Clinical trial NCT01850004
Conditions: Chronic Phase Chronic Myeloid Leukemia
Sponsor: Bristol-Myers Squibb
Start date: 2014-01-22; Completion date: 2021-10-08
Enrollment: 84 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study purpose is to test the hypothesis that Chronic Phase Chronic Myeloid Leukemia (CP-CML) patients with stable Complete Molecular Response (CMR) who discontinue Dasatinib treatment are able to maintain a sustained remission in the long-term, with undetectable or minimally detectable BCR-ABL residual disease.

Detailed description:
Primary Purpose: Protocol designed to evaluate remission of disease after treatment discontinuation. Treatment re-started if relapse occurs

Arms: arm 1: Dasatinib 50, 80, 100, 140, 180 mg tablets by mouth, once daily, up to 60 months
Interventions: intervention 1: Dasatinib
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Page:
1
Protocol Number:
CA180406
IND Number:
66,971
Ex-US
Non-IND
EUDRACT Number
2012-001421-27
Date:
08-Apr-2013
Revised Date
24-Jul-2017
Clinical Protocol CA180406
Open-Label Single Arm Phase 2 Study Evaluating Dasatinib Therapy Discontinuation In Patients 
With Chronic Phase Chronic Myeloid Leukemia (CP-CML) With Stable Complete Molecular 
Response (CMR) DASFREE
Revised Protocol Number: 04
Study Director/Medical Monitor
Patricia Martín-Regueira MD
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
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within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in 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 which BMS has transferred obligations, e.g., 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.
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SYNOPSIS
Clinical Protocol CA180406
Protocol Title:  Open-Label Single Arm Phase 2 Study Evaluating Dasatinib Therapy Discontinuation In Patients 
With Chronic Phase Chronic Myeloid Leukemia (CP-CML) With Stable Complete Molecular Response (CMR) 
DASFREE
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): At study entry, dasatinib will be discontinued in all enrolled patients. Dasatinib will be restarted if 
major molecular response is lost during the off-treatment period at the dose level received before study entry. The 
patient will remain on treatment for the duration of the study. Dose adjustment for toxicity and response is permitted 
during the retreatment period based on protocol guidelines. Dosing above 180 mg QD of dasatinib is prohibited.
Study Phase:  Phase 2
Research Hypothesis: CP-CML patients with stable complete molecular response (CMR) who discontinue 
dasatinib treatment are able to maintain a sustained remission in the long-term, with undetectable or minimally 
detectable BCR-ABL residual disease.
Objectives: The primary objective of this study is to assess the rate of major molecular response (MMR), defined 
as the proportion of subjects who maintain MMR (BCR-ABL transcripts < 0.1% on International Scale (IS)) at 
12 months after dasatinib discontinuation, without re-starting dasatinib treatment.
The secondary objectives of this study include assessment of the following: event-free survival (EFS) (defined as no 
loss of MMR) at 12 , 24, 36, 48 and 60 months after dasatinib discontinuation; relapse-free survival (RFS) at 6, 12, 
18, 24 months and every 6 months thereafter; BCR-ABL kinetics in those patients who experience intermittent loss 
of CMR (MR4.5) but no loss of MMR (ie, BCR-ABL blips); assessment of BCR-ABL kinetics in patients who are in 
CMR (MR4.5) or less when transcript levels are still measurable; rate of transformation to accelerated phase/blast 
crisis (AP/BC); progression free survival, and overall survival.
 
 
 
 
 
 
 
 
 
