Clinical trial NCT01274351
Conditions: Chronic Myelogenous Leukemia
Keywords: First line treatment newly diagnosed Philadelphia chromosome positive Chronic Myelogenous Leukemia Ph+ CML-CP major molecular response Social risk
Sponsor: Novartis Pharmaceuticals
Start date: 2011-01-25; Completion date: 2019-08-01
Enrollment: 112 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study was a local multicentric, open-label, non-randomized phase II study of nilotinib as a first line treatment in adult patients with newly-diagnosed Philadelphia chromosome-positive (Ph+) and chronic phase myeloid leukemia (CML-CP).

Detailed description:
This was a multicenter, open-label, single-arm, phase 2 study of nilotinib as a frontline treatment for patients with Ph+ CMLCP. All patients received oral nilotinib 300 mg twice daily for a planned treatment duration of 24 months or until early discontinuation.

The primary efficacy end point was the cumulative rate of Major Molecular Response (MMR) in all participants by 12 months. Secondary efficacy end points included the rate of Complete Cytogenic Response (CCyR) at 6 and 12 months; cumulative rates of MMR up to 24 months; time to and durability of MMR; and cumulative rate of Complete Haematologic Response (CHR) by 12 months.

Patient evaluations, including hematologic assessments, were conducted every 15 days during the first 3 months, monthly until month 12, and then every 3 months until the end of the study (24 months). All efficacy analyses were performed in the intent-to treat population.

Arms: arm 1: administered orally at a dose of 300 mg twice daily for 24 months
Interventions: intervention 1: Nilotinib
Intervention descriptions: intervention 1: administered orally at a dose of 300 mg twice daily for 24 months

Protocol documents:
Prot_000.pdf: 
Clinical Development and Medical Affairs 
AMN107 Tasigna® (nilotinib) 
Protocol No.CAMN107ETR02 / NCT01274351 
A multicenter, open-label, non-randomized phase II study of nilotinib as a 
first line treatment  in adult patients  with newly-diagnosed Philadelphia 
chromosome-positive (Ph+) and chronic phase myeloid leukemia (CML-CP) 
Author(s): 
Document type:  
Clinical Trial Protocol (Working Protocol)
Version no: 
2.0
Development phase: 
II
Release date: 
May 20, 2012
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis. 


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Clinical Study Protocol (Version No. 2.0) 
 
Protocol No. CAMN107ETR02 
 
 
 
 
Signature page  
 
Component name / number  
AMN107 Tasigna® (nilotinib)  
 
Protocol no.   
 
 
CAMN107ETR02  
 
 
Approved by:  
 
Signature of Novartis staff:  
 
 
Please write/print name  
(Oncology Medical 
Director)  
Signature 
Date  
 
 
 
Please write/print name  
(Medical Manager)  
Signature 
Date  
 
 
 
 
Chief Investigator’s Signature 
 
 
Please write/print name  
(Chief Investigator)  
Signature 
Date  
 


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Clinical Study Protocol (Version No. 2.0) 
 
Protocol No. CAMN107ETR02 
 
 
 
 
Signature page for the investigator 
 
 
 
Component name / number  
AMN107 Tasigna® (nilotinib)  
 
Protocol no.   
 
 
CAMN107ETR02 
 
 
I have read this protocol and I commit to conducting this study in accordance with all the 
conditions of the protocol and as per the principles outlined in Helsinki Declaration.  
 
 
 
Write/print name  
(Investigator)  
Signature 
Date  
 


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Clinical Study Protocol (Version No. 2.0) 
 
Protocol No. CAMN107ETR02 
 
 
 
Table of contents  
 
 
Table of contents  ............................................................................................................ 4  
 
List of tables  ................................................................................................................... 6  
 
List of figures  ................................................................................................................. 6  
 
List of abbreviations  ...................................................................................................... 7  
 
Glossary of terms ............................................................................................................ 9  
 
Protocol synopsis  ........................................................................................................... 10  
1  
Background  .................................................................................................................... 15  
 
1.1  
Chronic myeloid leukemia  ............................................................................... 15  
 
1.2  
Nilotinib ............................................................................................................ 16  
2  
Purpose and rationale  ..................................................................................................... 17  
3  
Study objectives  ............................................................................................................. 18  
 
3.1  
Primary objective(s) ......................................................................................... 18  
 
3.2 
Secondary objective(s) ..................................................................................... 18  
 
3.3 
Exploratory objectives  ..................................................................................... 19  
4  
Investigational plan  ........................................................................................................ 19  
5  
Population  ...................................................................................................................... 20  
 
5.1 
Inclusion criteria  .............................................................................................. 20  
 
5.2 
Exclusion criteria  ............................................................................................. 21  
6  
Treatment  ....................................................................................................................... 22  
 
6.1 
Investigational treatment and control drugs  .................................................... 22  
 
6.2 
Treatment arms  ................................................................................................ 22  
 
6.3 
Treatment assignment  ...................................................................................... 23  
 
6.4 
Treatment blinding............................................................................................ 23  
 
6.5 
Treating the subject........................................................................................... 23  
 
 
6.5.1  
Subject numbering .............................................................................. 23  
 
 
6.5.2 
Dispensing the study treatment .......................................................... 23  
 
 
6.5.3 
Supply, storage and tracking of study treatment ................................ 23  
 
 
6.5.4 
Instructions for prescribing and taking study treatment ..................... 24  
 
 
6.5.5 
Permitted dose adjustments and interruptions of study treatment ...... 24  
 
 
6.5.6 
Concomitant treatment ....................................................................... 27  
 
 
6.5.7 
Discontinuation of study treatment .................................................... 27  
 
 
6.5.8 
Emergency unblinding of study treatment ......................................... 30  
 
 
6.5.9 
Study steering committee  .................................................................. 30 
7 
Visit schedule and assessments  ...................................................................................... 31  
 
 


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7.1 
Screening and baseline  .................................................................................... 31  
 
7.2 
Information to be collected on screen failures  ................................................. 33  
 
7.3 
Subject demographics/other baseline characteristics ....................................... 33  
 
7.4 
Treatment exposure and compliance  ............................................................... 33  
 
7.5 
Efficacy  ............................................................................................................ 34  
 
 
7.5.1 
Molecular response  ............................................................................ 34  
 
 
7.5.2 
Cytogenetic response  ......................................................................... 35  
 
 
7.5.3 
Hematologic response  ....................................................................... 36  
 
 
7.5.4 
Treatment failure  ............................................................................... 37  
 
 
 
 38  
 
 
 
 38  
 
7.6  
Safety  ............................................................................................................ 38  
 
 
7.6.1 
Adverse events  ................................................................................... 38  
 
 
7.6.2 
Physical examination  ......................................................................... 39  
 
 
7.6.3 
Vital signs and body weight  .............................................................. 39  
 
 
7.6.4 
Performance status  ............................................................................. 40  
 
 
7.6.5 
Laboratory evaluations  ...................................................................... 40  
8 
Safety monitoring  .......................................................................................................... 41  
 
8.1 
Adverse events  ................................................................................................. 41  
 
8.2 
Serious adverse event reporting  ....................................................................... 42  
 
8.3 
Pregnancies  ...................................................................................................... 43  
 
8.4 
Data monitoring committee  ............................................................................. 43  
9  
Data review and database management  ......................................................................... 43  
 
9.1 
Site monitoring  ................................................................................................ 43  
 
9.2 
Data collection  ................................................................................................. 44  
 
9.3 
Database management and quality control  ...................................................... 44  
10 
Data analysis ................................................................................................................... 45  
 
10.1 
Populations for analysis .................................................................................... 45  
 
10.2 
Subject demographics/other baseline characteristics ....................................... 45  
 
10.3 
Treatments (rescue medication, other concomitant therapies, compliance)  .... 45  
 
10.4 
Analysis of primary variable(s)  ....................................................................... 46  
 
 
10.4.1 Variable  ............................................................................................. 46  
 
 
10.4.2 Statistical model, hypothesis and method of analysis  ....................... 46  
 
 
10.4.3 Handling of missing values/censoring/discontinuations  ................... 46  
 
 
10.4.4 Supportive analyses  ........................................................................... 46 
 
10.5 
Analysis of secondary variables  ...................................................................... 46  


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10.5.1 Efficacy (secondary)  .......................................................................... 46  
 
 
10.5.2  Safety  ................................................................................................. 47 
 
10.6 
Sample size calculation .................................................................................... 47  
 
10.7 
Power for analysis of key secondary variables  ................................................ 47  
 
10.8 
Interim analyses  ............................................................................................... 47  
11 
Ethical considerations  .................................................................................................... 47  
 
11.1 
Regulatory and ethical compliance  .................................................................. 47  
 
11.2 
Informed consent procedures  ........................................................................... 48  
 
11.3 
Responsibilities of the investigator and IRB/IEC/REB  ................................... 48  
 
11.4 
Publication of study protocol and results  ........................................................ 49  
12 
Protocol adherence  ......................................................................................................... 49  
 
12.1 
Protocol amendments ....................................................................................... 49  
13 
References  ...................................................................................................................... 50  
 
List of tables  
 
Table 6-1  
Summary of dose reduction guideline for non-hematologic toxicity  ......... 25  
Table 6-2 
Summary of dose reduction guideline for hematologic toxicity  ................. 26  
Table 6-3  
SOKAL risk estimation and definition  ....................................................... 29  
Table 7-1  
Assessment schedule  ................................................................................... 32  
Table 7-2  
ECOG Performance status  .......................................................................... 40  
 
List of figures  
 
Figure 4-1 
Investigational plan  ..................................................................................... 20 


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List of abbreviations  
ABL   
 
Abelson proto-oncogene  
AP  
 
 
Accelerated phase 
AE  
 
 
Adverse event  
ALT (SGOT)   
Alanine aminotransferase  
AST (SGPT)   
Aspartat aminotransferase  
BCR   
 
Breakpoint Cluster Region gene / BCR gene product 
BCR-ABL  
 
Fusion gene from BCR and ABL/Protein product from BCR-ABL 
BP  
 
 
Blastic phase 
BID 
  
 
bis in diem/two times daily  
BC  
 
 
Blast crisis  
WBC   
 
White blood cell  
CT  
 
 
Computed tomography  
BUN   
 
Blood urea nitrogen  
SAE   
 
Serious adverse event  
CTCAE NCI   
Common Terminology Criteria for Adverse Events 
WHO   
 
World Health Organization  
ECG   
 
Electrocardiography  
EMEA  
 
European Medicines Agency  
FDA   
 
Food and Drug Administration  
FISH   
 
Fluorescent in situ hybridization  
GI  
 
 
Gastrointestinal  
CTC   
 
Common Toxicity Criteria  
HDL   
 
High-density lipoprotein  
HLA   
 
Human Leukocyte Antigen  
IFN-α  
 
Interferon-α  
GCP   
Good Clinical Practice  
INR   
 
International normalization rate  
ITT  
 
 
Intent-to-Treat  
CP  
 
 
Chronic phase 
IRB/IEC/REB 
Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board 


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CML   
 
Chronic myeloid leukemia  
PCR   
 
Partial cytogenetic response  
LDH   
 
Lactate dehydrogenase   
LDL   
 
Low-density lipoprotein  
MedDRA  
 
Medical Dictionary for Regulatory Activities  
MMR   
 
Major molecular response  
mCR   
 
Minor cytogenetic response  
MCR   
 
Major cytogenetic response  
LLN   
 
Lower limit of normal  
ULN   
 
Upper limit of normal  
CRF   
 
Case Report Form  
PCR   
 
Polymerase chain reaction  
Ph+  
 
 
Philadelphia chromosome-positive  
PP  
 
 
Per Protocol  
QD  
 
 
Quoque die / once daily 
CRO   
 
Contract Research Organization   
CR  
 
 
Cytogenetic response  
CNS   
 
Central nervous system  
LVEF   
 
Left ventricular ejection fraction  
CHR   
 
Complete hematologic response  
CCyR   
 
Complete cytogenetic response  
ICH   
 
International Conference on Harmonization  
VLDL  
 
Very low-density lipoprotein  
DQF   
 
Data Questioning Form  


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Definition of terms  
Assessment   
A procedure used to generate data required by the study  
Enrollment 
Point/time of subject entry into the study; the point at 
which informed consent must be obtained (i.e. prior to 
starting any of the procedures described in the protocol). 
Investigational drug 
The study drug whose properties are being tested in the 
study; this definition is consistent with US CFR 21 
Section 312.3 and is synonymous with “investigational 
new drug.” 
Subject number 
A number assigned to each subject who enrolls in the 
study. When combined with the center number, a unique 
identifier is created for each subject in the study.  
Period   
A minor subdivision of the study timeline; divides 
phases into smaller functional segments such as 
screening, baseline, titration, washout, etc. 
Premature subject 
withdrawal 
Point/time when the subject exits from the study prior to 
the planned completion of all study drug administration 
and 
assessments; 
at 
this 
time 
all 
study 
drug 
administration 
is 
discontinued 
and 
no 
further 
assessments are planned.  
Stop study participation  
Point/time at which the subject comes in for a final 
evaluation visit or when study drug is discontinued, 
whichever is later.  
Study drug 
Any drug administered to the subject as part of the 
required study procedures; includes investigational drug 
and any control drugs. 
Study drug discontinuation 
Point/time when subject permanently stops taking study 
drug for any reason; may or may not also be the 
point/time of premature subject withdrawal.  
Variable  
Information used in the data analysis; derived directly or 
indirectly 
from 
data 
collected 
using 
specified 
assessments at specified time points. 
 


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Protocol synopsis   
 
Title of the study: A multicenter, open-label, non-randomized phase II study of nilotinib as a 
first line treatment in adult patients with newly-diagnosed Philadelphia chromosome-positive 
(Ph+) and chronic phase myeloid leukemia (CML-CP) 
Purpose of the study: This study is designed to investigate molecular and cytogenetic 
efficacy and safety profile of nilotinib in the treatment of early chronic phase of Ph+ CML in 
patients from different risk groups  
 
Objectives:  
Primary objective:  
 To investigate the efficacy of nilotinib in the treatment of early phase Ph+ CML 
(cumulative major molecular response [MMR] during the first 12 months)  
 
Secondary objectives:  
 To evaluate the rate of complete cytogenetic response (CCyR) at months 6 and 12 
 
 To evaluate the rate of 3-monthly molecular response 
 
  To evaluate hematologic response rate  
 
 To evaluate the safety profile of nilotinib treatment  
 
 To evaluate  time to  MMR and durability of the response  
 
 
  
  
 
  
 
 
  
 
 
Population: All eligible adult Ph + CML-CP patients who have been newly diagnosed 
cytogenetically during the past six months and who have not received treatment for CML 
other than anagrelide and hydroxyurea will be enrolled in the study.  
 
A total of 110 subjects will be enrolled despite risk stratification. 
 
 
Inclusion / exclusion criteria:  
The patients must fulfill all inclusion criteria during the 4 weeks prior to the study (bone 
marrow analyses may have been performed within the last 8 weeks) and should not meet any 
of the exclusion criteria.  
 
Inclusion criteria  
 Male and female patients ≥18 years old  
 ECOG performance status 0, 1 or 2 


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Protocol No. CAMN107ETR02 
 
 
 First CML-CP diagnosis should have been made during the past 6 months and 
Philadelphia chromosome resulting from translocation (9;22) should be confirmed 
cytogenetically. Standard conventional cytogenetic analysis is required. All of the 
following criteria of CML-CP diagnosis should be met: 
o <15% blast in peripheral blood smear and bone marrow 
o <30% blast in peripheral blood smear and bone marrow plus promyelocyte  
o <20% basophil in peripheral blood 
o ≥100 x 109/L (≥100.000/mm3) platelet 
o No 
evidence 
of 
extramedullary 
leukemic 
involvement, 
except 
for 
hepatosplenomegaly 
 Sufficient end-organ function with the following laboratory criterias:, total bilirubin < 
1.5 x ULN; SGOT and SGPT < 2.5 x ULN; creatinine < 1.5 x ULN; serum amylase 
and lipase ≤ 1.5 x ULN; alkaline phosphatase ≤ 2.5 x ULN unless associated with a 
tumor 
 Serum potassium, magnesium, calcium and phosphorus levels are equal to or above 
the lower limit of normal before the administration of the first dose of the study 
treatment. 
 Should have provided informed consent in written before any study-related procedure 
may be initiated.  
 
