 2000). Most patients however present in the 
chronic phase, characterized by splenomegaly and leukocytosis with generally few symptoms. 
The following sections will review response criteria and summarize the clinical trial. 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of nilotinib 
Nilotinib is a novel aminopyrimidine, available as an oral formulation that is an ATP 
competitive inhibitor of the protein tyrosine kinase activity of BCR-ABL, which prevents the 
activation of BCR-ABL dependent mitogenic and anti-apoptotic pathways (e.g. PI-3 kinase 
and STAT5), leading to the death of the BCR-ABL phenotype. Nilotinib also inhibits other 
oncogenic kinases including the FIP1L1-PDGFRA tyrosine kinase, which is often associated 
with hypereosinophilic syndrome and chronic eosinophilic leukemia, and the stem cell factor 
receptor c-Kit tyrosine kinase, which is associated with systemic mastocytosis and 
gastrointestinal stromal tumors. Following oral administration to animals, nilotinib is 
moderately absorbed with approximately 30% bioavailability, and is well tolerated.  
Data from preclinical studies demonstrate that nilotinib achieves higher intracellular 
concentrations than Gleevec/Glivec, and that nilotinib inhibits BCR-ABL tyrosine kinase 
activity and induces apoptosis at lower concentrations than Gleevec/Glivec (Le Coutre 2004, 
White 2005). In addition, two investigator-initiated trials with nilotinib 400 mg BID in newly 
diagnosed chronic phase Ph+ CML are ongoing. These pilot studies and the ongoing phase III 
study ENESTnd are described below. 
1.2.1.1 
Non-clinical experience 
For information on pre-clinical toxicity please refer to the current nilotinib [Investigator 
Brochure] (IB). 


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1.2.2 
Over view of imatinib 
Imatinib mesylate (Gleevec/Glivec) is a protein-tyrosine kinase inhibitor that inhibits the 
BCR-ABL  tyrosine  kinase,  the  constitutively  active  tyrosine  kinase  created  by  the 
Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It inhibits 
proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic 
cells from Philadelphia chromosome positive (Ph+) chronic myeloid leukemia. Imatinib is 
also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) 
and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. 
Imatinib is currently approved in most countries throughout the world. Imatinib was originally 
approved by the FDA in May 2001 and by the European Commission (EC) in November 2001 
for the treatment of adult patients with Philadelphia chromosome (BCR-ABL) positive CML 
in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis. 
Following the initial approval, the FDA and EC in December 2002 approved imatinib for 
patients with newly diagnosed Philadelphia chromosome (BCR-ABL) positive (Ph+) CML 
including pediatric patients, for whom bone marrow transplantation is not considered first line 
therapy. 
The approved recommended dosage of imatinib is 400 mg/day for adult patients in chronic 
phase and 600 mg/day for adult patients in accelerated phase or blast crisis. A phase III, 
randomized study for imatinib (TOPS) comparing a starting dose of 400 mg/day versus 800 
mg/day was conducted in newly diagnosed Ph+ CML-CP patients but did not show evidence 
of superiority of the 800 mg/day dose compared to 400mg/day. 
1.2.2.1 
Non-clinical experience 
For information on pre-clinical toxicity please refer to the current imatinib [Investigator 
Brochure] (IB). 


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Amended protocol-v01                                                                        Protocol No. CAMN107ECN02E1 


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2 
Rationale 
2.1 
Study rationale and purpose 


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Patients in CAMN107ECN02 may need continuous treatment when they complete the core 
study.  Protocol of CAMN107ECN02 mentioned offering possibility of extended treatment to 
patients who derive benefit from the study treatment, in the opinion of the investigator at the 
end of study CAMN107ECN02.  Therefore, extension study of CAMN107ECN02 is 
necessary.  Nilotinib has not yet been approved for treatment of newly diagnosed CML-CP in 
China. The purpose of this extension study is to provide extended nilotinib treatment to 
patients in nilotinib arm of CAMN107ECN02. To cover the promise and insure the same right 
to the patients in imatinib arm, extended imatinib treatment will also be provided. 
2.2 
Rationale for the study design 
As the extension study is for on-treatment patient from core study who can derive benefit 
from continuous treatment at the end of core study, this study design mainly follows that of 
the core study on treatment to have two treatment arms.  
Since core study will provide 3-year efficacy data and safety data of nilotinib in Chinese adult 
with newly diagnosed CML-CP, and imatinib have been approved as treatment in this 
indication for 6 years, this extension study only aim to get AE&SAE data.  
2.3 
Rationale for dose and regimen selection 
All dosages in core study are permitted in this study. Flexibility of dose adjustment is left to 
investigator based on their medical assessment. Since cross over is only feasible in patient 
who is not tolerant or is suboptimal responder to the treatment in core study, which should be 
deemed as not benefit from previous treatment, extension study won’t permit cross over 
between the two treatments.   
 
2.4 
Rationale for choice of combination drugs  
Not applicable 
2.5 
Rationale for choice of comparators drugs  
Patients who benefit from imatinib treatment should continue imatinib treatment to maintain 
response. Therefore, patients from this arm will be kept on imatinib treatment in extension 
study.  
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 
Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 10.4 
To assess safety of nilotinib and 
imatinib in Chinese adult with 
Frequency of 
AE/SAE 
 


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Objective 
Endpoint 
Analysis 
newly diagnosed Ph+ CML-CP 
Key secondary 
 
 
Not applicable 
 
 
Other secondary 
 
 
Not applicable 
 
 
Exploratory 
 
 
Not applicable 
 
 
 
4 
Study design 
4.1 
Description of study design 
The extension study follows the core study CAMN107ECN02, which is an open-label, two 
armed study. All patients enrolled in this extension study should be able to benefit from the 
treatment given in CAMN107ECN02 per investigator’s evaluation. Therefore, in this 
extension study patient will continue treatment of the drug (imatinib or nilotinib) which they 
are taking at the end of CAMN107ECN02. Treatment arms in CAMN107ECN02 will be 
retained. As long as we get EC approval and agreement from investigators, the selected sites 
for CAMN107ECN02 will be applied in this extension study. 
Patients will be enrolled after eligibility evaluation. During the extension study, follow-up 
visits at a frequency of 6 months are required referring to the core study and recommendation 
in Chinese CML guideline (Wang JX, 2013). No data collection plan is included in this 
extension study except safety data. Investigator will be asked to report AE, SAE and 
pregnancy in order to ensure compliance with pharmacovigilance requirement. AE&SAE 
information will be recorded in CRF and included in clinical database. In addition, SAE and 
pregnancy will be reported to Novartis safety database.  
4.2 
Timing of interim analyses and design adaptations  
Not applicable 
4.3 
Definition of end of the study  
The extension study will start from first patient last dose date in CAMN107ECN02 and end at 
the time of nilotinib first line treatment commercially available in China. The criteria of study 
end are applicable to both nilotinib arm and imatinib arm. After the extension study, patients 
will be able to get treatment by prescription if continuous treatment is necessary. As for 
patients who cannot afford imatinib or nilotinib, they can follow PAP process to apply GIPAP 
or TIPAP and get drug donation if they can pass economic and medical assessment. 


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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 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 patients who continuously derive benefit from the study treatment that he/she takes in 
CAMN107ECN02, in the opinion of the investigator, at the end of the core study can be 
enrolled in this extension study.  
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 extension phase have to meet all of the following criteria: 
1. Patient is currently on treatment in the core study CAMN107ECN02  
2. Patient who continues to derive benefit more than risk from the study treatment he/she 
takes in CAMN107ECN02, in the opinion of the investigator at the end of the study  
3. Written informed consent must be obtained prior to enrolling in the extension study. 
5.3 
Exclusion criteria 
Patients eligible for this extension phase must not meet any of the following criteria: 
1. Progression to CML-AP or BC 
2. Patient whose treatment assigned in CAMN107ECN02 is not appropriate any longer, per 
investigator’s assessment.  
3. History of non-compliance to medical regimens, or patients who are considered potentially 
unreliable and/or not cooperative. 
4. Women who are (a) pregnant and (b) women of child-bearing potential, defined as all 
women physiologically capable of becoming pregnant, unless they are using highly effective 
methods of contraception during dosing and at least 14 days after last dose of study 
medication. Highly effective contraception methods include: 
• 
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception 


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• 
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 screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject. 
• 
Combination of any two of the following (a+b or a+c, or b+c): 
a. 
Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for example 
hormone vaginal ring or transdermal hormone contraception. 
b. 
Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. 
Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six weeks 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.  
6 
Treatment 
6.1 
Study treatment 
Study treatment: nilotinib or imatinib, which follows the treatment assignment in the core 
study CAMN107ECN02 
Study drugs: nilotinib (AMN107, Tasigna) or imatinib (STI571, Gleevec/Glivec) 
6.1.1 
Dosing regimen 
Patients will continue treatment of the drug they are taking at the end of CMAN107ECN02. 
Treatment switch between imatinib and nilotinib when transferred from CAMN107ECN02 to 
this extension study is not permitted. During the extension study, patients who need treatment 
switch should be regarded as unable to derive benefit from continuous treatment and should 
be withdrawn from the extension study.  


