Clinical trial NCT01593254
Conditions: Chronic Phase Chronic Myeloid Leukemia
Sponsor: Bristol-Myers Squibb
Start date: 2012-09-12; Completion date: 2022-04-12
Enrollment: 262 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to test the hypothesis that patients with CML who have not achieved optimal response after 3 months of treatment with imatinib will have a better response by switching to dasatinib compared to staying on their original imatinib regimen.

Detailed description:

Arms: arm 1: Imatinib ≥400 mg tablets by mouth once daily (QD) or twice daily (BID) up to 60 months arm 2: Dasatinib 100 mg tablet by mouth QD up to 60 months
Interventions: intervention 1: Imatinib intervention 2: Dasatinib
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Official Title of Study:  
AN OPEN LABEL, RANDOMIZED (2:1) PHASE 2B STUDY OF DASATINIB VS IMATINIB IN 
PATIENTS WITH CHRONIC PHASE CHRONIC MYELOID LEUKEMIA WHO HAVE NOT ACHIEVED 
AN OPTIMAL RESPONSE TO 3 MONTHS OF THERAPY WITH 400 MG IMATINIB 
 
NCT Number: NCT01593254 
 
Document Date (Date in which document was last revised):  09-Mar-2018 




Clinical Protocol
CA180399
BMS-354825
Dasatinib
Revised Protocol No: 07
Date: 09-Mar-2018
2
confidence in the same manner as the contents of this document. Any person who receives 
this  document without  due  authorization  from  BMS  
is  requested  to  return  
it  to  BMS  or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to whom BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all  study personnel under your supervision, and archive the previous 
versions.
686
Draft 
930128686
0.2
v














Clinical Protocol
CA180399
BMS-354825
Dasatinib
SYNOPSIS
Clinical Protocol CA180399
Protocol Title: An open label, randomized (2:1) Phase 2B study  of dasatinib vs. imatinib in patients with chronic 
phase chronic myeloid leukemia who have not achieved an optimal response to 3 months of therapy with 400 mg 
imatinib
Investigational  Product(s),  Dose  and  Mode  of  Administration,  Duration  of  Treatment  with  Investigational 
Product(s):
Patients  
randomized  
to  
treatment  with  dasatinib  will  be  administered  dasatinib,  orally,  at  a  dose  of  100  mg  QD. 
Subjects may adjust the time they take dasatinib as long as they take the drug approximately every 24 hours. 
Patients randomized to treatment with imatinib will be administered imatinib, orally
, at a dose of ≥ 400 mg QD or
BID, depending on the dose chosen. 
600 mg dosing or every 
withdrawal of subject’s consent, the 
discontinue  
treatment,  
for  
reasons 
Patients  randomized  to  treatment  with 
switched to the treatment with dasatinib.
Study Phase: Phase 2b
Research Hypothesis:  This study proposes to test the hypothesis that patients with chronic phase chronic myeloid 
leukemia (CP-CML) with BCR-ABL transcript level >10% IS [International Standard] after 3 months of treatment 
with first-line imatinib 400mg will achieve a greater rate of major molecular response (MMR) by early switching to 
dasatinib  therapy  100 mg  QD  compared  with  continued  treatment  with  imatinib  at  any  dose  selected  by  the 
investigator.
Objective(s): The primary objective of the study is to compare the rate of MMR at 12 months after Day 1 initiation 
of  
first-line  
treatment  with imatinib  
in  patients  
randomized  at  month  3  
to  
treatment  with  dasatinib  100mg  QD  or
imatinib at any dose, after less than optimal response to first-line imatinib (BCR-ABL > 10% IS).
Secondary  objectives are to  compare  
the  
following  between  both  
treatment  arms: time  
to MMR;  
time  
to  MR4.5; 
Progression-free Survival (PFS); and Overall Survival (OS).
Revised Protocol No: 07
Date: 09-Mar-2018
9
693
Draft 
930128686
0.2
v




Clinical Protocol
CA180399
BMS-354825
Dasatinib
Statistical Considerations:
Sample Size:
This study  will test the hypothesis that patients with CP-CML  with less than one log BCR-ABL reduction (BCR-
ABL > 10% IS) after 3 months of treatment with first-line imatinib 400 mg will achieve a greater rate of MMR by 
early switching to dasatinib therapy 100 mg QD compared with staying  on  
imatinib  at  any  dose  selected  by  
the 
investigator.
MMR at 12 months after Day 1 initiation of first-line treatment with imatinib, in patients randomized at month 3 to 
treatment with dasatinib 100mg QD or imatinib at any dose is the primary endpoint in this study. The analysis will 
require the screening of approximately 860 subjects in order to randomize 258 subjects, 172 in dasatinib group and 
86  
in  
imatinib  group  under  
the  
following  design  assumptions  2:1  (dasatinib,  
imatinib)  
randomization  
ratio, (with 
randomization occurring no more than 8 weeks after the 3 month molecular analysis) 2-sided superiority test with 
α=0.05 and 90% power, and MMR at 12 months of 10% for imatinib and 25% for dasatinib.
Endpoints:
The primary
 endpoint is MMR at 12 months after Day 1 of first-line imatinib in patients randomized at month 3 to 
treatment with either dasatinib 100 mg QD or imatinib at any dose.
Secondary  endpoints  are  
time  
to  MMR,  
time  
to  molecular  
response (MR)
4 5progression  
free  survival (PFS),  and 
overall survival (OS).
Efficacy
All efficacy  analyses  will  be  performed  on  
the  dataset  of  
‘all randomized  subjects’ and  all  comparisons  between 
treatment arms will be carried out using two-sided α=0.05 level tests, unless specified otherwise.  
The primary endpoint analysis  will compare the MMR response rate achieved at 12 months from Day 1 treatment 
with  
first-line  
imatinib  between  dasatinib  and  
imatinib  arms  using the  Cochran-Mantel-Haenszel  
test  
stratified  by 
Sokal score (high, intermediate, low, and unknown) and time from molecular analysis to randomization (≤ 4 weeks 
vs > 4 weeks). The primary analysis will be performed on all randomized subjects. A 95% exact confidence interval 
(two-sided) for the difference in MMR rate at 12 months will be computed. 
Subjects who are crossed over after randomization to dasatinib will be considered non-responders for any response 
rate analysis. 
The  secondary  efficacy  endpoints  
include  
time  
to  MMR, time  
to  MR
4 5,  PFS,  and  OS.  
  These  endpoints  will  be 
tested hierarchically in the order listed.
Time to event endpoints will be estimated for each treatment group using Kaplan-Meier and Brookmeyer-Crowley 
methods. Time to event endpoints will be compared between the dasatinib group and imatinib group using a two-
sided  stratified  log-rank  test  with  Sokal  score  and  the  time  between  3  month  molecular  assessment  and 
randomization (≤ 4 weeks vs > 4 weeks) as the stratification factors.
Response rates for the tertiary
 endpoints listed above at each study visit and associated Clopper-Pearson two-sided 
95%  confidence  
intervals  will  be  estimated  
for  each  
treatment  group.   For  
the response rate  analyses,  any  subject 
Revised Protocol No: 07
Date: 09-Mar-2018
11
695
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
Safety: Descriptive statistics will be provided for safety data for all treated subjects.
The safety analysis  will report the frequency of all adverse events and the laboratory abnormalities, as well as the 
frequency  of  interruptions,  dose  reductions  and  treatment  discontinuation  for  toxicity.  Summary  tables  will  be 
presented by treatment arm.
Toxicity rates, using the worst CTC Grade per subject,  
for selected Grade 3 or above drug-related adverse events 
(e.g.,  fluid  retention,  pleural/pericardial  effusion,  congestive  heart  failure  (CHF),  cardiac  dysfunction,  rash, 
neutropenia, thrombocytopenia, anemia, leucopenia, AST, ALT, total bilirubin and dose reduction/interruption due 
to toxicity) will be compared between the two treatment arms using the Fisher exact test.
Adverse events occurring on or after Day 1 of receiving treatments and no later than 30 days following the last day 
of  
treatments  will  be  considered  on-study.  
  
In  
the absence  of  evidence  of  discontinuation  of  
therapy,  subjects are 
assumed to be still on-study.
In addition, the ECG analysis will report the frequency distributions of maximal QTc intervals (Fridericia) and the 
changes from baseline.
Revised Protocol No: 07
Date: 09-Mar-2018
12
696
Draft 
930128686
0.2
v




Draft 
930128686
0.2
v


















Clinical Protocol
CA180399
BMS-354825
Dasatinib
2.2 
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment  materials  (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator  Brochure  or  product 
labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports,  updates  and  other 
information (eg, expedited safety reports, amendments, and administrative  
letters) according to 
regulatory requirements or institution procedures.
2.3 
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
are  clearly  and  fully  informed  about  the  purpose,  potential  risks,  and  other  critical  issues 
regarding clinical studies in which the subject volunteers to participate. 
BMS  will  provide  
the  investigator  with  an  appropriate  (ie,  Global  or  Local)  sample  informed 
consent  
form  which  will  
include  all  elements  
required  by  
ICH,  GCP  and  applicable  
regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1. Provide  a  copy  of  the  consent  form  and  written  information  about  the  study  in  the
language in which the subject is most proficient prior to clinical study participation. The
language must be non-technical and easily understood.
2. Allow time necessary for subject or subject
's legally acceptable representative to inquire
about the details of the study.
3. Obtain  an  
informed  consent  
signed  and  personally  dated  by  
the  
subject  or the  
subject
's
legally acceptable representative and by the person who conducted the informed consent
discussion.
4. Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent
form and any other information to be provided to the subjects, prior to the beginning of
the study, and after any revisions are completed for new information.
5. If  
informed  consent  
is  
initially  given  by  a  
subject’s  
legally  acceptable  
representative  or
legal  guardian,  and  the  subject  subsequently  becomes  capable  of  making  and
communicating  his or her  
informed  consent during the study, consent  must additionally
be obtained from the subject.
6. Revise the informed consent whenever important new information becomes available that
is  relevant  to  the  subject
's  consent.  The  investigator,  or  a  person  designated  by  the
investigator,  should  fully  inform  the  subject  or  the  subject
's legally  acceptable
representative  or  legal  guardian,  of  all  pertinent  aspects of  the  study  and  of  any  new
Revised Protocol No: 07
Date: 09-Mar-2018
23
707
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
information  relevant  
to  
the  subject
's  willingness  to  continue  participation  
in  
the  study. 
This communication should be documented. 
The  confidentiality  of  records  that  could  identify  subjects  must  be  protected,  respecting  the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects
' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
shoul
y.
Please 
onal  information  regarding  the  BMS  Informed  Consent 
3
3.1
This 
prospective, multi-center, Phase 2b study conducted in 
patients with CP-CML who have achieved complete hematologic response (CHR) but who have 
more  
than 10%  IS  BCR-ABL  at  3  months  after  first-line  
treatment with  
imatinib  400mg  QD. 
Subjects will  be randomized to receive  either dasatinib 100mg QD or  
imatinib  with the option 
for dose increase following a standard of care approach.
10
Patients will sign the informed consent form before any screening assessment is conducted. The 
3- month molecular sample, part of the screening procedure required to establish eligibility, will 
be 
in  
the  central  
lab. Patients  
treated with  
imatinib  preceding  
the  3-month  molecular 
are considered the screened population. Screened patients 
ess after 3 months of imatinib 400 mg treatment are excluded fro
screen failures. The schematic for the study design 
Revised Protocol No: 07
Date: 09-Mar-2018
24
708
Draft 
930128686
0.2
v