Exclusion criteria  
 
 Being treated with tyrosine kinase inhibitors before the study start (awaiting the study 
start, in cases of emergencies where the disease should be treated, commercial 
products containing imatinib may be prescribed but the treatment period should not 
exceed 31 days).  
 Known CNS infiltration, confirmed cytopathologically.  
 Cardiac dysfunction [presence of any of the following: LVEF <45% (if available), 
inability to determine QT interval with ECG, acquired long QT syndrome or familial 
history of long QT syndrome, clinically significant ventricular or atrial 
tachyarrhythmia or history thereof, clinically significant resting bradycardia (<50 
beats/minute), QTc > 450msn as measured by QTcF in baseline ECG (if QTcF>450 
msn and electrolytes are not within normal ranges, the latter should be corrected and 
the subject should undergo screening again for QTc), history of myocardium infarct 
within the 12 months before the study start, other clinically significant cardiac 
disorders (e.g. instable angina, congestive heart failure or uncontrolled hypertension)]. 
 Serious or uncontrolled medical conditions (e.g., uncontrolled diabetes mellitus, active 
or uncontrolled infections).  
 Acute or chronic hepatic, pancreatic or serious renal diseases not associated with the 
disease, 
Patients with other primary malignancies; this excludes situations where the tumor is no 
longer clinically significant or does not necessitate active intervention. 
 Significant congenital or acquired bleeding disorders history not associated with 
cancer. 
 Previous radiotherapy involving ≥25% of the bone marrow. 
 Major surgery during the 4 weeks before the first day of the study or  patients not 
recovering following surgery  


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 Gastrointestinal (GI) dysfunction or GI disease which may significantly alter the 
absorption of the study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, small intestine resection or gastric by-pass surgery) 
 Patients treated with potent CYP3A4 inhibitors (e.g.; erythromycin, ketoconazole, 
itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil)  
 Patients currently receiving active treatment agents which may potentially prolong QT 
interval or in whom it is not possible to discontinue the treatment or to switch to 
another drug before the study treatment starts. 
 History of noncompliance with medical regimes.  
 Pregnant women (positive serum pregnancy test during the 7 days before the start of 
study treatment for women of childbearing potential) or breastfeeding women  
 Fertile male and female subjects who are not willing to take contraceptive measures 
throughout the study (in order to confirm that menopausal a woman does not have 
childbearing potential, she should have been amenorrheic for at least 12 months). 
Study and reference treatment: All enrolled subjects will be treated with nilotinib 
(AMN107 Tasigna®) 300 mg BID (600 mg/day) for 24 months. The study drug will be 
dispensed in open-label vials containing 150 mg strength capsules. Nilotinib should be taken 
at least 2 hours before breakfast and dinner with a glass of water. No oral intake, except 
water, is permitted within 1 hour following the dose. 
 
This study does not involve a reference treatment. 
 
Study plan: This is a local, multicenter, one-arm and non-randomized phase II clinical trial. 
This study will evaluate the efficacy and safety of nilotinib in a new group. Newly-diagnosed 
patients will enter a 2-week screening period. Those who meet eligibility criteria will be 
treated with nilotinib 300 mg BID for 24 months. For efficacy assessments, bone marrow 
aspiration and/or biopsy for will be used for cytogenetic analysis and peripheral blood will be 
used for RQ-PCR measurements of BCR-ABL transcriptions. Safety assessments will involve 
adverse events, laboratory profiles (hematology/biochemistry), ECG, and physical 
examinations. The patients will be evaluated every 15 days during the first 3 months, once 
every month for up to month 12 and then every three months.  
 
Efficacy assessments:  
Primary  
 MMR rate during 12 months is defined as BCR-ABL/control gene ratio of ≤ 0.1% as 
measured by RQ-PCR on an international scale (in %).  
Secondary  
 CCyR rate is defined as the ratio of patients with 0% Ph+ metaphases.  
 MMR rate is defined as BCR-ABL/control gene ratio of ≤0.1% as measured by RQ-
PCR on the international scale (%)  
 WBC <10 x 109/L, platelet <450 x 109/L, blood myelocyte + metamyelocyte <5%, 
absence of blast and promyelocyte in blood, basophiles <5%, absence of 
extramedullary involvement ( defined as complete hematologic response) 
 Time to MMR is defined as time to first documented MMR following treatment with 
the first dose 
 MMR duration defined as the duration from the first documented MMR to the first 
date when MMR is lost, or to progression or death (whichever is first) 


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Safety assessments:  
Primary 
 Rate, severity, seriousness and relationship to the study drug of adverse events  
Secondary  
 Laboratory profiles (hematology/biochemistry)  
 ECG  
 Physical examinations  
 
Data analysis: The primary efficacy variable in this study is the best cumulative MMR rate 
12 months after the administration of the first dose of the study treatment. Patients who 
withdraw prematurely or those who fail to provide data for the study will be considered as 
unfit for analysis and will be included in the ITT analysis as non-responders. Criteria to 
consider a subject as non-responder will be presented in another table. Only those subjects 
who achieve MMR within 12 months will be considered as responders. Analysis of secondary 
variables will be performed on ITT population.  
 
Efficacy variables for the primary and secondary objectives will be analyzed by descriptive 
statistics using summary statistics. Summary statistics will include n (number of 
observations), mean, standard deviation, median, minimum and maximum values for 
continuous variables as well as frequency and percentages for categorical variables. Missing 
values will not be replaced for secondary end points. All values will be assessed at month 6 
and 12, and then once every year if data is available and the ratio is the cumulative ratio up to 
a specific time point.  
 
Time variables up to any event will be shown with Kaplan-Meier curves.  
 


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All safety analyses will be performed on the safety population. Safety assessment will be 
based on primarily the incidence of adverse events and the number of subjects with laboratory 
values outside predetermined rates and number of patients with clinically significant ECG 
findings.  
 
An interim analysis is planned when 30% of the targeted number of patients is reached and 
these patients received six-month treatment with nilotinib. 
 


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1.  
Background  
 
1.1  
Chronic myeloid leukemia  
Chronic myeloid leukemia (CML) is a hematologic stem cell disease associated with a 
specific chromosome translocation known as the Philadelphia chromosome detected in 95% 
of patients (Nowell 1960, Rowley 1973). Molecular outcome of the translocation is fusion of 
the Abl proto-oncogene to the Bcr gene, resulting in production of an activated form of Abl 
protein-tyrosine kinase (Bartram 1983, Heisterkamp 1983). Expression of BCR-ABL protein 
may cause leukemia in mice, which suggests that this protein is the cause of the disease 
(Daley 1990, Kelliher 1990). Clinically, CML progresses through three different phases, 
gradually becoming more resistant to treatment: chronic phase (CP) (median duration 3-4 
years, median survival may extent up to 10 years with allogeneic bone marrow transplantation 
and is 5-6 years with interferon), accelerated phase (AP) (median duration 3-9 months; 
median survival 8-18 months) and blast crisis (BC) (median survival 3-6 month) (Enright 
2000). 
 
In chronic-phase CML, cytogenetic response criteria, which is based on the percentage of Ph+ 
cells in the bone marrow, is acknowledged as an important indicator of the disease state and 
treatment and represents the mainstay of monitoring the disease state in CML. Cytogenetic 
response (CyR) is a known determinant for prognosis in CML management and is used to 
predict patient outcome.  
 
During the past 25 years, Ph+CML treatment have evolved from treatment with non-specific 
cytotoxic agents to methods which combine cell destruction and immunologic control of the 
residual disease and, more recently, to imatinib, which is a tyrosine kinase inhibitor class 
agent that specifically targets the ABL portion of oncogenic BCR-ABL coded proteins. 
Conventional treatment may be given by a range of cytotoxic agents, mainly hydroxyurea. 
The treatment is safe and inexpensive and may be maintained on an outpatient basis and 
offers a good quality of life but neither prevents nor delays progression from chronic phase to 
accelerated or blast phases. Thus, all patients treated with conventional chemotherapy die 
within less than 10 years (median 4.5 years) (Goldman 2003). Conventional treatment is 
abandoned and may be indicated unless it is impossible to administer other treatments. 
Preferred treatment approach had been the allogeneic hemopoietic stem cell transplantation 
for at least 20 years since it was the only treatment procedure which was shown to actually 
treat the disease. Its use, however, is still limited with patients’ age (median age of patients 
with CML is 58) and requires a HLA-matching donor from patients’ families or from the 
international bone marrow donor registries. Besides, allogeneic hemopoietic stem cell 
transplantation still constitutes significant toxicity; transplantation-related mortality is 
approximately 30% and long-term leukemia-free survival is about 50% (Hehlmann 2007, 
Baccarani 2006, Barret 2003). Based on numerous prospective randomized studies on IFN-α 
versus conventional chemotherapy, interferon-α (IFN-α) had been the first choice of treatment 
in CML for about 10 years (1990-2000). Subsequent studies have shown that the efficacy of 
IFN-α was less in high-risk patients compared to the low-risk patients, who achieve greater 
benefit from this treatment: complete cytogenetic response was approximately 30% and 
elongations up to or even more than 10 years were observed.  


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IFN-α treatment is safe but toxic and not well-tolerated and about 35% of patients require 
treatment discontinuation (Baccarani 2003). Tyrosine kinase inhibitors are a new class of 
components designed and developed to target tyrosine kinase. A tyrosine kinase, imatinib 
mesylate, which inhibits ABL and other tyrosine kinases, was shown to specifically inhibit 
Ph+ cells and resulted in impressive number of hematologic and cytogenetic response in all 
phases of Ph+ leukemias (Hehlman 2007, Goldman 2001, Deininger 2005, Baccarani 2006, 
Kantarjian 2004, Hochhaus 2008). A prospective, randomized study using imatinib versus 
IFN-α showed than imatinib was superior to IFN-α by several orders of magnitude in 
hematologic response, cytogenetic response, time to progression and toxicity profile (O’Brien 
2003, Hughes 2003, Hochhaus 2007). Imatinib thus rapidly become the first choice of 
treatment for all phases of Ph+ CML, from the early chronic phase to the blastic phase. A 
range of second generation tyrosine kinase inhibitors were developed including nilotinib and 
were investigated in preclinical and clinical phases (Martinelli 2005, Kantarjian 2007) 
(Weisberg 2005, Golemovic 2005, Kantarjian 2006, Kantarjian 2007, Le Coutre 2008).  
 
1.2 
Nilotinib  
Nilotinib is an orally-available novel aminopyrimidine and an ATP competitive inhibitor of 
protein tyrosine kinase activity of BCR-ABL, which inhibits activation of BCR-ABL-
dependent mitogenic and anti-apoptotic pathways (e.g. PI-3 kinase and STAT5), thereby 
leading to BCR-ABL genotype demise. Nilotinib also frequently inhibits other oncogenic 
kinases 
including 
FIP1L1-PDGFRA 
tyrosine 
kinase, 
which 
is 
associated 
with 
hypereosinophilic syndrome and chronic eosinophilic leukemia, and stem cell factor receptor 
c-Kit tyrosine kinase, which is associated with systemic mastocytosis and gastrointestinal 
stromal tumors.  
 
Data from preclinical studies indicate that nilotinib reaches higher intracellular concentrations 
than imatinib and that nilotinib inhibits BCR-ABL tyrosine kinase activity and induce 
apoptosis at lower concentrations compared to imatinib (Le Coutre 2004, White 2005). In 
preclinical models, nilotinib was 20 to 50 times more potent than imatinib on CML cell lines 
sensitive to imatinib and was 3 to 7 times more potent in cell lines resistant to imatinib.  
  
In a phase I dose-escalation study, 119 patients with Ph+ CML and acute lymphocytic 
leukemia resistant to imatinib were treated with a single oral nilotinib dose of 50-1200 mg or 
400 mg and 600 mg nilotinib administered twice daily. Nilotinib produced higher hematologic 
and cytogenetic response rates in chronic phase CML patients who were resistant to imatinib, 
92 and 53% respectively (CCyR in 35%). (AMN107 Investigator Brochure Ed.4.0, 2008).  
 
Initial data from 132 patients resistant or tolerant to imatinib in a phase I study were reported 
by Kantarjian (2006). In this study, patients were treated with nilotinib for a median period of 
226 days (range 3-379 days). Complete hematologic response was achieved in 69% of the 
patients. Major cytogenetic response was achieved by 42%. Thirty-three patients (22%) 
achieved complete cytogenetic response.  
 
Nilotinib was also shown to have an acceptable tolerability profile (Kantarjian 2007). In a 
CML-CP population, the commonest GTC grade 3 hematologic anomalies were decreases in 
absolute lymphocyte (16.2%), neutrophil (14.8%), white blood cells (12.6%) and platelet 
(11.2%) counts. The commonest GTC grade 4 anomalies were reductions in platelet count 
(13.5%), neutrophils (11.6%) and absolute lymphocyte count (7.5%). 


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Furthermore, studies with patients with hematologic malignancies have demonstrated that 
nilotinib had a potential to mildly elongate QT interval at therapeutic concentrations. On day 
8 (steady-state), mean temporal changes in QT interval from baseline ranged from 5.7 msn 
(CML-CP patients) to 8.4 msn (CML-AP patients).   
 
It should be noted that most of the adverse events reported from the phase II leukemia studies 
with imatinib have also been reported from the phase I study with nilotinib, although 
incidence of peripheral edema was very low in the nilotinib study. In the Nilotinib phase I 
study, 400 mg twice daily (BID) dose level was associated with lower incidence of Grade 3 
neutropenia and Grade 3 hyperbilirubinemia compared to the 600 mg BID dose. Initial data 
from a phase II study with a patient group whose dosage was increased from 400 mg BID to 
600 mg BID due to suboptimal response did not demonstrate improved efficacy with the 
higher dose. Thus, 400 mg BID dose of imatinib was recognized as the dose with optimum 
efficacy and safety.  
 
Today, nilotinib treatment in patients with Ph+ CML who are resistant or intolerant to 
imatinib has been approved by the FDA and EMEA (Le Coutre 2008). Nilotinib is now being 
investigated in many studies as the first line treatment in Ph+ CML comparatively to imatinib.  
 
 
2 
Purpose and rationale  
Efficacy and safety of imatinib treatment in newly-diagnosed patients with chronic phase 
CML patients have been shown in several studies, including the landmark IRIS study. 
 
Although imatinib is very effective in chronic phase Ph + CML, leukemia persists in many of 
responders and there is always the risk of disease progression molecularly, cytogenetically 
and clinically.  
 
Nilotinib is a novel oral tyrosine kinase inhibitor with improved potency and selectivity 
compared to imatinib, since it fits better to ATP-binding pocket of imatinib. It seems 
reasonable to evaluate high potency and selectivity of nilotinib in patients with high Sokal 
risk in the high Sokal risk population to meet the unmet needs of these patients.  
 
GIMEMA (Rosti 2008) and MDACC (Cortes 2008) studies independently investigated the 
efficacy of nilotinib in newly diagnosed, treatment-naïve patients with Ph+-CML. Faster and 
more profound responses were demonstrated when the results reported from ASH 2008 were 
compared to published data of imatinib. CCR rates of evaluable patients at months 3 and 6 
were 78 and 96% in the GIMEMA study and 93 and 100% in the MDACC study, 
respectively. Major molecular response rates at month 6 in the GIMEMA and MDACC 
studies were 74 and 45%, respectively. These results are more impressive than those reported 
from IRIS study, which demonstrated 69% CCyR and 40% MMR at month 12.  
 
Further clinical data are required to demonstrate efficacy in different risk groups in order to 
evaluate the efficacy of nilotinib in newly diagnosed (de novo) patients regardless of Sokal 
scores.  
 
The present study was designed to investigate the efficacy of nilotinib (cumulative major 
molecular response [MMR] in 12 months)  
 


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3 
Study Objectives  
 
3.1  
Primary Objective(s)  
 
 To investigate the efficacy of nilotinib (cumulative major molecular response [MMR] 
in 12 months).  
 
3.2 
Secondary Objective(s)  
 To evaluate the rate of complete cytogenetic response (CCyR) at months 6 and 12  
 To evaluate periodically the rate of 3-monthly  molecular response  
 To evaluate complete hematologic response rate  
 To evaluate the safety profile of nilotinib treatment  
 To evaluate  time to MMR and durability of the response  
 
  
 
  
 
  
 
3.3 
Exploratory objective(s) 
Not applicable.  
 
4  
Investigational plan  
This is a local, multicenter, one-arm and non-randomized phase II clinical trial. This study 
will evaluate the efficacy and safety of nilotinib in a new group. Newly-diagnosed patients 
will enter a 2-weeek screening period. Those who meet eligibility criteria will be treated with 
nilotinib 300 mg BID for 24 months. For efficacy assessments, bone marrow aspiration and/or 
biopsy will be used for cytogenetic analysis and peripheral blood will be used for RQ-PCR 
measurements of BCR-ABL transcriptions. Safety assessments will involve adverse events, 
laboratory profiles (hematology/biochemistry), ECG, and physical examinations. The patients 
will be evaluated every 15 days during the first 3 months, once every month for up to month 
12 and then every three months. 
 