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The starting dose should be the same as the last dose that was given in the core study. After 
this, dose is based on the investigator’s judgment. All the doses permitted in 
CAMN107ECN02 will be acceptable in this extension study, (Table 6-1). The doses are also 
consistent with the recommendation for newly diagnosed CML-CP patients by Novartis CDS 
(core data sheet) of imatinib or nilotinib. Investigator can select appropriate dose among them 
for every patient.  Necessary dose adjustment among the doses is recommended during the 
study in case of toxicity or unsatisfactory response (please refer to section 6.3).  
Table 6-1 
Recommended dosing 
Drug 
Dose 
Imatinib 
400mg QD，300mg QD，600mg QD 
Nilotinib 
400mg QD，300mg BID 
 
6.1.1.1 
Nilotinib administration 
Patients in nilotinib arm will take 300 mg twice daily by mouth each morning and evening 
approximately 12 hours apart, or 400mg once daily.  
Nilotinib should NOT be taken with food. Patients should take nilotinib on an empty stomach. 
No food should be consumed for 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. Patients 
should be instructed to swallow capsules whole with a full 250-mL glass of water, and not to 
chew them. All patients must avoid grapefruit, star fruit, and Seville (bitter) oranges during 
the study. The juices of these fruits must also be avoided. Vomited doses should not be 
repeated. 
All dosages prescribed and dispensed to the patient, as well as all dose changes and missed 
doses during the study must be recorded on the Nilotinib Dosage Administration Record CRF. 
6.1.1.2 
Imaitnib administration 
Patients in imatinib 400 mg daily arm will receive imatinib daily dose of 300mg, 400mg or 
600mg all at once every day.  
Imatinib should be taken with food and a large glass of water. All patients must avoid 
grapefruit, star fruit, and Seville (bitter) oranges during the study. The juices of these fruits 
must also be avoided. Vomited doses should not be repeated. 
All dosages prescribed and dispensed to the patient, as well as all dose changes and missed 
doses during the study must be recorded on the Nilotinib Dosage Administration Record CRF. 
6.1.2 
Ancillary treatments  
Not applicable 


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6.1.3 
Rescue medication  
Not applicable 
6.1.4 
Guidelines for continuation of treatment 
Not applicable 
6.1.5 
Treatment duration 
Patient may continue treatment with the study drug all through the extension study, unless 
treatment is early discontinued at the discretion of the investigator or withdrawal of consent. 
In every visit, investigator should assess safety and efficacy to decide whether the patient 
should continue treatment in the extension study. 
6.2 
Dose escalation guidelines  
Not applicable 
6.3 
Dose modifications  
6.3.1 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. The following 
guidelines are recommended. 
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 
For the purpose of these dose reduction guidelines, toxicity is defined as any adverse event 
which is, with reasonable likelihood according to investigator’s judgment, caused by study 
drug. 
According to ICH E6 the investigator is responsible for all trial-related medical decisions. 
During and following a subject’s participation in a trial, the investigator should ensure that 
adequate medical care is provided to a subject for any adverse events, including clinically 
significant laboratory values, related to the trial. 
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 the list below, in Table 6-2 and Table 6-3. 
These guidelines provide general principles (such as dose-interruption until recovery rather 
than continuing study drug treatment at a lower dose as the first step in case of significant 
toxicity) and recommendations intended to support the investigator’s judgment and decisions 
about appropriate management of toxicity in the individual patient. 
The following guidelines must be strictly followed: 


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• No dose reductions below 300 mg/day for imatinib or 400 mg/day of nilotinib will be 
allowed. If a patient cannot tolerate a minimum dose of 300 mg/day of imatinib or 
400 mg/day of nilotinib he or she must be discontinued from the study. 
• Any non-hematological toxicity must be resolved within 28 days in order to resume 
study drug at the reduced dose. If a non-hematological toxicity does not resolve after 28 
days, the patient must be discontinued. 
•  In case of pancreatitis of Grade 3 study drug treatment must be interrupted and 
the Sponsor must be consulted immediately. 
• In case of pancreatitis of Grade 4 study drug treatment must be permanently stopped 
and the patient must be discontinued from study. 
•  In case of liver toxicity of Grade 4 study drug treatment must be interrupted and 
the Sponsor must be consulted immediately. 
• In case of related cardiac toxicity of Grade 4 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 


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Table 6-2 
Summary of dose reduction guidelines for study drug-related non-hematological toxicity and for ischemic 
vascular and cardiovascular events regardless of study drug relationship – IMATINIB 
Study drug and dose 
Imatinib 400 mg 
Imatinib 600 mg daily (as 600 mg QD) 
General non-hematological toxicity 
Grade 2 
(persisting > 7 days with 
optimal supportive care) 
Hold therapy and resume imatinib at 400 mg QD after 
recovery to ≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ 
Grade 1 is seen and then resume imatinib at 300 mg 
QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the 
patient must be discontinued from the study. 
If another recurrence is 
seen l→ discontinue. 
Hold therapy and resume imatinib at 600 mg after 
recovery to ≤Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery 
to ≤ Grade 1 is seen and then resume at next 
lower dose level 
l→ 400 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the 
patient must be discontinued from the study. If 
another recurrence is seen 
l→ discontinue.
≥ Grade 3 
Hold therapy and resume imatinib at 400 mg QD after 
recovery to ≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ 
Grade 1 is seen and then resume imatinib at 300 mg 
QD. 
If recovery to ≤ Grade 1 is greater than 28 days, 
the patient must be discontinued from the study. 
If another recurrence is seen  
          l→ discontinue. 
Hold therapy and resume imatinib 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 another recurrence is seen  
         l→ discontinue. 
Serum hypophosphatemia 
Grade 2 
Continue imatinib at 400 mg QD and start phosphate 
supplementation 
Continue imatinib at 600 mg QD and start 
phosphate supplementation 
Grade 3-4 
Hold therapy, start phosphate supplementation and 
resume imatinib at 400 mg QD after recovery to ≤ 
Grade 2 is seen. 
If grade 3-4 hypophosphatemia recurs despite 
supplementation, hold therapy again until recovery to ≤ 
Grade 
2 is seen and then resume imatinib at 300 mg QD. 
If another recurrence of grade 3-4 
hypophosphatemia is seen consult sponsor. 
Hold therapy, start phosphate supplementation 
and resume imatinib at 600 mg QD after 
recovery to ≤ Grade 2 is seen. 
If grade 3-4 hypophosphatemia recurs despite 
supplementation, hold therapy again until recovery 
to ≤ Grade 2 is seen and then resume imatinib at 
400 mg QD. 
If another recurrence of grade 3-4 
hypophosphatemia is seen consult sponsor 
 


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Study drug and dose 
Imatinib 400 mg 
Imatinib 600 mg daily (as 600 mg QD) 
Serum Creatinine 
Grade 2 
> 1.5 -3.0 x ULN 
Hold therapy and resume imatinib at 400 mg QD after 
recovery to ≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ 
Grade 1 is seen and then resume imatinib at 300 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient
must be discontinued from the study. 
 If another recurrence is seen 
l→ discontinue. 
Hold therapy and resume imatinib at 600 mg after recovery to 
≤Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ 
Grade 1 is seen and then resume at next lower dose level 
l→ 400 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the 
patient must be discontinued from the study. 
If another recurrence is 
seen l→ discontinue. 
≥ Grade 3 
≥ 3.0 x ULN 
Hold therapy and resume imatinib at 400 mg QD after 
recovery to ≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 1
is seen and then resume imatinib at 300 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the 
patient must be discontinued from the study. 
If another recurrence is seen 
l→ discontinue. 
Hold therapy and resume imatinib 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 another recurrence is 
seen l→ discontinue. 
Hepato-biliary [bilirubin, SGPT(AST), SGOT (ALT)] Note: If hyperbilirubinemia is primarily due to the indirect bilirubin component (with indirect 
bilirubin > direct bilirubin and direct bilirubin ≤ 15 µmol/L) and ALT ≤ Grade 1, AST ≤ Grade 1, ALP ≤ Grade 1, and hemolysis has been ruled out as per
institutional guidelines (e.g. by determination of hepatoglobin), imatinib may be continued at the same dose, at the discretion of the investigator. 
Grade 2 
Hold therapy and resume imatinib at 400 mg QD after recovery 
to ≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 
1 is seen and then resume imatinib at 300 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the 
patient must be discontinued from the study. 
If another recurrence is 
seen l→ discontinue. 
Hold therapy and resume imatinib at 600 mg after recovery to 
≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ 
Grade 1 is seen and then resume at next lower dose level 
l→ 400 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the 
patient must be discontinued from the study. 
If another recurrence is 
seen l→ discontinue. 
 