CA180399
BMS
Dasatinib
24  mont
to  60  months,  then  annually according  to  the  schedule 
Subjects 
r a ma 
of 60 months after randomization of the last subject on 
the  assigned  regimen  (dasatinib  or  imatinib),  unless  disease  progression,  treatment  failure  or 
unacceptable toxicity occurs, the subject withdraws consent, or the study is discontinued by the 
sponsor.  This  means  
that  
the  first  randomized  subject  could  be treated  on  study  for  up  
to  84
months or more depending on the actual date of the last patient’s first visit (LPFV).
For patients who continue their assigned treatment beyond 24 months, safety assessments will be 
conducted  every  6  months up  to  60  months  then  annually and  cytogenetic  assessment
(conventional or FISH
y of CCyR) as specified in the 
An end of treatment visit is 
who remain on the study after 
Month 60 
sment has occurred within 
3 months of study close, th
 visit. 
All subjects will be followed 
and OS. Contact with subjects 
who discontinue study therapy 
treatment failure or intolerance 
to study medication will be maintained annually after the end-of-treatment visit until the subject 
dies, the subject is lost to follow-up, or the study data collection has ended.  The study will end 5 
years after the last patient’s first visit.
Once  a  subject  is  
taken  off  treatment,  study-related  
toxicities  will  be  followed  at  least  every 
4 weeks until resolved to baseline (or CTC Grade 1), stabilized, or deemed irreversible. 
3.2 
Post Study Access to Therapy
At  
the  end  of  
the  study,  BMS  will  not  continue  
to  supply  study drug  
to  subjects/investigators 
unless BMS chooses to extend the study. The investigator should ensure that the subject receives 
appropriate standard of care to treat the condition under study.
According  to  the  BMS  post-study  drug  policy,  subjects  who  have successfully  completed 
participation  in  this  trial  and  who  are  medically  stable  on  the  current  regimen  at  study 
completion  and  who  do  not  have  access  to  the  marketed  drug  (or are  unable  to  receive 
reimbursement through other means) may be eligible to continue to receive the medication they 
were  originally  assigned  in  the  trial.  No  switches  will  be  allowed.  Only  locally  marketed 
products will be provided. The drugs provided to a subject will be limited to the marketed drugs 
made available in the clinical trial in which the subject was treated.  
If  a  newer  
formulation  of
marketed product is not available, an earlier formulation will be provided. Safety monitoring and 
evaluation  will  be  the  sole  responsibility  of  the  investigator.  Prior  to  
the  termination  of  any 
subject, BMS will provide and discuss available options with the principal investigator. 
BMS will no longer provide drug if any of the following occurs:
Revised Protocol No: 07
Date: 09-Mar-2018
26
710
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
Subject  no  longer  benefits  medically  on  current  regimen,  as  determined  by  the 
investigator
Subject is able to receive financial reimbursement through other means
Subject expires
3.3 
Study Population
Any patient beginning first line imatinib therapy fulfilling inclusion criteria (other than criterion 
2a)  and  exclusion  criteria  can  be  considered  for  the  study.  Informed  consent  must  be  signed 
before  any  screening  assessments  are  conducted. The  3  month  molecular  
response  assessment 
will be performed at the central lab as part of the study screening procedures. Screened patients 
with a BCR-ABL transcript level of 10% IS or less after 3 months of imatinib 400 mg treatment 
will be excluded from the study.
For entry (randomization) into the study, all of the following criteria MUST be met. 
3.3.1 
Inclusion Criteria
1. Signed Written Informed Consent
a) Patient willing and able to give informed consent.
2. Target Population
a) CP-CML Ph+ patients with CHR but with BCR-ABL level >10% IS 3months  of
imatinib 400mg treatment. (Imatinib transient dose adjustments due to AEs are allowed
with a maximum of 2 weeks interruption of treatment with imatinib (cumulative) within 
the 3 month period before randomization). Imatinib monotherapy must have been started 
within 6 months of CP-
on). 
b) Currently  tolerating 
with prior  imatinib  treatment 
interruption or dose reducti
treatment with 400 mg imatinib for 
two weeks immediately pri
inib.
c) ECOG performance statu
d) Adequate renal functio
tutional upper limit 
of normal (ULN). 
e) Adequate  hepatic  function  defined  as:  
total  bilirubin  ≤2.0  
times  the  institutional  ULN; 
alanine  aminotransferase  (ALT)  and  aspartate  aminotransferase  (AST) ≤2.5 times the 
institutional ULN. 
f) Serum Na, K, Mg, and total serum Ca or ionized Ca levels must be greater than or equal 
to the institutional lower limit of normal. Subjects with low K or Mg levels, total serum 
Ca and/or ionized Ca can be repleted to allow for protocol entry. 
Rescreening is permitted in the event of temporary biochemical abnormalities.
Revised Protocol No: 07
Date: 09-Mar-2018
27
711
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
3. Age and Reproductive Status
a) Men and women, ages 18 years
b) Women  of  childbearing  potential  (WOCBP)  must  have  a  negative serum  or  urine 
pregnancy  test  (minimum  sensitivity  25  IU/L  or  equivalent  units  of  HCG)  within  24 
hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception starting at the 
time of enrollment for the duration of treatment with study drug (dasatinib or imatinib)/ 
plus  30  days  (duration  of  ovulatory  cycle)  for  a  total  of  30  days  post-treatment 
completion.
e) Men  who  are  sexually  active  with  WOCBP  must  agree  to  follow  instructions  for 
method(s)  of  contraception  
for  
the  duration  of  
treatment  with  
study  drug  
(dasatinib  or 
imatinib) plus 90 days (duration of sperm turnover) for a total of 90 days post-treatment 
completion.
f) Male subjects whose partners are WOCBP  must use condoms,  
including  male  subjects 
who  are  azoospermic.  WOCBP  who  are  continuously  not  heterosexually  active  are 
exempt  from  contraceptive  requirements  but  still  must  undergo  pregnancy  testing  as 
described in this section.
Investigators  shall  counsel  WOCBP  and  male  subjects  who  are  sexually  active  with
WOCBP on the importance of pregnancy prevention and the implications of an unexpected 
pregnancy  Investigators  shall  advise  WOCBP  and  male  subjects  who  are  sexually  active 
with  WOCBP  on  the  use  of  highly  effective  methods  of  contraception.  Highly  effective 
methods of contraception have a failure rate of < 1% per year when used consistently and 
At
hods  of  contraception,  with  one 
either  highly  effective  or  less 
effect
3.3.2
a)
b) Subjects with clonal evolution  
in Ph+ cells observed  
in ≥2  metaphases at baseline  bone 
marrow  cytogenetic  test,  unless  the  same  abnormalities  were  present  at  diagnosis. 
Patients with no evidence of clonal evolution, including those patients whose cytogenetic 
testing fails or bone marrow aspiration is a dry tap at 3 months, are eligible for the study.
c) Subjects with less than CHR after 3 months of imatinib treatment or lost CHR after initial 
achievement 
d) Documented  T315I/A,  F317L,  or  V299L  mutations  
(if  already  available  – not  
required 
for screening)
Revised Protocol No: 07
Date: 09-Mar-2018
28
712
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
2. Medical History and Concurrent Diseases  
a) A serious uncontrolled medical disorder or active infection that would impair the ability
i) Alt
on are excluded, subjects
with  chronic  or 
be enrolled  
if  
they  meet  all  other 
eligibility  criteria.  See 
ions  regarding  subjects  with
positive HBV serology.
b)
of the following:
i) Congest
nths 
ii) Diagnosed or suspected congenital long QT syndrome
iii) Any  history  of  significant  ventricular  arrhythmias;  for  example  ventricular 
tachycardia (VT), ventricular fibrillation (VF), and Torsade de Points (TdP). 
iv) Prolonged QTc interval on pre-entry electrocardiogram
v) Any  history  of  second  or  third  degree  heart  block  (may  be  eligible if the subject
currently has a pacemaker)
vi) Unstable  angina  within  3  months  which  belongs  to  the  spectrum  of  clinical 
presentation of Acute Coronary Syndrome (ACS) 
vii) Prior myocardial infarction within 6 months
viii) Uncontrolled  hypertension:  
inability to  maintain  blood pressure  below the upper 
limit of 140/90 mmHg.
c) Pulmonary arterial hypertension
d) Pleural  or  pericardial  effusions  of  any  grade  at  randomization  are  excluded.  Subjects 
previously diagnosed with pleural/pericardial effusion of any grade resolved at the time 
of randomization are allowed.
e) History of significant bleeding disorder unrelated to CML, including 
i) Diagnosed congenital bleeding disorders (eg, von Willebrand’s disease)
ii) Diagnosed acquired  bleeding disorder within one  year (eg, acquired anti-factor VIII 
antibodies)
f) Prior or concurrent malignancy, except for the following:
i) Curatively treated basal cell or squamous cell skin cancer
ii) Cervical carcinoma in situ
iii) Adequately  treated  Stage  I  or  II  cancer  from  which  the  subject  is  currently  in 
complete remission
iv) Any other cancer from which the subject has been disease free for 3 years
Revised Protocol No: 07
Date: 09-Mar-2018
29
713
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
3. Prohibited treatments and/or other treatments
a) Subject with any anti-CML other than imatinib (except HU or anagralide) 
b)
c) Pri
bilization.  (Prior  collection  of
d)
to  have a  risk  of  causing 
4.
a) Subjects intolerant to imatinib 400mg QD prior to enrollment.
b) Subjects  with  known  hypersensitivity  to  excipients  of  dasatinib tablets (Tablet core: 
lactose  monohydrate,  microcrystalline  cellulose,  croscarmellose  sodium;  hydroxypropyl 
cellulose,  magnesium  stearate;  Film-coating:  hypromellose  titanium  dioxide  macrogol 
400).
5. Sex and Reproductive Status
a) Patients who are pregnant or breastfeeding or likely to become pregnant.
b) Men whose partner is unwilling or unable to avoid pregnancy.
6) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated 
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3 
Women of Childbearing Potential
A  women  of  childbearing  potential  (WOCBP)  is  defined  as  any  female  who  has  experienced 
menarche  and  who  has  not  undergone  surgical  sterilization  (hysterectomy  or  bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a  woman  over  age  45  years  in  the  absence  of  other  biological  or  physiological  causes.  In 
addition,  women  under  the  age  of  55  years  must  have  a  serum  follicle  stimulating  hormone, 
(FSH) level > 40mIU/mL to confirm menopause.*
*Women  treated  with  hormone  replacement  therapy,  (HRT)  are  likely  to  have  artificially 
suppressed  FSH  
levels and  may require a washout period  
in order to obtain a physiologic  FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the  washout  period  below  are  suggested  guidelines  and  the  investigators  should use  their 
judgment  in  checking  serum  FSH levels.  If  
the  serum  FSH  level  is  >40  mIU/ml  at  any  
time 
during the washout period, the woman can be considered postmenopausal:
Revised Protocol No: 07
Date: 09-Mar-2018
30
714
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
1 week minimum for vaginal hormonal products (rings, creams, gels)
4 week minimum for transdermal products
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4 
Concomitant Treatments
3.4.1 
Prohibited and/or Restricted Treatments
No other therapy for the treatment of CML with the exception ofHU or anagrelide  
is allowed. 
HU and anagrelide to treat clinically significant leukocytosis and thrombocytosis as determined 
by  the  treating  physician  will  be  permitted  while  the  subject  is  on  study.  The  use  of  HU  or 
anagrelide or any colony stimulating factors must be clearly documented in the CRF.
Medications associated with QT interval prolongation that are prohibited on this study include:
quinidine, procainamide, disopyramide
amiodarone, sotalol, ibutilide, dofetilide
erythromycins, clarithromycin
chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide
cisapride,  bepridil,  droperidol,  methadone,  arsenic,  chloroquine,  domperidone, 
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine. 
Refer to http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.html  
for a comprehensive list 
of drugs which may cause QTc prolongation and Torsade De Pointes.  Patients  are  prohibited 
from taking medications listed in the Known Risk of Torsade de Pointes Category.
ns
required  to  take  medications  that  inhibit  platelet
et agents or anticoagulants should be avoided in the setting 
  should  not  begin  taking  other  medications  known  to 
of medications known to prolong the QT interval is found 
the  investigator  believe  that  beginning  therapy  with  a
potentia
individual 
Caution 
a  list 
Additionally,  strong  to  moderate  CYP3A4  inhibitors  (eg,  ketoconazole,  itraconazole,
erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
Revised Protocol No: 07
Date: 09-Mar-2018
31
715
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
telithromycin)  may  significantly  increase  concentrations  of  dasatinib  and  should  be  used  with
caution when administered concurrently with dasatinib or imatinib. Strong to moderate CYP3A4 
ri
the  concentration 
th
with  dasatinib 
subjects  
should  
try  
to 
agents  may  be 
-
might  
increase the 
undergoing surgical procedures, including dental procedures, should be instructed to inform their 
doctors of this potential increased risk
Hydroxyurea/Anagrelide/Hematopoietic Growth Factors:
The  use  of  hydroxyurea  
to  keep  
the  WBC  <50,000/mm3is  permitted.  Anagrelide  may  also  be 
administered  to  control  platelet  counts  (>1,000,000/mm
3)  at  the  investigator’s  discretion.  No 
other  anti-cancer  agents  including  chemotherapy,  radiation  therapy  and  anti-cancer  biologic 
agents are permitted during this trial. Use of G-CSF, GM-CSF, erythropoietin or darbepoetin is 
allowed on study.
3.5 
Discontinuation of Subjects from Treatment
Subjects MUST discontinue study treatment for any of the following reasons:
Withdrawal of informed consent (subject’s decision to withdraw for any reason)
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in 
th
inued participation in the study is not in 
th
-Myers Squibb (BMS)
provide  consent  through  imprisonment  or  involuntary 
of  either  a  psychiatric  or  physical  (eg,  infectious  disease) 
In  e  
on o e 
ion  
in the  study  
is  not in the best
interest of the subject 
QTcF value >530 msec
If  pulmonary  arterial 
  drug  should  be  permanently 
discontinued.
Disease  progression  (as 
or  treatment  failure  despite  dose 
escalation
Revised Protocol No: 07
Date: 09-Mar-2018
32
716
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
Note: Patients who are in treatment failure (per ELN 2013) on imatinib therapy at any time 
point  during  the  treatment  will  be  crossed-over  to  the  dasatinib  arm  unless  they  harbor 
dasatinib resistant mutations.
All 
  with  protocol  specified  
follow-up 
this  
requirement  
is  when  a  subject 
withdraws 
ability  to  consent  freely  (i.e.,  is 
of  either  a  psychiatric  or  physical 
illness).
If  a 
e  reason  for withdrawal  must  be 
3.6 
Post Treatment Study Follow up
In  
this  study,  progression  and  overall  survival  are  key  endpoints  of  
the  study.  Post  
treatment 
study  follow-up  is  of  critical  importance  and  is  essential  
to  preserving  subject  safety  and  
the 
integrity of the study. Subjects who discontinue study treatment must continue to be followed for 
collection of outcome and/or survival follow-up data as required and in line with Section 5 until 
death or the conclusion of the study.
3.6.1 
Withdrawal of Consent
Subjects who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision  to  withdraw  consent  from  future  follow-up  in  writing,  whenever  possible.  The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to  whether  
the  withdrawal is  from  further  
treatment  with  study  drug  only  or  also  from  study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the  event  that  vital  status  (whether  the  subject  is  alive  or  dead)  is  being  measured,  publicly 
available  
information should  be used to determine vital  
status only  as appropriately directed  
in 
accordance with local law.
3.6.2 
Lost to Follow-Up
All  reasonable  efforts  must  be  made  
to  
locate  subjects  
to  determine  and  report  
their  ongoing 
status.  This  
includes follow-up  with  persons  authorized  by  
the  subject  as  noted  above.  Lost  
to 
follow-up  
is defined  by the  
inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If  the  investigator’s  use  of  third-party  representative  to  assist  in  the  follow-up  portion  of  the 
study  has  been  included  in  the  subject’s  informed  consent,  then  the  investigator  may  use  a 
Sponsor-retained  third-party  representative  to  assist  site  staff  with  obtaining  subject’s  contact 
information or other public  vital status data necessary to complete the  
follow-up portion of the 
Revised Protocol No: 07
Date: 09-Mar-2018
33
717
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
study.  The  site  staff  and  
representative  will  consult  publicly available  sources,  such  as  public 
health  registries  and  databases,  in  order  to  obtain  updated  contact  information.  If  after  all 
attempts, the subject remains lost to follow-up, then the last 
the invest
4 
TREATMENTS
All protocol-specified investigational produc
Revised Protocol No: 07
Date: 09-Mar-2018
34
718
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
4.1 
Study Treatments
Table 4.1: 
Product Description 
Product Description 
and Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Appearance
Storage Conditions
(per label)
Dasatinib
20 mg, 50 mg, 80 mg, 
100 mg and 140 mg
Various packaging 
configurations
Open label
Not applicable
White to off-white, 
biconvex, film-coated 
tablets
Refer to label on 
container or
package insert/
summary of product 
characteristics
Imatinib
100 mg, 400 mg
Various packaging 
configurations
Open label
Not applicable
Very dark yellow to 
brownish orange, film-
coated tablets
Refer to label on 
container or
package insert/
summary of product 
characteristics.
Revised Protocol No: 07
Date: 09-Mar-2018
35
719
Draft
930128686
0.2
v




Clinical Protocol
CA180399
BMS-354825
Dasatinib
The  permuted  block  randomization  procedure  will 
treatment 
arms within each of the following stratification 
or Unknown) and time between 3-month mo
vs >4 
weeks).
The study will be open for enrollment until the planned number of 258 subjects are randomized: 
172 in dasatinib arm and 86 in imatinib arm. 
Randomization will be stratified by:
1. 
Sokal score: High, Intermediate, Low, or Unknown 
2. 
Time between 3 month molecular assessment and randomization: 
(≤ 4 weeks vs > 4 weeks).
Specific instructions for the central enrollment and randomization procedures will be provided to 
the sites in a separate procedure manual. Only authorized personnel will be granted access to the 
telephone  system.  Prior  to  calling  the  IVRS  for  each  subject,  an  Enrollment  Information 
Worksheet should be completed, and a copy of the worksheet should be at hand. It is the 
responsibility  of  the  investigator  to  ensure  that  the  subject  is  eligible  for  the  study  before 
enrolling/registering the subject via IVRS. The following information will be required when the 
phone call is placed to the central enrollment center:
At enrollment:
1) Callers  User  ID  (identification)  and  PIN  (personal  identification  number),  which  are 
assigned to each authorized investigational site staff member by the IVRS vendor
2) Subject’s date of birth and gender
At randomization:
3) Sokal score (refer to below) 
4) Time between 3 month molecular assessment and randomization.
The  
information  provided  by  
the  
IVRS  will  consist  of  a  unique  
identification  number  
(subject 
number)  at  enrollment  and  assigned  
treatment  at  
randomization.  The subject number must be 
used on all further documentation and correspondence, including CRFs. 
The Sokal Score is calculated using the following formula, with data from the period of original 
diagnosis of CML and prior to the subject receiving any treatment for CML:
Score  =  Exp  0.0116  X  (age  in  years  – 43.4)  +  0.0345  X  (spleen  in cm below costal margin 
(maximum distance) – 7.51) + 0.188 X [(platelet count / 700)2- 0.563] + 0.0887 X (blast cells 
(in percent) – 2.10)
Revised Protocol No: 07
Date: 09-Mar-2018
37
721
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
Score
Risk Category
Score < 0.8 
Low risk
0.8 – 1.2
Intermediate risk
Score > 1.2 
High risk
Score Unknown:  
Unknown
4.3 
Selection and Timing of Dose for Each Subject
Dasatinib
Dasatinib will be administered orally at a dose of 100mg QD. Subjects may adjust the time they 
take dasatinib as lo
Subjects will be treated with dasatinib until disease 
toxicity,  the  investigator  and  the  subject  feel  that  it  is  in 
discontinue  
treatment,  withdrawal  of  subject’s  consent,  
for 
until a maximum of 60 months from th
Imatinib
Imatinib  will  be  administered  orally  at  a  dose  of 400mg 
chosen.  Each  dose  should  be  administered  with  a  meal  and  
taken with a large glass of water. 
Subjects may adjust the time they take imatinib as long as they take the drug every 24 hours for 
400mg  and  600mg  dosing  or  every  12  hours  for  400mg  BID  dosing  and  follow  instructions 
regarding meals. 
Subjects will  be treated with  
imatinib until disease progression, treatment  
failure, unacceptable 
toxicity, the investigator and the subject feel that it is in the  best  interest  of  the  subject  to 
discontinue  
treatment,  withdrawal  of  subject’s  consent  for  reasons  outlined  in  Section  3.5,  or 
until a maximum of 60 months from the randomization of the last patient.
4.3.1 
Dose Modifications
According to the response and the toxicity, dose modifications will  
follow the standard of care 
recommendations. 
Imatinib  doses  below  400mg  are  not  recommended  in  this  protocol  unless  considered by  the 
investigator as in the best interest of the patient.
Dasatinib  doses  below  50mg  are  not  recommended  in  this 
investigator as in the best interest of the patient.
Dosing above 180mg QD of dasatinib or 800mg/day of imat
4.3.2 
Dose Escalation Guidelines
Dose escalation for less than optimal response (according 
permitted in both arms unless intolerance is encountered.
Revised Protocol No: 07
Date: 09-Mar-2018
38
722
Draft 
930128686
0.2
v