Screening visit: Patients’ eligibility (inclusion/exclusion criteria) is assessed at this visit. 
Subsequent 
procedures/tests 
will 
include 
informed 
consent, 
medical 
history, 
inclusion/exclusion 
criteria, 
vital 
findings, 
physical 
examination, 
assessment 
of 
extramedullary involvement, concomitant drugs, ECOG performance status, serum pregnancy 
test, hematology, blood chemistry, bone marrow assessment (within the past 2 months), 
peripheral blood analysis.  
 
Baseline visit: This visit will be scheduled for 0 to 2 weeks following the screening visit. 
Baseline assessments will include vital findings, physical examination, additional 
inclusion/exclusion criteria, concomitant drugs, drug dispensing, ECG, hematology and blood 
chemistry. 
 


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Unscheduled visits: As required. Investigations for the cause of the unscheduled visits will be 
performed.  
 
 
5 
Population  
All eligible adult patients with Ph+ CML-CP who have been diagnosed cytogenetically during 
the past six months and who have not received treatment for CML other than anagrelide and 
hydroxyurea 
 will be 
enrolled in the study.  
 
A total of 110 patients will be enrolled.  
 
 
 and should not 
meet any of the exclusion criteria. 
 
 
5.1 
Inclusion criteria 
 
 Male and female patients ≥18 years old  
 ECOG performance status 0, 1 or 2 
 First CML-CP diagnosis should have been made during the past 6 months and 
Philadelphia chromosome resulting from translocation (9;22) should be confirmed 
cytogenetically . Standard conventional cytogenetic analysis is required. All of the 
following criteria of CML-CP diagnosis should be met: 
o <15% blast in peripheral blood and bone marrow 
o <30% blast in peripheral blood and bone marrow plus promyelocyte  
o <20% basophil in peripheral blood 
o ≥100 x 109/L (≥100.000/mm3) platelet 
o No 
evidence 
of 
extramedullary 
leukemic 
involvement, 
except 
for 
hepatosplenomegaly 
 Should not have received treatment for CML other than anagrelide and hydroxyurea. 


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 Sufficient end-organ function with the following laboratory criterias:, total bilirubin < 
1.5 x ULN; SGOT and SGPT < 2.5 x ULN; creatinine < 1.5 x ULN; serum amylase 
and lipase ≤ 1.5 x ULN; alkaline phosphatase ≤ 2.5 x ULN unless associated with a 
tumor  
 Serum potassium, magnesium, calcium and phosphorus levels are equal to or above 
the lower limit of normal before the administration of the first dose of the study 
treatment. 
 Should have provided informed consent in written before ant study-related procedure 
may be initiated.  
 
5.2 
Exclusion criteria 
 
 Being treated with tyrosine kinase inhibitors before the study start (awaiting the study 
start, in cases of emergencies where the disease should be treated, commercial 
products containing imatinib may be prescribed but the treatment period should not 
exceed 31 days).  
 Known CNS infiltration, confirmed cytopathologically.  
 Cardiac dysfunction [presence of any of the following: LVEF <45% (if available), 
inability to determine QT interval with ECG, acquired long QT syndrome or familial 
history of long QT syndrome, clinically significant ventricular or atrial 
tachyarrhythmia or history thereof, clinically significant resting bradycardia (<50 
beats/minute), QTc > 450 msn as measured by QTcF in baseline ECG (if QTcF>450 
msn and electrolytes are not within normal ranges, the latter should be corrected and 
the subject should undergo screening again for QTc), history of myocardium infarct 
within the 12 months before the study start, other clinically significant cardiac 
disorders (e.g. instable angina, congestive heart failure or uncontrolled hypertension)]. 
 Serious or uncontrolled medical conditions (e.g., uncontrolled diabetes mellitus, active 
or uncontrolled infections).  
 Acute or chronic hepatic, pancreatic or serious renal diseases not associated with the 
disease, 
 Patients with other primary malignancies; this excludes situations where the tumor is 
no longer clinically significant or does not necessitate active intervention. 
 Significant congenital or acquired bleeding disorders not associated with cancer. 
 Previous radiotherapy involving ≥25% of the bone marrow. 
 Major surgery during the 4 weeks before the first day of the study or those not 
recovering following surgery  
 Gastrointestinal (GI) dysfunction or GI disease which may significantly alter the 
absorption of the study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea malabsorption syndrome, small intestine resection or gastric by-pass surgery) 
 Patients treated with potent CYP3A4 inhibitors (e.g.; erythromycin, ketoconazole, 
itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil)  
 Patients currently receiving active treatment agents which may potentially prolong QT 
interval or in whom it is not possible to discontinue the treatment or to switch to 
another drug before the study start. 
 History of noncompliance with medical regimes.  
 Pregnant women (positive serum pregnancy test during the 7 days before the start of 
study treatment for women of childbearing potential) or breastfeeding women  


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 Fertile male and female patients who are not willing to take contraceptive measures 
throughout the study (in order to confirm that menopausal women does not have 
childbearing potential, she should have been amenorrheic for at least 12 months). 
 
6 
Treatment  
 
6.1  
Investigational treatment and control drugs 
The investigational drug is nilotinib (AMN107 Tasigna®) 150 mg strength capsules in open-
label vials.  
 
This study does not involve a reference treatment. 
 
6.2 
Treatment arms  
All enrolled subjects will be treated with nilotinib (AMN107 Tasigna®) 300 mg BID (600 
mg/day) for 24 months. 
 
6.3 
Treatment assignment  
Since this is an open-label study with one treatment arm, all subjects will be treated with the 
given regime. 
 
6.4 
Treatment blinding  
No blinding will be done since this is an open-label study with one treatment arm.  
 
6.5 
Treating the subject  
 
6.5.1  Subject numbering  
Each subject in the study will be identified by unique nine-digit number, which is a 
combination of four-digit the center number and five-digit patient number. Center number 
will be assigned to study centers by Novartis. After signing the informed consent form, each 
subject will be given a patient number by the investigator. At each center, the first enrolled 
subject will be given 
 and the following subjects will be assigned the subsequent 
numbers (e.g., 
 to the second subject and 
 to the third subject). Once a subject 
number is assigned to a subject, it will not be used for any other subjects. If the subject fails to 
start treatment for any reason, the reason will be stated on the Screening Log.  
 
6.5.2  Dispensing the study treatment  
The study drug nilotinib will be supplied by Novartis to each center.  
 
The study personnel will identify the study drug to be dispensed to patients to be used at the 
dose levels indicated on labels. The study personnel will record the subject number at both 
sections of the label before dispensing to the subject and will remove the outer part of the 
label and stick it on the source documents (Drug Label Form) containing the unique subject 
number.  
6.5.3 Supply, storage and tracking of study treatment 
Study drugs must be received at the study site by a designated person, handled and stored 
safely and properly, and kept in a secured location to which only the Investigator and 
designated staff have access. Upon receipt, the study drugs should be stored according to the 
instructions specified on the drug labels. Clinical materials should only be dispensed 
according to the protocol. 


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Drub labels will be in Turkish and will be in accordance with regulatory requirements of each 
country. They will contain information on storage conditions of the drug but will include no 
patient information other than the drug number.  
 
The Investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Drug accountability will be noted by the Monitor during 
site visits and/or at the completion of the trial. Subjects will be asked to return all unused 
study drugs and packaging at the end of the study or at the time of study drug discontinuation. 
 
At the conclusion of the study or during course of the study, if applicable, the investigator will 
send all the used and unused study drug supplies as well as the empty containers and a copy 
of the completed drug accountability ledger to the Novartis monitor or Novartis address 
provided in the investigator filed given to each center. 
 
6.5.4  Instructions for prescribing and taking study treatment 
All patients will undergo a preliminary assessment (screening visit) and will return within 2 
weeks following the screening for Baseline assessments if considered appropriate.  
 
Beginning on the after the baseline visit, all eligible subjects will receive 300 mg (600 
mg/day) nilotinib BID (AMN107 Tasigna®) for 24 months.  
 
Nilotinib must not be taken with food. Subjects must take nilotinib on empty stomach. They 
should not consume food during the 2 hours following treatment and they should take 
anything orally except water during the 1 hour following treatment. Subjects must be 
reminded to take the capsules as a whole and with a full glass of water and not to chew the 
capsules. All subjects must avoid grapefruit juice, starfruit and Seville orange throughout the 
study. Juices of these fruits should also be avoided. Doses eliminated with vomit must not be 
compensated with a new dose. Missed doses must not be taken. Nilotinib doses must be taken 
in 12-hour intervals.  
 
The investigator must promote compliance by instructing the subject to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject should be instructed to contact the investigator if he/she 
is unable for any reason to take the study drug as prescribed. 
 
All dosages prescribed and dispensed to the subject and any dosage changes during the study 
must be recorded on the Dosage Administration Record on CRF.  
 
If nilotinib is authorized and included in the reimbursement list following completion of the 
active treatment period, the subjects who are still on treatment will be switched to the 
commercial drug in one month.  
 
6.5.5 Permitted dose adjustments and interruptions of study treatment 
In order to main the subject safely on the study treatment, dose adjustments are permitted for 
patients who fail to tolerate the dose scheme described in the protocol, provided that the toxic 
symptoms disappear within 28 days in non-hematologic toxicities and in 42 days in 
hematologic toxicities ( Day limits are considered for each discontinuation). Please refer to 


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the following tables for dose adjustments. Any changes in the dose should be recorded on the 
Dosage Administration Record on CRF.  
 
CTCAE (NCI Common Terminology Criteria for Adverse Events) version 3.0 will be used 
for toxicity and adverse event reporting for this study. If there are multiple toxicities leading 
to dose reduction, then the highest dose reduction scheme will be used.  
 
6.5.5.1  Dose reduction guidance for study treatment-related non-hematologic toxicity  
Guidance for dose reduction in study treatment-related non-hematologic toxicity is 
summarized in Table 6-1. No dose reduction below 400 mg/day nilotinib will be permitted. If 
a subject is unable to tolerate the minimum dose of 400 mg/day nilotinib, he/she should not 
continue to the study. Any non-hematologic toxicity should be resolved within 28 days for the 
subject to resume the study treatment at the reduced dose. If a non-hematologic toxicity is not 
resolved after 28 days, the subject must be withdrawn from the study.  
 
Table 6-1 
Summary of dose reduction guideline for non-hematologic toxicity 
 
Grade  
Occurrence 
Dose modification  
1 
At any time 
No dose reduction 
2 or 3 
First or second 
incidence  
Discontinue nilotinib  
Weekly monitoring of laboratory values until < grade 2 
Resume with nilotinib 600 mg/day 
Third 
incidence  
Discontinue nilotinib  
Weekly monitoring of laboratory values until < grade 2 
Start with 400 mg/day nilotinib  
Increase nilotinib 600 mg/day one week later 
Fourth 
incidence  
Discontinue nilotinib  
Weekly monitoring of laboratory values until < grade 2 
Start with 400 mg/day nilotinib  
Contact with study steering committee, discuss whether 
nilotinib 600 mg/day may be administered  
4 
At any time  
Discontinue nilotinib  
Contact with the study steering  committee – discuss whether 
to resume nilotinib or discontinue permanently  
 
Cardiac AEs – Dose Reduction  
 
 QTc prolongation > 480 msn: discontinue nilotinib, perform serum electrolyte analysis 
(including potassium and magnesium) and, if below normal limits, correct with 
supplements. Concomitant medication should be considered.  
 If QTcF < 450 msn and returns to 20 msn limit of the baseline: resume nilotinib at the 
previous dose within 2 weeks. 
 If QTcF is 450-480 msn after two weeks, reduce the dose to 400 mg once daily. 
 If following 400 mg once daily dose QTcF returns to >480 msn, nilotinib should be 
discontinued.  
 
 
 


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6.5.5.2 Dose reduction guidance for study treatment-related hematologic toxicity  
Guidance for dose reduction in study treatment-related ≥ grade 3 non-hematologic toxicity is 
summarized in Table 6-2. No dose reduction should be made for Grade 1 and Grade 2 
hematologic toxicities. Any hematologic toxicity should be resolved within 42 days for the 
subject to resume the study treatment at the reduced dose. If a hematologic toxicity is not 
resolved after 42 days, please consult the study steering committee. 
 
 
Table 6-2 
 Summary of dose reduction guideline for hematologic toxicity 
Grade  
Occurrence 
Dose modification  
1 or 2 
At any time 
No dose reduction 
3 or 4 
First or second 
incidence  
Discontinue nilotinib  
Weekly monitoring of laboratory values until < grade 3 
Resume with nilotinib 600 mg/day  
Third 
incidence  
Discontinue nilotinib  
Weekly monitoring of laboratory values until < grade 3 
Resume with 400 mg/day nilotinib  
Increase nilotinib 600 mg/day one week later 
Fourth 
incidence  
Discontinue nilotinib  
Weekly monitoring of laboratory values until < grade 3 
Resume with 400 mg/day nilotinib  
Increase nilotinib 600 mg/day one month later  
Fifth incidence  Discontinue nilotinib  
Contact with the study steering  committee – discuss whether 
to resume nilotinib or discontinue permanently  
 
6.5.5.3 Guidance to re-increase the dose  
All efforts must be made to increase the nilotinib dose back to the previous dose (i.e., the dose 
before dose reduction). This applies to both hematologic and non-hematologic toxicities.  
 
 
6.5.5.4 Recommended treatment for some specific adverse events observed with nilotinib  
Dose reduction guidance provided in Table 6-1 and Table 6-2 should be followed. Additional 
guidance for treatment of the subject is listed below.  
 
6.5.5.4.1 Treatment of bone marrow suppression  
Bone marrow suppression may develop at any time during treatment with nilotinib. Colony-
stimulating factors (G-CSF and GM-CSF) including sargramostim and pegfilgrastim may 
develop in recurrent Stage 3 neutropenia. Treatment with recombinant erythropoietin is 
permitted.  
 


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6.5.5.4.2 Treatment of rash/itch  
Rash is mild and self-limited in most of the cases and may be treated with antihistaminics or 
topical steroids. In more severe cases, short-term treatment with an oral steroid may be 
initiated. Prednisone 25 mg is recommended for one week or until rash is resolved.  
 
6.5.5.4.3 Treatment of edema  
Subjects should be monitored closely for peripheral edema and fast increases in body weight. 
Treatment with diuretics may be started for edema. Patients who develop ≥ Stage 3 edema 
with cardio-respiratory symptoms must undergo relevant medical assessments such as 
echocardiography and chest radiography for underlying cardiac or respiratory conditions. 
Further tests may be indicated for optimum treatment of the condition.  
 
6.5.5.4.4 Treatment of hepatic toxicity  
Routine hepatic function tests as outlined in the visit schedule should be performed 
throughout the study. Dose reduction may be necessary and the decision to continue or 
discontinue nilotinib should be based on the individual clinical status.  
 
6.5.5.5 Monitoring toxicities  
Subjects who are permanently withdrawn from the study treatment due to an adverse event or 
abnormal laboratory finding associated with the study treatment should be monitored for once 
a week for 4 weeks or until the event is resolved or the subject is stabilized, whichever comes 
first. All subjects will be monitored for adverse events for 30 days after the administration of 
the last dose of the study treatment. Each subject prematurely withdrawing from the study will 
be monitored for survival every 3 months up to 2 years after the study start.  
 
6.5.6 Concomitant treatment  
In general, supportive treatments and concomitant medications and treatments necessary for 
subject safety are permitted provided that their use and the period of treatment (start and stop 
dates or that the treatment was ongoing at the time of most recent examination) are 
documented in subject records and relevant case report forms. This includes blood and 
platelet transfusions in subjects with anemia and thrombocytopenia.  
 
Treatment with other investigational drugs except nilotinib is not permitted. Other anti-cancer 
agents including chemotherapy and biologic agents are not permitted.  
 
6.5.7 Discontinuation of study treatment  
Subjects who discontinue treatment with the study drug will be considered as withdrawals 
after the final visit assessments or it they are lost to follow up.  
 