 
Study Design:  This is an open-label, single-arm study in adult patients with CP-CML who have received dasatinib 
as treatment for a minimum of 2 years at the time of enrollment and have confirmed dasatinib-induced complete 
molecular remission (defined as 4.5-log reduction of BCR-ABL transcript as determined by local standards) 
ongoing for at least 1 year prior to study entry. Eligible patients must have achieved a 1-log reduction in BCR-ABL 
transcript levels compared to baseline as determined by local standards or less than or equal to 10% IS [International 
Standard]) at 3 months for current dasatinib therapy.
Prospective patients will have been prescreened to confirm dasatinib-induced CMR stable for a minimum of 
9 months at a local laboratory prior to the first study sponsored screening assessment. CMR must be documented by 
at least 3 assessments, 2 - 6.5 months apart conducted at a local lab. Once stable CMR is confirmed at prescreening, 
patients are eligible for the study sponsored molecular analyses conducted via the central lab. If the first study 
sponsored molecular analysis assessment confirms CMR, the assessment will be repeated after 3 months. Patients 
are eligible for enrollment if both assessments from the central lab confirm CMR (MR4.5). For any patient not 
eligible for enrollment on the basis of a central laboratory test that does not confirm CMR, rescreening is allowed 
9 months (or longer) after the time of the last central lab screening failure. 
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Once all entry criteria are met, patients will be enrolled. At the time of enrollment, dasatinib will be discontinued.
Patients will be monitored for maintenance of MMR (BCR-ABL transcripts < 0.1% IS). At the loss of MMR, 
dasatinib treatment will be resumed at the dose level the patient received before dasatinib was discontinued at study 
entry. Patients who have restarted treatment with dasatinib due to loss of MMR will remain on treatment for the 
duration of the study. Dose escalations and adjustments in case of toxicities are permitted as described in 
Section.4.3.1.
A rise of PCR > 0.0032% (4.5 log reduction) IS after discontinuation of dasatinib should not trigger dasatinib 
re-initiation, if the BCR-ABL transcripts remain below 0.1% on IS. 
All patients on study will be followed for 5 years after enrollment. The study will end 5 years after the first visit of 
the last enrolled patient.
AP/BC =accelerated phase/blast crisis; CMR = complete molecular response.
IS = International Scale; SCT = stem cell transplant; Month = 30 days
CMR (MR4.5) defined as 0.0032% (IS) or 4.5 log reduction of BCR-ABL transcript as determined 
by local standards
Study Population:
CP CML patients on dasatinib treatment for a minimum of 2 years with confirmed stable 
dasatinib-induced CMR (MR4.5) for a minimum of 12 months prior to enrollment and no prior accelerated 
phase/blast crisis (AP/BC) or stem cell transplant (SCT). Eligible patients must have achieved a 1-log reduction in 
BCR-ABL transcript levels compared to baseline as determined by local standards, or less than or equal to 10% IS 
[International Standard]) at 3 months for current dasatinib therapy. Patients eligible for SCT are not eligible for this 
study. Eligible patients must meet all prescreening and screening criteria. 
Study Assessments: Safety assessments include: physical examination (including vital signs and performance 
status), signs and symptoms, serum chemistry, ECG (baseline and if clinically indicated), echocardiogram, and chest 
x-ray as (both as if clinically indicated). Adverse events will be assessed throughout this study using the current 
version of the NCI CTCAE guide. Efficacy assessments include: complete blood count (CBC) with differential, 
platelets, cytogenetics (if clinically indicated), and molecular analysis (qualitative polymerase chain reaction 
[Q-PCR]). Patient-reported outcomes will be assessed by the MDASI-CML QOL questionnaire (severity and impact 
of cancer-related symptoms) and the EORTC-QLQ-C30 questionnaire (self-reported measure of quality of life). The 
schedule of study assessments is presented in Section 5.1, Flow Chart/Time and Events Schedule.
Statistical Considerations:
Sample Size: 
This is an open label single arm study with no comparative objective. 
Under the assumption of a 75% MMR rate at 12 months after dasatinib discontinuation, a sample size of 74 
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patients will ensure a 20% width for a 95% confidence interval. To accommodate an expected 5 % drop-out 
rate, a total of 79 patients will be enrolled into this trial.
Endpoints:
The primary endpoint is the MMR rate at 12 months after dasatinib discontinuation. 
Secondary endpoints include event-free survival (EFS) at 12 months, relapse-free survival (RFS) at 6, 12, 
18, 24 months and every 6 months thereafter after dasatinib discontinuation, assessment of BCR-ABL 
kinetics, the rate of transformation to AP/BC, progression free survival (PFS) and overall survival (OS). 
Exploratory endpoints include identifying prognostic factors for maintaining MMR at 12 months after 
dasatinib discontinuation without re-starting dasatinib, e.g. age (years), gender (male/female), Sokal risk 
group, time from diagnosis (months), time in dasatinib-induced stable CMR (MR4.5) prior to 
discontinuation (months), occurrence of BCR-ABL blips (changes in residual level that do not have clinical 
relevance and does not imply loss of MMR) (Yes/No), history of pleural effusion (Yes/No), history of 
lymphocytosis (Yes/No) (lymphocytes > 3.6 x 109 L); the proportion of subjects who achieve molecular 
response and cytogenetic response after relapse; time to molecular re-response (rMMR and rCMR) and 
cytogenetic re-response (rCCyR and rPCyR) after re-initiating dasatinib in patients who lose MMR after 
discontinuation; healthcare resource utilization that is incurred during discontinuation of study treatment 
and during treatment (re-start of dasatinib); the frequency and CTCAE grade of adverse events during
discontinuation of study treatment 
and during treatment (re-start of dasatinib); and quality of life 
assessments: EORTC-QLQ-C30 and MDASI-CML (following discontinuation of study treatment and 
during treatment).
Analyses:  No formal statistical testing will be performed. Summary statistics will be provided for subject 
disposition, baseline characteristics (demographics, medical history, etc.), dosing, efficacy, safety, and 
health outcome endpoints using the enrolled subject population. Also, efficacy will be summarized using 
the evaluable subject population. Health resource utilization data will be assessed using descriptive 
statistics and will be reported in an analysis separate from the clinical study report.
Efficacy will be described for each of the following subgroups: patients in CMR (MR4.5) 24 months or 
> 24 months prior to dasatinib discontinuation, patients’ with dasatinib as first line or second/third line
treatment.
MMR rate at 12 months will be summarized by point estimate and Clopper-Pearson two-sided 95% 
confidence intervals. EFS at 12, 24, 36, 48 and 60 months, RFS at 6, 12, 18, 24 months and every 6 months 
thereafter, the proportion of subjects who achieve molecular response after relapse, rate of transformation 
to AP/BC, and rate of OS will be estimated using Kaplan-Meier method.  
Time to event endpoints including EFS, RFS, time to re-gaining MMR and CMR for subjects who 
experience MMR loss and re-start dasatinib, PFS, and OS will be summarized using Kaplan-Meier 
estimates and Brookmeyer-Crowley methods. Censoring details are provided in the protocol and will be 
further specified in the statistical analysis plan (SAP).
Exploratory analysis to identify prognostic factors will be analyzed using Cox Proportional Hazard models. 
Interim Analysis: The Sponsor will conduct continuous review and reporting of safety throughout the study as 
required by GCP and routine pharmacovigilance standards. 
In case of any progression from chronic phase through accelerated or blast crisis during the discontinuation phase, 
the steering committee and the internal date monitoring committee (IDMC) will be consulted and the case will be 
discussed to decide potential early study termination.
An interim analysis is planned when all patients have been followed until month 12 (calculated from discontinuation 
of dasatinib). This analysis will assess specific safety and efficacy endpoints and will be detailed in the statistical 
analysis plan.
Regular reviews (at least 2 times a year and ad-hoc as necessary) of safety and efficacy data listings and 
pharmacovigilance reports will be performed. These reviews will be conducted by an internal data monitoring 
committee (IDMC) made up of representatives who are independent from the study team. The structure, roles, and 
responsibilities of the IDMC, as well as the timing of analyses, monitoring guidelines, and content of the reports will 
be detailed in the charter of the IDMC.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
 
 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1. INTRODUCTION AND STUDY RATIONALE .................................................... 
 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
 