CA180399
BMS
Dasatinib
4.3.2.1
For  
hematologic  or  non-hematologic 
toxicities 
may be re-escalated to 100mg QD, 
if at 
ogic toxicities, (b) 
there is 
reduction, and (c) there are no 
additional
For
or  
treatment  failure  (according  
to 
ELN
increased to 140mg QD provided 
that (a) th
ere  
is  no recurrence of the toxicity 
which  led  
e 
on,  
ere  are  no  
tional grade  2  non-hematologic 
toxicities.
4.3.2.2 Imatinib
Doses greater than 600mg are not recommended in patients with mild renal impairment (CrCL = 
40 - 59 mL/min). For patients with  moderate renal  
impairment (CrCL = 20 - 39 mL/min), doses 
greater than 400mg are not recommended. Imatinib should be used with caution  
in patients with 
severe renal impairment.
For  subjects  dose-reduced  
to  a  
lower  dose  of  
imatinib  due  
to  hematologic  or  non-hematologic 
toxicities as described in Section 4.3.3, the dose of imatinib may be increased to the initial dose 
if at least 1 month after the dose reduction: (a) there are no Grade 3/4 hematologic toxicities, (b) 
there  is  no  recurrence  of  the  toxicity  which  led  to  the  dose  reduction,  and  (c)  there  are  no 
additional Grade 2 non-hematologic toxicities. 
For subjects at the randomization dose of imatinib with less than optimal response but not in the 
failure  category  (according  to  ELN  2013  criteria  [Appendix  8]),  the  imatinib  dose  may  be 
increased to a maximum of 800mg provided that (a) there are no Grade  3/4  hematologic 
toxicities, (b) there is no recurrence of the toxicity which led to the dose reduction, and (c) there 
are no additional grade 2 non-hematologic toxicities
4.3.3 
Dose Reduction Guidelines
The Dose Reduction Guidelines for imatinib and dasatinib are summarized in Table 4.3.3.
Dose  interruptions  or  reductions  for  dasatinib- or  imatinib-related  adverse  events  (possibly, 
probably  or  certainly  related)  are  described  in  Table  4.3.3.  For  an  individual  subject,  dose 
interruptions,  
reductions  and  
treatment  discontinuation  may  be more  or  less  conservative  
than 
indicated below based on the clinical judgment of the investigator.
Revised Protocol No: 07
Date: 09-Mar-2018
39
723
Draft 
930128686
0.2
v






Clinical Protocol
CA180399
BMS-354825
Dasatinib
4.4 
Blinding/Unblinding
Not applicable.
4.5 
Treatment Adherence
Patient adherence  will  be  evaluated  through  a  patient-reported  questionnaire.  The  Morisky 
Medication  Adherence  Scale-8  items, (MMAS-8), is  a  validated  self-reported  measure  of
medication  adherence.  The  scale  is  a  commonly  used  adherence  tool  composed  of  yes/no 
questions  about  past  medication  use,  and  it  is  simple  to  use.  Each  item  measures  a  specific 
medication-taking  behavior.  Response  categories  are  yes/no  
for each  
item  with  a  dichotomous 
response and a 5-point Likert response for the last item.  Patients with higher scores are predicted 
to be more adherent to prescribed therapies, while patients with lower scores are at greater risk 
for nonadherent behavior.
4.6 
Destruction and Return of Study Drug
4.6.1 
Destruction of Study Drug
For  this  study,  study  drugs  (those  supplied  by  BMS  or  sourced  by  the  investigator)  such  as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any  unused  study  drugs  can  only  be  destroyed  after  being  inspected  and  reconciled  by  the 
responsible  Study  Monitor  unless  study  drug  containers  must  be immediately  destroyed  as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:
On-site disposal practices must not expose humans to risks from
 the drug.
On-site  disposal  practices  and  procedures  are  in  agreement  with  applicable  laws  and 
regulations, including any special requirements for controlled or hazardous substances.
Written procedures for on-site disposal are available and followed. The procedures must 
be filed with the site’s SOPs and a copy provided to BMS upon request.
Records  are  maintained  
that  allow  
for  
traceability  of  each  container,  
including  
the  date 
disposed of, quantity disposed, and identification of the person disposing the containers. 
The  method  of  disposal,  ie,  incinerator,  licensed  sanitary  landfill,  or  licensed  waste 
disposal vendor must be documented.
Accountability  and  disposal  records  are  complete,  up-to-date,  and  available  for  the 
Monitor to review throughout the clinical trial period.
If  conditions  for  destruction  cannot  be  met  the  responsible  Study  Monitor  will  make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
Revised Protocol No: 07
Date: 09-Mar-2018
42
726
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
5 
STUDY ASSESSMENTS AND PROCEDURES
5.1 
Flow Chart/Time and Events Schedule 
Table 5.1A: 
Screening Procedural Outline (CA180399)
Procedure
Screening Visit 
Visit 1 
(Randomization)
Notes
Randomization may occur up to 8 weeks after the 
screening molecular analysis. 
Eligibility Assessments
Eligibility assessments may be conducted prior to the 
screening molecular analysis. 
Informed Consent
X
Inclusion/Exclusion Criteria
X
Medical History
X
Serology for Hepatitis B virus 
X
Hepatitis B surface antigen (HBsAg) and antibody to
Hepatitis B core antigen (also known as total hepatitis B
core antibody; anti-HBc). Hepatitis B serologic testing 
to be conducted at any time during screening or at 
Visit 1. HBV testing results within 1 year prior to Visit 1 
are permitted.
For subjects randomized and treated prior to 
Amendment 07 (ie, incorporation of HBV serology test), 
a HBV serology test has to be performed once, if HBV 
testing was not conducted within 1 year prior to 
randomization. 
Pregnancy test
X
Revised Protocol No: 07
Date: 09-Mar-2018
43
727
Draft
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
Table 5.1A: 
Screening Procedural Outline (CA180399)
Procedure
Screening Visit 
Visit 1 
(Randomization)
Notes
Randomization may occur up to 8 weeks after the 
screening molecular analysis. 
Review Contraception Requirements 
X
Mutational analysis
X
Safety Assessments
Physical Examination, vital signs and 
performance status
X
Assessment of signs and symptoms
X
Concomitant medications
X
Adverse Events Assessment
X
ECG
X
ECGs at baseline (screening), then as clinically 
indicated 
Echocardiogram
X
Serum chemistry
X
Obtained within 72 hours prior to randomization.
Chest X-ray
X
Efficacy-Laboratory Tests
CBC with diff, platelets
X
Obtained within 72 hours prior to randomization.
Cytogenetics 
X
Conventional cytogenetic assessment required at 
screening to ensure absence of clonal evolution. 
Molecular analysis (Q-PCR)
X
Screening molecular analysis by Q-PCR will be 
Revised Protocol No: 07
Date: 09-Mar-2018
44
728
Draft
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
Table 5.1A: 
Screening Procedural Outline (CA180399)
Procedure
Screening Visit 
Visit 1 
(Randomization)
Notes
Randomization may occur up to 8 weeks after the 
screening molecular analysis. 
performed 3 months (1 month = 30 days) (+/- 2 weeks) 
after first dose of imatinib.  Q-PCR will be performed 
in a centralized lab.
Morisky Medication Adherence Scale
X
Clinical Drug Supplies
Randomize
Dispense/prescribe study drugs 
X
X
Those supplied by the sponsor or sourced by the 
investigator 
Revised Protocol No: 07
Date: 09-Mar-2018
45
729
Draft
930128686
0.2
v














Clinical Protocol
CA180399
BMS-354825
Dasatinib
Table 5.1C: 
Procedural Outline Months 30 - Study Close/End of Treatment (CA180-399) 
Procedure
Treatment Period
End of 
Treatmentb
or at the 
study close 
(60 months 
after LPFV)
Notes
All time-points calculated from Day 
1 of first-line tx w/imatinib or from 
Day 1 of tx w/dasatinib for cross-
over patients. 
All visits are  ± 10 days
The study will continue up to 60 
months after the last patient, first 
visit. 
End of treatment visit is required 
for all patients. 
Months
30, 36, 42, 48, 54, 60
Month 72a
and yearly until the study close
Safety Assessments
Physical Examination, 
vital signs and 
performance status
X
X
X
Assessment of signs
and symptoms
X
X
Adverse Events 
Assessment
X
X
Concomitant medications
X
X
ECG
initiation if ≥ 2 months have 
elapsed since the most recent ECG 
and echocardiogram.
Revised Protocol No: 07
Date: 09-Mar-2018
52
736
Draft
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
Table 5.1C: 
Procedural Outline Months 30 - Study Close/End of Treatment (CA180-399) 
Procedure
Treatment Period
End of 
Treatmentb
or at the 
study close 
(60 months 
after LPFV)
Notes
All time-points calculated from Day 
1 of first-line tx w/imatinib or from 
Day 1 of tx w/dasatinib for cross-
over patients. 
All visits are  ± 10 days
The study will continue up to 60 
months after the last patient, first 
visit. 
End of treatment visit is required 
for all patients. 
Months
30, 36, 42, 48, 54, 60
Month 72a
and yearly until the study close
Pregnancy Test
Monthly
Monthly
X
For WOCPB, a pregnancy test 
must be performed monthly. When 
a monthly study visit is not 
required, a home pregnancy test 
must be performed, and the results 
Review Contraception 
Requirements 
At every study visit 
At every
 study visit
Echocardiogram 
since the most recent ECG and 
echocardiogram.
Chest X-Ray
As clinically indicated
Serum chemistry
X
X
X
Revised Protocol No: 07
Date: 09-Mar-2018
53
737
Draft
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
Table 5.1C: 
Procedural Outline Months 30 - Study Close/End of Treatment (CA180-399) 
Procedure
Treatment Period
End of 
Treatmentb
or at the 
study close 
(60 months 
after LPFV)
Notes
All time-points calculated from Day 
1 of first-line tx w/imatinib or from 
Day 1 of tx w/dasatinib for cross-
over patients. 
All visits are  ± 10 days
The study will continue up to 60 
months after the last patient, first 
visit. 
End of treatment visit is required 
for all patients. 
Months
30, 36, 42, 48, 54, 60
Month 72a
and yearly until the study close
Efficacy Assessments
CBC w diff, platelets
X
X
X
Cytogenetics (Conventional or 
FISH [peripheral blood])
X
X
X
Conventional cytogenetics are 
recommended until CCyR is 
achieved and confirmed.  FISH-PB
is allowed as a substitute for 
conventional assessment, especially 
after CCyR is achieved, to confirm 
the durability of response.
Molecular analysis/Q-PCR
X
X
X
Q-PCR labs will be performed in a 
centralized lab and expressed on an 
international scale. For patients not 
in MMR at month 24, molecular 
analysis by Q-PCR will continue to 
be performed every 3 months until 
MMR is achieved.
Mutational analysis 
X
X
X
Samples for mutational analysis 
will be drawn at screening and 
every 3 months through month 24, 
every 6 months from month 24 until 
the end of study, and then stored. 
Samples can also be drawn at an 
Revised Protocol No: 07
Date: 09-Mar-2018
54
738
Draft
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
Table 5.1C: 
Procedural Outline Months 30 - Study Close/End of Treatment (CA180-399) 
Procedure
Treatment Period
End of 
Treatmentb
or at the 
study close 
(60 months 
after LPFV)
Notes
All time-points calculated from Day 
1 of first-line tx w/imatinib or from 
Day 1 of tx w/dasatinib for cross-
over patients. 
All visits are  ± 10 days
The study will continue up to 60 
months after the last patient, first 
visit. 
End of treatment visit is required 
for all patients. 
Months
30, 36, 42, 48, 54, 60
Month 72a
and yearly until the study close
unscheduled visit if the clinical 
status triggers an unscheduled visit.  
Mutational analysis will be 
performed on stored samples, at 
time of any suboptimal response, 
treatment failure, progression, at 
the end of treatment or prior to any 
change in therapy.
Dispense/prescribe Study Drug
X
Morisky Medication Adherence 
Scale (MMAS-8)
X
X
aPatients who remain  on the study after Month 60 
(60 months after LPFV). If the yearly assessment has 
b Survival Follow-up: In addition to the End-of-
at the end of study close, contact with subjects for su
who discontinue before the end of the study) will be 
maintained annually (±14 days) after the End-of-T
overall survival information,  until the subject dies, the 
subject is lost to follow-
study assessments until discontinuation or progression as 
the visit schedule must start at Day 1 defined as the day of 
55
739