6.5.7.1 Progression  
The following are recognized as disease progression and such subjects must not continue to 
the study: 
1. Death  
2. Accelerated phase (AP) defined as any of the following: 
o ≥15% blast in peripheral blood or bone marrow but <30% blast in both 
peripheral blood and bone marrow  
o ≥30% blast in peripheral blood and bone marrow plus promyelocytes  
o ≥20% basophil in peripheral blood 


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o Thrombocytopenia not associated with the treatment (>100 x 109/L)  
3. Blast crisis defined as any of the following: 
o ≥30% blast in peripheral blood  
o Development of extramedullary involvement, except for hepatosplenomegaly 
(i.e., chloroma) 
 
6.5.7.2 Identifying intolerance  
Subjects may be withdrawn from the study due to intolerance. Intolerance is defined as 
follows:  
 Persisting or recurring Stage 3 and 4 adverse events or those that require treatment 
cessation despite optimum supportive care, 
 Nilotinib-associated Stage 2 adverse events which last ≥ one month and recur > 3 
times despite dose reduction or treatment cessation.  
 
 
6.5.7.3 SOKAL risk identification  
For risk identification, the following criteria should be met at the time of diagnosis, prior to 
any treatment:  
 
 Age  
 Spleen size (below the rib margin, in cm – maximum distance)  
 Platelet count  
 Blasts (%) in peripheral blood  
 
As demonstrated in the table below, the risk is calculated according to the international 
prognostic formula.  
 
 
Table 6-3 SOKAL risk estimation and definition 
 
 
Age (years) 
0.0016 (age – 43.4) 
Spleen (below the rib margin, in cm – 
maximum distance) 
0.0345 (spleen – 7.51) 
Platelet count (x109/L) 
0.188 [(Platelet2:700) – 0.563] 
Myeloblasts in peripheral blood (%) 
0.0887 (myeloblasts – 2.10) 
Basophils in peripheral blood (%) 
/ 
Eosinophils in peripheral blood (%) 
/ 
RELATIVE RISK 
Exponential of total  
LOW 
<0.8 
MODERATE  
0.8-1.2 
HIGH 
>1.2 
 
6.5.7.4  End of Treatment   
Subjects may withdraw at any time of their own accord or may be withdrawn by the 
investigator. If premature withdrawal occurs for any reason, the investigator must make every 
effort to determine the primary reason for a subject’s premature withdrawal from the study 
and record this information on the Study Completion on CRF. 
 


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Subjects may withdraw from the study at any time in case of progression or treatment failure. 
They may also withdraw due to treatment intolerance.  
 
6.5.7.5 Withdrawal  
The subjects may withdraw from the study prematurely due to any of the following reasons:  
 
 Adverse event(s) 
 Abnormal laboratory value(s) 
 Abnormal test result(s) 
 Disease progression  
 Nilotinib inefficacy based on the criteria for this study. 
 Subject’s condition no longer requires treatment (may be beneficial in patients 
undergoing bone marrow transplantation). 
 Protocol violation 
 Subject withdraws informed consent  
 Lost to follow-up 
 Pregnancy  
 Executive issues 
 Death  
 
A complete end-of-study visit assessment should be performed within 7 days following the 
administration of the last study treatment for each subject who prematurely withdraw from the 
study (before the two years of study period is complete). End-of-study assessments will 
include adverse events, concomitant drugs and treatments, physical examination, vital 
findings, ECOG performance status, biochemistry, hematology findings, extramedullary 
involvement, PCT analyses and bone marrow assessments. Whenever a subject withdraws 
from the study, Study Completion page of CRF should be completed. If an end-of-study 
assessment is performed within 7 days after withdrawal, it is not necessary to repeat this 
assessment. 
 
Any information on the event that leads to withdrawal, including cofactors, should be 
included on CRF.  
 
Subjects who are permanently withdrawn from the study treatment due to an adverse event 
associated with the study treatment will be monitored for once a week for 4 weeks or until the 
event is resolved or the patient is stabilized, whichever comes first. All subjects prematurely 
withdrawing from the study will be monitored for survival every 3 months up to 2 years after 
the study start. 


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Mutation analysis will be performed for patients who withdraw due to inefficacy of treatment 
with nilotinib and in whom progression occurs during treatment with nilotinib.  
 
6.5.8 Emergency unblinding of study treatment 
Not applicable. This is an open-label study. 
 
6.5.9  Study steering committee  
The coordinator and three investigators of the trial, one independent international physician 
and one Novartis member will form the study’s steering committee.  
 
The steering committee was created for three purposes:  
 to recommend treatment in case of SAEs. The committee should be consulted to in the 
following defined cases: recurrent Stage 3/4 hematologic AE, recurrent Stage 2/3 non-
hematologic AE and Stage 4 non-hematologic AE. 
 to monitor SAEs and to recommend treatment cessation or continuation following 
SAEs 
 to recommend treatment cessation due to inefficacy  
 
Novartis member will only be responsible of communicating the decisions of the study 
steering committee to relevant center(s). 
 
7 
Visit schedule and assessments  
Table 7-1 lists all assessments and the visits at which these assessments will be performed are 
marked with an “X”. At all visits, the subjects should be seen on the designated day or at the 
earliest time possible.  
 
Patients, who prematurely withdraw from the study for any reason, should be scheduled for a 
visit as soon as possible, at which time all of the assessments listed for the final visit will be 
performed.  
 
At minimum, they should be contacted to perform safety assessments within the 30 days 
following the last treatment with the study drug. Proof of efforts to contact with the subject 
should be documented in patient records. 
 
All data listed in Table 7.1 and obtained with the assessments described below in detail 
should be supported by subject’s source information.  
 
7.1 
Screening and baseline  
Informed consent in written should be obtained before any study-related procedure may be 
initiated. 
 
Screening assessments to confirm eligibility should be performed before administration of the 
first study treatment. Bone marrow aspiration should have been performed by 8 weeks before 
the first dose and the results should have been obtained before administration of the first dose 
of the study treatment.  
 
At least 20 bone marrow cell metaphases are required for all cytogenetic assessments. FISH 
analysis is acceptable if bone marrow analysis is not possible. In addition, a peripheral blood 
sample will be analyzed with PCR.  


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A complete physical examination including baseline laboratory analyses (including 
hematology, chemistry, serum potassium, calcium and magnesium), performance status and 
body weight should be performed prior to the first dose of study treatment. Potassium and/or 
magnesium levels of subjects whose potassium and/or magnesium levels were <LLN at the 
screening should be corrected with supplements and their levels should be within normal 
limits before administration of the first dose of the study treatment.  
 
If an assessment has already been made within the 48 hours before administration of the first 
dose of the study treatment as a part of screening assessments, this assessment need not be 
repeated on day 1.   
 
During the first 3 months of treatment, all routine assessments should be performed within ± 1 
day of the date specified in the assessment schedule. All routine assessments after Visit 8 
(until month 12 is completed) should be performed within ± 3 days of the dates specified in 
the assessment schedule. ± 7 day deviations will be acceptable for the visit scheme between 
months 12 and 24. One cycle (one month) is considered as 4 weeks (i.e. 28 days). 
 


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Table 7-1  
Assessment schedule  
Period 
Screening 
Treatment and monitoring 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Day (d)/Month (m) 
D -14 to 1 
D1 
D15 
D30 
D45 
D60 
D75 
D90 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
M15 
M18 
M21 
M24 
Screening info 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical 
history, disease 
history, previous 
treatments  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance 
status  
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Serum pregnancy 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital findings, 
physical exam., 
body weight  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Extramedullary 
involvement 
X  
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone marrow 
assessments a 
X 
 
 
 
 
 
 
X  
 
 
X  
 
 
 
 
 
X  
 
 
 
X  
Peripheral blood 
sample  
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X  
X 
X  
X 
Nilotinib dose and 
compliance  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant drugs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Mutation analysis b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Study completion 
form  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  


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a Bone marrow analyses will be performed at scheduled visits or until the subject achieves CCR or MMR.  
b Mutation analysis will be performed for patients who withdraw because nilotinib is not effective and in whom if progression occurs during treatment with nilotinib. 


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7.2 
Information to be collected on screen failures 
In case of screen failure, patient’s demographic information as well as the primary reason why 
he/she was not eligible for this study will be recorded on the relevant section of the CRF 
(ineligible screened patients).  
 
7.3  
Subject demographics/other baseline characteristics  
Subject’s age and gender will be documented in the relevant page of the CRF. Bone marrow 
screening to confirm CCyR will be performed during the last 8 weeks following 
administration of last study treatment. Peripheral blood sample analysis to measure molecular 
response should be performed within 28 days after the administration of the first study dose. 
Bone Marrow Analysis CRF will be used to collect information on the cytogenetic status and 
Previous antineoplastic agents CRF will be used to collect information on previous 
medications.  
 
Relevant conditions and surgeries during the 5 years before the study (a longer period of time 
for disease-related history, if feasible) as well as concomitant conditions, date of 
diagnosis/surgery and information whether there is an ongoing problem will be recorded.  
 
Information on surgeries, including previous antineoplastic agents, radiotherapy and surgical 
biopsies will be collected. 
 
Date of first CML diagnosis and the best previous response will be collected.  
 
7.4  
Treatment exposure and compliance  
All doses of study drug prescribed and taken by the subject, start date and end date of 
treatment, dose and dose adjustments, if applicable, will be recorded in Dose Administration 
Record.  
 
Treatment compliance will be evaluated by the investigator and/or study personnel by 
examining the number of capsules and the information provided by the subject. This 
information must be recorded on source documents at every visit.  
 
The date and time nilotinib dose is dispensed (morning or evening doses, as appropriate) will 
be recorded in the relevant Dose Administration Record of the CRF. 
 
All prescription and non-prescription medicinal products including vitamins and blood 
transfusions will be entered in the Concomitant medications/non drug therapies CRF. The 
records will include the trade name of the medicines, start date and end date and the rationale 
for administration. 
 
Information on whether the patient completed or withdrawn from the study, reasons for 
withdrawal and the last dose of study treatment will be entered in the Study Completion CRF. 
  
For each patient who prematurely withdraws from the study, survival information as well as 
information on the patient’s the disease state will be collected every three months for a period 


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of 2 years. 
 
  
 
All comments on the conduct of the trial will be entered in the comments section of the CRF.  
 
If repeat assessments are necessary (e.g., ECG, laboratory tests, vital findings, etc.) the reason 
for the repeat assessment should be entered in the additional visits section of the CRF.  
 
7.5 
Efficacy  
 
7.5.1  Molecular response  
Molecular response (MR) will be evaluated in all patients. BCR-ABL transcript level will be 
determined by a RQ-PCR test using peripheral blood and will be analyzed in a central 
laboratory. This central laboratory is standardized as a national laboratory as a part of the 
EUTOS molecular monitoring project and its conversion factor was set. For each sample, the 
ratio of BCR-ABL transcripts to control gene transcript and a reference standard will be 
calculated as percentage concerted to the international scale (Hughes and Branford 2006).  
 
Major molecular response is defined as follows:  
 
 MMR rate is defined as BCR-ABL/control gene ratio of ≤ 0.1% as measured by RQ-
PCR with two repeat analyses on an international scale (in %). 
 Time to MMR is defined as the time from the administration of the first dose to the 
first documented MMR 
 MMR duration is defined as the duration from the first documented MMR to the first 
date when MMR is lost, or to progression or death (whichever is first) 
 
MMR loss is defined as % BCR-ABL/control gene ≤0.1% on the international scale 
 
7.5.1.1 Sampling for molecular response  
20 ml peripheral blood will be collected from each subject at all visits scheduled for blood 
sampling to monitor molecular response under study treatment. PCR sample collected on day 
1 before dose administration will be used for all subsequent PCR comparisons. The samples 
will be forwarded to the central laboratory for baseline BCR-ABL transcript level 
measurements. Samples will be collected from all patients at the end of months 1, 3, 6, 9 and 
12, and then at the end of every three months for 2 years. The blood will be analyzed by 
quantitative PQ-PCR for presence of BCR-ABL transcripts. If a ≥ 5-fold increase in BCR-
ABL transcripts compared to the lowest level measured in the study is obtained, this should be 
confirmed by a second analysis. If ≥ 4-fold reduction is measured in MMR or BCR-ABL 
transcripts levels compared to standard baseline levels, the response will be confirmed by a 
second analysis.  
 
Each center will be provided with the kits for PCR sampling. At each sampling point, 20 ml 
of peripheral will be collected in four 10 ml sterile EDTA tubes contained in the kits. 
Following sampling, the tubes should be inverted gently 8-10 times to prevent clotting. The 
tubes must be stored at 4-8ºC. The samples are to be transferred to the reference laboratory in 
cold boxes.  


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RNA extraction and reverse transcriptase (RT) - polymerase chain reaction (PCR)  
Total cellular RNA trizol extraction will be obtained by izopropanol precipitation and ethanol 
70% wash. RNA will be measured by spectrophotometer at 260 nm and its integrity will be 
studied by agarose 2% gel electrophoresis. 1 µg of the total cellular RNA will be reverse 
transcribed to xDNA by random hexamer primer and 200 U M-MLV reverse transcripts.    
 
Real-time quantitative RT-PCR  
Real time RT-PCR will be performed using the LightCycler480 system. ABL will be used as 
the control gene to compensate RNA quality differences and the absolute contents of BCR-
ABL mRNAs will be normalized to ABL mRNA content. Primers and probes for BCR-ABL, 
ABL were determined through collaboration of 25 individual centers from 10 European 
countries (European Concerted Action, SANCO), as reported by Gabert et al. (Leukemia 
(2003) 17, 2318–2357). Plasmids containing sequences of the same genes in plasmid pME-2 
will be used. Quantitative real-time RT-PCR (RQ-PCR) will be performed three times for 
BCR-ABL, total ABL transcripts for cDNAs of all samples. Seven series of dilutions will be 
used for 4_106 copies of pME-2 for each reaction to provide an external control in each PCR 
study. Preliminary runs were performed to optimize the real-time PT-PCR equipment. 
Integrity and quality of the RNA will be checked by gel electrophoresis. In addition, ABL CT 
higher than 28 will be considered functionally damaged and no further analyses will be 
performed. Finally, if BCR-ABL Ct is higher than the cut-off value on the relative standard 
curve of the study (VT corresponds to a copy), the sample will be considered negative (below 
the limit detectable by the MRD technique). Average of each triple measurement will be 
calculated; BCR-ABL/ total ABL ratios will be estimated and will be presented in 
percentages. Single outliers will be excluded from the calculation of mean values: e.g. to 
consider BCR-ABL positive, at least 2 out of 3 samples should be positive.  
 
7.5.2 Cytogenetic response  
Cytogenetic response will be taken as the percentage of bone marrow Ph+ metaphases and 
will be defined as follows (at least 20 metaphases should be reviewed):  
 
 Complete (CCyR) – 0% Ph+ metaphase  
 
 Partial (PCyR) - 1 to 35% Ph+ metaphase  
 
 Major (MCyR) – 0 to 35% Ph+ metaphase  
 
 Minor (mCyR) - 36 to 65% Ph+ metaphase  
 
 Minimal - 66 to 95% Ph+ metaphase  
 
 No response - 96 to 100% Ph+ metaphase  
 
Major response (0 to 35% Ph+ metaphase) combines both the complete and partial responses.  
 


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Loss of complete cytogenetic response: Any increase from 0% in Ph+ bone marrow. This 
should be regarded as disease progression.  
 
Loss of partial cytogenetic response: Any increase from 1 to >35% in Ph+ bone marrow. 
This should be regarded as disease progression. 
 
7.5.2.1 Bone marrow and cytogenetic analyses  
Bone marrow aspiration and/or biopsy and bone marrow cytogenetic analysis to evaluate Ph+ 
metaphases should be performed within 8 week before the administration of the first dose of 
study treatment. Bone marrow aspiration and/or biopsies for cytogenetic analysis to assess 
response will be performed at the end of months 6 and 12 or until the patient achieves CCyR 
or MMR. Bone marrow cytogenetic analyses will also be performed at the end of study visits 
or in the event of premature subject withdrawal. These evaluations can be performed within 
14 days of the scheduled visit or within 21 of the study end.  
 
Cytogenetic analysis should be performed centrally by standardized methods. For cytogenetic 
response evaluation, FISH analysis is only acceptable if bone marrow aspiration is not 
possible. Twenty metaphases should be studied for each bone marrow aspiration sample. 
Percentage of Ph+ chromosome metaphases, metaphase count, number of those positive for 
Ph chromosome, cellularity and percentage of blasts and promyelocytes will be recorded in 
Bone marrow CRF. These assessments will be performed and analyzed locally.  
 
No further CR assessment will be performed for the subjects who achieve CCyR or MMR.  
 
Bone marrow (BM) analyses should be performed at least once a year, and in case of CHR or 
MCyR loss and to confirm MMR loss. 
 
If additional bone marrow assessments are made, their results should be recorded in the CRF 
as unscheduled visit.  
 