 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2. ETHICAL CONSIDERATIONS .............................................................................. 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3. INVESTIGATIONAL PLAN ................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.5 Discontinuation of Subjects from Treatment or from Study ............................ 
3.6 Post Treatment Study Follow up....................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4. TREATMENTS ........................................................................................................ 
4.1 Study Treatments .............................................................................................. 
4.1.1 Investigational Product ............................................................................ 
4.1.2 Non-investigational Product .................................................................... 
4.1.3 Handling and Dispensing ........................................................................ 
4.2 Method of Assigning Subject Identification ..................................................... 
4.3 Selection and Timing of Dose for Each Subject ............................................... 
4.3.1 Dose Adjustments ..................................................................................... 
4.3.1.1 Dose Escalation .............................................................................. 
4.3.1.2 Dose Reduction Guidelines ............................................................. 
4.4 Blinding/Unblinding ......................................................................................... 
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4.5 Treatment Compliance ...................................................................................... 
4.6 Destruction and Return of Study Drug ............................................................. 
4.6.1 Destruction of Study Drug ....................................................................... 
4.6.2 Return of Study Drug ............................................................................... 
4.7 Retained Samples for Bioavailability / Bioequivalence ................................... 
5. STUDY ASSESSMENTS AND PROCEDURES .................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Safety endpoints ....................................................................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Efficacy Endpoints ................................................................................... 
5.4.1.1 Definition of Hematologic Response .............................................. 
5.4.1.2 Definition of Cytogenetic Response ................................................ 
5.4.1.3 Definition of Molecular Response .................................................. 
5.4.1.4 Event free survival .......................................................................... 
5.4.1.5 Relapse (during off treatment period) ............................................. 
5.4.1.6 Progression free survival ................................................................ 
5.4.2 Progression .............................................................................................. 
5.4.3 Overall Survival ....................................................................................... 
5.5 Pharmacokinetic Assessments .......................................................................... 
 
5.7 Outcomes Research Assessments ..................................................................... 
 
 
5.8 Other Assessments ............................................................................................ 
5.8.1 Hematology .............................................................................................. 
5.8.2 Serum chemistry Tests.............................................................................. 
5.8.3 Bone Marrow/Peripheral Blood (FISH). ................................................. 
5.8.4 Molecular Analysis .................................................................................. 
5.8.5 Pregnancy Test......................................................................................... 
5.9 Results of Central Assessments ........................................................................ 
6. ADVERSE EVENTS ................................................................................................ 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7. DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES.......................................................................................................
8. STATISTICAL CONSIDERATIONS...................................................................... 
8.1 Sample Size Determination ............................................................................... 
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8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.3.4 Safety Endpoints....................................................................................... 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
 
 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9. STUDY MANAGEMENT ....................................................................................... 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10. GLOSSARY OF TERMS ....................................................................................... 
11. LIST OF ABBREVIATIONS ................................................................................. 
 
APPENDIX 1 PREGNANCY TESTING LOG ........................................................... 
 
 
 
APPENDIX 3 MEDICAL CONDITIONS AND DRUGS WHICH MAY CAUSE 
QTC PROLONGATION AND TORSADE DE POINTES (NOT ALL 
INCLUSIVE) .......................................................................................................... 
APPENDIX 4 COMMON CYP3A4 SUBSTRATES (NOT ALL INCLUSIVE) ........ 
 
APPENDIX 5 COMMON CYP3A4 INHIBITORS (NOT ALL INCLUSIVE) .......... 
 
APPENDIX 6 COMMON CYP3A4 INDUCERS (NOT ALL INCLUSIVE) ............. 
 
APPENDIX 7 SOKAL AND HASFORD: CALCULATION OF RELATIVE RISK . 
 
APPENDIX 8 METHODS OF CONTRACEPTION ................................................... 
 
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1.2
Research Hypothesis 
CP-CML patients treated with dasatinib for a minimum of 2 years who have achieved stable CMR 
(defined as dasatinib-induced MR4.5 for a minimum of 12 months before study entry), who 
discontinue dasatinib treatment are able to maintain a sustained remission in the long-term, with 
undetectable or minimally detectable BCR-ABL residual disease.
In this trial, CMR is defined as 0.0032% or 4.5 log reduction of BCR-ABL transcript levels.
1.3
Objectives(s)
1.3.1
Primary Objectives
The primary objective of this study is to assess the rate of MMR, defined as the proportion of 
subjects who maintain MMR (BCR-ABL transcripts < 0.1% on International Scale13,14) at 
12 months after dasatinib discontinuation, without re-starting dasatinib. 
1.3.2
Secondary Objectives
The secondary objectives of this study are to assess the following: 

Event-free survival (defined as survival with no loss of MMR) [Section 5.4.1.3]) at 12, 24, 36, 
48 and 60 months after dasatinib discontinuation

Relapse-free survival at 6, 12, 18, 24 months and every 6 months thereafter. Relapse is defined 
in Section 5.4.1.4

Assessment of BCR-ABL kinetics in those patients who experience loss of CMR (MR4.5) but 
no loss of MMR (BCR-ABL  kinetics are any changes in residual level that do not have clinical 
relevance)

Assessment of BCR-ABL kinetics in patients who are in CMR (MR4.5) or less where transcript 
levels are still measurable