Clinical Protocol
CA180399
BMS-354825
Dasatinib
5.2 
Study Materials
Special  materials  
that  are  needed  for  
this  
trial  are  a  12-lead ECG  machine,  centrifuge  and  a  
-
20°C or -70°C freezer. Home pregnancy tests and Pregnancy Testing Logs will be furnished by 
the Sponsor.
5.3 
Safety Assessments
Signs  and  symptoms  present  within 2  weeks  of  starting  
therapy  (regardless  of  relationship  
to 
current disease)  will  be obtained at baseline (screening). Study drug toxicities will  be  assessed 
continuously. Adverse events will be evaluated according to the NCI CTCAE Version 4.0.
A  physical  examination  (including  assessment  of  spleen  and  liver  size),  weight,  performance 
status and  vital signs, and concomitant  medications, will  be conducted at screening, during the 
treatment period at Months 4 or 5, and 6, and then every 3 months until Month 24. From Month 
24 to Month 60, safety assessments will be obtained every 6 months, and after Month 60, safety 
assessments will be done annually, until disease progression or discontinuation of study therapy 
and at the end-of-treatment visit.
Chest  X-Rays  will  be  performed  at  baseline  
(screening),  and  as clinically  
indicated  
throughout 
the study. 
A 12-
indicated. Additional ECGs will  be done at the 
subject’s 
safety and  
in  case of  non-study drug treatment  modificatio
onging 
medication (other than the ones explicitly prohibited; refer to 
For pati
be 
iation if ≥ 2 months has elapsed since the most recent ECG 
and 
nt crosses over, s/he starts a second line treatment and the 
visit 
sit schedules for crossover patients will be calculated from 
the date 
(Day 1) and  assessments at Month 3, Month 6.  Month 12, 
etc, 
calculated  
from that date.  Patients who cross over will  be 
followed 
24 months, and every 6 months up to 60 months and then 
annually
Table 5.1B.
Once  a  
subject  
is  
taken  off  
treatment,  
study-related  
toxicities  will  be  
followed  at  
least  every  4
weeks until resolved to baseline (or CTC Grade 1), stabilized, or deemed irreversible. 
HBV Serology
Although  subjects  with  acute  hepatitis  B  virus  (HBV)  infection are  excluded,  subjects  with 
chronic or resolved hepatitis B infection may be enrolled as long as they meet all other eligibility 
criteria.
Consultation with a physician with expertise in the treatment of  HBV  is  recommended  for 
subjects who test positive for HBV serology. Subjects who are carriers of HBV should be closely 
Revised Protocol No: 07
Date: 09-Mar-2018
56
740
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
monitored for clinical and laboratory signs of active HBV infection throughout therapy and for 
several  months  
following termination of therapy.  
In subjects who develop reactivation of HBV 
while receiving dasatinib, prompt consultation with a physician with expertise in the treatment of
HBV is recommended.
5.3.1 
Safety endpoints
5.3.1.1 
Definition of Intolerance 
Intolerance of treatment is defined as recurrent Grade 3 hematologic toxicity or Grade 2 non-
hematologic  toxicity  despite  dose  reduction  necessitating  discontinuation  of  protocol  therapy. 
Adverse events and other symptoms will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
5.3.1.2 
Safety/Toxicity
Toxic effects will be assessed continuously. Safety and tolerability for both treatment groups will 
be reported for all treated subjects. Adverse events and other symptoms will be graded according 
to the NCI CTCAE version 4.0. Number of dose interruptions, dose  reductions  and  
treatment 
discontinuations for drug-related toxicity will be analyzed.
5.4 
Efficacy Assessments
For the assessment of efficacy, CBC with differential and PLT count, cytogenetics and molecular 
analysis/Q-PCR  will  be  conducted  at  baseline (screening).  During  the  treatment  period, 
hematology and molecular analysis/QPCR will be conducted at Months 4 or 5, Month 6 and then 
every 3 months until Month 24, and every 6 months up to 60 months, then annually until the end 
of the study. For patients not in MMR at Month 24, molecular analysis by Q-PCR will continue 
to be performed every 3 months until MMR is achieved.
For  patients  who  cross  over  to  dasatinib a  CBC  with  differential  will  be  done  at  2  weeks, 
hematology  and  molecular  analysis/QPCR  will  be  conducted  at  Month 3  from  the  date  of 
crossover, and then every 3 months until Month 24, and every 6 months thereafter until the end 
of the study.
Cytogenetics (conventional or FISH-PB peripheral blood) will be conducted at Month 6 and 12, 
every 6 months until CCyR and then annually. Conventional cytogenetics are recommended until 
CCyR  is  achieved  and  confirmed.    FISH-PB  peripheral  blood is  allowed  as  a  substitute  for 
conventional  assessment,  especially  after  CCyR  is  achieved,  to confirm  the  durability  of
response.  Samples  for  mutational  analysis  will  be  drawn  at  screening  and  every  3  months 
through month 24, every 6 months from month 24 up to 60 months, then annually until the end 
of the study, and then stored. Mutational analysis will be performed on stored samples, at time of 
any  suboptimal response, treatment  
failure, progression, at the end of treatment or prior to any 
change in therapy. Samples for mutational analysis can also be drawn at an unscheduled visit if 
the clinical status triggers an unscheduled visit. 
Revised Protocol No: 07
Date: 09-Mar-2018
57
741
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
5.4.1 
Efficacy Endpoints
Efficacy endpoints will be 
5.4.1.1
A complete hematologic response 
are  met  
in 
peripheral blood (PB) sampling:
WBC ≤10,000/mm3
Platelets <450,000/mm3
Peripheral bl
No blasts or promyelocytes in peripheral blood
<5% myelocytes plus metamyelocytes in peripheral blood
No extramedullary involvement (including no hepatomegaly or splenomegaly).
5.4.1.2 
Definition of Cytogenetic Response
Cytogenetic  response  (CyR)  is  based  on  the  prevalence  of  Ph+  cells  in  metaphase  from  BM 
sample. 
The criteria for evaluation of CyR are as follows:
Complete Cytogenetic Response (CCyR):  0% Ph+ cells in metaphase in BM
Partial Cytogenetic Response (PCyR):  1 to 35% Ph+ cells in metaphase in BM
Minor Cytogenetic Response:  36 to 65% Ph+ cells in metaphase in BM
Minimal Cytogenetic Response:  66 to 95% Ph+ cells in metaphase in BM
No Cytogenetic Response:  96 to 100% Ph+ cells in metaphase in BM
Major Cytogenetic Response (MCyR) is defined as CCyR plus PCyR
5.4.1.3 
Definition of Molecular Response
Molecular  response  will  be  assessed  using  BCR-ABL  transcript  levels  measurement  by 
RQ-PCR.
An  MMR  is  defined  according  to the  recommendations  of  Hughes  et al.
5 The  standardized 
baseline,  as  established  
in  
the  
IRIS  
trial,  
is  
taken  
to  
represent  100% on the  
international  scale, 
and a 3-log reduction in BCR-ABL transcripts from the standardized baseline (MMR) is fixed at 
0.1%. The ratio BCR-ABL/ABL or BCR is independent of the used control-gene. In this study, 
ABL or other housekeeping gene, will be used as the control-gene.
An  MR4,5will  be defined  as  a 4.5-log reduction  
in BCR-ABL  
transcript  
from the standardized 
baseline  (0.0032%  IS,  either  detectable  disease 0.0032%  BRC-ABL  (IS)  or  undetectable 
Revised Protocol No: 07
Date: 09-Mar-2018
58
742
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
disease in cDNA (in same volume used for BCR-ABL) with 32,000 ABL transcripts. An MR4
will  be  defined  as  a  4-log  reduction  in  BCR-ABL  transcript  from  the  standardized  baseline 
(either  detectable  disease 0.01% BCR-ABL (IS) or undetectable disease in cDNA (in same 
volume used for BCR-ABL) with 10,000 ABL transcripts.
The rate of MMR at 12 months is defined as the proportion of subjects who achieved an MMR at 
12  months  (primary  endpoint)  after  Day  1  initiation  of  first-line  treatment  with  imatinib,  in 
patients randomized at month 3 to treatment with dasatinib 100mg QD or imatinib at any dose. 
Further assessments of MMR and other levels of molecular response rates will occur at various 
timepoints (refer to study assessments).
5.4.1.4 
Time to Molecular Response 
A subject’s time to MMR is defined as the time from the randomization date until measurement
criteria are first met for MMR. 
5.4.2 
Definition of Progression
5.4.2.1 
Progression on Study Therapy
Any  of the  
following  events  occurring  while  a  subject  
is  continuously  on  study  
therapy  would 
define  progression.  Subjects  should  be  on  
the  maximum 
investigator) before criteria for progression are considered.
Criteria for accelerated or blast crisis CML are met 
criteria).
Death from any cause during treatment.
The date of progression will  be defined  as the date when 
Subjects meeting any criterion for progression will be removed from protocol therapy.
Note:  Loss  of  a  previously  achieved  hematologic  or  cytogenetic response  is  considered  a 
treatment failure, not disease progression. 
5.4.2.2 
Failure to First-line Treatment 
Treatment failure to first-line therapy is defined as: 
1. Any of the disease progression parameters above
2. At 3 months: less than complete hematologic response (These subjects will not be eligible 
for randomization) and/or No CyR (Ph+ >95%)
3. At 6 months:  BCR-ABL >10% and/or Less than PCyR (Ph+ >35%)
4. At 12 months:  BCR-ABL >1% and/or Less than CCyR (Ph+ >0%)
5. At  any  
time  during  
treatment,  
loss  of  CHR  or  CCyR;  Confirmed loss  of  MMR  (In  
two 
consecutive  tests,  of  which  one  with  a  BCR-ABL1  transcripts  level  ≥ 1%),  BCR-ABL1 
kinase domain mutations poorly sensitive to imatinib; newly emerging CCA/Ph+  
Note: Patients failing imatinib therapy at any time point will be crossed-over to the dasatinib arm 
unless they harbor dasatinib-resistant mutations.
Revised Protocol No: 07
Date: 09-Mar-2018
59
743
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
5.4.2.3 
Overall Survival
Overall survival (OS) is defined as the time between randomization date and death date.  
5.5 
Pharmacokinetic Assessments
Not applicable.
5.6 
Biomarker Assessments
Not applicable.
5.7 
Outcomes Research Assessments
Treatment adherence will be assessed through a patient-reported questionnaire (i.e., MMAS). 
The  Morisky  Medication  Adherence  Scale-8  items, (MMAS-8), is  a  validated  self-reported 
measure  of  medication  adherence.  The  scale  
is  a  commonly  used  adherence  
tool  composed  of 
yes/no questions about past medication use that is simple to use. Each item measures a specific 
medication-taking  behavior.  Response  categories  are  yes/no  
for each  
item  with  a  dichotomous 
response and a 5-point Likert response for the last item.  Patients with higher scores are predicted 
to be more adherent to prescribed therapies, while patients with lower scores are at greater risk 
for nonadherent behavior. 
5.8 
Other Assessments 
5.8.1 
Laboratory Assessments
Hematology  
tests  will  be  done  
to  assess  
the  subject’s  safety  and  hematologic  
response.  Serum 
chemistry tests and pregnancy tests will be done to assess the subject’s safety.
Bone  marrow  aspirates  or  FISH [peripheral  blood] will  be  performed to monitor the subject’s 
CyR. 
Other parameters and/or increased frequency of examinations may be needed depending on the 
findings  during  
the  study.  If  a  subject  experiences  an  adverse event  of  pleural  effusion  and  a 
thoracentesis is performed, the results of the pleural fluid analysis must be recorded on the CRF. 
5.8.1.1 
Hematology
CBC, differential and PLT will be obtained within 72 hours prior to randomization, at Months 4 
or 5, or 6 (one month after randomization) and then every 3 months until Month 24. Following 
Month 24, hematology tests will be obtained every 6 months up to 60 months, then annually until 
disease progression or end of study therapy and at the end-of-treatment visit. 
For patients randomized (or crossing over) to dasatinib a CBC at 2 weeks of dasatinib initiation 
is required (Additional office visit not required: CBC results can be faxed to investigators from 
local lab and assessed according to dasatinib labeling recommendations.)
For patients who cross over to dasatinib, CBC, differential and PLT will be obtained at Month 3
from the date of the first treatment with dasatinib, and then every 3 months until Month 24, and 
every 6 months up to 60 months, then annually until the end of the study.
Revised Protocol No: 07
Date: 09-Mar-2018
60
744
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
5.8.1.2 
Bone Marrow 
BM aspirates will be obtained prior to randomization, then at months 6 and 12.
BM  aspirates  obtained  3  weeks  prior  to  
the  3-month  molecular  analysis  time  point  and  until 
randomization  are  acceptable  for  this  study  even  if  the  BM  aspirate  was  obtained  before  the 
informed consent signature.
After  the  first  12  months  of  treatment,  a  BM  aspirate  will  be  obtained  every  6  months  until 
CCyR is achieved and confirmed, then every 12 months thereafter.
Conventional  cytogenetics  is  recommended  until  CCyR  is  achieved  and  confirmed.  FISH 
(peripheral  blood)  is  allowed  as  a  substitute  for  conventional assessment  (at  all  time  points 
except screening), especially after CCyR is achieved, to confirm the durability of response.
5.8.1.3 
Serum Chemistry Tests
BUN,  creatinine,  ALT,  AST,  alkaline  phosphatase,  total  bilirubin,  LDH,  Na,  K,  Mg,  P,  
total 
serum  or ionized  Ca  and  uric  acid  will  be  obtained  at  pre-treatment  
(within  72  hours  prior  
to 
randomization) at Month 4 or 5, 6 and then every 3 months until Month 24. Following month 24, 
serum  chemistry  tests  will  be  obtained  every  6  months  up  to  60 months,  then  annually  until 
disease progression or end of study therapy and at the end-of-treatment visit.  
For patients who cross over to dasatinib, BUN, creatinine, ALT, AST, alkaline phosphatase, total 
bilirubin, LDH, Na, K, Mg, P, total serum or ionized Ca and uric acid will be obtained at Month
3 from the first day of treatment with dasatinib, and then every 3  months  until  Month  24,  and 
every 6 months thereafter until the end of the study.
Only tests listed above are required to be collected and reported in the CRF.
5.8.1.4 
Pregnancy Test
For  women  of  child-bearing  potential,  a  negative  serum 
sensitivit
prior to start of study therapy, monthly, and 30 days
When a monthly study visit is not required, WOCBP will 
test and to record the test date and results on the 
Pregnancy test log must be brought to every study visit; l
5.9 
Results of Central Assessments
Molecular  assessment  will  be  performed  in  a  central  laboratory,  and  results  will  be 
communicated  to  the  investigator  site  on  a  regular  basis  (eg,  within  2-3  weeks).  Screening 
molecular  assessment will  condition  the  eligibility  for  randomization.  Subsequent  molecular 
results may lead to treatment dosing modification.
6 
ADVERSE EVENTS
An Adverse Event (AE)is defined as any new untoward medical occurrence or worsening of a
preexisting  medical condition  
in a clinical  
investigation  subject administered an  
investigational 
(medicinal) product and that does not necessarily have a causal relationship with this treatment. 
Revised Protocol No: 07
Date: 09-Mar-2018
61
745
Draft 
930128686
0.2
v