Bone marrow samples will be transferred to the reference laboratory for cytogenetic analysis 
in cold boxes. 
 
7.5.3 Hematologic response  
Hematologic response includes any of the following:  
 
1. Complete hematologic response (CHR)  
 
2. Absence of leukemia evidences in the peripheral blood, without a complete peripheral 
blood recovery  
 
CHR is defined as all of the following for ≥ 4 weeks:  
 
1. Normalization of peripheral blood count  
 WBC count < 10 x 109/L  
 Platelets < 450 x 109/L  
2. Normal WBC subgroups distribution  
 No blast(<1%) and promyelocyte in circulating peripheral blood  


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 A total level of myelocytes plus metamyelocytes of <5% will be allowed in peripheral 
blood; higher level of immature granulocyte will not be permitted. 
 Less than 5% basophiles.  
 
3. Absence of any disease-related symptoms and evidence of an extramedullary disease 
including disorders of the liver and spleen.  
 
CHR loss: Any of the following, provided that the findings is confirmed by a second analysis 
after ≥1 month:  
 
 Increased WBC count up to >20.0 x 109/L  
 Increased platelet count up to ≥600 x 109/L  
 Gradually increasing splenomegaly extending ≥5 cm below the inferior intercostals 
margin. This should be confirmed after 4 weeks. No extramedullary disease. 
 Presence of ≥5% myelocyte + meta myelocyte in peripheral blood 
 Presence of blast or promyelocyte in peripheral blood 
 
Increased WBC count, which is defined as a two-fold increase in WBC count at least one 
month apart being at least >20.0 x 109/L during the second month in subjects who did not 
achieve CHR, indicating progression. Subjects must be maintained on the maximum tolerated 
dose of nilotinib. The condition where there is no evidence of leukemia but peripheral blood 
did not recover completely is defined as follows:    
 No circulation blood blasts  
 ANC ≥1.0 x 109/L  
 Platelet count ≥ 20 x 109/L (independent of platelet transfusion and no evidence of 
bleeding)  
 No evidence of extramedullary involvement  
 
7.5.4 Treatment failure  
Treatment failure with nilotinib is defined as follows in this study:  
 
 Response less than complete hematologic response at month 6 is below CHR or 
absence of any cytogenetic response (CR) (Ph+ > 95%) 
 Response less than partial cytogenetic response at month 12 (Ph+ > 35%) 
 Response less than complete cytogenetic response at month 18 (Ph+ > 0%) 
 Loss of CHR, PCyR or CCyR, progression to AP/BP and increased WBC count at any 
time 
 
 
  
 
 
 
 
 
 


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7.6 
Safety  
Safety assessments will include adverse events and serious advers events, concomitant 
medication/treatments for their treatment, laboratory parameters including hematology and 
blood chemistry, body weight, physical examination and ECG monitoring.  
  
7.6.1 Adverse events  
In line with the objectives of this protocol, an adverse event is the appearance or worsening of 
any undesirable sign, symptom, or medical condition occurring after informed consents are 
signed, even if the event is not considered to be related to study drug.  
 
CTCAE version 3.0 common toxicity criteria will be used for adverse events in this study. If 
no CTCAE grading is available for an adverse event, then the terms mild, moderate, severe 
and life-threatening or Grades 1-4 will be used. CTCAE grade 5 (death) will not be used in 
this study. This information will be entered in the Study End Survival Information CRF 
instead.  
 
Adverse events occurring before the study start but after informed consent forms are signed 
will be recorded in the Medical History/Current Medical Status Case Report form. Abnormal 
laboratory values or test results will constitute adverse events only if they induce clinically 
significant clinical signs or symptoms (i.e., if a value or result results in discontinuation or 
represents a Serious Adverse Reaction by itself) or require therapy (i.e., all hematologic 
anomalies requiring transfusion or cytokine treatment). These should be recorded in the 
Adverse Event CRF together with findings, symptoms and relevant diagnoses. Adverse events 
that occur after start of treatment with study drug will be recorded in Adverse Events CRF. 
 
The occurrence of adverse events should be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are voluntarily 
reported by the subject during or between visits or through physical examination, laboratory 
tests, or other assessments. All adverse events must be investigated to determine the 
following: 
 
1. Grade (CTCAE Grade 1-4)  
2. Its relationship to the study drug (suspected/not suspected) 
3. Its duration (start and end dates or if continuing at final exam) 
4. Actions taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant 
medication 
given; 
non-drug 
therapy 
given; 
patient 
hospitalized/patient’s 
hospitalization prolonged). 
5. Whether it constitutes a serious adverse event (SAE) (please see Section 9.2 for 
definition and reporting SAEs) 
 


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All adverse events should be treated appropriately. These treatments may include possible 
temporary interruptions or permanent discontinuation of the study drug, starting or stopping 
concomitant medication, changes in the frequency and content of examinations, 
hospitalizations or other medically indicated interventions. Once an adverse event is detected, 
it should be followed until its resolution and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the study 
drug(s), the interventions required to treat it, and the outcome. 
 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates 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. 
 
7.6.2 Physical examination  
A physical examination will be performed according to the visit schedule (see Table 7-1). 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the start of study drug must be 
included in the Relevant Medical History/Current Medical Conditions CRF. Significant 
findings after the start of study drug which meet the definition of an Adverse Event must be 
recorded on the Adverse Event CRF. 
 
No case report form to enter normal findings of physical examinations is available. However, 
these findings must be included in subject’s source documentation.  
 
7.6.2.1 Extramedullary involvement  
Physical examination findings consistent with extramedullary leukemia involvement (e.g., 
lymph nodes, liver and spleen sizes) will be recorded. Only those lymph nodes considered 
related to the disease will be taken into account. 
 
If the only evidence of a blast crisis is an extramedullary involvement outside liver and 
spleen, this must be confirmed histologically and/or by biology (particularly for lymph nodes) 
and the data should be entered in the CRF.  
 
7.6.3  Vital findings and body weight  
Heart rate, blood pressure, body temperature and body weight as shown in Table 7-1 should 
be noted in patient chart and recorded in the CRF. Height will only be measured at screening 
and will be recorded in the CRF. 
 
Subjects should be weighed according to the visit schedule to detect early signs of liquid 
retention (see Table 7-1) and they should also be instructed to check their weights regularly at 
home (i.e., three times a week). Additional body weight checks other than those performed 
during visits to evaluate performance status will not be recorded in the CRF but they must be 
included in source documentation of the study center. 
 


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The subjects will be encouraged to check their body weight and to inform the investigator in 
case of any increases >2 kg from their previous weight. Weight increases ≥ 2 kg must be 
carefully investigated and appropriate measures must be taken.  
 
7.6.4 Performance status  
Performance status will be recorded in the CRF according to the ECOG criteria described in 
Table 7-1 and Table 7-2.  
 
Table 7-2 ECOG Performance Status  
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead  
 
 
7.6.5  Laboratory Assessments  
Laboratory assessments will be performed by a certified central laboratory according to the 
visit schedule (see Table 7-1). If a subject has parameters from another laboratory at any time, 
the sponsor must obtain the certificate and normal ranges and unit tables of this laboratory.  
 
Clinically relevant abnormal laboratory parameters (e.g., those that require dose adjustment 
and/or interruption of the study drug, those that result in clinical symptoms or sings or require 
treatment) occurring at any time throughout the study must be recorded in the relevant CRF 
laboratory page as well as relevant comment page of the CRF, whether or not required by the 
protocol. 
 
When abnormal laboratory values or test results constitute adverse events (i.e., when they 
trigger clinical signs/symptoms or require treatment) these should be recorded in the Adverse 
event CRF. If abnormal laboratory values or test results induce clinically significant signs or 
symptoms (i.e., if a value or result necessitates discontinuation or represents a Serious 
Adverse Reaction by itself) or require treatment (i.e., all hematologic anomalies requiring 
transfusion or cytokine treatment), these should be recorded in the Adverse Event CRF 
together with findings, symptoms and relevant diagnoses.  
 
7.6.5.1 Hematology  
Hematology laboratory assessments will be performed by a certified central laboratory. 
Hematologic assessments will include hemoglobin, hematocrit, total WBC count, platelet 
count and differentials (neutrophil, band, lymphocyte, monocyte, eosinophil, basophil, 


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promyelocyte, myelocyte, metamyelocyte and blast percentage) and will be performed 
according to the visit schedule (Table 7-1).  
 
7.6.5.2 Biochemistry  
Blood chemistry laboratory assessments will be performed by a certified central laboratory. 
Biochemistry will include urea or BUN, creatinine, uric acid, albumin, total protein, total 
bilirubin (direct or indirect), alkaline phosphatase, AST (SGOT), ALT (SGPT), LDH, sodium, 
chloride, (fasting) glucose, calcium, lipase, amylase, potassium, magnesium and phosphor and 
lipid profile (HDL, LDL, VLDL, triglycerides and total cholesterol), INR (International 
Normalization Ratio) and Hemoglobin A1c. These will be performed according to the visit 
schedule (Table 7-1).  
 
In addition to the routine biochemistry assessments outlined in the visit schedule, subjects 
must have their serum potassium and magnesium levels in case of QTc elongation or at the 
discretion of the investigator. Routine biochemistry assessments outlined in the visit schedule 
will be recorded in the CRF. Additional electrolyte results (potassium and magnesium) will 
not be entered in the CRF or clinical database unless they require supportive treatment or 
substitution treatment. If supportive treatment and substitution treatment required, the 
laboratory anomaly should be documented in the CRF as scheduled or unscheduled laboratory 
result and should also be recorded as an adverse event. If supportive treatment and 
substitution treatment is given, these should be indicated as concomitant medication. Other 
additional results should be included only in the source documentation at the study center.  
 
7.6.5.3 Pregnancy test  
Women of childbearing potential are required to undergo a serum pregnancy test at screening. 
In order to confirm that menopausal woman does not have childbearing potential, she should 
have been amenorrheic for at least 12 months.  
 
7.6.5.4 Electrocardiography (ECG)  
12-lead electrocardiography will be performed according to the scheme presented in Table 7-
1. 
 
8  
Safety monitoring  
 
8.1  
Adverse events  
Any serious adverse events in this clinical study will be reported immediately by the 
Investigator to Novartis on Novartis Serious Adverse Event Report Form and faxed to 
Novartis Turkey Drug Safety Department within 24 hours.  
 
A serious adverse event is an undesirable sign, symptom, or medical condition defined 
according to the following criteria: 
 is fatal or life-threatening  
 requires inpatient hospitalization or prolongation of existing hospitalization  
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 


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 is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
 
These events will not constitute an adverse event if the hospitalization is for: 
 the medical care was scheduled before enrollment 
 elective treatment for a pre-existing condition that is unrelated to the indication under 
study  
 treatment on an emergency outpatient basis (for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission)  
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
 
Every SAE, regardless of suspected causality, occurring after the subject has provided 
informed consent and until 4 weeks after the subject has stopped study participation must be 
reported. This includes the study protocol period overlapping with the standard treatment 
given.  
 
A serious adverse event, recurrent episodes, complications, or progression of the initial SAE 
must be reported as follow-up to the original episode, regardless of when the event occurs. An 
SAE that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
 
Pregnancies in subjects on study drug must be reported by completing Novartis Clinical Trial 
Pregnancy Form. 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. 
 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 9.2. 
 
8.2  
Serious adverse event reporting  
Every SAE, regardless of suspected causality, should be reported by the investigator to 
Novartis within 24 hours after learning of its occurrence. Previously reported serious adverse 
events should be reported with relevant follow-up information within 24 hours by the 
investigator within 24 hours after learning of its occurrence. The investigator must complete a 
Serious Adverse Event Report form and fax the completed and signed form to Novartis 
Turkey Drug Safety Department within 24 hours.  
 
Follow-up information is sent to Novartis Turkey Drug Safety Department, 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 recurrence, complication and worsening of the original event 
should be reported as follow-up to that event. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 


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broken or not, and whether the subject continued or withdrew from study participation. Please 
refer to Novartis guidelines for directions on completing the Serious Adverse Event Report 
Form.  
 
Contact information: Investigators are required to report any serious adverse events by 
completing the serious adverse event report form within 24 hours to Ms. 
 
from Novartis Turkey Drug Safety Department using the contact information below:  
Tel: 
 or 
  
Fax: 
  
 
8.3 
Pregnancies  
To ensure patient safety, each pregnancy in a patient on study drug 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 local Novartis Drug Safety & Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
 
Investigators are required to report any pregnancies during the study by completing the 
pregnancy report form within 24 hours to Ms. 
 from Novartis Turkey Drug 
Safety Department using the contact information below:  
Tel: 
 or 
  
Fax: 
 
 
Follow-up information of pregnancies must also be reported to Novartis within 24 hours of 
learning of its occurrence. 
 
8.4 
Data monitoring committee  
No data monitoring committee has been assigned for this study. 
 
9  
Data review and database management 
 
9.1  
Site monitoring  
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative 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 and to Good 
Clinical Practice, the progress of enrollment, and to ensure that study drug 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, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. Data not requiring a separate written record will be defined before study start 
and will be recorded directly on the CRFs. The investigator must also keep the original 
informed consent form signed by the patient (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, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed. 
 
9.2  
Data collection  
Designated investigator staff will enter the data required by the protocol to Novartis CRFs 
printed on three-layer paper not requiring carbon paper. Field monitors will visit the site 
regularly to check the completeness of patient records and the accuracy of entries on the CRFs 
and will instruct the site personnel to perform necessary corrections and additions. CRFs will 
be transferred to the Date management and a copy will be stored at the site. When CRFs are 
received by the Data Management, proofs of receipt will be documented and will be reviewed 
again before data entry.  
 
9.3 
Database management and quality control  
Very management will only be performed by a CRO responsible for data management. Data 
captured from the CRFs will be entered to the database through an electronic verification 
system with a single entry.  
 
The entered data will then be checked systematically by the data management personnel using 
verification software and error messages printed out from database lists. Obvious mistakes 
will be corrected by the data management personnel. Other errors and missing information 
will be entered to Data Query Forms and will be forwarded back to the investigational site for 
correction. Signed original and corrected Data Query Forms together with CRFs will be 
maintained at the investigational site and a copy will be sent to Novartis, enabling entry of the 
corrected data to the database. All important safety and efficacy data should undergo a quality 
control check before the database lock. 
 
Concomitant 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. 
 
Any protocol violation that may have occurred will be determined at the end of the study. The 
database will be locked after this process is completed and the completeness and accuracy of 


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the database is confirmed. Any changes to the database after this time will require written 
confirmation of the Study Statistician and Statistics Reporter and the Steering Committee of 
the study.  
 
10  
Data analysis 
 
10.1  Populations for analysis  
Safety population will consist of all subjects who received at least one dose of study drug and 
have at least one post-baseline safety assessment. A report by a subject indicating no adverse 
experience will constitute a safety assessment. 
 
ITT population will consist of all subjects who provided informed consent form. 
 
Per protocol population will consist of all subjects in the ITT population with no major 
protocol violation reported. All reported protocol violations will be classified as major or 
minor in a review meeting before database lock. 
 
The population intended to be treated for demographical and baseline characteristics will be 
used in all ITT efficacy evaluations. Per protocol population will be used for per protocol 
analyses for primary efficacy endpoint and some important secondary efficacy variables.  
 
Safety analysis will be performed with the safety population. 
 
10.2 
Subject demographics/other baseline characteristics  
Historical data and demographical characteristics will be presented using summary statistics.  
 
Summary statistics will include n (number of observations), mean, standard deviation, 
median, minimum and maximum values for continuous variables as well as frequency and 
percentages for categorical variables. 
 
10.3 
Treatments (rescue medication, other concomitant therapies, compliance)  
Exposure to study drug and administered doses of the study treatment will be presented using 
summary statistics. Summary statistics will include n (number of observations), mean, 
standard deviation, median, minimum and maximum values for continuous variables as well 
as frequency and percentages for categorical variables. 
 
Concomitant medications given before and after treatment with study drug will be 
summarized by treatment groups. WHO Drug Reference List will be used to code 
medications.  
 
10.4 
Analysis of primary variable(s)  
 
10.4.1  Variable  
The primary efficacy endpoint in this study is the best cumulative MMR rate at month 12, 
measured as RQ-PCR and defined as ≤0.1% BCR-ABL/% control gene reported in % on the 
international scale.  


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10.4.2 Statistical model, hypothesis and method of analysis 
The primary objective is to determine the best cumulative MMR ratio obtained with nilotinib 
300 mg BID treatment of 12 months  
 
The IRIS study reported major molecular responses obtained by 40% of patients with newly-
diagnosed chronic phase CML after treatment with imatinib 400 mg. 
 