Rate of transformation to AP/BC

Progression free survival

Overall survival.
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1.5
Overall Risk/Benefit Assessment
Dasatinib has demonstrated a favorable risk-benefit profile in patients resistant or intolerant to 
imatinib and in newly diagnosed patients with CP-CML.  
Although maintenance therapy with imatinib or a second-generation TKIs such as dasatinib, are 
generally well tolerated for most patients, chronic toxicities (even if low grade) can impair a 
patient’s daily quality of life.8 In addition, there is potential for late-emerging toxicities that could 
develop, given that the current experience with TKIs only spans little more than a decade.8
Dasatinib is potentially harmful to the developing fetus, and pregnancy must be avoided during 
treatment periods. In this study, investigators will counsel women of childbearing potential and 
male subjects who are sexually active with women of child bearing potential on the importance of 
pregnancy prevention and the implications of an unexpected pregnancy during treatment with 
dasatinib.
For these reasons, one critical goal of CML treatment is to identify those patients who may be able 
to achieve long-lasting disease remission, without the need for ongoing treatment.
This trial will generate data by following patients for 5 years after treatment discontinuation, and 
assessing long-term stability of CMR (MR4.5) achieved on dasatinib, recurrence rate, patients
quality of life off dasatinib treatment and, importantly, the ability to regain a molecular response 
in those patients who relapse after treatment withdrawal.
Patients who have attained a sustained CMR (MR4.5) while receiving dasatinib 100 mg QD,2 given 
either as first or as second line treatment, will be eligible for this study.
The rationale for this trial supports the hypothesis that the benefit of maintaining the deepest level 
of response achieved with dasatinib predicts better long-term disease control and outcome and 
might theoretically cure some patients who are newly diagnosed with CP CML. Moreover, the risk 
of being off treatment is balanced by the expectation of an increased quality of life: in fact, drug-
related side effects,19 even if manageable, impose an additional burden of morbidity and may be 
associated with reduced treatment compliance.8,20
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2.
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonization (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of 
the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
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.
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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 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. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to refuse 
participation in, or to be withdrawn from, the clinical study at any time should be considered by 
the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3.
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is an open-label, single-arm study in adult patients with CP-CML who have received dasatinib 
treatment for a minimum of 2 years at the time of enrollment and have confirmed dasatinib-induced 
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complete molecular remission (defined as 4.5-log reduction of BRC-ABL transcript as 
determined by local standards) ongoing for at least 1 year immediately prior to study entry. 
Prospective patients will be prescreened to confirm dasatinib-induced CMR stable for a minimum 
of nine months. CMR must be documented by at least three assessments, 2-6.5 months apart 
conducted at a local lab. Once stable CMR is confirmed at prescreening, patients are eligible for 
the study sponsored molecular analyses conducted via the central lab. If the first study sponsored 
molecular analysis assessment confirms CMR, the assessment will be repeated after three months. 
Patients are eligible for enrollment if both assessments from the central lab confirm CMR (MR4.5). 
Once all entry criteria are met, patients will be enrolled and dasatinib will be discontinued 
Patients will be monitored for maintenance of MMR (BCR-ABL transcripts < 0.1% IS). In case of 
loss of MMR, dasatinib treatment will be resumed at the dose level the patient was receiving before 
dasatinib was discontinued at study entry. Patients who have restarted treatment due to loss of 
MMR will remain on treatment for the duration of the study. Dose escalations and adjustments in 
case of toxicities are permitted as described in Section 4.3.1, Dose Adjustments.
A rise of PCR > 0.0032% (4.5 log reduction) IS after discontinuation of dasatinib should not trigger 
dasatinib re initiation, if the BCR-ABL transcripts remain below 0.1% on IS. 
All patients on study will be followed for 5 years after enrollment. The study will end 5 years after 
the first visit of the last enrolled patient.
The study design schematic is presented in Figure 3.1-1.
Figure 3.1-1:
Study Design Schematic
AP/BC =accelerated phase/blast crisis; CMR = complete molecular response.
IS = International Scale; SCT = stem cell transplant; Month = 30 days
CMR (MR4.5) defined as ≤ 0.0032% (IS) or 4.5 log reduction of BCR-ABL transcript as 
determined by local standards
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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.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Patients must be informed of the investigational nature of this study and of alternative 
standard therapeutic options and must provide written informed consent.
2. Target Population
a) Men and women diagnosed with CP-CML, on treatment with dasatinib for a minimum of 
2 years at the time of enrollment and in dasatinib-induced complete molecular remission 
(defined as 0.0032% or 4.5 log reduction of BCR-ABL transcript as determined by 
local standards) ongoing for at least 1 year prior to study entry.
i)
Patients are eligible for the screening assessment from the central lab if they have been 
in stable dasatinib induced CMR for a minimum of nine months, documented by at 
least three assessments, conducted 2 - 6.5 months apart, at a local lab. The first 
screening assessment conducted at the central lab will be repeated after three months, 
if the first assessment confirms CMR (MR 4.5). Patients are eligible for enrollment if 
both assessments from the central lab confirm MR4.5. For any patient not eligible for 
enrollment on the basis of a central laboratory test that does not confirm CMR, 
rescreening is allowed 9 months after (or longer) from the last central lab screening 
failure. These patients must have documented stable CMR at the local lab, and must 
meet all other criteria, before rescreening. 
b) Subjects who have received dasatinib beyond first or second line treatment and meet other 
enrollment criteria are eligible for the study provided prior TKIs were discontinued due to 
intolerance or lack efficacy, although only one instance of lack of efficacy to TKI is 
allowed.
c) ECOG PS of 0-1 (Appendix 2)
d) Life expectancy of > 1 year 
e) Adequate renal function defined as serum creatinine 3.0 times the institutional ULN
f)
Adequate hepatic function defined as: total bilirubin 3.0 times the institutional ULN; 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 5 times the 
institutional upper limit of normal (ULN).
In cases where the patient needs to restart dasatinib therapy, caution will be used in case of 
hepatic impairment.
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g) 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. Patients with low K, Mg levels, total serum Ca 
and/or ionized Ca may be repleted to allow for protocol entry. Rescreening is permitted in 
the event of temporary biochemical abnormalities.
h) Not applicable per Amendment 02.
3. Age and Reproductive Status
a) Men and women, ages 18 
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 restart of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception at the restart of 
treatment with study drug (dasatinib) and for the duration treatment 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 90 days after study entry (withdrawal of dasatinib), at restart of study 
drug (dasatinib) and for the duration of treatment with study drug (dasatinib) 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 
correctly
At a minimum, subjects must agree to the use of two methods of contraception, with one 
method being highly effective and the other method being either highly effective or less 
effective as listed in Appendix 8.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a)
Not applicable per Amendment 02.
b) Patients who have not achieved a 1-log reduction in BCR-ABL transcript levels compared 
with baseline as determined by local standards or > 10% IS [International Standard]) 
documented at 3.0-6.5 months since the initial start of dasatinib therapy. 
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c) Patients who have previously undergone hematopoietic stem cell transplantation (SCT) or 
who are scheduled for SCT
d) Not applicable per Amendment 02.
e) Previous diagnosis of CML accelerated phase or blast crisis. 
2. Medical History and Concurrent Diseases
a) Prior or concurrent malignancy, except 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
b) A serious uncontrolled medical disorder or active infection that would impair the ability of 
the subject to receive protocol therapy in case re-initiation of dasatinib is needed.
i)
Although subjects with acute hepatitis B virus (HBV) infection are excluded, subjects 
with chronic or resolved hepatitis B infection may be enrolled if they meet all other 
eligibility criteria. See Section 5.3 for recommendations regarding subjects with 
positive HBV serology.
c) Uncontrolled or significant cardiovascular disease, including any of the following: 
i)
Not Applicable per Amendment 02.
ii) Diagnosed or suspected congenital long QT syndrome
iii) Any history of significant ventricular arrhythmias for example ventricular tachycardia 
(BT), ventricular fibrillation (VF), and Torsade de Points (TdP).  
iv) prolonged QTc interval on pre-entry electrocardiogram that is considered clinically 
significant according to investigator’s criteria
v) Any history of second- or third-degree heart block (may be eligible if the subject 
currently has a pacemaker)
vi) Not applicable per Amendment 02
vii)Not applicable per Amendment 02
viii)
Not applicable per Amendment 02
d) Not applicable per Amendment 02
e) Subjects with prior history of pericardial effusion or pleural effusion that required 
thoracentesis are excluded. Subjects with prior history of pericardial or pleural effusion 
that was clinically manageable and a maintained CMR for 1 year on a stable dose of 
dasatinib are allowed. 
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f)
History of significant bleeding disorder unrelated to CML, including 
i)
Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease) 
ii) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII 
antibodies) 
3. Physical and Laboratory Test Findings
a)
Not applicable per Amendment 02.
4. Allergies and Adverse Drug Reaction
a) 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) Patients with a history of non-compliance to CML treatment and monitoring requirements 
b) Prisoners or subjects who are involuntarily incarcerated
c) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
7. Additional Criteria for Patients Eligible to Re-start Dasatinib
a) Any patient who has lost MMR and is eligible for re-starting dasatinib therapy must not 
have developed a condition that precludes dasatinib use, e.g., pulmonary arterial 
hypertension.  Such a subject will be dropped from treatment with dasatinib and treated 
according to the investigator’s choice.
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 
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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.