Clinical Protocol
CA180399
BMS-354825
Dasatinib
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
a  visit  
to  
the  emergency  room  or  other  hospital  department  <  24  hours,  
that does  not 
result in admission (unless considered an important medical or life-threatening event)
elective surgery, planned prior to signing consent
admissions as per protocol for a planned medical/surgical procedure
routine  health assessment requiring admission  
for baseline/trending of  health status (eg, 
routine colonoscopy)
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
admission  encountered  for  another  life  circumstance  that  carries  no  bearing  on  health 
status  and  requires  no  medical/surgical  intervention  (eg,  lack of  housing,  economic 
inadequacy, caregiver respite, family circumstances, administrative reason).
6.1.1 
Serious Adverse Event Collection and Reporting 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not  related  to  study  drug,  must  be  collected,  including  those  thought  to  be  associated  with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuation of dosing.
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs whether related or not related to study drug and pregnancies must be reported to BMS (or 
designee) within 24 hours. SAEs  must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms).  When using paper forms, the reports 
are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: See Contact Information list.
SAE Facsimile Number: See Contact Information list.
For  studies  capturing  SAEs/pregnancies  through  electronic  data capture  (EDC),  electronic 
submission is the required method for reporting. The paper forms should be used and submitted 
immediately, only in the event the electronic system is unavailable for transmission. When paper 
forms are used, the original paper forms are to remain on site.
SAE Telephone Contact(required for SAE and pregnancy reporting): See Contact Information
list.
Revised Protocol No: 07
Date: 09-Mar-2018
63
747
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If  an  ongoing  SAE  changes  
in  
its  
intensity  or  
relationship  
to  study  drug  or  
if  new  
information 
becomes  available,  a  follow-up  SAE  report  should  be  sent  within  24  hours  to  the  BMS  (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2 
Nonserious Adverse Events
Anonserious adverse eventis an AE not classified as serious.
6.2.1
The 
ion  should  begin  at  initiation  of  study  drug  after 
rando
. 
to  
resolution  or  stabilization,  or  
reported  as  SAEs  
if  
they 
become 
Follow-up  is  also  required  for  nonserious  AEs  
that  cause 
interrupti
 drug and for those present at the end of study treatment 
as 
ous AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion  of  supplemental  CRFs  may  be  requested  for  AEs  and/or  
laboratory  abnormalities 
that are reported/identified during the course of the study.
6.3 
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
Any laboratory test result that is clinically significant or meets the definition of an SAE 
Any  laboratory  test  result  abnormality  that  required  the  subject  to  have  study  drug 
discontinued or interrupted
Any  laboratory  test  result  abnormality  that  required  the  subject  to  receive  specific 
corrective therapy.
It is expected that wherever possible, the clinical  
rather than  
laboratory term would  be used  by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4 
Pregnancy
If,  
following  
initiation of the  
investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of study exposure, including during at 
least 5 half lives after product administration, the investigator must immediately notify the BMS 
(or designee) Medical Monitor of this event and complete and forward a Pregnancy Surveillance 
Form  to  BMS  (or  designee)  within  24  hours  and  in  accordance  with  the  SAE  reporting 
procedures described in Section 6.1.1
In  most  cases,  
the  study  drug  will  be  permanently  discontinued in  an  appropriate  manner  
(eg, 
dose tapering if necessary for subject safety).
Revised Protocol No: 07
Date: 09-Mar-2018
64
748
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation  with  BMS,  the  pregnant  subject  may  continue  study drug,  after  a  thorough 
discussion of benefits and risk with the subject.
Protocol required procedures for study discontinuation and follow-up must be performed on the 
subject  unless  contraindicated by  pregnancy  (eg,  x-ray  studies).  Other  appropriate  pregnancy 
follow-up procedures should be considered if indicated.
Follow-up  
information  
regarding  
the  course of  
the  pregnancy,  
including  perinatal  and  neonatal 
outcome  and  where  applicable,  offspring  information  must  be  reported  on  the  Pregnancy 
Surveillance form
Any 
 participant should be reported to 
6.5
An 
on of any dose of a product 
that is 
occurrences of overdose must be 
6.6
Wherever  possible,  
timely  confirmation  of  initial  liver-related  
laboratory  abnormalities  should 
occur prior to the reporting of a potential DILI event. All occurrences  of  potential  DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1for reporting details).
Potential drug induced liver injury is defined as: 
1. 
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2. 
Total  bilirubin  >  2  times  ULN,  without  initial  findings  of  cholestasis  (elevated  serum 
alkaline phosphatase),
AND
3. 
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including,  but  not  
limited  
to,  viral  hepatitis,  pre-existing  chronic  or  acute  
liver  disease,  or  
the 
administration of other drug(s) known to be hepatotoxic.
6.7 
Other Safety Considerations
Any  significant  worsening  noted  during  interim  or  final  physical  examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
Revised Protocol No: 07
Date: 09-Mar-2018
65
749
Draft 
930128686
0.2
v




Clinical Protocol
CA180399
BMS-354825
Dasatinib
8.2 
Populations for Analyses
The following data sets will be used in this study.
Enrolled subjects:  All subjects who signed an informed consent
Randomized subjects:  All subjects who are randomized
Treated  subjects:  
  All  subjects  who  are  randomized  and  receive  at  least  one  dose  of
study treatment
All  enrolled  subjects  will  be  used  in  the  tabulation  of  subject  disposition.    All  randomized 
subjects  will  be  used  in  the  analysis  of  demographics,  baseline  characteristics  and  efficacy. 
Safety and extent of exposure will be analyzed based on all treated subjects.
All analyses will be performed by treatment arm as randomized, except the analyses for dosing 
and safety, which will be analyzed by treatment arm as treated.
8.3 
Endpoints
8.3.1 
Primary Endpoint(s) 
The primary endpoint for this study is the proportion of randomized subjects who achieve MMR 
at  12 months  after  the  first  day  (Day  1)  treatment  with  first-line  imatinib  in  patients  in  each 
treatment group.
8.3.2 
Secondary Endpoint(s) 
The 
mparing  randomized  
treatment  arms  will  be  
tested  in  
the 
follo
67
751
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
1. Time to MMR
2. Time to  MR4.5
3. PFS
4. OS
8.3.4
Efficacy
 en
onths is the proportion of randomized subjects who 
achieve  MMR  at  12  months  
from  Day  1  
treatment  with  
first-line  
imatinib (up to 9 months after 
their randomization date). 
The secondary endpoints include the following: 
Time to MMR (or MR4.5) is the time  between randomization date and  
first date that MMR (or 
MR4.5)  criteria  are  satisfied.  Subjects  who  do  not  achieve  MMR  (or  MR4.5)  will  be  censored 
according to rules that will be detailed in the statistical analysis plan (SAP). 
Overall Survival (OS) is the time from randomization date to death date. Subjects who have not 
died will be censored on the last date they are known to be alive. Additional details and rules will 
be specified in the SAP.
Progression-Free Survival (PFS) is the time from randomization date to progression date or death 
date, whichever occurs first. Subjects who neither progress nor die will be censored. Additional 
details and rules will be specified in the SAP.
Revised Protocol No: 07
Date: 09-Mar-2018
68
752
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
Safety
Intolerance  of  
treatment,  defined  as  
recurrent Grade 3  hematologic  
toxicity  or Grade  2  non-
hematologic  toxicity  despite  dose  reduction  necessitating  discontinuation  of  protocol  therapy. 
Adverse  events  and  other  
symptoms  will  be  assessed  continuously  and  
reported for  all  
treated 
subjects, and will  be graded according to the NCI CTCAE Version 4.0. Other safety endpoints 
include  
laboratory abnormalities, ECG abnormalities, as well as the  
frequency of  
interruptions, 
dose reductions and treatment discontinuation for toxicity.
8.4 
Analyses
8.4.1 
Demographics and Baseline Characteristics
Descriptive  statistics  will  be  provided  for  demographic  data  and  baseline  (screening)  patient 
characteristics data for all randomized subjects by and across strata.
8.4.2 
Efficacy Analyses
All efficacy analyses will  be performed on the population of  
‘all randomized subjects’, and all 
comparisons  between  treatment  arms  will  be  carried  out  using  two-sided  α=0.05  level  tests, 
unless specified otherwise.  
Revised Protocol No: 07
Date: 09-Mar-2018
69
753
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
Primary endpoint
The primary endpoint analysis will compare the MMR response rate achieved at 12 months from
Day  1  treatment  with  first-line  imatinib  between  the  dasatinib and  imatinib  arms  using  the 
Cochran-Mantel-Haenszel  test  stratified  by  Sokal  score  (High,  Intermediate,  Low,  and 
Unknown)  and  
time  from  molecular  analysis  
to  
randomization  
(≤4 weeks  vs  >4  weeks).  
  The 
primary analysis will be performed on all randomized subjects. A 95% exact confidence interval 
(two-sided) for the difference in MMR rate at 12 months will be computed.  
For  the  response  rate  analyses,  any  subjects  who  fail  treatment  after  randomization  will  be 
considered  non-responders.  Additionally,  subjects  who  cross-over  to  dasatinib  after 
randomization will be considered non-responders at and subsequent to the time of cross-over for 
any response rate analysis. 
Secondary endpoints
The secondary efficacy endpoints include time to MMR, time to MR4.5PFS, and OS.
Time  to  event  endpoints  will  be  estimated  for each  treatment  group  using  Kaplan-Meier  and 
Brookmeyer-Crowley methods. Time to event endpoints will be compared between the dasatinib 
group and imatinib group using a two-sided stratified log-rank test with Sokal score and the time 
between  3  month  molecular  assessment  and  randomization  (≤4  weeks  vs  >4  weeks)  as  the 
stratification  factors.  In  addition,  competing  risk  methodology  will  be  taken  into  account  for 
patients who die or receive a bone marrow transplant.
A  sensitivity  analysis  of  PFS  and  OS  will  be  performed  on  the  randomized  subjects  where 
subjects who are crossed over to dasatinib after treatment failure on imatinib will be censored at 
the date of crossover.  
The  secondary  endpoints  will  only  be  considered  for  comparison between the two treatment 
groups if the primary endpoint is significant.  The secondary endpoints are ranked as follows:
1. Time to MMR
2. Time to  MR4.5
3. PFS
4. OS
Statistical testing will proceed sequentially at α=0.05 for each endpoint as long as the preceding 
endpoint was statistically significant.  Testing will stop as soon as an endpoint is not significant.
Revised Protocol No: 07
Date: 09-Mar-2018
70
754
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
8.4.3 
Safety Analyses
Descriptive statistics will be provided for safety data for all treated subjects 
Revised Protocol No: 07
Date: 09-Mar-2018
71
755
Draft 
930128686
0.2
v




Clinical Protocol
CA180399
BMS-354825
Dasatinib
9 
STUDY MANAGEMENT
9.1 
Compliance
9.1.1 
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol
must be discussed with, and  be prepared  by, BMS. The  
investigator should  not implement any 
deviation  or  change  to  
the  protocol  without  prior  review  and  documented  approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to  obtaining  
IRB/IEC  approval/favorable  opinion,  as  soon  as  possible  
the  deviation  or  change 
will be submitted to:
IRB/IEC for review and approval/favorable opinion
BMS
Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If  an  amendment  substantially  alters  the  study  design  or  increases  the  potential  risk  to  the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable  opinion;  
(2)  
the  
revised  
form  must  be  used  
to obtain  consent  
from  subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must
be used to obtain consent from new subjects prior to enrollment.
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2 
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data  quality  and  study  integrity.  On  site  
they  will  review  study  records  and  directly  compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. 
In  addition,  
the  study  may  be  evaluated  by  BMS  
internal  auditors  and  government  
inspectors 
who  must be allowed access to CRFs, source documents, other study  
files, and  study  
facilities. 
BMS audit reports will be kept confidential.
The  investigator  must  notify  BMS promptly  of  any  inspections  scheduled  by  regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.3 
Investigational Site Training
Bristol-Myers Squibb or designee will provide quality investigational staff training prior to study 
initiation.  Training  
topics  will  
include  but  are  not  
limited  
to:  GCP,  AE  
reporting,  study  details 
Revised Protocol No: 07
Date: 09-Mar-2018
73
757
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
and  procedure,  electronic  CRFs, study documentation,  informed  consent,  and  enrollment  of
WOCBP.
9.2 
Records
9.2.1 
Records Retention
The  
investigator  must  
retain  all  study  
records and  source  documents  for  
the  maximum  period 
required  by  applicable  regulations  and  guidelines,  or  institution  procedures,  or  for  
the  period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If  the  investigator  withdraws  from  the  study  (eg,  relocation,  retirement),  
the  records  shall  be 
transferred  
to  a  mutually  agreed  upon  designee  
(eg,  another  
investigator, IRB).  Notice  of  such 
transfer will be given in writing to BMS.
9.2.2 
Study Drug Records
It  is  the  responsibility  of  the  investigator  to  ensure  that  a  current  disposition  record  of 
investigational  product  (those  supplied  by  BMS  or  the  site)  is maintained at each study site 
where  study  drug  is  inventoried  and  dispensed.  Records  or  
logs must  comply  with  applicable 
regulations and guidelines and should include:
amount received and placed in storage area
amount currently in storage area
label identification number or batch number 
amount dispensed to and returned by each subject, including unique subject identifiers
amount transferred to another area/site for dispensing or storage
non-study disposition (eg, lost, wasted) 
amount destroyed at study site, if applicable
amount returned to BMS
retained samples for bioavailability/bioequivalence, if applicable 
dates  and  initials  of  person  responsible  for  investigational  product 
dispensing/accountability, as per the Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
For protocol-defined IMP sourced by the site (not supplied by BMS), the site will record the lot 
number,  if  possible,  and  if  lot  number  is  not  available,  will  instead  record  the  prescription 
provider and prescription number.
Revised Protocol No: 07
Date: 09-Mar-2018
74
758
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
9.2.3 
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or  entered  as  a  control  
in  
the  
investigation.  Data  
that  are  derived  from source  documents  and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. 
For  sites  using  
the  
ICON  electronic  data  capture tool,  electronic  CRFs  will  be  prepared  
for  all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left  blank  only  
in  
those  circumstances  permitted  by  study-specific  CRF  completion  guidelines 
provided by BMS. 
The  confidentiality  of  records  that  could  identify  subjects  must  be  protected,  respecting  the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated  by the  
investigator or qualified physician who  
is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool. 
The  investigator  must  retain a  copy  of  the  CRFs  including  records of the changes and 
corrections.
Each  individual  electronically  signing  electronic  CRFs  must  meet  BMS  
training  requirements 
and  must  only  access  the  BMS  electronic  data  capture  tool  using  the  unique  user  account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3 
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected considering the following criteria:
External Principal Investigator designated at protocol development
National Coordinating Investigator 
Study Steering Committee chair or their designee
Subject recruitment (eg, among the top quartile of enrollers)
Involvement in trial design
Regional  
representation  
(eg,  among  
top  quartile  of  enrollers  
from a specified region or 
country)
Other criteria (as determined by the study team)
Revised Protocol No: 07
Date: 09-Mar-2018
75
759
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and  must  adhere  
to  BMS’s  publication  
requirements  as  set  forth in  
the  approved  clinical  
trial 
agreement  (CTA).  All  draft  publications,  including  abstracts  or  detailed  summaries  of  any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the  CTA.  BMS  shall  have  the  right  to  delete  any  confidential  or  proprietary  information 
contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
Revised Protocol No: 07
Date: 09-Mar-2018
76
760
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
10 
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the 
investigator or BMS as related to the investigational
product
Unexpected Adverse 
Reaction
An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved 
investigational product)
Revised Protocol No: 07
Date: 09-Mar-2018
77
761
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
11 
LIST OF ABBREVIATIONS
Term 
Definition
ALL 
Acute Lymphoblastic Leukemia
AE(s)  
Adverse Events(s)
ALT 
Alanine aminotransferase
ANC 
Absolute Neutrophil Count
AP
Accelerated Phase
Ara-C 
Cytosine arabinoside
AST  
Aspartate aminotransferase
ATP 
Adenosine Triphosphate
BID 
Bis In Diem (twice a day)
BM 
Bone Marrow
BMS  
Bristol-Myers Squibb
BP
Blast Phase
BUN 
Blood Urea Nitrogen
Ca
Calcium
CBC 
Complete Blood Count
cCHR 
Confirmed Complete Hematological Response
CCyR 
Complete Cytogenetic Response
CyR 
Cytogenetic Response
CHR 
Complete Hematologic Response
CI
Confidence Interval
CML 
Chronic Myeloid Leukemia
CNS 
Central Nervous System
CP
Chronic phase
CRF 
Case Report Form
CSF 
Cerebro Spinal Fluid
CTCAE 
Common Terminology Criteria for Adverse Events
CYP  
Cytochrome P
ECG  
Electrocardiogram
ECOG 
Eastern Co-Operative Group
eg 
exempli gratia (for example)
ESR 
Expedited Safety Report 
FSH 
Follicle Stimulating Hormone 
FISH 
Fluorescent-In Situ Hybridization
GCP 
Good Clinical Practice
GI
Gastro-Intestinal 
HCG 
Human Chorionic Gonadotropin
HRT 
Hormone Replacement Therapy
HU 
Hydroxyurea
Revised Protocol No: 07
Date: 09-Mar-2018
78
762
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
Term 
Definition
ICH 
International Conference on Harmonization 
IDMC 
Internal Data Monitoring Committee
i.e.  
id est (that is)
IEC 
Independent Ethics Committee
IM
Imatinib mesylate
-IFN 
Interferon-
INR  
International Normalized Ratio
IRB  
Institutional Review Board
IS
International Standard
IU 
International Unit
IV
Intra Venous
IVRS 
Interactive Voice Response System
K
Kalium (Potassium)
LDH 
Lactate Dehydrogenase
LVEF 
Left Ventricular Ejection Fraction
M
Month
MCyR 
Major cytogenetic response
mg  
Milligram
Mg  
Magnesium
M
microMolar
MMR 
Major Molecular Response
MR 
Molecular response
MR4.5
4.5- log reduction in BCR-ABL transcript from the standardized 
baseline (0.0032% IS). 
MR4
4-log reduction in BCR-ABL transcript from the standardized baseline
(0.01% IS).
msec 
Millisecond
N 
Number (of subjects or observations)
Na
Natrium (Sodium)
NCI 
National Cancer Institute
nM
nanoMolar
OS
Overall Survival
P
Phosphorus
PB
Peripheral Blood
PCR 
Polymerase Chain Reaction
PCyR 
Partial Cytogenetic Response
PDGF 
Platelet-Derived Growth Factor
PFS  
Progression-free Survival
pH
-log
10hydrogen ion concentration
Ph+ 
Philadelphia chromosome positive
Revised Protocol No: 07
Date: 09-Mar-2018
79
763
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
Term 
Definition
PLT 
Platelets
p.o. 
Per os (by mouth)
PS
Performance Status
PTK 
Protein Tyrosine Kinase
q
Every
QD 
once daily
QPCR 
Quantitative polymerase chain reaction
QT
The interval between the beginning of the Q-wave and the end of the 
T-wave on an electrocardiogram 
QTc(F) 
QT interval corrected (according to Fridericia’s formula)
RQ-PCR 
Real-time quantitative polymerase chain reaction
SAE 
Serious Adverse Event
S(m)PC 
Summary of Product Characteristics
SOP 
Standard Operating Procedures
SRC 
a protein tyrosine kinase
ULN 
upper limit of normal
WBC 
White Blood Cell
WOCBP  
Women Of Child Bearing Potential
Revised Protocol No: 07
Date: 09-Mar-2018
80
764
Draft 
930128686
0.2
v