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Study drug and dose 
Imatinib 400 mg 
Imatinib 600 mg daily (as 600 mg QD) 
≥ Grade 3 
Hold therapy and resume imatinib at 400 mg QD after recovery to 
≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 1 
is seen and then resume imatinib at 300 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient 
must be discontinued from the study. 
If another recurrence is seen 
l→ discontinue. 
Hold therapy and resume imatinib 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 another recurrence is seen 
l→ discontinue. 
Pancreatitis (with abdominal symptoms plus amylase and/or lipase elevation) 
Grade 2 
Hold therapy 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 imatinib at 400 mg after recovery to ≤ 
Grade 1 is seen. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient 
must be discontinued from the study. 
If toxicity recurs 
l→ discontinue. 
Hold therapy 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 at the next lower dose level after 
recovery to ≤ Grade 1 
l→ 400 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient 
must be discontinued from the study. If toxicity recurs 
l→ discontinue. 
Grade 3 
Hold therapy and consult Sponsor 
Hold therapy and consult Sponsor 
Grade 4 
Hold therapy. The patient must be discontinued from study 
Hold therapy. The patient must be discontinued from study 
 


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Study drug and dose 
Imatinib 400 mg 
Imatinib 600 mg daily (as 600 mg QD) 
Elevated amylase and/or lipase without symptoms 
≥ Grade 3 
Hold therapy 
Re-start imatinib at 300 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 without symptoms consider appropriate 
diagnosis procedures such as abdominal CT or ultrasound to 
exclude pancreatitis. After recovery to ≤ Grade 1, 
l→ continue dosing at 300 mg QD based on investigator’s 
discretion 
Hold therapy and re-start imatinib at the next lower dose level 
after recovery to ≤ 
Grade 1 
l→ 400 mg QD; 
If recovery to ≤ Grade 1 is greater than 28 days, the patient 
must be discontinued from the study. 
If toxicity recurs without symptoms consider appropriate 
diagnosis procedures such as abdominal CT or ultrasound to 
exclude pancreatitis. After recovery to ≤ Grade 1, 
l→ continue dosing based on investigator’s 
discretion 
Diarrhea 
Note: Anti-diarrheal medication is recommended at the first sign of loose stools or overt diarrhea. If diarrhea cannot be controlled with optimal anti-diarrheal 
treatments, take the following actions: 
≥ Grade 3 
Hold therapy and resume imatinib at 400 mg QD after recovery 
to ≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 1 
is seen and then resume imatinib at 300 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient 
must be discontinued from the study. 
If toxicity recurs 
l→ discontinue. 
Hold therapy and resume imatinib 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 toxicity recurs 
l→ discontinue. 
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 therapy and resume imatinib at 400 mg QD; after recovery 
to ≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 1 
is seen and then resume imatinib at 300 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient 
must be discontinued from the study. 
If toxicity recurs 
l→ discontinue. 
Hold therapy and resume imatinib 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 toxicity recurs 
l→ discontinue. 


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Study drug and dose 
Imatinib 400 mg 
Imatinib 600 mg daily (as 600 mg QD) 
Skin rash 
Note: Institute symptomatic therapy as appropriate. If skin rash does not resolve with optimal treatments, take the following actions:
Grade 2 
Hold therapy and resume imatinib at 400 mg QD; after recovery 
to ≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 
1 is seen and then resume imatinib at 300 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the 
patient must be discontinued from the study. 
If another recurrence is 
seen l→ discontinue. 
Hold therapy and resume imatinib at 600 mg after recovery to ≤ 
Grade 1 is seen. If toxicity recurs, hold therapy again until 
recovery to ≤ Grade 1 is seen and then resume at next lower 
dose level 
l→ 400 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the 
patient must be discontinued from the study. 
If another recurrence is 
seen l→ discontinue.
≥ Grade 3 
Hold therapy and resume imatinib at 400 mg QD; after recovery 
to ≤ Grade 1 is seen 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 1 
is seen and then resume imatinib at 300 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the 
patient must be discontinued from the study. 
If another recurrence is 
seen l→ discontinue 
Hold therapy and resume imatinib 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 another recurrence is seen 
l→ discontinue. 
 
 


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Study drug and dose 
Imatinib 400 mg 
Imatinib 600 mg daily (as 600 mg QD) 
Cardiac QTc prolongation 
QTcF > 480 msec 
Hold therapy when an ECG with a QTcF > 480 msec by automated reading is identified at the site. 
• 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 the QTcF returns to 
< 450 msec and is within 20 msec of baseline within 2 weeks. 
If the QTcF is repeated and is more than 20 msec greater than baseline or between 450 msec and 480 msec the dose of study 
drug is to be reduced as follows: 
• Imatinib 400 mg not to be dose reduced. 
• Imatinib 600 mg daily will be reduced to 400 mg daily. 
ECGs must be repeated 7 days after dose re-start for all patients who had therapy held due to QTcF > 480 msec. 
If QTcF of > 480 msec recurs, the patient must be discontinued. 
The investigator should contact the sponsor 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. 
 
 


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Study drug and dose 
Imatinib 400 mg 
Imatinib 600 mg daily (as 600 mg QD) 
Ischemic vascular and Ischemic Cardiovascular events 
Grade 2 
Hold therapy and refer patients for assessment by a vascular or 
cardiovascular specialist. 
Resume imatinib at 400 mg QD after recovery to ≤ Grade 1 is 
seen. 
If another recurrence is seen 
l→ discontinue . 
If recovery to ≤ Grade 1 is greater than 28 days, the patient 
must be discontinued from the study. 
The event should be evaluated to determine the relationship to 
study treatment (i.e. suspected or not suspected). Additionally, 
the patient should be assessed for other potential risk factors 
for the event. 
Hold therapy and refer patient for assessment by a vascular or 
cardiovascular specialist. 
Resume imatinib next lower dose level after recovery to ≤ 
Grade 1 is seen 
l→ 400 mg QD. 
Further dose de-escalation to highest tolerable dose allowed if 
appropriate. 
Patients who do not tolerate 300 mg QD must discontinue 
treatment. 
If another recurrence is seen 
l→ discontinue. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient 
must be discontinued from the study. 
The event should be evaluated to determine the relationship to 
study treatment (i.e. suspected or not suspected). Additionally, 
the patient should be assessed for other potential risk factors 
for the event.
Grade 3 or Grade 4 
Hold therapy, and refer patient for assessment by a vascular or 
cardiovascular specialist. 
Consideration should be given for discontinuation from the 
study for event. 
The patient must be discontinued from the study if recovery to 
Grade 2 is greater than 28 days. 
The event should be evaluated to determine the relationship to 
study treatment (i.e. suspected or not suspected). Additionally, 
the patient should be assessed for other potential risk factors 
for the event.
Hold therapy, and refer patient for assessment by a vascular or 
cardiovascular specialist. 
Consideration should be given for discontinuation from the 
study for event. 
The patient must be discontinued from the study if recovery to 
Grade 2 is greater than 28 days. 
The event should be evaluated to determine the relationship to 
study treatment (i.e. suspected or not suspected). Additionally, 
the patient should be assessed for other potential risk factors 
for the event.
 
 
 


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Table 6-3 
Summary of dose reduction guidelines for study drug-related non-hematological toxicity and for ischemic 
vascular and cardiovascular events regardless of study drug relationship- NILOTINIB 
 
Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) 
General non-hematological toxicity 
Grade 2 
(persisting > 7 days with optimal 
supportive care) 
Hold therapy and resume nilotinib at 300 mg BID after recovery to ≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 1 is seen and then resume nilotinib at 400 
mg QD. If recovery to ≤ Grade 1 is greater than 28 days, the patient must be discontinued from the 
study 
If another
≥ Grade 3 
Hold therapy 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 toxicity recurs 
l→ discontinue.
Serum hypophosphatemia 
Grade 2 
Continue nilotinib at 300 mg BID and start phosphate supplementation. 
Grade 3-4 
Hold therapy, start phosphate supplementation and resume nilotinib at 300 mg BID after recovery to ≤ Grade 2 is seen. 
If grade 3-4 hypophosphatemia recurs despite supplementation, hold therapy again until recovery to ≤ Grade 2 is seen 
and then resume nilotinib at 400 mg QD. 
If another recurrence of grade 3-4 hypophosphatemia is seen consult sponsor.
Serum creatinine 
Grade 2 
> 1.5 -3.0 x ULN 
Hold therapy and resume nilotinib at 300 mg BID after recovery to ≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 1 is seen and then resume nilotinib at 400 
mg QD. If recovery to ≤ Grade 1 is greater than 28 days, the patient must be discontinued from the 
study. 
If another
≥ Grade 3 
≥ 3.0 x ULN 
Hold therapy 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 toxicity recurs 
l→ discontinue. 