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
The prohibited and restricted treatment sections are applicable throughout any period when 
dasatinib is prescribed, i.e., during screening and during the restart of dasatinib when the study 
drug will be administered until the end of the study.
3.4.1
Prohibited and/or Restricted Treatments
The following treatments are prohibited throughout any period when dasatinib is prescribed, ie, 
during screening and during the restart of dasatinib when the study drug will be administered until 
the end of the study.  
Medications associated with QT interval prolongation that are prohibited in 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.
3.4.2
Other Restrictions and Precautions
The following restrictions and precautions apply throughout any period when dasatinib is 
prescribed i.e., during screening and during the restart of dasatinib when the study drug will 
be administered until the end of the study.
Caution should be exercised if subjects are required to take medications that inhibit platelet 
function or anticoagulants. Antiplatelet agents or anticoagulants should be avoided in the setting 
of Grade 3 or 4 thrombocytopenia.
Ideally, subjects should not be taking other medications known to prolong the QT interval. A 
partial list of medications known to prolong the QT interval is found in Appendix 3. However, 
should the investigator believe that therapy with a potentially QT prolonging medication (other 
than the ones explicitly prohibited) is vital to an individual subject’s care, then additional ECG(s) 
will be done at the investigator’s discretion to ensure the subject’s safety.
Caution is warranted when administering dasatinib to subjects taking drugs that are highly 
dependent on CYP3A4 for metabolism and have a narrow therapeutic index. See Appendix 4 for 
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a list of common CYP3A4 substrates. Systemic exposures to these medications could be increased 
while receiving dasatinib.21
Additionally, strong to moderate CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin) may significantly increase concentrations of dasatinib and should be used with 
caution when administered concurrently with dasatinib or imatinib. Strong to moderate CYP3A4 
inducers (eg, rifampicin) may decrease the concentration of dasatinib and should be used with 
caution when administered concurrently with dasatinib or imatinib. See Appendix 5 and Appendix 
6 for a list of CYP3A4 inhibitors and inducers respectively.
In vitro solubility data indicate that dasatinib may have decreased solubility and absorption at pH 
> 4. Until further data are available, subjects should try to avoid taking proton pump inhibitors and 
H2 antagonists. Short-acting antacid agents (eg, aluminum or magnesium hydroxide, calcium 
carbonate) may be taken, but it is recommended that these not be taken 2 hours before or 2 hours 
after dosing of dasatinib.
Based on pre-clinical data, dasatinib might increase the likelihood of bleeding. Hence, subjects 
undergoing surgical procedures, including dental procedures should be instructed to inform their 
doctors of this potential increased risk
Hematopoietic Growth Factors:
The use of G-CSF, GM-CSF, erythropoietin or darbepoetin is allowed in this study.
3.5
Discontinuation of Subjects from Treatment or from Study
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment, or to be withdrawn from study while off therapy