Compared to IRIS data, nilotinib is expected to produce a 15% improvement in MMR rates 
with a significance level at 5%.  
 
Cumulative MMR rate at 12 months will be presented with 80% confidence interval. Primary 
analyses will be performed on the ITT population.  
 
10.4.3 Handling of missing values/censoring/discontinuations  
Subjects who withdraw prematurely or those who fail to provide data for the study for other 
reasons will be designated as premature withdrawal or inevaluable, respectively, and will be 
included in the ITT analysis as non-responders. Only those who achieve MMR by month 12 
will be considered as responders. 
  
10.4.4 Supportive analyses  
In addition, per protocol population will also be analyzed for the primary endpoint.  
 
10.5 
Analysis of secondary variables  
 
10.5.1  Efficacy (secondary)  
Efficacy variables for secondary variables will be analyzed descriptively using summary 
statistics. Summary statistics will include n (number of observations), mean, standard 
deviation, median, minimum and maximum values for continuous variables as well as 
frequency and percentages for categorical variables. Missing values for secondary endpoints 
will not be replaced. All ratios will be assessed at month 6 and 12, and then once every year if 
data is available and the ratio is the cumulative ratio up to a specific time point.  
 
Time variables up to any event will be shown with Kaplan-Meier curves.  
 
10.5.2 Safety  
All safety analyses will be performed on the safety population. Safety assessment will be 
based on primarily the incidence of adverse events and the number of subjects with laboratory 
values outside predetermined rates and number of patients with clinically significant ECG 
findings.  
 
Adverse events will be coded by primary system organ class and by preferred terms in 
accordance with the Medical Dictionary for Regulatory Activities (MedDRA). A study drug-
related adverse event is defined as an adverse event which the investigator suspects to be 
related with the study treatment. Adverse events will be summarized by presenting the 
number and percentage of subject having any adverse event according to each primary system 


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organ class and preferred terms. The most severe event of a preferred term will be used for an 
individual patient in summaries presented by event severity. Summary tables presenting 
treatment-emergent adverse events and their severity will be prepared.   
 
If an AE or SAE is observed more than once in an individual patient, then this AE or SAE 
will be counted once by presenting the most severe instance and its relation to the study 
treatment.  
 
Data listing on adverse events will list the severity of an AE, whether it is related to the study 
treatment and whether it is serious.  
 
Other information collected will be listed as appropriate. All statistical tests to analyze the 
data will be performed to elucidate interesting comparisons which are to be discussed in the 
future.  
 
10.6  Sample size calculation 
The sample size was calculated using the exact test for single proportion to attain 15% 
improvement in MMR rates compared to IRIS data. 
 
The sample calculated by 80% confidence interval consists of 110 subjects accounting for a 
10% drop-out during the two-year follow-up.  
  
10.7  Power for analysis of key secondary variables 
This study will not be powered for secondary efficacy endpoints. 
 
 
  
 
 
 
11  
Ethical considerations  
 
11.1  Regulatory and ethical compliance  
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations and with the ethical principles laid down in the Declaration of Helsinki.  
 
11.2 
Informed consent procedures  
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
subject. In cases where the subject’s representative gives consent, the subject should be 
informed about the study to the extent possible given his/her understanding. If the subject is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 


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protocol). The process of obtaining informed consent should be documented in the subject 
source documents. 
 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC/REB, and a 
copy of the approved version must be provided to the Novartis monitor after IRB/IEC/REB 
approval. 
 
Women of childbearing potential should be informed that taking the study drug may involve 
unknown risks to the fetus in case pregnancy occurs during the study and they should agree to 
practice contraception throughout the study in order to be able to participate in the study. If 
there is a doubt that the subject will actually comply with this requirement, then she should 
not be included in the study.    
 
11.3 
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. As per local regulations, the protocol and the 
proposed informed consent form must be reviewed and approved by Independent Ethics 
Committees of each study site and then the central ethics committee at the Ministry of Health 
before the study start. A signed and dated statement that the protocol and informed consent 
have been approved by the IRB/IEC/REB must be given to Novartis before study initiation. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs/REBs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must 
inform Novartis immediately that this request has been made. 
 


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11.4 
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 trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
 
Final results based on the final analysis of the study will be written by the study steering 
committee. The draft paper will be communicated to the local Novartis medical team for 
review.  
 
Authors of the paper will be the investigators who will be responsible of more than 10% of 
the eligible subjects (as per the inclusion criteria) and will be acting on behalf of Novartis 
Pharma-Turkey. All other contributors to the study will be mentioned in the 
acknowledgements section, unless specified otherwise by the Study Steering Committee.  
 
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. However, he/she may 
contact the study monitor to request approval of a protocol amendment which cannot be 
introduced since the competent authorities did not authorize. 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 
Protocol amendments  
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC/REB at the 
study site should be informed within 10 working days. 


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13 
References  
 
Baccarani M, et al. Evolving concepts in the management of chronic myeloid leukemia: 
recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006; 
108: 1809-20. 
Baccarani M, et al. Interferon alpha for for chronic myeloid leukaemia. Semin Hematol. 2003 
Jan;40(1 Suppl 1):22-33. 
Baccarani M, et al;  Comparison of imatinib 400 mg and 800 mg daily in the frontline 
treatment of high-risk, Philadelphia positive chronic myeloid leukemia: a European leukemia 
net study Blood.2009:113 :4497-4504 
Barrett J, Allogeneic stem cell transplantation for chronic myeloid leukaemia. Semin 
Hematol. 2003;40(1 Suppl 1):59-71. 
Bartram CR, et al (1983) Translocation of c-Abl correlates with the presence of a Philadelphia 
chromosome in chronic myelogenous leukemia. Nature; 306: 277-80. 
Cortes et al (2008) Blood; 112(11) abstract #446. 
Cortes et al (2008) Haematologica;93(s1):160-61. 
Daley GQ, et al (1990) Induction of chronic myelogenous leukemia in mice by the p 210 
bcr/Abl gene of the Philadelphia chromosome. Science; 247: 824-30. 
Deininger M, et al (2005) The development of imatinib as a therapeutic agent for chronic 
myeloid leukemia. Blood;105(7):2640-53. 
Druker et al (2003) N Eng J Med;348:994-1004. 
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. 
Giles FJ, et al. Nilotinib in patients (pts) with philadelphia chromosome positive (ph+) 
chronic myelogenous leukemia in blast crisis (CML-BC) who are resistant or intolerant to 
imatinib. Blood 2007; 110 (s11):310a, ASH abstract #1025. 
Giles FJ, et al. Nilotinib therapy after dasatinib failure in patients with imatinib-resistant or-
intolerant chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or 
blast crisis (BC). Blood 2007; 110 (s11):311a, ASH abstract #1029. 
Goldman JM, Druker BJ. Chronic myeloid leukemia: current treatment options. Blood. 2001 
Oct 1;98(7):2039-42. 
Goldman JM, Management of chronic myeloid leukaemia.Semin Hematol. 2003 Jan;40(1 
Suppl 1). 
Golemovic M, et al. AMN107, a novel aminopyrimidine inhibitor of BCR-ABL, has in vitro 
activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res 2005; 11: 4941-
47. 
Hehlmann R, et al. Chronic myeloid leukemia. Lancet 2007; 370: 342-50. 
Heisterkamp N, et al (1983) Localization of the c-Abl oncogene adjacent to a translocation 
break point in chronic myelocytic leukemia. Nature; 306: 239-42. 


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Hochhaus A, et al. IRIS 6-year follow-up: sustained survival and declining annual rate of 
transformation in patients with newly diagnosed chronic myeloid leukemia in chronic phase 
(CML-CP) treated with imatinib. Blood 2007; 110 (s11): 15a, ASH abstract #25. 
Hochhaus A, et al. Favorable long-term follow-up results over 6 years for response, survival, 
and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after 
failure of interferon-alfa treatment. Blood 2008; 111: 1039-1043. 
Hughes TP, et al. Frequency of major molecular responses to imatinib or interferon alfa plus 
cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003 Oct 
9;349(15):1423-32. 
Hughes TP, Branford S (2006) Molecular monitoring of BCR-ABL as a guide to clinical 
management in chronic myeloid leukemia. Blood Reviews; 20, 29-41. 
Cortes JE, et al. Efficacy of nilotinib (AMN107) in patients (Pts) with newly diagnosed, 
previously untreated philadelphia chromosome (Ph)- positive chronic myelogenous leukemia 
in early chronic phase (CML-CP). J Clin Oncol 26: 2008 (May 20 suppl; abstr 7016). 
Jabbour E, et al. Current and emerging treatment options in chronic myeloid leukemia. Cancer 
2007; 109: 2171-81. 
Kantarjian H, et al. Integrating the new generation of targeted therapies for chronic 
myelogenous leukemia. Semin Hematol. 2007; 44. 
Kantarjian H, et al. Nilotinib (formely AMN107), a highly selective BCR-ABL tyrosine 
kinase inhibitor, is effective in patients with Philadelphia chromosome positive chronic 
myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 
2007; 110:3540-3546. 
Kantarjian H, et al. Nilotinib in imatinib-resistant CML and philadelphia chromosomepositive 
ALL. NEJM 2006; 354:2542-51. 
Kantarjian HM, et al ASH (2006) A phase II study of nilotinib, a novel tyrosine kinase 
inhibitor administered to imatinib-resistant and -intolerant patients with chronic myelogenous 
leukemia (CML) in chronic phase (CP). 
Kantarjian HM, et al. Long-term survival benefit and improved complete cytogenetic and 
molecular response rates with imatinib mesylate in Philadelphia chromosome-positive 
chronic-phase chronic myeloid leukemia after failure of interferon-alpha.Blood. 2004 Oct 
1;104(7):1979-88 
Kantarjian HM, et al. Nilotinib is highly active and safe in chronic phase chronic 
myelogenous leukemia (CML-CP) patients with imatinib-resistance or intolerance. Blood 
2007; 110 (s11):226a, ASH abstract #735. 
Kelliher MA, 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. 
Le Coutre P, 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. 
Le Coutre P, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine 
kinase inhibitor, is active in patients with imatinib-resistant or intolerant accelerated-phase 
chronic myelogenous leukemia. Blood 2008; 111: 1834-39. 


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Le Coutre P, et al. Nilotinib is safe and effective in accelerated phase chronic myelogenous 
leukemia (CML-AP) patients with imatinib resistance or intolerance. Blood 2007; 110 
(s11):145a ASH abstract #471. 
Martinelli G, et al. New tyrosine kinase inhibitors in chronic myeloid leukemia. 
Haematologica 2005; 90: 534-41. 
Nowell PC, Hungerford DA (1960) A minute chromosome in chronic granulocytic leukemia. 
Science; 132: 1497-1501. 
O'Brien SG, et al. Imatinib compared with interferon and low-dose cytarabine for newly 
diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003 Mar 
13;348(11):994-1004. 
Rosti G. et al., Nilotinib 800 mg daily as first line treatment of chronic myeloid leukemia in 
early chronic phase: results of a phase 2 trial of the GIMEMA CML working party. Blood 
2008;112(11) abstract # 181. 
Rowley JD (1973) A new consistent abnormality in chronic myelogenous leukemia identified 
by quinacrine, fluorescence and Giemsa staining. Nature; 243:290-93. 
Saglio et al. Nilotinib Demonstrates Superior Efficacy Compared With Imatinib in Patients 
With Newly Diagnosed CML-CP: Results From the International Randomized Phase III 
ENESTnd Trial  ASH 2009 Abs LBA#1 
Sokal JE, Prognostic discrimination in “ good-risk” chronic granulocytic leukemia Blood 
1984 63: 789-799  
Weisberg E, et al. Characterization of AMN107, a selective inhibitor of native and mutant 
BCR-ABL. Cance Cell 2005; 7:129-141. 
White D, 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. 
 

SAP_001.pdf: 
Clinical Study SAP CAMN107ETR02 / NCT01274351
A multicenter, open-label, non-randomized phase II study of 
nilotinib as a first line treatment in adult patients with newly-
diagnosed Philadelphia chromosome-positive (Ph+) and 
chronic phase myeloid leukemia (CML-CP) 
Document type  
Statistical Analysis Plan 
Version Number :  02 
Release date: 
14– Mar – 2014 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Statistical Analysis Plan 
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Table of contents 
Table of contents ........................................................................................................................ 2 
1 
Abbreviations and Definitions ............................................................................................ 4 
2 
Introduction ......................................................................................................................... 5 
2.1 
Chronic myeloid leukemia ...................................................................................... 5 
2.2 
Nilotinib ................................................................................................................... 6 
3 
Study objectives .................................................................................................................. 7 
3.1 
Primary Objective(s) ............................................................................................... 7 
3.2 
Secondary Objective(s) ........................................................................................... 7 
3.3 
Exploratory objective(s) .......................................................................................... 7 
4 
Study Methods ..................................................................................................................... 7 
4.1 
General Study Design and Plan ............................................................................... 7 
4.2 
Study population ...................................................................................................... 8 
4.2.1 
Inclusion criteria ..................................................................................... 9 
4.2.2 
Exclusion criteria .................................................................................... 9 
4.3 
Treatment Blinding ................................................................................................ 10 
4.4 
Study Variables ..................................................................................................... 10 
5 
Sample size ........................................................................................................................ 11 
6 
General Considerations ..................................................................................................... 11 
6.1 
Timing of Analyses ............................................................................................... 11 
6.2 
Analysis Populations ............................................................................................. 11 
6.3 
Covariates and Subgroups ..................................................................................... 11 
6.4 
Missing Data .......................................................................................................... 12 
6.5 
Interim Analyses and Data Monitoring ................................................................. 12 
6.5.1 
Purpose of Interim Analyses ................................................................. 12 
6.5.2 
Planned Schedule of Interim Analyses ................................................. 12 
6.5.3 
Scope of Adaptations ............................................................................ 12 
6.5.4 
Stopping Rules ...................................................................................... 13 
6.5.5 
Analysis Methods to Minimise Bias ..................................................... 13 
6.5.6 
Adjustment of Confidence Intervals and p-values ................................ 14 
6.5.7 
Interim Analysis for Sample Size Adjustment...................................... 14 
6.5.8 
Practical Measures to Minimise Bias .................................................... 14 
6.5.9 
Documentation of Interim Analyses ..................................................... 14 
6.6 
Multi-centre Studies .............................................................................................. 14 
6.7 
Multiple Testing .................................................................................................... 14 
7 
Summary of Study Data .................................................................................................... 14 
7.1 
Subject Disposition ................................................................................................ 16 
Follow-Up .......................................................................................................................... 16 


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Allocation .......................................................................................................................... 16 
Enrollment ........................................................................................................................ 16 
Analysis ............................................................................................................................. 16 
7.2 
Protocol Deviations ............................................................................................... 16 
7.3 
Demographic and Baseline Variables ................................................................... 17 
7.4 
Concurrent Illnesses and Medical Conditions ....................................................... 17 
7.5 
Prior and Concurrent Medications......................................................................... 17 
7.6 
Treatment Compliance .......................................................................................... 17 
8 
Efficacy Analyses .............................................................................................................. 17 
8.1 
Primary Efficacy Analysis ..................................................................................... 17 
8.2 
Secondary Efficacy Analyses ................................................................................ 17 
8.3 
Exploratory Efficacy Analyses .............................................................................. 18 
9 
Safety Analyses ................................................................................................................. 18 
9.1 
Extent of Exposure ................................................................................................ 18 
9.2 
Adverse Events ...................................................................................................... 18 
9.3 
Deaths, Serious Adverse Events and other Significant Adverse Events ............... 18 
9.4 
Pregnancies ............................................................................................................ 19 
9.5 
Clinical Laboratory Evaluations ............................................................................ 19 
9.6 
Other Safety Measures .......................................................................................... 19 
10 Pharmacokinetics .............................................................................................................. 19 
11 Other Analyses .................................................................................................................. 19 
12 Figures ............................................................................................................................... 20 
13 Reporting Conventions ...................................................................................................... 22 
14 Technical Details ............................................................................................................... 22 
15 Summary of Changes to the Protocol ................................................................................ 22 
16 References ......................................................................................................................... 22 
 