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Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) 
Hepato-biliary [bilirubin, SGPT(AST), SGOT (ALT)] 
Note: If hyperbilirubinemia is primarily due to the indirect bilirubin (with indirect bilirubin > direct bilirubin and direct bilirubin ≤ 15 µmol/L) and ALT ≤ Grade 1, 
AST ≤ Grade 1, ALP ≤ Grade 1, and hemolysis has been ruled out as per institutional guidelines (e.g. by determination of hapatoglobin), nilotinib may be 
continued at the same dose, at the discretion of the investigator.
Grade 2 
Hold therapy and resume nilotinib at 300 mg BID after recovery to ≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 1 is seen and then resume nilotinib at 400 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be discontinued from the study. 
If another recurrence is seen 
l→ discontinue.
≥ Grade 3 
Hold therapy 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 toxicity recurs 
l→ discontinue. 
Pancreatitis (with abdominal symptoms plus amylase and/or lipase elevation) 
Grade 2 
Hold therapy 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.
Grade 3 
Hold therapy and consult sponsor 
Grade 4 
Hold therapy. The patient must be discontinued from study 
Elevated amylase and/or lipase without symptoms 
≥ Grade 3 
Hold therapy 
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 without symptoms consider appropriate diagnostic procedures such as abdominal CT or ultrasound to exclude 
pancreatitis. After recovery to ≤ Grade 1, 
l→ continue dosing at 400 mg QD based on investigator’s discretion.
Diarrhea 
Note: Anti-diarrheal medication is recommended at the first sign of loose stools or overt diarrhea. If diarrhea cannot be controlled with optimal anti-diarrheal 
treatments, take the following actions: 
 


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Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) 
≥ Grade 3 
Hold therapy 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 toxicity recurs 
l→ discontinue.
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 therapy 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 toxicity recurs 
l→ discontinue. 
Skin rash 
Note: Institute symptomatic therapy as appropriate. If skin rash does not resolve with optimal treatments, take the following actions: 
Grade 2 
Hold therapy and resume at nilotinib 300 mg BID after recovery to ≤ Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 1 is seen and then resume nilotinib at 400 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be discontinued from the study 
If another recurrence is seen 
l→ discontinue
≥ Grade 3 
Hold therapy 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 toxicity recurs 
l→ discontinue. 
 


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Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) 
Cardiac QTc prolongation 
QTcF > 480 msec 
Hold dosing when an ECG with a QTcF > 480 msec by automated reading is identified at the site. 
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. 
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 
ECGs must be repeated 7 days after dose re-start for all patients who had therapy held due to QTcF > 480 msec. 
If QTcF of > 480 msec recurs, the patient is to be discontinued. 
The investigator should contact the sponsor regarding any questions that arise if a patient with QTcF prolongation should be 
maintained on study. 
Ischemic vascular and Ischemic Cardiovascular event 
Grade 2 
Hold therapy 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 is seen 
l→ discontinue. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be discontinued from the study. 
The event should be evaluated to determine the relationship to study treatment (i.e. suspected or not suspected). Additionally, the 
patient should be assessed for other potential factors for the event. 
Grade 3* or Grade 4* 
Hold therapy, and refer patient for assessment by a vascular or cardiovascular specialist. 
Consideration should be given for discontinuation from the study for event. 
The patient must be discontinued from the study if recovery to ≤ Grade 2 is greater than 28 days. 
The event should be evaluated to determine the relationship to study treatment (i.e. suspected or not suspected). Additionally, the 
patient should be assessed for other potential factors for the event. 
* Patient should be assessed for potential risk factors for the event including causality secondary to CML therapy. 
 


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Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) 
Cardiac “other” 
Grade 2 or Grade 3 
Hold therapy 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. 
 
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 is presented in Table 6-4 and Table 6-5. No 
dose adjustments should be made for Grade 1 or 2 hematologic toxicity for either imatinib or nilotinib. These guidelines provide some 
general principles (such as dose-interruption until recovery rather than continuing study drug treatment at a lower dose as the first step in 
case of significant toxicity) 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.  


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Table 6-4 
Summary of dose reduction guidelines for study drug-related hematological toxicity – IMATINIB 
Study drug and dose 
Imatinib 400 mg daily 
Imatinib 600 mg daily (as 600 mg QD) 
≥ Grade 3 
Hold therapy and resume imatinib at 400 mg QD after recovery to 
≤ Grade 1, if recovery occurs within 14 days 
If toxicity persists for 15-28 days or recurs, hold therapy and 
resume at next 
lower dose level after recovery to ≤ Grade 1: 
l→ 300 mg QD. 
If recovery to ≤ Grade 1 is greater than 28 days, consult sponsor. 
If another recurrence is seen l→ discontinue. 
Hold therapy and resume at 600 mg QD after recovery to ≤ Grade 
1, if recovery occurs within 14 days 
If toxicity persists for 15-28 days or recurs, hold therapy and 
resume at next 
lower dose level after recovery to ≤ Grade 1: 
l→ 400 mg QD 
If recovery to ≤ Grade 1 is greater than 28 days, consult sponsor. 
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. 
Table 6-5 
Summary of dose reduction guidelines for study drug-related hematological toxicity – NILOTINIB 
Study drug and dose 
Nilotinib 600 mg daily (as 300 mg BID) 
≥ Grade 3 
Hold therapy and resume at nilotinib 300 mg BID after recovery to ≤ Grade 1, if recovery occurs within 14 days 
If toxicity persists for 15-28 days or recurs, hold therapy and resume at next lower dose 
level after recovery to ≤ Grade 1: 
l→ 400 mg QD 
If recovery to ≤ Grade 1 is greater than 28 days, consult sponsor. 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. 


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6.3.1.3 
Summary of guidelines for dose re-escalation of imatinib 
Re-escalation of the dose of imatinib to the previously administered dose level (i.e., dose level 
from which dose was reduced) is permitted. This applies to either dose reductions due to 
hematological or non-hematological toxicities if the following criteria are met for 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 
For patients whose imatinib dose was 400 mg prior to dose reduction to 300 mg, the dose would 
be increased to 400 mg if the above described criteria are met at least one month after dose 
reduction. 
For patients whose imatinib dose was 600 mg (as 600 mg QD) prior to dose reduction to 400 
mg, the dose would be increased to 600 mg (as 600 mg QD) if the above criteria are met at least 
one month after dose reduction. 
For patients whose imatinib dose was 600 mg (as 600 mg QD) prior to dose reduction to 300 
mg, the dose would be increased to 400 mg if the above criteria are met at least one month 
before increasing the dose to 600 mg (as 600 mg QD). 
For patients whose imatinib dose was reduced, dose re-escalation should be done in a step- wise 
manner by increasing the dose by one dose-level at a time (i.e., 300 to 400 to 600 mg). 
Subsequent dose escalation to the next dose-level should be done at least one month later. 
6.3.1.4 
Summary of guidelines for dose re-escalation of nilotinib 
Re-escalation of the dose of nilotinib to the previously administered dose level (i.e., dose level 
from which dose was reduced) is permitted. This applies to either dose reductions due to 
hematological or non-hematological toxicities 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. 
For patients whose nilotinib dose was 600 mg (as 300 mg BID) prior to dose reduction to 400 
mg QD, the dose would be increased to 600 mg (as 300 mg BID) if the above described criteria 
are met at least one month after dose reduction. 
 