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject

Pregnancy

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness.
All subjects who discontinue investigational product should comply with protocol specified 
follow-up procedures as outlined in Section 5. The only exception to this requirement is when a 
subject withdraws consent for all study procedures including post-treatment study follow-up or 
loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment 
of either a psychiatric or physical illness).
If study treatment is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
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3.6
Post Treatment Study Follow up
In this study, overall survival is a key endpoint of the study. Post study follow-up is of critical 
importance and is essential to preserving subject safety and the integrity of the study. Subjects who 
discontinue the study must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Section 5 Study Procedures and Assessments 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 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 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 known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
4.
TREATMENTS
Study drugs include Investigational Medicinal Products (IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial. See 
Table 4.1 for product description.
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4.1
Study Treatments
Table 4.1-1:
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
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4.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is dasatinib. 
4.1.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products. 
This protocol does not include non-investigational products. 
4.1.3
Handling and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed 
and contact BMS immediately.
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
For non-investigational product, if marketed product is utilized, it should be stored in accordance 
with the package insert, summary of product characteristics (SmPC), or similar.
4.2
Method of Assigning Subject Identification
This is an open-label, single arm study. Subjects will be identified according to the standard trial
procedure of each site.
4.3
Selection and Timing of Dose for Each Subject
For all patients enrolled in the study, dasatinib will be discontinued upon study entry.
Patients will be closely monitored for maintenance of MMR (BCR-ABL transcripts < 0.1% on 
International Scale) after dasatinib withdrawal. In case of loss of MMR during the off treatment 
period, dasatinib treatment will be resumed at the dose the patient received before dasatinib was 
discontinued at study entry.
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A rise of PCR > 0.0032% (4.5 log reduction on IS) during the treatment discontinuation period
should not trigger a dasatinib re-initiation, as long as the BCR-ABL transcripts remain below 0.1% 
on IS.
4.3.1
Dose Adjustments
Dasatinib dose adjustments are allowed during the restart of treatment with the study drug for 
patients losing MMR. 
Dose adjustments for response and toxicity are permitted as presented in Table 4.3.1-1.  
Table 4.3.1-1:
Dose Modification Levels
Dose Level
Dasatinib
Escalation (+2)
Escalation (+1)
180 mg daily
140 mg daily
Labeled Dose
100 mg daily
Reduction (-1)
80 mg daily
Reduction (-2)
50 mg daily 
In subjects for whom the dose has been reduced to 80 mg QD of dasatinib after dasatinib restart 
due to hematologic or non-hematologic toxicities as described below, the dose of dasatinib should 
be re-escalated to 100 mg QD, if at least 1 month after the dose reduction the following occurs: (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. 
4.3.1.1
Dose Escalation
Dasatinib may be increased to 140 mg QD during the retreatment period provided that (a) there 
are no Grade 3 or Grade 4 hematologic toxicities (b) there are no additional Grade 2 
non-hematologic toxicities. Dosing above 180 mg QD of dasatinib is prohibited.
4.3.1.2
Dose Reduction Guidelines
The dose reduction guidelines for dasatinib are summarized in Table Table 4.3.1.2-1.
Dose interruptions or reductions for dasatinib related adverse events occurring on study during the 
retreatment period are described in Table 4.3.1.2-1. 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.
Dasatinib doses below 50 mg are not recommended in this protocol, unless considered by the 
investigator to be in the best interest of the subject. 
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Table 4.3.1.2-1:
Summary of Dose Reduction Guidelines
Dasatinib
Hematologic
Grade 1/2
No Dose Interruption/Reduction
Grade 3 ANC and/or 
platelets*
Hold therapy
Resume @ 100 mg after recovery to Gr1
If recurrence
Hold therapy
Resume @ 80 mg after recovery to  Gr1
If recurrence @ 80
Hold therapy
Re-challenge @ 80 mg after recovery to Gr1
If recurrence after re-challenge
Reduction to 50 mg is required
Non-hematologic
Grade 2
Hold therapy
Resume @ 100 mg after recovery to Gr1
If recurrence @ 100
Hold therapy
Resume @ 80 mg after recovery to Gr1
If recurrence @ 80
Reduction to 50 mg is required
If recurrence @ 50
Consider treatment discontinuation
Grade 3
Hold therapy
Resume @ 80 mg after recovery to Gr1
If recurrence @ 80
Hold therapy
Resume at 50 mg after recover to Gr 1
If recurrence @ 50
Consider treatment discontinuation
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Table 4.3.1.2-1:
Summary of Dose Reduction Guidelines
Dasatinib
Febrile Neutropenia
Gr3 neutropenia with Temp 
38.5C (101.3F)
Hold therapy
Initiate appropriate treatment until ANC 1,000/mm3 and temperature 
< 38C (100.4F). Resume @ 80 mg
If recurrence @ 80
Dose reduction to 50 mg is required
If recurrence @ 50
Treating physician must judge whether to rechallenge @ 50 OR discontinue 
treatment due to intolerance.
Liver Function Tests
Bilirubin > 3x institutional 
ULN
Hold until bilirubin levels have returned to a < 1.5 x institutional ULN.
Resume @ 80 mg
AST/ALT > 5x institutional 
ULN
Hold until AST/ALT levels have returned to < 2.5 x institutional ULN
Resume @  80 mg
Bleeding
Subjects who have evidence of bleeding or hemorrhage of any grade at any 
site may have dose adjustments or interruption at the discretion of the 
investigator
Gr3 anemia/ lymphopenia
No dose reductions.
Subjects developing anemia may be transfused or prescribed erythropoietin at 
the investigator’s discretion.
PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has 
rarely been reported in association with dasatinib treatment as a late event (median onset 29 months 
(range 8-75)). Patients who develop dyspnea and fatigue after initiation of dasatinib should be 
evaluated for common causes. In accordance with recommendations for management of non-
hematologic adverse reactions, the dose of dasatinib should be reduced or therapy interrupted 
during this evaluation. If no explanation is found, or if there is no improvement with dose reduction 
or interruption, a diagnosis of PAH should be considered and guidance from a cardiopulmonary 
physician sought if necessary. The diagnostic approach and follow up should follow locally 
applicable, standard practice guidelines including specialist referral, if country practice requires it. 
If PAH is confirmed, dasatinib should be permanently discontinued.
4.4
Blinding/Unblinding
Not applicable.
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Dasatinib
4.5
Treatment Compliance
When treatment with dasatinib is restarted, compliance will be monitored by drug accountability 
(pill count), as well as recording study drug administration in the subject’s medical record and 
CRF.
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.
4.6.2
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible BMS Study Monitor. 
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. 
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Dasatinib
4.7
Retained Samples for Bioavailability / Bioequivalence
At the time of receipt of the investigational product by the investigator, BMS will specify the 
appropriate number of containers or units to select for retention, the conditions of sample storage,
the required duration of sample retention, and provisions for returning or disposing of the 
investigational product. When samples are selected, containers or units should be placed in 
packaging with a tamper evident seal provided by BMS. Package labeling should clearly identify 
the contents as bioavailability/bioequivalence (BA/BE) samples and state that the investigational 
product should be stored in the restricted area with limited access.
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Dasatinib
5.
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening and Baseline Assessments
Procedure
Screening 1
Screening 2
Visit 1
(Baseline)
Notes