Clinical Protocol
CA180399
BMS-354825
Dasatinib
APPENDIX 1 
ADDITIONAL ETHICAL CONSIDERATIONS
1 
INFORMED CONSENT PROCEDURES
BMS  will  provide  
the  investigator  with  an  appropriate  (ie,  Global  or  Local)  sample  informed 
consent  
form  which  will  
include all  elements  
required  by  
ICH,  GCP  and  applicable  
regulatory 
requirements. The sample  
informed consent form will adhere to the ethical principles that have 
their  origin  in  
the  Declaration  of  Helsinki.  If  
the  investigator  makes  changes  
to  
the  
informed 
consent  form  sample,  BMS  will  ensure  all  required  elements  and local  regulatory  and  legal 
requirements are met.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access  to  subject  records.  Prior  
to  
the  beginning  of  the  study,  the  investigator  must  have  the 
IRB/IEC’s  written  approval/favorable  opinion  of  the  written  informed  consent  form  and  any 
other information to be provided to the subjects.
The investigator must provide the subject, or, in those situations where consent cannot be given 
by subjects, their legally acceptable representative with a copy of the consent form and written 
information about the study in the language in which the subject is most proficient. The language 
must  be  non-technical  and  easily  understood.  The  
investigator  should  allow  
time  necessary  
for 
subject or subject
's legally acceptable representative to inquire about the details of the study, then 
informed  consent  must  be  signed  and  personally  dated  by  the  subject  or  
the  subject
's  legally 
acceptable representative and by the person who conducted the informed consent discussion. The 
subject or legally acceptable representative should receive a copy of the signed informed consent
and any other written information provided to study subjects prior to subject
's participation in the
study.
1.1 
Subjects Unable to Give Written Informed Consent
1.1.1 
Minors
For  minors,  according  to  local  legislation,  one  or  both  parents  or  a  legally  acceptable 
representative must be informed of the study procedures and must  sign  the  informed  consent 
form approved for the study prior to clinical study participation. (In the event that the parents or 
legal guardians are unable to read, then an impartial witness should be present during the entire 
informed  consent  discussion).  Whenever feasible,  minors  who  are judged  to  be  of  an  age  of
reason must also give their written assent by signing and dating the completed informed consent. 
All local laws, rules and regulations regarding informed consent of minors must be followed.
1.1.2 
Subjects Experiencing Acute Events or Emergencies
A  legally  acceptable  representative  or  legal  guardian  must  provide  informed  consent  when 
consent  of  the  subject  is  not  possible  prior  to  clinical study participation,  eg,  for  subjects 
experiencing an acute medical event such as myocardial infarction or stroke. Informed consent of 
the subject must additionally be obtained if they become capable of making and communicating 
their  
informed consent during the clinical study. All  
local  
laws, rules and regulations regarding 
informed consent of adult subjects incapable of giving informed consent must be followed.
Revised Protocol No: 07
Date: 09-Mar-2018
84
768
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
1.1.3 
Mentally Impaired or Incapacitated Subjects
Investigators (or  whoever  required  by  local  regulations) should  determine  whether  or  not  a 
mentally impaired or incapacitated subject is capable of giving informed consent and should sign 
a statement to that effect. If the subject is deemed mentally competent to give informed consent, 
the  
investigator should  
follow standard procedures. If the  subject  
is deemed  not to be  mentally 
competent  to  give  informed  consent,  a  fully  informed  legal  guardian  or  legally  acceptable 
representative can be asked to give consent for, or on behalf of, the subject. All local laws, rules 
and regulations regarding informed consent of mentally impaired or incapacitated subjects must 
be followed.
Patients  who  are  involuntarily hospitalized  because  of  mental  illness  must  not  be  enrolled  in 
clinical studies
1.1.4 
Other Circumstances
Subjects  who are  
imprisoned  or  
involuntarily  detained for  
treatment  of  either  a  psychiatric  or 
physical (eg, infectious disease) illness must not be enrolled in clinical studies. 
In  circumstances  where  a  
subject’s  only  access  
to treatment  
is  
through  enrollment  
in  a  clinical
study,  eg,  for  subjects  in  developing  countries  with  limited  resources  or  for  subjects  with  no 
marketed treatment options, the investigator must take special care to explain the potential risks 
and benefits associated with the study and ensure that the subject is giving informed consent.
When  a  subject  may  be  in  a  dependent  relationship  with  the  investigator,  a  well-informed 
physician  who  is  not  engaged  in  the  clinical study and  is  completely  independent  of  the 
relationship between the subject and investigator should obtain the subject’s informed consent.
1.1.5 
Illiterate Subjects
If the subject, or, in those situations where consent cannot be given by the subject, their legally 
acceptable representative is unable to read, a reliable and independent witness should be present 
during  
the  entire  informed  consent  discussion.  The  choice  of  
the  witness  must  not  breach  
the 
subject’s rights to confidentiality. A reliable independent witness is defined as one not affiliated 
with  the  institution  or  engaged  in  the  investigation.  A  family member  or  acquaintance  is  an
appropriate  independent  witness.  After  the  subject  or  legally  acceptable  representative  orally 
consents and has signed, if capable, the witness should sign and personally date the consent form 
attesting  that  the  information  is  accurate  and  that  the  subject, or, in those situations where 
consent cannot be given by subjects, their legally acceptable representative has fully understood 
the content of the informed consent agreement and is giving true informed consent.  
1.2 
Update of Informed Consent
The  informed  consent  and  any  other  information  provided  to  subjects, or, in  those  situations 
where consent cannot be given by subjects, the subject
's legally acceptable representative, should 
be  revised  whenever  important  new  information  becomes  available that is relevant to the 
subject
's  consent,  and  should  receive  IRB/IEC  approval/favorable  opinion  prior  to  use.  The 
investigator,  or  a  person  designated  by  
the  investigator  should  fully  inform  
the  subject  or  
the 
subject
's  
legally  acceptable  
representative  of  all  pertinent  aspects of the study and of any new 
Revised Protocol No: 07
Date: 09-Mar-2018
85
769
Draft 
930128686
0.2
v


Clinical Protocol
CA180399
BMS-354825
Dasatinib
information  relevant  to  the  subject
's  willingness  to  continue  participation  in  the  study.  This 
communication should be documented. 
During a subject
's participation in the study, any updates to the consent form and any updates to 
the written information will be provided to the subject.
Revised Protocol No: 07
Date: 09-Mar-2018
86
770
Draft 
930128686
0.2
v
































Dasatinib
CA180399
BMS-354825
Protocol Amendment 01
3 
This document contains information confidential and proprietary to Bristol-Myers Squibb
Changes to the Protocol  
1) Title page:Hesham Mohamed is now only listed once as both study director and 
central medical monitor
2) Synopsis:
a) Investigational Products: Added treatment failure as a reason for withdrawal
b) Figure Caption: changed  “into treatment” to “prior to molecular test date” 
c) Changed wording of “treatment compliance” to “treatment adherence”
d) Added MMAS-8 as a metric for compliance and deleted patient diary
e) Added Unknown as a category for Sokal score
f) “Will require enrollment of 600 patients” changed to “screening of 600 patients.”
3) Document History: Amendment 01 added to study history 
4) Section  2.3 Informed Consent: removed patient proxy language 
6) Section 3.3.1 Inclusion Criteria, Subsection 2a) Target Population: Added 
statement allowing transient dose adjustment of imatinib for AEs
7) Section 3.3.2 Exclusion CriteriaSubsection 2) Medical History and Concurrent 
Disease, Subsection iv: Removed 450 msec from definition of prolonged QTC 
interval
8) Section 3.5 Discontinuation of Subjects from Study Treatment:
a) Treatment failure added as a reason for discontinuation
b) “Who in treatment failure (per ELN2009)” added to NOTE 
786
Draft 
930128686
0.2
v































































SAP_001.pdf: 
Official Title of Study:  
AN OPEN LABEL, RANDOMIZED (2:1) PHASE 2B STUDY OF DASATINIB VS IMATINIB IN 
PATIENTS WITH CHRONIC PHASE CHRONIC MYELOID LEUKEMIA WHO HAVE NOT ACHIEVED 
AN OPTIMAL RESPONSE TO 3 MONTHS OF THERAPY WITH 400 MG IMATINIB 
 
NCT Number: NCT01593254 
 
Document Date (Date in which document was last revised):  09-Mar-2018 


1
STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
AN OPEN LABEL, RANDOMIZED (2:1) PHASE 2B STUDY OF DASATINIB VS 
IMATINIB IN PATIENTS WITH CHRONIC PHASE CHRONIC MYELOID LEUKEMIA 
WHO HAVE NOT ACHIEVED AN OPTIMAL RESPONSE TO 3 MONTHS OF 
THERAPY WITH 400 MG IMATINIB
PROTOCOL (S) CA180399
VERSION # 1.0
1602
Draft  
930128686
0.1
v




Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.3.2 
Demographics and Other Baseline Characteristics 
...................................................16 
7.3.3 
Medical history 
...........................................................................................................17 
7.3.4 
Physical examinations 
................................................................................................17 
7.4 
Extent of Exposure .....................................................................................................17 
7.5 
Concomitant medications 
...........................................................................................18 
7.6 
Efficacy Analyses 
.......................................................................................................18 
7.6.1 
Primary Efficacy Analysis 
..........................................................................................18 
7.6.2 
Secondary Efficacy Analyses 
......................................................................................18 
7.6.2.1 
Time to MMR and MR4.5 analysis
 ...............................................................................19 
7.6.2.2 
Progression Free Survival (PFS) Analysis 
.................................................................19 
7.6.2.3 
Overall Survival (OS) Analysis 
...................................................................................20 
 
 
7.6.3.1 
BCR-ABL Mutations 
...................................................................................................21 
7.6.3.2 
Molecular and Cytogenetic Response ........................................................................22 
7.7 
Safety Analyses ..........................................................................................................24 
7.7.1 
Adverse Events 
............................................................................................................24 
7.7.2 
Death
 ...........................................................................................................................25 
7.7.3 
Clinical Laboratory Evaluations 
................................................................................25 
7.7.3.1 
Hematology
 .................................................................................................................26 
7.7.3.2 
Serum Chemistry 
.........................................................................................................26 
7.7.4 
Electrocardiograms, Echocardiograms and Chest X-rays 
.........................................26 
7.7.5 
Vital Signs 
...................................................................................................................26 
7.7.6 
Physical Examination 
.................................................................................................26 
7.7.7 
Pregnancy
 ...................................................................................................................27 
7.7.8 
ECOG Performance Score .........................................................................................27 
7.8 
Pharmacokinetics
 ........................................................................................................27 
 
 
1604
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1605
Draft  
930128686
0.1
v




Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
6 
 
2 
 STUDY 
 
DESCRIPTION 
 
2.1 
 Study 
 
Design 
 
This study is an open-label, randomized, prospective, multi-center, Phase 2b study conducted in 
patients with CP-CML who have achieved complete hematologic response (CHR) but who have 
more than 10% IS BCR-ABL at 3 months after first line treatment with imatinib 400 mg QD. 
Approximately 1,100 patients will be enrolled for screening into this study. Patients who are 
screened as eligible for the protocol will be randomized to receive either dasatinib 100 mg QD or 
imatinib with the option to increase dose following a standard of care approach. 
Patients will sign the informed consent form before any screening assessment is conducted. The 
3- month molecular sample, part of the screening procedure required to establish eligibility, will 
be analyzed in the central lab. Patients treated with imatinib preceding the 3-month molecular 
response assessment are considered the screened population. Screened patients with a transcript 
level of 10% IS or less after 3 months of imatinib 400 mg treatment are excluded from the study 
and will be considered screen failures. 
The study design schema is presented in  
Figure 2.1-1. 
1607
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
7 
 
Figure 2.1-1:   
Study Design 
 
Randomization may take place up to a maximum of 8 weeks after the 3-month molecular 
analysis.  Randomization will be stratified by Sokal score (high, intermediate, low, unknown) 
and time between the 3-month molecular assessment and randomization (≤ 4 weeks, > 4 weeks).  
During the study, patients randomized to the imatinib treatment group who meet the ELN 2013 
criteria of failure (Appendix 2) will be crossed over to the dasatinib treatment group, unless the 
patients have dasatinib resistant mutations. 
Patients will be treated for a maximum of 60 months after randomization of the last patient on 
the assigned regimen (dasatinib or imatinib), unless disease progression, treatment failure or 
unacceptable toxicity occurs, the patient withdraws consent, or the study is discontinued by the 
sponsor. This means that the first randomized patient could be treated on study for up to 84 
months or more depending on the actual date of the last patient’s first visit (LPFV). 
1608
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
8 
 
2.3   
Blinding and Unblinding 
Not applicable. This is an open-label study. 
1609
Draft  
930128686
0.1
v




Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
10 
 
 
2.5   
Data Monitoring Committee 
An internal data monitoring committee (IDMC) consisting of senior expert representatives of the 
Sponsor who are independent from the study team will be established.  This committee will 
include at a minimum two physicians and a statistician.  This committee will regularly assess 
study progress at defined intervals (at least 3 times a year and ad hoc as necessary) and review 
safety data by arm including all SAEs, grade 3 and 4 AEs and discontinuations and examine 
critical efficacy endpoints (i.e. MMR, time to MMR, PFS) of the study.   
1611
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
11 
 
The structure, roles, and responsibilities of the IDMC, as well as the timing of analyses, 
monitoring guidelines, and content of the reports are detailed in the charter of the IDMC 
3 
 OBJECTIVES 
 
3.1 
 Primary 
 
The primary objective is to compare the rate of MMR at 12 months after Day 1 initiation of first-
line treatment with imatinib, in patients randomized at month 3 to treatment with dasatinib 
100mg QD or imatinib at any dose, after less than optimal response to first-line imatinib (BCR-
ABL > 10% IS). 
3.2 
 Secondary 
 
The secondary objectives are to compare the following between both treatment arms: 
  
Time to MMR 
  
Time to MR4.5 
  
Progression Free Survival (PFS) 
  
Overall Survival (OS) 
4 
 ENDPOINTS 
4.1 
 Primary 
 
Endpoints 
 
The primary endpoint for this study is the proportion of randomized patients who achieve MMR 
12 months after the first day (Day 1) of treatment with first-line imatinib (up to 9 months after 
their randomization date) in patients in each treatment group.  Additional details will be specified 
in section 7. 
4.2 
 Secondary 
 
Endpoints 
 
Secondary endpoints include additional examination of time to MMR, time to MR4.5, PFS and 
OS. 
1612
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
12 
 
4.2.1   
Time to MMR and time to MR4.5 
Time to MMR is defined as the time between the randomization date and the first date that MMR 
criteria are satisfied.  Patients who do not achieve MMR will be censored according to rules that 
will be detailed in section 7. 
Time to MR4.5 is defined as the time between the randomization date and first date that the MR
4.5 
criteria are satisfied.  Patients who do not achieve MR
4.5 will be censored according to rules that 
will be detailed in section 7. 
4.2.2   
Progression Free Survival (PFS) 
PFS is defined as the time from the randomization date to the date of either progression or death 
due to any cause whichever occurs first.  Patient who neither progress nor die will be censored.  
Additional details and rules will be specified in section 7 
4.2.3 
 Overall 
 
Survival 
 
(OS) 
 
OS is defined as the time from the randomization date to death date and will include deaths from 
any cause.  Patients who do not die will be censored using the last date of follow-up or end of 
study date.  Additional details and rules will be specified in section 7. 
1613
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
13 
 
4.3.3 
 Safety 
 
Safety endpoints will include incidence of AEs, serious AEs, AEs leading to discontinuation, and 
AEs leading to death as well as marked abnormalities in clinical laboratory tests, vital sign 
measurements, ECGs, chest x-ray and physical examinations.  Safety analysis details will be 
specified in section 7. 
 