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6.3.1.5 
Suggested management of selected adverse events for imatinib and 
nilotinib 
Dose reduction guidelines listed in Table 6-2, Table 6-3, Table 6-4, and Table 6-5 must be 
followed. Additional guidelines for management of patients are listed below. 
6.3.1.5.1 Management of cholesterol increases 
Blood lipid panel tests should be performed at baseline and throughout the study as indicated in 
the visit schedule. If test results warrant intervention, investigators should follow their local 
standards of practice or treatment guidelines, which may recommend treatment even for grade 1 
cholesterol elevation. Before prescribing a lipid lowering medication, the possibility of drug-
drug interactions should be considered due to the moderate inhibitory effect of nilotinib or 
imatinib on CYP3A4 isoenzyme that is involved in the metabolic pathway of as some statins 
(HMG-CoA reductase inhibitors) are also metabolized via the CYP3A4 pathway.  
6.3.1.5.2 Management of glucose increases 
Blood glucose tests should be performed at baseline and throughout the study as indicated in the 
visit schedule. If blood glucose results warrant intervention, investigators should follow their 
local standards of practice and treatment guidelines in order to normalize blood glucose levels. 
6.3.1.5.3 Management of other cardiac risk factors 
Patients should be assessed or monitored for any other cardiac risk factors such as family 
history, cardiovascular events in the past medical history, smoking, hypertension, and obesity. If 
the assessment for presence of any other cardiovascular risk factors warrants intervention, 
investigators should follow their local standards of practice or treatment guidelines. 
6.3.1.5.4 Management of ischemic vascular or cardiovascular events 
Newly-diagnosed or worsened ischemic vascular or cardiovascular events have occurred in a 
relatively small number of CML-CP patients while on study medication. If a patient experiences 
such an adverse event the Investigator should ensure that the patient is assessed by a vascular or 
cardiovascular specialist. Further recommendations for the management of ischemic vascular or 
cardiovascular-related events are outlined in Table 6-2 or Table 6.3.  
6.3.1.5.5 Management of myelosuppression 
Myelosuppression can occur at any time during imatinib or nilotinib therapy. Use of colony 
stimulating growth factors (G-CSF and GM-CSF) such as sargramostim, filgrastim, and 
pegfilgrastim may be initiated with recurrent grade 3 neutropenia. The use of recombinant 
erythropoietin is also permitted as per local clinical practice. 
6.3.1.5.6 Management of skin rash/pruritus 
In most cases, rash is mild, self-limiting, and manageable with antihistamines or topical steroids. 
A short course of oral steroids may be initiated for the management of more severe cases. 
Prednisone 25 mg is recommended for one week or until rash has resolved. 
 


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6.3.1.5.7 Management of edema 
Patients should be monitored closely for peripheral edema and rapid weight gain. The use of 
diuretics may be initiated for the management of edema. Patients who develop ≥ Grade 3 edema 
associated with cardio-respiratory symptoms should receive immediate medical evaluations for 
the development of concomitant cardiac or respiratory diagnoses as indicated, such as an 
echocardiogram and a chest X-ray. Other medical tests may also be necessary to best manage 
the medical condition. 
6.3.1.5.8 Management of liver toxicity 
Routine LFTs should be performed throughout the study as indicated in the visit schedule. Dose 
reduction may be warranted and the decision to continue imatinib or nilotinib needs to be made 
in light of the clinical situation (see dose reduction table). Alternative etiologies for LFT 
abnormalities such as viral hepatitis should be considered as clinically indicated. 
6.3.1.5.9 Dose modification for patients on nilotinib and oral anticoagulants other than 
coumarin derivatives 
For  patients  on  treatment  with  oral anticoagulants other  than  coumarin derivatives (see 
Section 7.6.4) , the following guidelines will apply for thrombocytopenia: If platelets ≤ 100 x 
109/L, withhold treatment with study drug until recovery to at least > 100 x 109/L and resume 
treatment at same dose. If recurrence of platelets ≤ 100 x 109/L, then withhold treatment until 
recovery to at least > 100 x 109/L and resume treatment at the minimum dose of 300 mg/day for 
imatinib. The nilotinib dose may be reduced to a minimum of 400 mg/day. If the platelet count 
remains below 100 x 109/L, then imatinib or nilotinib should be ceased or management with 
anticoagulation therapy re-evaluated at the discretion of the Investigator. 
6.3.1.5.10 
Platelet aggregation inhibitors 
For patients on treatment with platelet aggregation inhibitors and platelets ≤ 100 x 109/L, 
modification of platelet aggregation inhibitor therapy and/or study drug interruption/dose 
reduction should be considered by the investigator as clinically appropriate. Advice from SMC 
may be requested via the Sponsor. 
6.3.2 
Follow-up for toxicities 
Patients whose treatment is permanently discontinued due to a study drug related adverse event 
or abnormal laboratory value is recommended to must be followed at least once a week for 4 
weeks, until resolution or stabilization of the event, whichever comes first. All patients will be 
followed for serious adverse events for 30 days following the last dose of study drug. 
6.3.3 
Anticipated risks and safety concerns of the study drug 
Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules are included in this protocol. Recommended guidelines for 
prophylactic or supportive treatment for expected toxicities, including management of study-
drug induced adverse events, i.e., hyperglycemia, skin toxicity and diarrhea are provided in 
Section 6.3.1. Refer to preclinical toxicity and or clinical data found in the [Investigator’s 
Brochure]. 


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6.4 
Concomitant medications 
6.4.1 
Permitted concomitant therapy 
In general, concomitant medications and therapies deemed necessary for the supportive care and 
safety of the patient are allowed. 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. 
6.4.2 
Permitted concomitant therapy requiring caution and/or action  
Cytochrome P450 3A4 substrates 
Both nilotinib and imatinib are a moderate CYP3A4 inhibitor in vivo. Because of the potential 
risk for drug-drug interactions, the systemic exposure of other drugs known to be sensitive 
substrates of CYP3A4 and also to have a narrow therapeutic index should be used with caution.  
Antacid drugs: 
Nilotinib has a pH-dependent solubility; therefore, in order not to impact nilotinib 
pharmacokinetics, administration of the following antacid drugs (if necessary) should be as 
follows: 
- 
H2 blocker (famotidine) may be administered approximately 10 hours before or 
approximately 2 hours after the dose of nilotinib, 
- 
Antacid 
(hydroxide/magnesium 
hydroxide/simethicone) 
may 
be 
administered 
approximately 2 hours before or approximately 2 hours after the dose of nilotinib. 
Cytochrome P450 2D6 and 2C9 substrates 
Caution should be exercised when co-administering imatinib with substrates of CYP2D6 and 
CYP2C9. 
Others 
Patients should be informed of a possible drug interaction with acetaminophen (paracetamol) 
and asked to restrict the use of over-the-counter and prescription medicines containing 
acetaminophen (paracetamol). As such, special care has to be given to the concomitant use of 
acetaminophen/paracetamol (e.g., Tylenol® or Percocet®) with imatinib and nilotinib. 
Patients on anticonvulsants should have regular monitoring of plasma concentration of these 
agents. 
6.4.3 
Prohibited concomitant therapy 
The concomitant administration of investigational drugs other than imatinib or nilotinib is not 
allowed. The administration of any other anticancer agents including chemotherapy and 
biologic agents is not permitted.  
All patients must avoid grapefruit, star fruit, and Seville (bitter) oranges during the study. The 
juices of these fruits must also be avoided. 


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During the course of the study, concomitant administration of agents known to prolong the QT 
interval is contraindicated. Please see azcert.org/medical-pros/drug-lists/printable-drug-list.cfm 
for a comprehensive list of agents that prolong the QT interval. 
Avoid the concomitant use of strong CYP3A4 inhibitors and inducers (refer to Appendix 1 in 
Section 14.1). Should treatment with strong CYP3A4 inhibitors or inducers be required, it is 
recommended that therapy with imatinib or nilotinib be interrupted. Close monitoring of 
prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 
inhibitors or inducers. For further details refer to the current imatinib and nilotinib  
[Investigator’s Brochure]. 
 