Visit 1 window is open until all entry criteria are 
satisfied unless otherwise specified.

Screening 2: 90 days 10 days after Screening 1.
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Serum chemistry and CBC with diff, platelets: Visit 1 
only, within 72 hrs prior to study entry
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. 
Results must be recorded on the CRF.
See Section 5.3 for recommendations regarding subjects 
with positive HBV serology.
Medical History
X
X
Pregnancy Test
X
X
At screening 
Review Contraception 
Requirements
X
X
Review contraception requirements presented in 
Section 3.3.1 and Appendix 8 with both WOCBP and male 
subjects.
Safety Assessments
Physical Examination, vital 
signs and Performance Status 
(PS)/Sokal (or Hasford) score
X
Assessment of signs and  
symptoms
X
Concomitant medications
X
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Table 5.1-1:
Screening and Baseline Assessments
Procedure
Screening 1
Screening 2
Visit 1
(Baseline)
Notes

Visit 1 window is open until all entry criteria are 
satisfied unless otherwise specified.

Screening 2: 90 days 10 days after Screening 1.
Adverse event assessment
X
ECG
X
Echocardiogram
X
Only if clinically indicated 
Serum chemistry
X
Within 72 hrs prior to study entry. 
Chest X-ray
X
Chest X-ray only if clinically 
indicated, or there is evidence of 
shortness of breath.
Efficacy-related Laboratory 
tests 
CBC with diff, platelets
X
Within 72 hrs prior to study entry.
Mutational analysis
X
Blood sample to be stored and analyzed later if 
mutations are detected in other assessments during the 
study
Molecular analysis (Q-PCR)
X
X
Q-PCR labs will be performed in a centralized lab and 
expressed on an international scale (IS)
Screening 2 molecular analysis (90 days after 
Screening 1 assessment) is required to confirm CMR 
(MR4.5).
Patient-reported Outcomes
(MDASI)-CML symptom-
burden assessment
X
Patient must complete the PROs during the study visit: 
at the beginning of the visit is preferred.
PRO assessments are not required and are not 
applicable to patients who had a legally accepted 
EORTC-QLC-C30 assessment
X
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Dasatinib
Table 5.1-1:
Screening and Baseline Assessments
Procedure
Screening 1
Screening 2
Visit 1
(Baseline)
Notes

Visit 1 window is open until all entry criteria are 
satisfied unless otherwise specified.

Screening 2: 90 days 10 days after Screening 1.
representative sign the informed request at study 
entry.
Health Care Resource 
Utilization Assessment
X
Clinical Drug Supplies
Dasatinib will be discontinued after all screening criteria are met and 
baseline assessments are completed.
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BMS-354825
Dasatinib
Table 5.1-2:
On study Assessment: Off Treatment (Dasatinib Discontinued) Assessments
Procedure
Off Treatmenta,b
Notes
Visit window is 10 days for assessment 
every 3 or 6 months. 5 days for monthly 
assessments. 
Assessments will continue throughout the 5 
year study period.
Safety Assessments
Physical Examination, vital signs and Performance 
Status (PS)
Every 3 months
Assessment of signs and symptoms 
Every 3 Months
Adverse event assessment
Every 3 Months
If a pt is taken off study due to AE, follow-up 
visits are required q 4 weeks until toxicities 
resolve to baseline or Grade ≤1, stabilize, or 
are deemed irreversible.
Concomitant medications
Every 3 Months
ECG
As clinically indicated
Echocardiogram
As clinically indicated
Serum chemistry
Every 3 months 
HBV Serology
Only once for subjects not previously tested 
within 1 year prior to Visit 1.
HBV serology test results must be recorded in the 
CRF.
See Section 5.3 for recommendations for subjects 
with positive HBV serology.
Chest X-ray
As clinically indicated
Pregnancy test
X
One month after discontinuation of dasatinib.
Review Contraception Requirements
X
Review contraception requirements presented 
in Section 3.3.1 and Appendix 8 with both 
WOCBP and male subjects
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Dasatinib
Table 5.1-2:
On study Assessment: Off Treatment (Dasatinib Discontinued) Assessments
Procedure
Off Treatmenta,b
Notes
Visit window is 10 days for assessment 
every 3 or 6 months. 5 days for monthly 
assessments. 
Assessments will continue throughout the 5 
year study period.
Efficacy Assessments
CBC with diff, platelets
Every 3 months
CBC may be done more frequently if 
clinically indicated.
Cytogenetics
At loss of MMR.b
   
Bone marrow aspirate/biopsy or peripheral 
blood (FISH) will be performed within 4 
weeks of loss of MMR. For adequate 
cytogenetic results, peripheral blood (FISH) 
should ideally be performed when the ANC > 
500/mm3
Molecular analysis/Q-PCR
Year 1: Monthly  
Year 2-5: Every 3 months (see note for 
exceptions) 
Q-PCR analyses to be performed in a 
centralized lab and expressed in International 
Scale units
Exceptions to Years 2-5, 3 monthly assessment