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1 
Abbreviations and Definitions 
ABL Abelson proto-oncogene 
ALT (SGOT) Alanine aminotransferase 
AST (SGPT) Aspartat aminotransferase 
BCR Breakpoint Cluster Region gene / BCR gene product 
BCR-ABL Fusion gene from BCR and ABL/Protein product from BCR-ABL 
BID bis in diem/two times daily 
SAE Serious adverse event 
CTCAE NCI Common Terminology Criteria for Adverse Events 
WHO World Health Organization 
ECG Electrocardiography 
EMEA European Medicines Agency 
FDA Food and Drug Administration 
GI Gastrointestinal 
CTC Common Toxicity Criteria 
HDL High-density lipoprotein 
HLA Human Leukocyte Antigen 
IFN-α Interferon-α 
INR International normalization rate 
ITT Intent-to-Treat 
CP Chronic phase 
IRB/IEC/REB Institutional Review Board/Independent Ethics Committee/Research Ethics Board 
CML Chronic myeloid leukemia  
PCR Partial cytogenetic response  
LDH Lactate dehydrogenase  
LDL Low-density lipoprotein  
MMR Major molecular response  
CRR Cytogenetic response rate 
mCR Minor cytogenetic response  
MCR Major cytogenetic response  
ULN Upper limit of normal  
CRF Case Report Form  
PCR Polymerase chain reaction  
Ph+ Philadelphia chromosome-positive  
PP Per Protocol  
CRO Contract Research Organization  
CR Cytogenetic response  
CNS Central nervous system  
LVEF Left ventricular ejection fraction  
CCyR Complete cytogenetic response  
VLDL Very low-density lipoprotein  


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2 
Introduction 
2.1 
Chronic myeloid leukemia 
Chronic myeloid leukemia (CML) is a hematologic stem cell disease associated with a specific 
chromosome translocation known as the Philadelphia chromosome detected in 95% of patients 
(Nowell 1960, Rowley 1973). Molecular outcome of the translocation is fusion of the Abl proto-
oncogene to the Bcr gene, resulting in production of an activated form of Abl protein-tyrosine kinase 
(Bartram 1983, Heisterkamp 1983). Expression of BCR-ABL protein may cause leukemia in mice, 
which suggests that this protein is the cause of the disease (Daley 1990, Kelliher 1990). Clinically, 
CML progresses through three different phases, gradually becoming more resistant to treatment: 
chronic phase (CP) (median duration 3-4 years, median survival may extent up to 10 years with 
allogeneic bone marrow transplantation and is 5-6 years with interferon), accelerated phase (AP) 
(median duration 3-9 months; median survival 8-18 months) and blast crisis (BC) (median survival 3-
6 month) (Enright 2000).  
In chronic-phase CML, cytogenetic response criteria, which is based on the percentage of Ph+ cells in 
the bone marrow, is acknowledged as an important indicator of the disease state and treatment and 
represents the mainstay of monitoring the disease state in CML. Cytogenetic response (CyR) is a 
known determinant for prognosis in CML management and is used to predict patient outcome.  
During the past 25 years, Ph+CML treatment have evolved from treatment with non-specific cytotoxic 
agents to methods which combine cell destruction and immunologic control of the residual disease 
and, more recently, to imatinib, which is a tyrosine kinase inhibitor class agent that specifically targets 
the ABL portion of oncogenic BCR-ABL coded proteins. Conventional treatment may be given by a 
range of cytotoxic agents, mainly hydroxyurea. The treatment is safe and inexpensive and may be 
maintained on an outpatient basis and offers a good quality of life but neither prevents nor delays 
progression from chronic phase to accelerated or blast phases. Thus, all patients treated with 
conventional chemotherapy die within less than 10 years (median 4.5 years) (Goldman 2003). 
Conventional treatment is abandoned and may be indicated unless it is impossible to administer other 
treatments. Preferred treatment approach had been the allogeneic hemopoietic stem cell 
transplantation for at least 20 years since it was the only treatment procedure which was shown to 
actually treat the disease. Its use, however, is still limited with patients’ age (median age of patients 
with CML is 58) and requires a HLA-matching donor from patients’ families or from the international 
bone marrow donor registries. Besides, allogeneic hemopoietic stem cell transplantation still 
constitutes significant toxicity; transplantation-related mortality is approximately 30% and long-term 
leukemia-free survival is about 50% (Hehlmann 2007, Baccarani 2006, Barret 2003). Based on 
numerous prospective randomized studies on IFN-α versus conventional chemotherapy, interferon-α 
(IFN-α) had been the first choice of treatment in CML for about 10 years (1990-2000). Subsequent 
studies have shown that the efficacy of IFN-α was less in high-risk patients compared to the low-risk 
patients, who achieve greater benefit from this treatment: complete cytogenetic response was 
approximately 30% and elongations up to or even more than 10 years were observed. 
IFN-α treatment is safe but toxic and not well-tolerated and about 35% of patients require treatment 
discontinuation (Baccarani 2003). Tyrosine kinase inhibitors are a new class of components designed 
and developed to target tyrosine kinase. A tyrosine kinase, imatinib mesylate, which inhibits ABL and 
other tyrosine kinases, was shown to specifically inhibit Ph+ cells and resulted in impressive number 
of hematologic and cytogenetic response in all phases of Ph+ leukemias (Hehlman 2007, Goldman 
2001, Deininger 2005, Baccarani 2006, Kantarjian 2004, Hochhaus 2008). A prospective, randomized 
study using imatinib versus IFN-α showed than imatinib was superior to IFN-α by several orders of 


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magnitude in hematologic response, cytogenetic response, time to progression and toxicity profile 
(O’Brien 2003, Hughes 2003, Hochhaus 2007). Imatinib thus rapidly become the first choice of 
treatment for all phases of Ph+ CML, from the early chronic phase to the blastic phase. A range of 
second generation tyrosine kinase inhibitors were developed including nilotinib and were investigated 
in preclinical and clinical phases (Martinelli 2005, Kantarjian 2007) (Weisberg 2005, Golemovic 
2005, Kantarjian 2006, Kantarjian 2007, Le Coutre 2008). 
2.2 
Nilotinib  
Nilotinib is an orally-available novel aminopyrimidine and an ATP competitive inhibitor of protein 
tyrosine kinase activity of BCR-ABL, which inhibits activation of BCR-ABL-dependent mitogenic 
and anti-apoptotic pathways (e.g. PI-3 kinase and STAT5), thereby leading to BCR-ABL genotype 
demise. Nilotinib also frequently inhibits other oncogenic kinases including FIP1L1-PDGFRA 
tyrosine kinase, which is associated with hypereosinophilic syndrome and chronic eosinophilic 
leukemia, and stem cell factor receptor c-Kit tyrosine kinase, which is associated with systemic 
mastocytosis and gastrointestinal stromal tumors.  
Data from preclinical studies indicate that nilotinib reaches higher intracellular concentrations than 
imatinib and that nilotinib inhibits BCR-ABL tyrosine kinase activity and induce apoptosis at lower 
concentrations compared to imatinib (Le Coutre 2004, White 2005). In preclinical models, nilotinib 
was 20 to 50 times more potent than imatinib on CML cell lines sensitive to imatinib and was 3 to 7 
times more potent in cell lines resistant to imatinib.  
In a phase I dose-escalation study, 119 patients with Ph+ CML and acute lymphocytic leukemia 
resistant to imatinib were treated with a single oral nilotinib dose of 50-1200 mg or 400 mg and 600 
mg nilotinib administered twice daily. Nilotinib produced higher hematologic and cytogenetic 
response rates in chronic phase CML patients who were resistant to imatinib, 92 and 53% respectively 
(CCyR in 35%). (AMN107 Investigator Brochure Ed.4.0, 2008).  
Initial data from 132 patients resistant or tolerant to imatinib in a phase I study were reported by 
Kantarjian (2006). In this study, patients were treated with nilotinib for a median period of 226 days 
(range 3-379 days). Complete hematologic response was achieved in 69% of the patients. Major 
cytogenetic response was achieved by 42%. Thirty-three patients (22%) achieved complete 
cytogenetic response.  
Nilotinib was also shown to have an acceptable tolerability profile (Kantarjian 2007). In a CML-CP 
population, the commonest GTC grade 3 hematologic anomalies were decreases in absolute 
lymphocyte (16.2%), neutrophil (14.8%), white blood cells (12.6%) and platelet (11.2%) counts. The 
commonest GTC grade 4 anomalies were reductions in platelet count (13.5%), neutrophils (11.6%) 
and absolute lymphocyte count (7.5%). 
Furthermore, studies with patients with hematologic malignancies have demonstrated that nilotinib 
had a potential to mildly elongate QT interval at therapeutic concentrations. On day 8 (steady-state), 
mean temporal changes in QT interval from baseline ranged from 5.7 msn (CML-CP patients) to 8.4 
msn (CML-AP patients).  
It should be noted that most of the adverse events reported from the phase II leukemia studies with 
imatinib have also been reported from the phase I study with nilotinib, although incidence of 
peripheral edema was very low in the nilotinib study. In the Nilotinib phase I study, 400 mg twice 
daily (BID) dose level was associated with lower incidence of Grade 3 neutropenia and Grade 3 
hyperbilirubinemia compared to the 600 mg BID dose. Initial data from a phase II study with a patient 
group whose dosage was increased from 400 mg BID to 600 mg BID due to suboptimal response did 
not demonstrate improved efficacy with the higher dose. Thus, 400 mg BID dose of imatinib was 
recognized as the dose with optimum efficacy and safety.  
Today, nilotinib treatment in patients with Ph+ CML who are resistant or intolerant to imatinib has 
been approved by the FDA and EMEA (Le Coutre 2008). Nilotinib is now being investigated in many 
studies as the first line treatment in Ph+ CML comparatively to imatinib. 


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3 
Study objectives 
 
3.1 
Primary Objective(s)  
 
The primary objective of this study is to evaluate the efficacy of Nilotinib by determining the 
cumulative major molecular response (MMR) rates in 12 months in adult patients with newly-
diagnosed Philadelphia chromosome-positive and chronic phase myeloid leukemia. 
 
3.2 
Secondary Objective(s)  
 
To evaluate the rate of complete cytogenetic response (CCyR) at months 6 and 12  
 
To evaluate periodically the rate of 3-monthly molecular response  
 
To evaluate complete hematologic response rate  
 
To evaluate the safety profile of nilotinib treatment  
 
To evaluate time to MMR and durability of the response  
 
  
 
  
 
  
 
3.3 
Exploratory objective(s)  
Not applicable. 
4 Study Methods 
4.1 General Study Design and Plan 
This is a local, multicenter, one-arm and non-randomized phase II clinical trial. This study will 
evaluate the efficacy and safety of nilotinib in a new group. Newly-diagnosed patients will enter a 
2-weeek screening period. Those who meet eligibility criteria will be treated with nilotinib 300 
mg BID for 24 months. For efficacy assessments, bone marrow aspiration and/or biopsy will be 
used for cytogenetic analysis and peripheral blood will be used for RQ-PCR measurements of 
BCR-ABL transcriptions. Safety assessments will involve adverse events, laboratory profiles 
(hematology/biochemistry), ECG, and physical examinations. The patients will be evaluated 
every 15 days during the first 3 months, once every month for up to month 12 and then every 
three months. 
Screening visit: Patients’ eligibility (inclusion/exclusion criteria) is assessed at this visit. Subsequent 
procedures/tests will include informed consent, medical history, inclusion/exclusion criteria, vital 
findings, physical examination, assessment of extramedullary involvement, concomitant drugs, ECOG 
performance status, serum pregnancy test, hematology, blood chemistry, bone marrow assessment 
(within the past 2 months), peripheral blood analysis.  


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Baseline visit: This visit will be scheduled for 0 to 2 weeks following the screening visit. Baseline 
assessments will include vital findings, physical examination, additional inclusion/exclusion criteria, 
concomitant drugs, drug dispensing, ECG, hematology and blood chemistry.  
 
 
 
 
 
 
 
  
Unscheduled visits: As required. Investigations for the cause of the unscheduled visits will be 
performed. 
 
 
 
All scheduled visits will be performed as close as possible to the scheme given in Figure 4-1. 
Should deviations from the scheme presented in Figure 4-1 occur, all remaining visits must be 
performed according to the original plan. 
 
4.2 
Study population  
All eligible adult patients with Ph+ CML-CP who have been diagnosed cytogenetically during the 
past six months and who have not received treatment for CML other than anagrelide and 
hydroxyurea (excluding imatinib treatment for a maximum duration of 31 days) will be enrolled 
in the study.  
A total of 110 patients will be enrolled.  
The patients must have fulfilled all inclusion criteria during the 2 weeks prior to the study (bone 
marrow analyses may have been performed within the last 8 weeks) and should not meet any of 
the exclusion criteria.  


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4.2.1 
Inclusion criteria  
 
Male and female patients ≥18 years old  
 
ECOG performance status 0, 1 or 2  
 
First CML-CP diagnosis should have been made during the past 6 months and Philadelphia 
chromosome resulting from translocation (9;22) should be confirmed cytogenetically . 
Standard conventional cytogenetic analysis is required. All of the following criteria of CML-
CP diagnosis should be met:  
 
<15% blast in peripheral blood and bone marrow  
 
<30% blast in peripheral blood and bone marrow plus promyelocyte  
 
<20% basophil in peripheral blood  
 
≥100 x 109/L (≥100.000/mm3) platelet  
 
No evidence of extramedullary leukemic involvement, except for hepatosplenomegaly  
 
Should not have received treatment for CML other than anagrelide and hydroxyurea.  
 
Sufficient end-organ function with the following laboratory criterias:, total bilirubin < 1.5 x 
ULN; SGOT and SGPT < 2.5 x ULN; creatinine < 1.5 x ULN; serum amylase and lipase ≤ 1.5 
x ULN; alkaline phosphatase ≤ 2.5 x ULN unless associated with a tumor  
 
Serum potassium, magnesium, calcium and phosphorus levels are equal to or above the lower 
limit of normal before the administration of the first dose of the study treatment.  
 
Should have provided informed consent in written before ant study-related procedure may be 
initiated.  
4.2.2 
Exclusion criteria  
 
Being treated with tyrosine kinase inhibitors before the study start (awaiting the study start, in 
cases of emergencies where the disease should be treated, commercial products containing 
imatinib may be prescribed but the treatment period should not exceed 31 days).  
 
Known CNS infiltration, confirmed cytopathologically.  
 
Cardiac dysfunction [presence of any of the following: LVEF <45% (if available), inability to 
determine QT interval with ECG, acquired long QT syndrome or familial history of long QT 
syndrome, clinically significant ventricular or atrial tachyarrhythmia or history thereof, 
clinically significant resting bradycardia (<50 beats/minute), QTc > 450 msn as measured by 
QTcF in baseline ECG (if QTcF>450 msn and electrolytes are not within normal ranges, the 
latter should be corrected and the subject should undergo screening again for QTc), history of 
myocardium infarct within the 12 months before the study start, other clinically significant 
cardiac disorders (e.g. instable angina, congestive heart failure or uncontrolled hypertension)].  
 
Serious or uncontrolled medical conditions (e.g., uncontrolled diabetes mellitus, active or 
uncontrolled infections).  
 
Acute or chronic hepatic, pancreatic or serious renal diseases not associated with the disease,  
 
Patients with other primary malignancies; this excludes situations where the tumor is no longer 
clinically significant or does not necessitate active intervention.  
 
Significant congenital or acquired bleeding disorders not associated with cancer.  
 
Previous radiotherapy involving ≥25% of the bone marrow.  
 
Major surgery during the 4 weeks before the first day of the study or those not recovering 
following surgery  


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 
Gastrointestinal (GI) dysfunction or GI disease which may significantly alter the absorption of 
the study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea 
malabsorption syndrome, small intestine resection or gastric by-pass surgery)  
 
Patients treated with potent CYP3A4 inhibitors (e.g.; erythromycin, ketoconazole, 
itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil)  
 
Patients currently receiving active treatment agents which may potentially prolong QT interval 
or in whom it is not possible to discontinue the treatment or to switch to another drug before 
the study start.  
 
History of noncompliance with medical regimes.  
 
Pregnant women (positive serum pregnancy test during the 7 days before the start of study 
treatment for women of childbearing potential) or breastfeeding women  
 
Fertile male and female patients who are not willing to take contraceptive measures 
throughout the study (in order to confirm that menopausal women does not have childbearing 
potential, she should have been amenorrheic for at least 12 months).  
4.3 Treatment Blinding 
No blinding will be done since this is an open-label study with one treatment arm. 
 