 
  
 
 
 
 
  
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1614
Draft  
930128686
0.1
v




Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
15 
 
7.1 
 General 
 
Methods 
 
In the analyses described below (except where noted), counts and percentages will be reported 
for discrete variables with inclusion of unknown or missing values as a separate category. The 
mean, SD, median, range (minimum and maximum), and number of non-missing values will be 
reported for each continuous measure.   
All efficacy analyses will be performed using randomized patients excluding site 84 and all 
comparisons will be made between the two treatment groups as randomized unless noted 
otherwise.  Analysis will be adjusted for the stratification factors including Sokal score 
categories (high, intermediate, low, unknown) and by time between 3-month molecular 
assessment and randomization categories (≤ 4 weeks, > 4 weeks) where appropriate.   
In the instance of a missing or partial adverse event (AE) date, when the month and year are non-
missing, the day will be imputed as the 1st of the month unless the 1st of the month is before the 
first dose of randomized treatment in which case the start day will be the day of the first dose of 
randomized treatment. For all non-AE data, in the instance of a missing day in a date that has a 
non-missing month and year, the day will be imputed as the 15th of the month.  For all partial 
dates, in the case of a missing day and month (the date has only the year), the day and month will 
be imputed as July 1st, unless that date is prior to the first dose date in which case the first dose 
date will be used. 
The following conversion factors will be used to convert days to months or years: 1 month   
30.4375 days and 1 year   365.25 days. 
1616
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
16 
 
Duration (e.g., time from randomization to first dosing date) will be calculated as last date minus 
first date plus 1 (duration   last   first + 1). 
All statistical tests will be two-sided. An alpha level of 0.05 will be used to determine statistical 
significance unless otherwise specified.  No imputation of missing longitudinal data will be 
performed.  All statistical analysis will be conducted using SAS software, Version 9.2 (or later) 
of the SAS System10. 
7.2 
 Study 
 
Conduct 
 
7.2.1 
 Accrual 
  
The following will be summarized for all enrolled patients:  
•   
Number of patients accrued by investigational site 
•   
Number of patients accrued by month. 
•   
Number of patients accrued by the randomization strata (i.e., Sokal score categories 
(high, intermediate, low, unknown) and by time between 3-month molecular assessment 
and randomization (≤ 4 weeks, > 4 weeks). 
A by-patient listing of accrual will be produced. 
7.2.2   
Relevant Protocol Deviations 
The relevant protocol deviations will be summarized for all randomized patients.  The protocol 
deviations will be programmatically determined from the clinical database.  
A by-patient listing of relevant protocol deviations will be produced along with a by-patient 
listing of all patients excluded from the primary efficacy analysis. 
7.3 
 Study 
 
Population 
 
7.3.1 
 Patient 
 
Disposition 
 
The number of patients enrolled, randomized or not randomized (with the reason for screen 
failure) will be presented.  Those patients who were randomized will be further categorized 
according to whether the patient received treatment.  The number of patients who discontinue 
treatment along with corresponding reason will be tabulated.  The number of patients 
randomized to imatinib and who experienced treatment failure (with the reason for first-line 
imatinib treatment failure) will be presented.  The number of patients randomized to imatinib and 
crossing over to dasatinib will also be summarized.  
Patient disposition data will also be presented in a by-patient listing. 
7.3.2   
Demographics and Other Baseline Characteristics 
Descriptive statistics will be reported for demographic data and patient characteristics (at 
screening) for all randomized patients by and across strata.  Variables to be summarized include 
age, sex, and race.  Age will be calculated by subtracting the patient’s date of birth from his or 
her screening visit date and dividing this difference by 365.25.  
1617
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
17 
 
In addition, the baseline Sokal score, time between 3-month molecular assessment and 
randomization, vital signs (including height and weight) at baseline, ECOG performance status at 
baseline will be summarized by treatment group. 
7.3.3 
 Medical 
 
history 
 
A summary of medical history/current medical conditions will be summarized by system organ 
class (SOC), coded according the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA) for all randomized patients. 
A by-patient listing of medical history in the randomized patients will be provided. 
7.3.4 
 Physical 
 
examinations 
 
Patients with abnormal baseline physical examination will be tabulated by examination criteria 
for all randomized patients. A by-patient listing will be provided. 
7.4   
Extent of Exposure 
According to the response and toxicity, dose modifications will follow the standard of care 
recommendations.  Dose interruptions or reductions for dasatinib- or imatinib-related adverse 
events (possibly, probably or certainly related) are described in APPENDIX 1. For an individual 
patient, dose interruptions, reductions and treatment discontinuation may be more or less 
conservative than indicated in APPENDIX 1 based on the clinical judgement of the investigator. 
Treatment exposure, dose reductions and interruptions will be summarized as follows by 
treatment group as treated for all treated patients: 
•   
Average daily dose (mg) and duration (days) of treatment  
•   Number and percentage of patients with at least 1 dose reduction, number of dose 
reductions, and reasons for reduction 
•   
Number and percentage of patients with at least 1 dose interruption, number of dose 
interruptions, and reasons for interruption 
 
Number and percentage of patients with at least 1 dose escalation, number of dose 
escalations, and reasons for escalation 
•   Number and percentage of patients with treatment discontinuation, and reasons for 
discontinuation 
For patients who were randomized and treated in the imatinib treatment group, the above will 
also be summarized for the following groups: 
•   
Patients who didn’t cross over to dasatinib: averge daily dose (mg), duration (days) of 
treatment, dose reduction and interruptions for imatinib 
•   Patients who crossed over to dasatinib: average daily dose (mg), duration (days) of 
treatment, dose reduction and interruptions respectively for imatinib before cross over, and for 
dasatinib after cross over    
A summary of each patient’s exposure will be presented in a listing. 
1618
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
18 
 
7.5 
 Concomitant 
 
medications 
 
A summary of concomitant medications will be presented within each treatment group by 
therapeutic drug class and generic drug name for the enrolled population.  
A by-patient listing of concomitant medications in the randomized patients will be provided. 
 
7.6 
 Efficacy 
 
Analyses 
 
7.6.1   
Primary Efficacy Analysis 
The primary efficacy analysis is to compare the rate of MMR at 12 months after Day 1 initiation 
of first-line treatment with imatinib, in patients randomized at month 3 to treatment with 
dasatinib 100mg QD or imatinib at any dose, after less than optimal response to first-line 
imatinib (BCR-ABL > 10% IS).   
MMR is defined as a 3-log reduction in BCR-ABL transcripts from the standardized baseline, 
which represents 100% on the international scale, so a 3-log reduction is fixed at 0.1% for 
MMR.
For the response rate analyses, any patients who fail treatment after randomization will be 
considered non-responders. Additionally, patients who cross-over to dasatinib after 
randomization will be considered non-responders at and subsequent to the time of cross-over for 
any response rate analysis. 
Response rates and Clopper-Pearson two-sided 95% confidence intervals will be estimated for 
each treatment group.  Differences in response rates between the treatment groups will be 
assessed using the Cochran-Mantel-Haenszel (CMH) test stratified by Sokal score categories 
(high, intermediate, low, and unknown) and time from 3-month molecular analysis to 
randomization (  weeks vs  weeks).  A two-sided 95% exact confidence interval for the 
difference in MMR rate at 12 months will be computed.   
The primary analysis will be performed on randomized patients excluding site 84, repeated using 
all randomized patients and  all treated patients as sensitivity analyses. 
7.6.2   
Secondary Efficacy Analyses 
Time to event endpoints including time to MMR, MR4.5, PFS, and OS will be estimated for each 
treatment group at 6, 12, 18, 24, 36, 48 and 60 months using Kaplan-Meier method with the 
Brookmeyer-Crowley method used in the calculation of the confidence intervals. Time to event 
endpoints will be compared between the dasatinib group and imatinib group using a two-sided 
stratified log-rank test with categories from the Sokal score and the time between 3 month 
molecular assessment and randomization as the stratification factors.  
In addition, competing risk methodology will be used to account for patients who die or receive a 
bone marrow transplant.  Cumulative incidence functions for time to MMR, MR4.5 adjusted for 
the competing risk of death or receipt of a bone marrow transplant will be estimated. Fine and 
Gray11 method will be used to model the cumulative incidence function by defining the hazard of 
1619
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
19 
 
the cumulative incidence function, known as the subdistribution hazard, and impose the 
proportional hazards assumption on the subdistribution hazards.  Gray’s test12 will be used to 
analyze time to MMR, MR4.5 to compare between the dasatinib group and imatinib group.  
Kaplan-Meier plots will also be presented for time to MMR, MR4.5, PFS, and OS.  
The above analyses of time to event endpoints will be performed on randomized patients 
excluding site 84 and repeated for all randomized patients as a sensitivity analysis.   
The secondary endpoints will only be considered for comparison between the two treatment 
groups if the primary endpoint is significant. The secondary endpoints will be analyzed 
sequentially based on the following order: 
1. Time to MMR 
2. Time to MR4.5 
3. PFS 
4. OS 
Statistical testing will proceed sequentially at α 0.05 for each endpoint as long as the preceding 
endpoint was statistically significant. Testing will stop as soon as an endpoint is not significant. 
7.6.2.1   Time to MMR and MR4.5 analysis 
Time to MMR is the time between randomization date and first date that MMR criteria are 
satisfied. Patients who do not achieve MMR will be censored according to rules that are 
summarized in Table 7.5-1. 
Time to MR4.5 is defined in the same way as time to MMR with censoring according to rules that 
are summarized in Table 7.5-1.   
MR4.5 is defined as a 4.5-log reduction in BCR-ABL transcript from the standardized baseline 
(0.0032% IS, either detectable disease   0.0032% BCR-ABL (IS) or undetectable disease in 
cDNA (in same volume used for BCR-ABL) with   32,000 ABL transcripts.   
7.6.2.2   Progression Free Survival (PFS) Analysis 
PFS is the time from randomization date to progression date or death date, whichever occurs 
first. Patients who neither progress nor die will be censored. Additional details and rules are 
specified in Table 7.5-1.   
A recent ELN 2013 publication reaffirmed that progression is defined as transformation to 
accelerated phase or blast crisis. Any of the following events occurring while a patient is 
continuously on study therapy would define progression.  Patients should be on the maximum 
tolerated dose (as determined by the investigator) before criteria for progression are considered. 
 Criteria for accelerated phase CML are met at any time 
o The presence of   15%, but < 30% blasts in the blood or bone marrow 
1620
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
20 
 
o At least 30% blasts plus promyelocytes in the blood or bone marrow 
o At least 20% peripheral basophils 
o Thrombocytopenia (fewer than 100,000 platelets/mm3) unrelated to treatment 
 Criteria for blast phase CML are met at any time 
o At least 30% blasts in the blood or bone marrow 
o Extramedullary involvement (e.g., chloromas), but not hepatosplenomegaly 
 Death from any cause during treatment. 
The date of progression is defined as the date when any of the above criteria is first met. Patients 
meeting any criterion for progression will be removed from protocol therapy.  The loss of a 
previously achieved hematologic or cytogenetic response is considered a treatment failure, not 
disease progression. 
Treatment failure to first-line therapy is defined as: 
1. Any of the disease progression parameters above 
2. At 3 months: less than complete hematologic response (These patients will not be eligible for 
randomization) and/or No CyR (Ph+ >95%) 
3. At 6 months: BCR-ABL >10% and/or Less than PCyR (Ph+ >35%) 
4. At 12 months: BCR-ABL >1% and/or Less than CCyR (Ph+ >0%) 
5. At any time during treatment, loss of CHR or CCyR; Confirmed loss of MMR (In two 
consecutive tests, of which one with a BCR-ABL1 transcripts level   1%), BCR-ABL1 kinase 
domain mutations poorly sensitive to imatinib; newly emerging CCA/Ph+ 
PFS will be analyzed similarly as OS. 
Note: Patients failing imatinib therapy at any time point will be crossed-over to the dasatinib arm 
unless they harbor dasatinib-resistant mutations. 
7.6.2.3  Overall  
Survival  
(OS)  
Analysis  
OS is defined as the time from the randomization date to the death date and includes deaths from 
any cause. Patients who have not died will be censored on the last date they are known to be 
alive. Additional details and rules are specified in Table 7.5-1. 
1621
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
 
21 
 
Table 7.5-1:   
Censoring Rules for Time to Event Analyses 
Time to 
Endpoint 
Event/Censoring  Event/Censoring Date 
MMR 
MR4.5 
1) Event 
 
2.1) Censoring 
 
 
2.2) Censoring 
The first date that MMR (or MR4.5) criteria are satisfied 
 
Date of last molecular assessment (if patients don’t meet MMR [or 
MR4.5]) 
 
Visit 1 date (randomization date) (if patient have no post-baseline 
molecular assessment) 
PFS  
1.1) Event 
 
1.2) Event 
 
2.1) Censoring 
 
 
2.2) Censoring 
Date of progression 
 
Date of death (if patients die without progression) 
 
Date of last molecular assessment (if patients have no progression 
and no death) 
 
Visit 1 date (randomization date) (if patient has no post-baseline 
progression assessment and no death reported) 
OS  
1) Event  
 
2) Censoring 
Date of Death 
 
Date of last known alive (if patients have no death reported) 
 