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 signs ICF and is retained as the primary identifier for the patient throughout his/her 
entire participation in the trial. The Subject No. consists of the Center Number (Center No.) (as 
assigned by Novartis to the investigative site) with a sequential patient number suffixed to it, so 
that each subject is numbered uniquely across the entire database. Upon signing the informed 
consent form, the patient is assigned to the next sequential Subject No. available to the 
investigator. 
6.5.2 
Treatment assignment or randomization 
In this extension study, enrolled patients take the treatment they are having at the end of the 
core study. There will not be treatment assignment or randomization again in the beginning of 
the extension study. 
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 CRF. 
Novartis will be responsible for supply of labelled drug. Drug strength (Table 6-6 Drug supply) 
will be the same as in the core study. Drug will be dispensed to patients by whole bottles/boxes. 
Patient should bring the drug bottles or boxes with remaining drug back to investigator in every 
scheduled or unscheduled visit.   
Table 6-6 
Drug supply 
Drug 
Strength 
Imatinib 
100mg tablet 
Nilotinib 
150mg capsule; 200mg capsule 


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Investigator need to finish medical assessment to judge whether patient can still derive benefit 
from continuous treatment in very visit.  
6.6.1 
Study drug packaging and labeling 
Medication labels will be in the local language and comply with the legal requirements of China. 
They will include storage conditions for the drug and the medication number but no information 
about the patient. 
6.6.2 
Drug supply and storage 
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, nilotinib and imatinib the study treatment should be 
stored according to the instructions specified on the drug labels and in the [Investigator’s 
Brochure].  
6.6.3 
Study drug compliance and accountability 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit. 
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 study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
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. All data obtained from these assessments must be supported in the patient’s source 
documentation.  
Table 7-1 
Visit evaluation schedule 
 
Category 
Protocol 
Section  
Enrollment 
Follow up during treatment 
Every 6 (+/-1) months 
End of 
study 
treatment 
(EOT) 
End of 
study 
(EOC) 
Visit Name (NCDS 
studies) or Visit 
Number (NOVDD 
studies) 
 
 
1 
Visit 2,3,4 etc. 
777 
 
Patients’ previous 
study, site and subject 
number 
D 
7.1.2 
x 
 
 
 
Obtain Informed 
Consent 
D 
7.1.2 
x 
 
 
 
Demography  
D 
7.1.2 
x 
 
 
 
Inclusion/exclusion 
criteria 
D 
7.1.2.1 
x 
 
 
 
Urine pregnancy test * 
D 
7.2.2.5 
x 
x 
x 
 
Adverse event 
D 
8 
x 
x 
x 
x 
Study Drug 
administration  
D 
6.1 ,6.2 
and 6.3 
x 
x 
x 
 
*Urine pregnancy test should be done monthly at home 
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. 
For those patients who don’t meet inclusion/exclusion criteria, the Demography CRF page must 
also be completed. No other data of these patients will be entered into the clinical database. 
7.1.2.1 
Eligibility screening  
Not applicable 
7.1.2.2 
Information to be collected on screening failures 
Not applicable 


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7.1.3 
Run-in period  
Not applicable. 
7.1.4 
Treatment period 
Study treatment can be given as soon as eligibility is confirmed. Treatment will last till the end 
of the extension study or premature discontinuation of patients.  
During treatment period, safety information including AE/SAE is required to be collected in 
CRF. Urine pregnancy test must be done every month as home and the result should be input in 
CRF when patient come back for visit. 
Dosage and drug administration and any change should be recorded all through the study. 
7.1.5 
End of treatment visit including study completion and premature 
withdrawal 
At the time patients discontinue study treatment, a visit should be scheduled as soon as possible, 
at which time all of the assessments listed for the End of Treatment (EOT) visit will be 
performed. An End of Treatment Phase Disposition CRF page should be completed, giving the 
date and reason for stopping the study treatment. 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following the 
last dose of study treatment. 
Patients who 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 premature withdrawal from the study and record 
this information on the End of Treatment Disposition CRF page. 
7.1.5.1 
Criteria for premature patient withdrawal 
Patients may be withdrawn from the study if any of the following occur: 
• discovery of patient ineligibility;  
• pregnancy;  
• intolerance which requires treatment permanently discontinuation 
• death 
• lost to follow-up 
• staying in the study would be inappropriate（investigators can withdraw patients if 
treatment provided by the extension study cannot benefit them or is not the best 
available treatment for them any longer）  
• patient is non-compliant to protocol requirement 


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• Other reasons: patient can be withdrawn from the extension study before closing of it for 
any other reason 
7.1.5.2 
Replacement policy  
Not applicable 
7.1.6 
Follow up period 
All patients must have safety evaluations for 30 days after the last dose of study treatment. 
At the end of this period, the investigator should contact the patient to inquire about any AE 
observed during this period. This could be done via a phone contact. Following this there are no 
further follow-up study visits. 
Patients lost to follow up should be recorded as such on the CRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
This extension study will not include efficacy data collection. Therefore, efficacy assessment is 
not mandatory. But it is still recommended that every patient can be assessed for hematology 
response, cytogenetic response and molecular response every 6 months.   
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. 
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). 


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Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should be 
continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose of 
study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 3.0, which is the same as in the core study. 
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 though a Death form. 
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) 
or 
Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes, 
investigational treatment, Yes, the study treatment (non-investigational), Yes, both and/or 
indistinguishable). 
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. 
Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)  
7. 
Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event 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. 


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Signs and symptoms clearly associated with the disease under study should NOT be reported as 
AEs unless they are newly emergent (i.e. not previously observed in the patient), judged by the 
Investigator to be unusually severe or accelerated, or if the Investigator considers deterioration 
of disease-related signs and symptoms to be caused directly by the study drug. If there is any 
uncertainty about an AE being due solely to the disease under study, it should be reported as an 
AE or SAE as appropriate. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis at 
the time of progression or hemoptysis concurrent with finding of disease progression) will be 
reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
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 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 
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,  


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• 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 
The core study CAMN107ECN02 requires 30 days safety follow up after last dose. SAE 
reported from both the core study and this extension study will be captured in Novartis safety 
database. To avoid data duplication in Novartis safety database, SAE reporting is exempted in 
this study if the very event has been reported as SAE in the core study CAMN107ECN02.  
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 SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department. 
The telephone and telefax number of the contact persons in the local department of Drug Safety 
and Epidemiology (DS&E), specific to the site, are listed in the investigator folder provided to 
each site. The original copy of the SAE Report Form and the fax confirmation sheet must be 
kept with the case report form documentation at the study site. 


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Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology 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 
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 Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment of 
the possible relationship to the study treatments and 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 Investigator 
Brochure. Additional safety information collected between IB updates will be communicated in 
the form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
8.6 
Data Monitoring Committee  
Not applicable 


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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. 
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results. 
9.2 
Site monitoring 
Before extension study initiation, at a site initiation visit or at an investigator’s meeting, 
Novartis personnel (or designated CRO) will review the protocol and CRFs with the 
investigators and their staff. During the study, the field monitor will visit the site regularly to 
check the completeness of patient records, the accuracy of entries on the CRFs, 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. 


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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, and laboratory data, electrocardiograms, the results of any other tests or 
assessments if related to AE/SAE and dose adjustment. All information recorded on CRFs 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 CRF 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 CRFs are performed 
according to the study-specific monitoring plan. 
9.3 
Data collection 
For studies using paper CRFs, designated investigator staff must record the information 
required by the protocol onto the Novartis CRFs that are printed on multi-part, non-carbon-
required paper. Field monitors will review the CRFs for completeness and accuracy and instruct 
site personnel to make any required corrections or additions. The harvested CRFs will be 
forwarded to the Medical Documents Reception Center of Novartis by field monitors or by the 
investigational site, with one copy being retained at the investigational site. 
The Principal Investigator is responsible for assuring that the data recorded on CRFs is 
complete, accurate, and that entry and updates are performed in a timely manner. 
9.4 
Database management and quality control 
For studies using paper CRFs, data will be entered into a fully validated study database by 
Novartis Data Management personnel (or designated CRO). Following entry from the CRFs, 
the data are systematically checked by Novartis Data Management personnel (or designated 
CRO) using programmed checks and data review tools/reports. Data Query Forms (DQF) are 
created for discrepancies or missing values and sent to the investigational site for resolution. 
Original signed responses to the DQFs must be returned to Novartis Data Management (or 
designated CRO) so that resolutions can be entered into the database. Copies of the resolved 
DQFs are kept with the CRFs at the investigator site. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
10 
Statistical methods and data analysis 
No statistical analysis is planned for this extension study. In this study, safety data will be 
descriptively summarized, and all data collected will be listed. Detailed methods of presenting 
data will be specified in the study RAP (or SAP). 
Categorical data will be presented as frequencies and percentages. 


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10.1 
Analysis sets 
As the primary objective of this extension study is to assess the safety of the two treatments, 
only safety data will be collected besides demographics and treatment information. 
10.1.1 
Safety Set 
The Safety Set includes all patients who received at least one dose of study medication. Patients 
will be analyzed according to the study treatment they actually received. 
10.2 
Patient demographics/other baseline characteristics 
Demographic data at the enrollment will be listed for all patients. 
10.3 
Treatments (study treatment, concomitant therapies, compliance) 
Usage of concomitant medications/therapies will not be collected in this study. Data of study 
treatment will be listed. 
10.4 
Primary objective 
The primary objective of this extension study is to assess safety of nilotinib and imatinib in 
newly diagnosed Ph+ CML-CP patients who derive benefit from the study treatment, in the 
opinion of the investigator at the end of study CAMN107ECN02. 
10.4.1 
Variable 
All AEs recorded during the study will be summarized by system organ class and or preferred 
term, severity (based on CTCAE grades), type of AE, and relation to the treatment. Deaths 
reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated by type of AE.  
For all safety analyses, the Safety Set will be used. All listings and tables will be presented by 
treatment they actually received. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
Not applicable 
10.4.3 
Handling of missing values/censoring/discontinuations 
Not applicable 
10.4.4 
Supportive analyses 
Not applicable 
10.5 
Secondary objectives 
Not applicable 
10.6 
Exploratory objectives  
Not applicable. 