4.4 
Study Variables 
 
Period 
Screening 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Day (d)/Month (m) 
D -14 to 1 
D1 
D15 
D30 
D45 
D60 
D75 
D90 
M4 
M5 
M6 
M
7 
M
8 
M
9 
M1
0 
M1
1 
M1
2 
M1
5 
M1
8 
M2
1 
M2
4 
Screening info 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical history, 
disease history, previous 
treatments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance 
status 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital findings, physical 
exam., body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Extramedullary 
involvement 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone marrow 
assessments 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Peripheral blood sample 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Nilotinib dose and 
compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant drugs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mutation analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Study completion form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


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5 Sample size  
The sample size was calculated using the exact test for single proportion to attain 15% improvement in 
MMR rates compared to IRIS data.  
The sample calculated by 80% confidence interval consists of 110 subjects accounting for a 10% 
drop-out during the two-year follow-up.  
6 General Considerations 
6.1 Timing of Analyses 
The final analysis will be performed when 110 subjects have completed visit 24 or dropped out 
prior to visit 24. 
6.2 Analysis Populations 
The analyses in this study will be conducted in three seperate groups. First group will be the safety 
population, which will consist of all subjects who received at least one dose of study drug and have at 
least one post-baseline safety assessment. A report by a subject indicating no adverse experience will 
constitute a safety assessment. 
The second group will be the ITT population, which will consist of all subjects who provided 
informed consent form.  
And the last group of analyses will be conducted in the per protocol population, which will consist of 
all subjects in the ITT population with no major protocol violation reported. All reported protocol 
violations will be classified as major or minor in a review meeting before database lock.  
The population intended to be treated for demographical and baseline characteristics will be used in all 
ITT efficacy evaluations. Per protocol population will be used for per protocol analyses for primary 
efficacy endpoint and some important secondary efficacy variables.  
Safety analysis will be performed with the safety population. 
6.3 Covariates and Subgroups 
Since this is an open-label study with one treatment arm and disease-specific inclusion and 
exclusion criteria, no sub-groups will be formed, and no stratification will be made during the 
interim analysis. The major aim in the interim analyses is to determine the molecular and 
hematological response rates, and to determine the major adverse event rates in the study 
population. 
 
 The final analyses of the study will be conducted in aforementioned three 
separate groups (safety, ITT, and per protocol populations) and stratifications will be made at this 
stage. The sub-groups (or strata) will be formed according to clinically important demographic 
and clinical variables (such as age, gender, major adverse events, progression of the disease, etc.). 
For the sake of preventing the inflation of statistical significance, the interim analyses will be 
conducted for descriptive statistics only. But, if the findings in these analyses shows significant 
results for unfavored high frequency of adverse events or decreased survival, necessary analytical 
statistical analyses should be performed. In this case, alpha-spending considerations will be 
subject to the determination of statistical significance, and preferably O’Brien-Fleming approach 
should be utilized for calculating the p values of inferential statistical analyses. 
 


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6.4 Missing Data 
Subjects who withdraw prematurely or those who fail to provide data for the study for other reasons 
will be designated as premature withdrawal or inevaluable, respectively, and will be included in the 
ITT analysis as non-responders. Only those who achieve MMR by month 12 will be considered as 
responders.  
6.5 Interim Analyses and Data Monitoring 
6.5.1 Purpose of Interim Analyses 
Interim analyses will be conducted to inform the steering committee about the descriptive data of 
primary outcome measure – namely MMR, adverse event frequency and survival of the patients. 
If no critical values of adverse events and/or survival data is determined, no revisions will be 
needed in the protocol of the study. But if needed, descriptive data, and some on-demand 
inferential statistics may be used for deciding the revisions on the protocol.  
 
 
6.5.2 Planned Schedule of Interim Analyses 
 
An interim analysis is planned when 30% of the targeted number of subjects for this study is 
reached and these patients received nilotinib treatment for 6 months. Only one interim analyse 
should be performed during the study. This interim analyse will be mainly focused on descriptive 
characteristics of the treatment effects of Nilotinib, and the analyses will be particulary performed 
to determine the molecular and hematological response rates, and to determine the major adverse 
event rates in the study population. 
 
  
 
6.5.3 Scope of Adaptations 
If the interim analyses show significant adverse effects and/or decreased survival in patients 
treated with Nilotinib, then the analyses should be detailed according to the demographic and key 
clinical characteristics of the study population, and additional data should be provided to help the 
steering committee to decide the necessary revisions in the protocol. The scope of adaptations 
should be constituted according to the following outcomes of the study: 
 
 Molecular Response Rate 
This data will be provided as follows: 
 
Cumulative MMR rate 
N= 
n (%) 
3rd Month (Visit 8)  
 
6th Month (Visit 11) 
 
9th Month (Visit 14) 
 
12th Month (Visit 17) 
 
 
 Cytogenetic Response Rate 
This data will be provided as follows: 


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Cytogenetic response rate 
 
 
 
80% Confidence Interval 
N Mean (SD) Lower Bound Upper Bound 
CRR at 6th Month 
 
 
 
 
CRR at 12th Month 
 
 
 
 
 
 Survival rates 
This data will be provided as follows: 
 
Survival rates 
 
Cumulative Survival Rate 
Time 
Estimate 
Standart Error 
… 
… 
… 
 
 
 Adverse events 
This data will be provided as follows: 
 
Adverse Events 
Frequency 
Percent 
Elevated bilirubins 
 
 
Leucocytosis 
 
 
Ischemic heart disease 
 
 
Total 
100,0 
 
 
6.5.4 Stopping Rules 
The study will not be stopped due to the findings in the interim analyses, unless unexpected high 
mortality rates or adverse events are reported. In the case of elevated adverse event rates or 
mortality, which will still be in the acceptable limits, some modifications may be applied in the 
treatment protocol according to the steering committee. 
 
6.5.5 Analysis Methods to Minimise Bias 
Since this is an open-label study with one treatment arm, statistical analyses will primarily include 
descriptive data of the study population. As the descriptive analyses will not include subgroup 
comparisons, bias will be automatically avoided. Key analyses of primary and secondary efficacy and 
safety parameters will also include individual patient data to elucidate the unfavored situations. At the 
final pooled analyses of the study ITT, PP and safety group analyses will be performed separately, to 
cover the all spectrum of the clinical aspects of the treatment, and this will also prevent the biased 
results of the outcomes of the trial. 
  


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6.5.6  Adjustment of Confidence Intervals and p-values 
The interim analyses will mainly provide descriptive data about the primary and secondary efficacy 
and safety parameters, and 80% confidence intervals of means will be provided when needed. As the 
descriptive analyses will have no analytical statistics, p values will not be modified for the interim 
analyses. But, if the descriptive date provides critical information about efficacy or safety profile of 
the treatment, then analytical statistics will be performed in subgroup analyses, and according to the 
alpha-spending function approach, O’Brien Fleming method will be used to determine the critical p 
value to be used in analytical statistics. 
6.5.7 Interim Analysis for Sample Size Adjustment 
Sample size will not be adjusted according to the interim analyses, since no power analyses will 
be performed in interim analyses. 
6.5.8 Practical Measures to Minimise Bias 
Data management will only be performed by a CRO responsible for data management. Data captured 
from the CRFs will be entered to the database through an electronic verification system with a single 
entry.  
No blinding will be done since this is an open-label study with one treatment arm. 
6.5.9 Documentation of Interim Analyses 
Interim analyses will be conducted by the responsible CRO and the documents will be preserved 
for future use. 
6.6 Multi-centre Studies 
This is a multicenter study with 15 participating institutions. 
6.7 Multiple Testing 
The first set of analyses in this study will primarily based on to provide descriptive data about the 
study and its effects in study population. Therefore, no subgroups will be formed for the 
comparative analyses. But, if descriptive data of the primary and secondary endpoints reveal 
clinically significant findings, then the multiple group comparisons may be subject to the 
inferential analyses. In such a case, a Type-I error level of 5% will be preserved for multiple 
group comparisons, and Bonferroni correction will be utilized for preventing the statistical 
significance inflation in post-hoc pairwise comparisons.  
7 Summary of Study Data 
The data gathered in this study will be presented in summary tables. The central tendency of 
numerical variables will be presented in means or medians, and the dispersion will be presented as 
standart deviations, interquartile ranges or minimum-maximum values, where appropriate. 
Categorical variables will be shown in frequency (n) and percents. Examples of both the 
numerical and categorical data is shown below: 
 


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Cytogenetic response rate 
 
 
 
80% Confidence Interval 
N Mean (SD) Lower Bound Upper Bound 
CRR at 6th Month 
 
 
 
 
CRR at 12th Month 
 
 
 
 
 
Cumulative MMR rate 
N= 
n (%) 
3rd Month (Visit 8)  
 
6th Month (Visit 11) 
 
9th Month (Visit 14) 
 
12th Month (Visit 17) 
 
 
Since the objective of the statistical analyses in this study is providing the descriptive data about 
the primary and secondary endpoints, no stratifications will be made in the descriptive tables. But, 
if further comparative analyses will be necessary according to the relevant demographic or 
clinical vairables, the descriptive tables should be stratified according to these variables.  
 


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7.1 Subject Disposition 
 
The numbers in the following chart will be completed upon the interim and final analyses.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2 Protocol Deviations 
Subjects who discontinue treatment with the study drug will be considered as withdrawals after 
the final visit assessments or if they are lost to follow up. The subjects may withdraw from the 
study prematurely due to any of the following reasons: 
 Adverse event(s) 
 Abnormal laboratory value(s) 
 Abnormal test result(s) 
 Disease progression 
 Nilotinib inefficacy based on the criteria for this study. 
 Subject’s condition no longer requires treatment (may be beneficial in patients 
undergoing bone marrow transplantation). 
 Protocol violation 
Assessed for eligibility (n=) 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Allocated to intervention (n=) 
 Received allocated intervention (n=) 
 Did not receive allocated intervention (give 
reasons) (n= 0 ) 
Allocation 
Analysis 
Follow-Up 
Enrollment 


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 Subject withdraws informed consent 
 Lost to follow-up 
 Pregnancy 
 Executive issues 
 Death 
7.3 Demographic and Baseline Variables 
Subject’s age and gender will be documented in the relevant page of the CRF. Bone marrow screening 
to confirm CCyR will be performed during the last 8 weeks following administration of last study 
treatment. Peripheral blood sample analysis to measure molecular response should be performed 
within 28 days after the administration of the first study dose. Bone Marrow Analysis CRF will be 
used to collect information on the cytogenetic status and Previous antineoplastic agents CRF will be 
used to collect information on previous medications.  
Relevant conditions and surgeries during the 5 years before the study (a longer period of time for 
disease-related history, if feasible) as well as concomitant conditions, date of diagnosis/surgery and 
information whether there is an ongoing problem will be recorded.  
Information on surgeries, including previous antineoplastic agents, radiotherapy and surgical biopsies 
will be collected.  
Date of first CML diagnosis and the best previous response will be collected. 
7.4 Concurrent Illnesses and Medical Conditions 
The summary statistics will be produced in accordance with section 7.3. 
 
7.5 Prior and Concurrent Medications 
Concomitant medications given before and after treatment with study drug will be summarized by 
treatment groups. WHO Drug Reference List will be used to code medications. All prescription and 
non-prescription medicinal products including vitamins and blood transfusions will be entered in the 
Concomitant medications/non drug therapies CRF. The records will include the trade name of the 
medicines, start date and end date and the rationale for administration. 
7.6 Treatment Compliance 
Treatment compliance will be evaluated by the investigator and/or study personnel by examining 
the number of capsules and the information provided by the subject. This information will be 
recorded on source documents at every visit.  
8 Efficacy Analyses 
 
8.1 Primary Efficacy Analysis 
The primary efficacy endpoint in this study is the best cumulative MMR rate at month 12, measured as 
RQ-PCR and defined as ≤0.1% BCR-ABL/% control gene reported in % on the international scale.  
 
8.2 Secondary Efficacy Analyses 
Efficacy variables for secondary variables will be analyzed descriptively using summary statistics. 
Summary statistics will include n (number of observations), mean, standard deviation, median, 


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minimum and maximum values for continuous variables as well as frequency and percentages for 
categorical variables. Missing values for secondary endpoints will not be replaced. All ratios will be 
assessed at month 6 and 12, and then once every year if data is available and the ratio is the 
cumulative ratio up to a specific time point.  
Time variables up to any event will be shown with Kaplan-Meier curves. 
8.3 Exploratory Efficacy Analyses 
Not applicable 
9 Safety Analyses 
All safety analyses will be performed on the safety population. Safety assessment will be based on 
primarily the incidence of adverse events and the number of subjects with laboratory values outside 
predetermined rates and number of patients with clinically significant ECG findings.  
 
9.1 Extent of Exposure 
Physical examination findings consistent with extramedullary leukemia involvement (e.g., lymph 
nodes, liver and spleen sizes) will be recorded. Only those lymph nodes considered related to the 
disease will be taken into account.  
If the only evidence of a blast crisis is an extramedullary involvement outside liver and spleen, this 
must be confirmed histologically and/or by biology (particularly for lymph nodes) and the data should 
be entered in the CRF.  
9.2 Adverse Events 
A serious adverse event is an undesirable sign, symptom, or medical condition defined according to 
the following criteria:  
 
is fatal or life-threatening  
 
requires inpatient hospitalization or prolongation of existing hospitalization  
 
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  
These events will not constitute an adverse event if the hospitalization is for:  
 
the medical care was scheduled before enrollment  
 
elective treatment for a pre-existing condition that is unrelated to the indication under study  
 
treatment on an emergency outpatient basis (for an event not fulfilling any of the definitions of 
a SAE given above and not resulting in hospital admission)  
 
routine treatment or monitoring of the studied indication, not associated with any deterioration 
in condition  
 
social reasons and respite care in the absence of any deterioration in the patient’s general 
condition  
 
9.3 Deaths, Serious Adverse Events and other Significant Adverse Events 
The summary statistics will be produced in accordance with section 9.2. 


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9.4  Pregnancies 
Women of childbearing potential are required to undergo a serum pregnancy test at screening. In order 
to confirm that menopausal woman does not have childbearing potential, she should have been 
amenorrheic for at least 12 months.  
9.5 Clinical Laboratory Evaluations 
Blood chemistry laboratory assessments will be performed by a certified central laboratory. 
Biochemistry will include urea or BUN, creatinine, uric acid, albumin, total protein, total bilirubin 
(direct or indirect), alkaline phosphatase, AST (SGOT), ALT (SGPT), LDH, sodium, chloride, 
(fasting) glucose, calcium, lipase, amylase, potassium, magnesium and phosphor and lipid profile 
(HDL, LDL, VLDL, triglycerides and total cholesterol), INR (International Normalization Ratio) and 
Hemoglobin A1c.  
In addition to the routine biochemistry assessments outlined in the visit schedule, subjects must have 
their serum potassium and magnesium levels in case of QTc elongation or at the discretion of the 
investigator. Routine biochemistry assessments outlined in the visit schedule will be recorded in the 
CRF. Additional electrolyte results (potassium and magnesium) will not be entered in the CRF or 
clinical database unless they require supportive treatment or substitution treatment. If supportive 
treatment and substitution treatment required, the laboratory anomaly should be documented in the 
CRF as scheduled or unscheduled laboratory result and should also be recorded as an adverse event. If 
supportive treatment and substitution treatment is given, these should be indicated as concomitant 
medication. Other additional results should be included only in the source documentation at the study 
center.  
9.6 Other Safety Measures 
Not applicable 
10 Pharmacokinetics 
Not applicable 
11 Other Analyses 
Min, max and mean values of treatment duration from the first dose through out the treatment 
period. 
Number of patients having dose reductions and/or which AEs lead to dose reductions. 
Details of cardiovascular events with MedDRA coding. 
Details of laboratory values of the patients having mutations. 
Details of laboratory values of the patients having study treatment related thrombocytopenia. 
Analysis of the patients having hyperglycemia. 
Patient numbers by socal risk groups. 
CCyR by socal risk groups. 
MMR by socal risk groups. 
 


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12 Figures 
Bar charts for categorical data and Kaplan-Meier survival curves will be used in this study. 
Examples for these graph are shown below: 
 
 
 
 


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13 Reporting Conventions 
P-values ≥0.001 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001”. The mean, standard deviation, and any other statistics other than quantiles, will be 
reported to one decimal place greater than the original data. Quantiles, such as median, or 
minimum and maximum will use the same number of decimal places as the original data. 
Estimated parameters, not on the same scale as raw observations (e.g. regression coefficients) will 
be reported to 3 significant figures.  
14 Technical Details 
Statistical analyses will be performed by an expert statistician employed by an independent CRO, 
and by using PASW Statistics 18 and Stata 11. 
15 Summary of Changes to the Protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that must 
be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB approval. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is expected to 
take any immediate action required for the safety of any patient included in this study, even if this 
action represents a deviation from the protocol. In such cases, Novartis should be notified of this 
action and the IRB/IEC/REB at the study site should be informed within 10 working days. 
16 References 
Not applicable.