A sensitivity analysis of Time to MMR, Time to MR4.5, PFS and OS will be performed on the 
randomized patients excluding site 84. For patients who are crossed over to dasatinib after 
treatment failure on imatinib, they will be censored at the date of crossover, if they haven’t 
experienced events prior to the date of crossover.  If sufficient data exist, the effect of patients 
crossing over treatments on time to MMR, MR4.5, PFS, and OS will be explored using a Cox 
proportional hazards model with switch in treatment as a dichotomous, time-dependent (i.e., 
interaction with time to switch to dasatinib), covariate. Time to switch to dasatinib (months) will 
be calculated as (The crossover date - The randomization date +1) / 30.4375. 
1622
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
22 
 
7.6.3.2  Molecular  
and  
Cytogenetic  
Response  
Molecular Response 
To assess the molecular response over time, MMR, MR4.5 and MR4 response rates will be 
assessed at 6, 12 (MR
4.5 and MR
4 only since MMR at 12 months is primary endpoint), 15, 18, 
24, 36, and 48 months for the randomized patients excluding site 84.  MMR, MR4.5 or MR
4 
response rate is the proportion of randomized patients who achieve MMR, MR
4.5 or MR
4 at each 
time point from Day 1 treatment with first-line imatinib.  Response rates at each time point and 
associated Clopper-Pearson two-sided 95% confidence intervals will be estimated for each 
treatment group.  For the response rate analyses, any patients who fail treatment after 
randomization and are crossed over or discontinued from the study will be considered non-
responders.  Difference in response rates at each time point between two treatment groups will be 
assessed using the CMH test, controlling for Sokal score (high, intermediate, low, and unknown) 
and the time between the 3-month molecular assessment and randomization (  weeks vs 
weeks).  
MR4 is defined as a 4-log reduction in BCR-ABL transcript from the standardized baseline 
(either detectable disease  0.01% BCR-ABL (IS) or undetectable disease in cDNA (in same 
volume used for BCR-ABL) with   10,000 ABL transcripts. 
Cytogenetic Response 
To assess the cytogenetic response over time, complete cytogenetic response (CCyR) and major 
cytogenetic response (MCyR) will be assessed at 6, 12, and 18 months for the randomized 
patients excluding site 84. The rate of CCyR and MCyR is defined as the proportion of 
randomized patients who achieved CCyR or MCyR at each time-point from Day 1 treatment 
with first-line imatinib.  The response rates at each time point will be analyzed using the same 
method for molecular responses at each time point.  
Cytogenetic Response: cytogenetic response is based on the prevalence of Ph+ cells in 
metaphase from BM sample.  
The criteria for evaluation of CyR are based on the percentage of Ph+ cells in metaphase 
and are specifically categorized as follows: 
CCyR 
   
  
  
  
  
 
-> 
 
0% 
 
Partial cytogenetic response (PCyR)     
 -> 1-35% 
MCyR 
   
  
  
  
  
 
-> 
 
0-35% 
 
(CCyR 
 
plus 
 
PCyR) 
 
Minor cytogenetic response     
   
 -> 36 to 65% 
Minimal cytogenetic response   
   
 -> 66 to 95% 
No cytogenetic response      
   
 -> 96 to 100% 
1623
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
23 
 
If Ph+ cells in metaphase from BM sample data using conventional cytogenetic 
assessment are not available, fluorescence in situ hybridization (or FISH [peripheral 
blood]) method is allowed as a substitute. Previous research has shown that these data are 
highly correlated2.  The same categorizations will be applied. 
Benefit of Early Switch 
The benefit, evaluated by response rates and survival, of early switch to dasatinib (at 3 month) 
over switch at time of imatinib failure (based on ELN 2013 Criteria of failure) later on in the 
randomized patients will be summarized.  Response rates MMR, MR
4.5, MR
4, CCyR, and 
MCyR, PFS and OS for patients who crossed over are defined similarly as for the patients who 
did not crossover in the primary and secondary analyses. The patients are categorized into three 
groups for this analysis: randomized to dasatinib; randomized to imatinib and crossed over to 
dasatinib later; randomized to imatinib and no crossover. Response rates over time and Clopper-
Pearson two-sided 95% confidence intervals will be estimated for each of the three groups. 
Kaplan-Meier and Brookmeyer-Crowley methods will be used for analysis of PFS and OS for 
each of the three groups. 
In order to further investigate the relationship with the time to switch to dasatinib, log reduction 
in BCR-ABL will be summarized by three treatment groups above at 6, 12, 24, 36, 48 and 60 
months since randomization to explore if there are any trends or patterns among the subjects in 
the three groups. 
Medication Compliance 
To explore the correlation of medication compliance (treatment adherence) with disease 
response, medication compliance (treatment adherence) will be assessed using MMAS-8.  The 
MMAS-8 is a validated self-reported measure of medication adherence. The scale is a commonly 
used adherence tool composed of yes/no questions about past medication use that is simple to 
use. Each item measures a specific medication-taking behavior.  Response categories are yes/no 
for each item with a dichotomous response and a 5-point Likert response for the last item. 
Patients with higher scores are predicted to be more adherent to prescribed therapies, while 
patients with lower scores are at greater risk for non-adherent behavior.  Descriptive statistics of 
patient MMAS-8 scores will be presented at each study visit for each treatment group for the 
randomized patients. Analysis of response rates of primary and secondary clinical endpoints 
(MR
4.5 and MR
4 ) will be stratified by level of patient adherence (MMAS-8 score), if there are at 
least 10 patients in each category for each treatment group. Patient adherence will also be 
incorporated into time-to-event analysis for MMR and MR
4.5 by including MMAS-8 score, 
along with treatment group, Sokal score (high, intermediate, low, and unknown), the time 
between 3-month molecular measurement to randomization (  4 weeks, > 4 weeks) in 
proportional hazards models of these endpoints. 
1624
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
24 
 
7.7 
 Safety 
 
Analyses 
 
Safety assessments will include incidence of AEs, serious AEs, AEs leading to discontinuation, 
as well as marked abnormalities in clinical laboratory tests, chest x-ray, pregnancy test for 
women of child-bearing potential, vital sign measurements, ECGs, and physical examinations.  
Descriptive statistics (counts and percents) will be provided for all treated patients (regardless of 
crossover status) by treatment group using as treated treatment information, as well as for 
patients who crossed over from imatinib to dasatinib and were treated with dasatinib.  
7.7.1 
 Adverse 
 
Events 
 
AEs will be coded according to the latest version of MedDRA.  The intensity of AEs will be 
graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE), Version 4.0. 
AEs occurring on or after Day 1 of receiving randomized treatment and no later than 30 days 
following the last day of treatment will be considered treatment emergent.  In the absence of 
evidence of discontinuation of therapy, patients are assumed to be still on-study.  
For patients crossing over from imatinib to dasatinib during the study, the actual (as treated) 
treatment will be determined based on the cross over date and AE starting date.  Treatment 
emergent AEs for patients who cross over to dasatinib are defined as those AEs that occur after 
the first dose date of dasatinib and no later than 30 days following the last day of treatment.   
Treatment-related AEs, defined as an adverse event which was determined to be related by 
physician, will be summarized.  If a patient experiences multiple occurrences of the same AE 
with different relationship to study medication categories, the patient will be counted once as 
treatment-related.  In the event has the relationship to study drug as missing, the relationship to 
study drug will be taken as “related” in all relevant statistical analyses.   
The intensity of AEs will be graded 1 to 5.  If a patient experiences the same AE more than once 
with different toxicity grade, then the event with the highest grade will be tabulated in “by 
grade” tables.  In addition, AEs with missing intensity will be presented in the summary table as 
an intensity category of “Missing.” 
AEs of special interest in this study include: 
 Musculoeskeletal disorders 
 Connective tissue disorders 
 Vascular disorders 
Tables summarizing the number of patients experiencing AEs and patient incidence for AEs will 
be generated for each of the following summaries by treatment group regardless of crossover as 
well as for patients who crossed over from imitinab to dasatinib and were treated with dasatinib: 
•   
Overall summary of AEs 
•   
AEs presented by MedDRA system organ class and preferred term 
•   
All AEs by worst CTCAE grade category 
1625
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
25 
 
•   
Treatment-related AEs presented by MedDRA system organ class and preferred term 
•   
Treatment-related AEs by worst CTCAE grade category 
•   
Serious AEs presented by MedDRA system organ class and preferred term 
•   
Treatment-related serious AEs by MedDRA system organ class and preferred term 
•   
AEs leading to study discontinuation 
•   
AEs with fatal outcome. 
 
AEs of special interest by worst CTCAE grade category  
 
Treatment-related AE’s of special interest by worst CTCAE grade category 
Adverse events due to intolerance of study treatment will also be summarized. Intolerance of 
treatment is defined as recurrent ≥Grade 3 hematologic toxicity or ≥Grade 2 non-hematologic 
toxicity despite dose reduction necessitating discontinuation of protocol therapy.   
The above summaries will be generated by treatment group regardless of crossover as well as for 
patients who crossed over from imatinib to dasatinib and were treated with dasatinib. 
Toxicity rates, using the worst CTCAE Grade per patient, for selected Grade 3 treatment-related 
adverse events (fluid retention, pleural/pericardial effusion, CHF, cardiac dysfunction, rash, 
neutropenia, thrombocytopenia, anemia, leucopenia, AST, ALT, total bilirubin and dose 
reduction/interruption due to toxicity) will be compared between the two treatment groups using 
the Fisher exact test.  
In addition, each unique AE will be summarized by treatment group with number of events (i.e., 
0 event, 1 event, 2-3 events, > 4 events). 
Corresponding by-patient data listings for all adverse events, adverse events leading to 
discontinuation, and adverse events with fatal outcome will be provided for the randomized 
patients.  
A by-patient data listing for all serious adverse events will be provided for the enrolled patients. 
The summary tables and listings will reflect the actual treatment for the safety analysis unless 
specified otherwise. 
7.7.2 
 Death 
 
A listing and a table will be provided to summarize all deaths and deaths within 30 days after the 
date of last dose. 
7.7.3 
 Clinical 
 
Laboratory 
 
Evaluations 
 
Clinical laboratory values from the laboratory tests will be graded according to NCI CTCAE, 
Version 4.0 for applicable tests.  Normal ranges will be used to determine the categories of High, 
Low, and Normal for lab tests that have no severity grade, if available.   
A listing of patients with laboratory abnormalities will be provided. 
1626
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
26 
 
7.7.3.1  Hematology  
The worst NCI CTCAE grade for white blood cell (WBC) counts, absolute neutrophil counts 
(ANC), absolute lymphocyte counts, platelet counts, and hemoglobin during the treatment period 
will be summarized for all treated patients by treatment group as well as for patients who cross 
over to dasatinib and treated with dasatinib.   
Hematology lab results and changes from baseline by visit during the treatment period will be 
summarized. 
7.7.3.2  Serum  
Chemistry  
The worst NCI CTCAE grade for AST (SGOT), ALT (SGPT), alkaline phosphatase (ALP), total 
bilirubin, serum creatinine, Na, K, Mg, and P will be summarized during the treatment period 
will be summarized for all treated patients by treatment group as well as for patients who cross 
over to dasatinib and treated with dasatinib. 
Serum chemistry lab results and changes from baseline by visit during the treatment period will 
be summarized.     
7.7.4   
Electrocardiograms, Echocardiograms and Chest X-rays 
The 12-lead ECG to determine baseline QT interval corrected (QTc) will be documented at 
baseline and as clinically indicated.  Echocardiogram and chest x-ray measurements will be 
documented at baseline and as clinically indicated.   
Electrocardiograms (ECGs), echocardiogram, and chest x-ray measurements will be summarized 
by visit during the treatment period for all treated patients by treatment group as well as for 
patients who cross over from imitinab to dasatinib. 
In addition, the ECG analysis will report the frequency distributions of maximal QTc intervals 
(Fridericia) and the changes from baseline. 
Corresponding by-patient listings for ECGs, echocardiogram, and chest x-rays will be provided 
7.7.5 
 Vital 
 
Signs 
 
Vital sign measurements (systolic blood pressure (BP), diastolic BP, heart rate, and temperature) 
will be summarized by visit during the treatment period for all treated patients by treatment 
group (regardless of crossover) as well as for patients who crossed over from imitinab to 
dasatinib. 
A by-patient listing of vital sign measurements will be provided. 
7.7.6 
 Physical 
 
Examination 
 
Physical examination parameters will be summarized by visit during the treatment period for all 
treated patients by treatment group as well as for patients who cross over to dasatinib and treated 
with dasatinib. 
All physical examination abnormal findings will be listed.  
1627
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
27 
 
7.7.7 
 Pregnancy 
 
A by-patient listing of pregnancy test results will be provided. 
7.7.8 
 ECOG 
 
Performance 
 
Score 
 
Eastern Cooperative Oncology Group (ECOG) performance status score will be collected at 
baseline and during the treatment period. ECOG performance score will be summarized by visit 
during the treatment for all treated patients by treatment group as well as for patients who cross 
over to dasatinib and treated with dasatinib. 
Post-baseline ECOG performance score cross-tabulated by worst (highest) score with the score 
(0, 1 or 2) at baseline (shift table) may be also be needed.  
7.8 
 Pharmacokinetics 
 
Not applicable. 
7.9 
 Biomarker 
 
Analyses 
 
Not applicable. 
7.10 
 Interim 
 
Analyses 
 
The primary analysis will be based on the Month 12 evaluation although descriptive summaries 
will be produced through the conclusion of all patients’ participation in the trial. 
An interim analysis is planned when all 258 patients have been followed until Month 12 
(calculated from day 1 of initiation of first line imatinib. i.e., at the time of the primary endpoint 
final analysis). This analysis will assess the secondary efficacy endpoints as well as safety 
endpoints. At yearly interim looks (year 1, year 2, year 3, year 4), the four secondary efficacy 
endpoints will be tested sequentially at an alpha level of 0.0001. At the final analysis (year 5), 
the four secondary efficacy endpoints will be tested sequentially at an alpha level of 0.0496. 
Secondary endpoints are sequentially ranked as follows:  
1. Time to MMR 
2. Time to MR4,5  
3. PFS 
4. OS 
8 
 CONVENTIONS 
 
Unless specified otherwise, the following conventions may be used for imputing partial dates for 
analyses requiring dates:  
•   
If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day. 
•   If both the day and the month are missing, “July 1” will be used to replace the missing 
information. 
•   
If a date is completely missing, it will be considered as missing. 
1628
Draft  
930128686
0.1
v


Statistical Analysis Plan 
CA180399 
BMS-354825 
dasatinib 
28 
 
For adverse events: 
•   
If only the day of the month is missing, the first day of the month will be used to replace 
the missing day unless the 1st of the month is before the first dose of study treatment.  In 
that case the start day will be the day of the first dose of treatment. 
•   
If both the day and the month are missing, “January 1” will be used to replace the missing 
information unless January 1 is before the first dose of study treatment.  In that case the 
start day and month will be the day and month of the first dose of treatment.  
•   
If a date is completely missing, it will be considered as missing. 
For death dates, the following conventions will be used for imputing partial dates: 
•   If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. The imputed date will be compared to the last known date alive + 1 day and 
the maximum will be considered as the death date. 
•   
If the month or the year is missing, the death date will be imputed as the last known date 
alive + 1 day.  
•   
If the date is completely missing but the reason for death is present the death date will be 
imputed as the last known date alive + 1 day  
The following conversion factors will be used to convert days to months or years: 1 month   
30.4375 days and 1 year   365.25 days. 
Duration will be calculated as follows: Duration   (Last date - first date + 1) 
Last known date alive will be defined based on all appropriate dates collected on the CRF. 
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted. 
9   
CONTENT OF REPORTS 
All analyses described in this SAP will be included in the Clinical Study Report(s) except where 
otherwise noted. Refer to the Data Presentation Plan for mock-ups of all tables and listings. 
1629
Draft  
930128686
0.1
v