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10.7 
Interim analysis 
No interim analysis is planned for this study. 
10.8 
Sample size calculation 
The size of this study depends on the number of patients who complete the study of 
CAMN107ECN02 and their eligibility to this extension. There are 234 patients currently on 
treatment in CAMN107ECN02, so the sample size of this extension study will not be larger 
than this number. 
10.9 
Power for analysis of key secondary variables 
Not applicable 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and 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. 


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


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The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
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 but not later than 10 working days. 


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13 
References (available upon request) 
Atallah E, Kantarjian H, Cortes J (2007) In reply to ‘Cardiotoxicity of the cancer therapeutic 
agent imatinib mesylate’ Nature; 13: 14. 
Baccarani M, Druker B, Cortes J, et al (2009) 24 Month update of the TOPS study: a phase III, 
randomized, open-label study of 400 mg/d versus 800 mg/d of imatinib mesylate in patiens with 
newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase. Blood (ASH 
Annual Meeting Abstracts); 114: Abstract 337 
Bartram CR, deKlein A, Hagemeijer A, et al (1983) Translocation of c-Abl correlates with the 
presence of a Philadelphia chromosome in chronic myelogenous leukemia. Nature; 306: 277- 
80. 
Cortes J, Baccarani M, Guilhot F, et al (2010) Phase III, randomized, open-label study of daily 
imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously 
untreated chronic myeloid leukemia in chronic phase using molecular endpoints: tyrosine kinase 
inhibitor optimization and selectivity study. Journal of Clinical Oncology; 28: 424-430 
Cortes J, Jones D, O’Brien S, et al (2009) Nilotinib as Front-Line Therapy for Patients with 
Chronic Myeloid Leukemia in Early Chronic Phase. Journal of Clinical Oncology; 28: 392-397 
Cortes J, O’Brien S, Jones D, et al (2009) Efficacy of nilotinib in patients with newly diagnosed, 
previously untreated Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in 
early chronic phase. Blood (ASH Annual Meeting Abstracts); 114: Abstract 341 
Daley GQ, Van Etten RA, Baltimore D (1990) Induction of chronic myelogenous leukemia in 
mice by the p 210 bcr/Abl gene of the Philadelphia chromosome. Science; 247: 824-30. 
Druker B, Guilhot F, O’Brien S, et al (2006a) Five-Year Follow-up of Patients Receiving 
Imatinib for Chronic Myeloid Leukemia N Engl J Med 2006; Dec 7;355(23):2408-2417. 
Enright H, McGlave P (2000) Chronic myelogenous leukemia. In: Hoffman R, Benz EJ, Shattil 
SJ et all, eds. Hematology: Basic Principles and Practice, Third Edition. New York:Churchill-
Livingstone, Inc., 1155-71. 
Gambacorti C, Tornaghi L, Franceschino A, et al (2007) in reply to ‘Cardiotoxicity of the 
cancer therapeutic agent imatinib mesylate’ Nature; 13:14 
Heisterkamp N, Stephenson JR, Groffen J, et al (1983) Localization of the c-Abl oncogene 
adjacent to a translocation break point in chronic myelocytic leukemia. Nature; 306: 239-42. 
Hughes TP, et al (2010) ENESTnd update: continued superiority of nilotinib versus imatinib in 
patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Blood; 
116 (21): 94-95 [abstract 207] 
Kantarjian H, Giles F, Bhalla K, et al (2009) Update on imatinib-resistant chronic myeloid 
leukemia patients in chronic phase (CML-CP) on nilotinib therapy at 24 months: clinical 
response, safety, and long-term outcomes. Blood (ASH Annual Meeting Abstracts); 114: 
Abstract 1129 
Kantarjian H, Giles F, Wunderle L, et al (2006), Nilotinib in Imatinib-resistant CML and 


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Philadelphia Chromosome Positive ALL. New England Journal of Medicine; 354: 2542-51. 
Kantarjian H, Talpaz M, O’Brien S, et al (2004a) High-dose imatinib mesylate therapy in newly 
diagnosed Philadelphia chromosome positive chronic phase chronic myeloid leukemia. Blood; 
103:2873-2878. 
Kantarjian HM, Cortes JE, O’Brien S, et al (2003) Imatinib mesylate therapy in newly 
diagnosed patients with Philadelphia chromosome positive chronic phase chronic myelogenous 
leukemia: high incidence of early complete and major cytogenetic responses. Blood; 101:97-
100. 
Kelliher MA, McLaughlin J, Witte ON, et al (1990) Introduction of a chronic myelogenous 
leukemia-like syndrome in mice with v-Abl and BCR/ABL. Proc Natl Acad Sci USA 87;6649-
53. 
Kerkela R, Grazette L, Yacobi R, et al (2006) Cardiotoxicity of the cancer therapeutic agent 
imatinib mesylate. Nature Medicine advance online publication July 23, 2006. 
Le Coutre P, Baskaynak G, Tamm I, et al (2004) Activity and induction of apoptosis of the 
specific tyrosine kinase inhibitor nilotinib in bcr-Abl + cell lines and in imatinib resistant 
primary cells from CML patients. Blood; 104(11), abstract #762. 
Nowell PC, Hungerford DA (1960) A minute chromosome in chronic granulocytic leukemia. 
Science; 132: 1497-1501. 
O'Brien S, Guilhot F, Larson R, et al (2003) Imatinib compared with interferon and low- dose 
cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J 
Med.;348(11): 994-1004. 
Rosti G, Palandri F, Castagnetti F, el al (2009) Nilotinib for the frontline treatment of Ph+ 
chronic myeloid leukemia. Blood; 114; 4933-4938 
Saglio G, Kim DW, Issaragrisil S, et al (2009) Nilotinib demonstrates superior efficacy 
compared with imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic 
phase: results from the international randomized phase III ENESTnd trial. Blood (ASH Annual 
Meeting Abstracts); Abstract LBA-1 
White D, Saunders V, Engler J, et al (2005) Low baseline intrinsic sensitivity to imatinib (high 
IC50) in CML patients is due to reduced Oct-1 mediated influx. Intrinsic sensitivity to nilotinib 
does not correlate with that of imatinib and uptake of nilotinib is not Oct-1 mediated. Blood; 
106(11), abstract #1081. 
Wang JX, et al(2013). Chinese guideline of diagnosis and treatment of chronic myelogenous 
leukemia. Zhonghua Xue Ye Xue Za Zhi. 34(5) 464-70. 


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14 
Appendix 
14.1 
Appendix 1 List of CYP3A4 inducers and inhibitors 
These lists are compiled based on the FDA’s “Guidance for Industry, Drug Interaction Studies”, 
the Indiana University School of Medicine’s Drug Interactions Database, and the University of 
Washington’s Drug Interaction Database. Refer to Novartis Oncology Clinical Pharmacology 
Internal Memorandum, Drug-drug interactions (DDI) Database (last updated 30 August 2010) 
for update or more details. 
Table 14-1 
List of medications metabolized by CYP3A4, strong, moderate and weak 
inhibitors of CYP3A4 to be used with caution 
CYP3A4 substrates permitted but 
patients should be carefully monitored 
for drugs indexed 1 and 2 
Strong inhibitors
Moderate 
inhibitors 
Weak 
inhibitors 
alfentanil1,2 
fentanyl2 
clarithromycin 
aprepitant 
alprazolam 
fluticasone1 
diergotamine2 
conivaptan 
atazanavir 
AMD070 
cyclosporine2 
adinazolam 
indinavir 
cimetidine 
amlodipine 
maraviroc1 
alprazolam 
itraconazole 
ciprofloxacin 
azithromycin 
midazolam1 
amlodipine 
ketoconazole 
darunavir 
bicalutamide 
alpha-
dihydroergocryptine1 
aripiprazole 
lopinavir 
diltiazem 
chlorzoxazone
sildenafil1 
chlorpheniramine 
mibefradil 
erythromycin 
cilostazol 
tipranavir1 
diazepam 
nefazodone 
fluconazole 
cyclosporine 
triazolam1 
estazolam 
nelfinavir 
grapefruit juice 
fluvoxamine 
perospirone1 
nisoldipine 
posaconazole 
imatinib 
ginkgo 
darifenacin1 
quinine 
ritonavir 
tofisopam 
goldenseal 
ebastine1 
trazodone 
saquinavir 
verapamil 
isoniazid 
eletriptan1 
nitrendipine 
telithromycin 
 
lacidipine 
eplerenone1 
mevastatin 
troleandomycin 
 
M100240 
everolimus1 
lovastatin1 
voriconazole 
 
oral 
contraceptives
felodipine1 
atorvastatin1 
 
 
peppermint oil
brotizolam1 
simvastatin1 
 
 
propiverine 
budesonide1 
fluvastatin 
 
 
ranitidine 
buspirone1 
 
 
 
ranolazine 
sirolimus1,2 
 
 
 
roxithromycin 
ergotamine2 
 
 
 
Seville orange 
juice 
 
 
 
 
tabimorelin 
1 Sensitive substrates: drugs whose plasma AUC values have been shown to increase 5-fold or higher 
when co-administered with a potent inhibitor of the respective enzyme. 
2 Substrates with narrow therapeutic index (NTI): drugs whose exposure-response indicates that 
increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious safety 
concerns (e.g., Torsades de Pointes). 


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Note: 
• Inhibitor classification: Strong inhibitors may result in a substrate AUC > 5-fold 
increase. 
• Moderate inhibitors may result in a substrate AUC ≥ 2-fold increase and < 5-fold 
increase. 
• Weak inhibitors may result in a substrate AUC ≥ 1.25-fold increase and < 2-fold 
increase. 
Table 14-2  Medications that can inhibit CYP3A4  
Note:  
• Inducer classification: 
• Strong inducers may result in a substrate AUC decreased by ≥ 80%. 
• Moderate inducers may result in a substrate AUC decreased by 50-80%. 
• Weak inducers may result in a substrate AUC decreased by 20-50%. 
 
Strong inducers 
Moderate inducers 
Weak inducers 
Unclassified inducers 
avasimibe 
bosentan 
amprenavir 
topiramate 
carbamazepine 
efavirenz 
aprepitant 
 
dexamethasone* 
etravirine 
armodafinil (R-modafinil) 
 
phenobarbital 
modafinil 
echinacea 
 
phenytoin 
nafcillin 
garlic 
 
rifabutin 
ritonavir 
gingko 
 
rifampin 
talviraline 
glycyrrhizin 
 
rifapentin* 
tipranavir 
methylprednisolone 
 
St. John's wort 
 
nevirapine 
 
 
 
oxcarbazepine 
 
 
 
pioglitazone 
 
 
 
prednisone 
 
 
 
pleconaril 
 
 
 
rufinamide 
 
 
 
troglitazone 
 
* Discrepancies on the level of induction of these drugs exist in the literature; however, they are listed in 
the “strong inducers” group in order to be consistent with the Tasigna Labeling. 

SAP_000.pdf: 
Clinical Development 
AMN107 (Nilotinib, Tasigna) 
CAMN107ECN02E1 / NCT02272777
An open-label multi-center study of imatinib and nilotinib in 
CAMN107ECN02 on-treatment patients with Philadelphia chromosome 
positive chronic myelogenous leukemia in chronic phase after the end of 
CAMN107ECN02 core study  
(ENESTChina extension study) 
RAP Module 3 – Detailed Statistical Methodology 
Author: 
, Trial Statistician 
Document type: 
RAP Documentation 
Document status: 
Final Version 4 
Release date: 
14-Jan-2019
Number of pages: 
7 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous version of RAP module 3 
Version 
Date 
Changes 
1.0 
21-Apr-2015 
Final version 1.0 
2.0 
Dec.2016 
Updated to add Hepatitis B testing results. 
3.0 
Mar.2017 
Updated the sample size 234 and delete “important” from DV table. 
4.0 
Jan.2019 
Add exposure analysis for section 1.5. 
 
 
 
 
 
 
 


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Table of contents 
1 
Statistical methods planned in the protocol and determination of sample size ................... 4 
1.1 
Statistical and analytical plans ................................................................................. 4 
1.2 
Subjects and treatments ........................................................................................... 4 
1.2.1 
Analysis sets ............................................................................................ 4 
1.2.2 
Treatments ............................................................................................... 4 
1.3 
Patient demographics and other baseline characteristics ......................................... 4 
1.3.1 
Patient disposition ................................................................................... 4 
1.3.2 
Protocol deviation ................................................................................... 4 
1.4 
Efficacy evaluation .................................................................................................. 5 
1.5 
Safety evaluation ..................................................................................................... 5 
1.6 
Other topics .............................................................................................................. 5 
1.7 
Determination of sample size .................................................................................. 5 
1.8 
Changes from protocol specified analyses .............................................................. 6 
 


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1 
Statistical methods planned in the protocol and 
determination of sample size 
Data will be analyzed by Novartis or designee using SAS® version 9.2 or higher (SAS 
Institute Inc., Cary, NC, USA) according to the data analysis Section 10 of the study Protocol. 
1.1 
Statistical and analytical plans 
Summary tables will be provided for patient disposition, protocol deviation, and safety data. 
The data will also be listed. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented, unless otherwise 
stated. 
1.2 
Subjects and treatments  
1.2.1 
Analysis sets 
As the primary objective of this extension study is to assess the safety of the two treatments, 
only safety data will be collected in addition to demographics and treatment information.  
Safety Set 
The Safety Set consists of all patients who received at least one dose of study medication. The 
statement that a patient had no AE (on Adverse Event CRF page) constitutes a safety 
assessment. Patients will be analyzed according to the study treatment they actually received 
at the beginning the extension study. 
1.2.2 
Treatments 
Study treatments are: nilotinib (AMN107, Tasigna) and imatinib (STI571, Glivec). In this 
study patient will continue treatment of the drug (imatinib or nilotinib) which they are taking 
at the end of CAMN107ECN02. 
1.3 
Patient demographics and other baseline characteristics 
Demographics at the enrollment will be listed for all patients. 
Usage of concomitant medications/therapies will not be collected in this study. Data of study 
treatment will be listed. 
1.3.1 
Patient disposition 
The number of patients completed the study as well as the primary reason for early 
discontinuation will be summarized. 
1.3.2 
Protocol deviation 
Patients with following protocol deviations will be listed: 


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1. Inclusion Criteria/Exclusion Criteria: the subject was entered in the trial, but did not meet 
the eligibility for one or more of the Inclusion or Exclusion criteria defined in the protocol 
2. Study Drug Administration: the subject did not take the study drug as per protocol 
3. Discontinuation Criteria: the subject met criteria defined in the protocol for 
discontinuation but was not discontinued from study 
4. Prohibited Concomitant Medication: the subject took prohibited concomitant medication 
as defined in the protocol 
1.4 
Efficacy evaluation 
Not applicable to this study. 
1.5 
Safety evaluation 
Treatment exposure is defined as last dose date minus start date of study drug + 1, actual dose 
intensity is defined as total dose/treatment exposure, relative dose intensity is defined as 
actual dose intensity/assigned total daily dose (600 mg). All these variables will be 
summarized using descriptive statistics (N, mean, standard deviation, minimum, median and 
maximum). And actual dose intensity category will be summarized using frequency counts 
and percentages. 
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. 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA). All AEs 
will be listed by patient and those collected during pre-study period are to be flagged. The 
incidence of AE will be summarized by system organ class (SOC) and or preferred term (PT), 
severity (based on CTCAE v3.0, the same one applied in the core study), and relation to study 
drug. Note that AEs from pre-study will not be analyzed (see section 1.8). 
Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated by SOC, 
PT and treatment. 
The result of Hepatitis B testing will be summarized and listed.  
For all safety analyses, the Safety Set will be used. All listings and tables will be presented 
according to the treatment actually taken.  
1.6 
Other topics 
Urine pregnancy test results for female patients will be listed. 
1.7 
Determination of sample size 
The sample size of this study is not based on statistical consideration. Patients that completed 
the study of CAMN107ECN02 will be screened for eligibilities to enter this extension study. 
The upper bound of the sample size of this extension study is 234, the number of patients who 
completed study of CAMN107ECN02. 


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1.8 
Changes from protocol specified analyses 
In protocol section 8.1 it specified that conditions that were already present at the time of 
informed consent should be recorded in the Medical History page of the patient’s CRF. 
However due to the roll-over feature of the study the CRF did not include a Medical History 
page, these continuing conditions were recorded in Adverse Event page, and could be 
identified by the comparing the start date of AE with the informed consent date of the patient, 
e.g AEs with a start date before informed consent are pre-study AEs and will not be included 
into analysis. These ‘AEs’ are to be flagged in the AE listing.  


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