Subjects with BCR-ABL kinetics who 
experience the first episode of intermittent 
loss of CMR (MR4.5) (“blips” but no 
MMR loss), will have Q-PCR levels 
measured monthly for 3 months after the 
event. If MMR is maintained, Q-PCR 
levels will continue to be measured every 3 
months.
Mutational analysis
X
Mutational Analysis will be conducted any 
time there is loss of MMR, loss of CCyR or 
Loss of CHR. Samples to be drawn and stored 
for future exploratory analysis.
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BMS-354825
Dasatinib
Table 5.1-2:
On study Assessment: Off Treatment (Dasatinib Discontinued) Assessments
Procedure
Off Treatmenta,b
Notes
Visit window is 10 days for assessment 
every 3 or 6 months. 5 days for monthly 
assessments. 
Assessments will continue throughout the 5 
year study period.
Patient-reported outcomes
(MDASI) CML symptom burden assessment
Every 6 months and at loss of MMRb
Patient must complete the PROs during the 
study visit: at the beginning of the visit is 
preferred.
PRO assessments are not required and are not 
applicable to patients who had a legally 
accepted representative sign the informed 
request at study entry.
EORTC-QLC-C30
Every 6 months and at loss of MMRb
Health Care Resource Utilization Assessment
Every 3 months
Health care resource utilization will be 
assessed at each visit.
MMR = major molecular response; CCyR = complete cytogenic response; CMR= complete molecular response (MR4.5); Month = 30 days
a During the off-treatment period, each assessment time point is counted from Visit 1, the day dasatinib was discontinued.
b Patients with loss of MMR during the off-treatment period will be restarted on dasatinib at the dose received before dasatinib was discontinued at study entry. 
See Table 5.1-3 for study assessments at dasatinib restart and during treatment with dasatinib.
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Dasatinib
Table 5.1-3:
On Treatment (Dasatinib Restart) Assessments
Procedure
Restart 
dasatinib 
treatmenta,b
On treatment with 
dasatinibb
End of study visit
Notes

Visit window is 10 days for assessment every 3 
or 6 months. 5 days for monthly assessments.

Assessments will continue throughout the 
5-year study period.
Safety Assessments
Physical Examination, 
vital signs and 
Performance Status (PS)
X
Every 3 months
X
Assessment of signs and 
symptoms                           
X
Every 3 months
X
Adverse event 
assessment
X
Every 3 months
X
If a pt is taken off tx due to AE, follow-up visits are 
required q 4 weeks until toxicities resolve to 
baseline or Grade 1), stabilize, or are deemed 
irreversible.
Concomitant 
medications
X
Every 3 months
X
ECG
X
As clinically indicated
An ECG will be performed prior to dasatinib 
restart if 2 months has elapsed since the most 
recent ECG 
Echocardiogram
X
As clinically indicated
Serum chemistry
X
Every 3 months and as 
clinically indicated
X
Within 72 hours prior to restart. 
HBV Serology
Only once for subjects not previously tested within 1 year prior to 
Visit 1.
HBV serology test results must be recorded in the CRF.
See Section 5.3 for recommendations for subjects with 
positive HBV serology.
Chest X-Ray
As clinically indicated
Pregnancy test
X
Monthly
X
Within 24 hours prior to restart of study drug, and 
monthly thereafter during the on treatment study 
periods. During those months when a study visit is 
not required, a home pregnancy test must be 
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CA180406
BMS-354825
Dasatinib
Table 5.1-3:
On Treatment (Dasatinib Restart) Assessments
Procedure
Restart 
dasatinib 
treatmenta,b
On treatment with 
dasatinibb
End of study visit
Notes

Visit window is 10 days for assessment every 3 
or 6 months. 5 days for monthly assessments.

Assessments will continue throughout the 
5-year study period.
performed and the results entered on the Pregnancy 
Testing Log (Appendix 1). A pregnancy test is 
required 30 days after the last dose of study drug. 
A home pregnancy test that is positive for 
pregnancy must be confirmed at the study site.
Review Contraception 
Requirements
X
Every 3 Months
X
Review contraception requirements presented in 
Section 3.3.1 and Appendix 8 with both WOCBP and 
male subjects at restart, every 3 months, and at the end of 
study visit.
Efficacy Assessments
.
CBC with diff, platelets
X
Weekly: Month 1 and 2 after 
restart
Monthly thereafter
X
During the retreatment period, CBC will be 
performed weekly during the first two months after 
restart and then monthly thereafter or as clinically 
indicated. Additional office visits are not required; 
results are assessed by the investigator according to 
dasatinib labeling recommendations. Results do not 
require entry into the study database, unless an 
abnormal result requires adverse event reporting
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CA180406
BMS-354825
Dasatinib
Table 5.1-3:
On Treatment (Dasatinib Restart) Assessments
Procedure
Restart 
dasatinib 
treatmenta,b
On treatment with 
dasatinibb
End of study visit
Notes

Visit window is 10 days for assessment every 3 
or 6 months. 5 days for monthly assessments.

Assessments will continue throughout the 
5-year study period.
Cytogenetics
At the loss of 
MMR
Bone marrow aspirate/biopsy or peripheral blood 
(FISH) will be performed within 4 weeks of loss of 
MMR 
For adequate cytogenetic results, bone marrow 
(BM) or peripheral blood (FISH) should ideally be 
performed when the ANC > 500/mm3
Every 6 months until MMR has been regained, 
yearly thereafter. 
If CCyR is not maintained, every 6 months
Molecular analysis/
Q-PCR
X
Monthly for the first 3 
months, then every 3 months
thereafter
X
Q-PCR analyses to be performed in a centralized 
lab and expressed in International Scale units
Mutational analysis
X
See Note
X
Mutational analysis must be done at loss of MMR 
and/or failure to respond to dasatinib re-
introduction or transformation to an advanced 
phase. Samples to be drawn and stored for future 
exploratory analysis.
Patient-reported 
outcomes
(MDASI) CML 
symptom burden 
assessment
At loss of 
MMR
Every 3 months
X
Patient must complete the PROs during the study 
visit: at the beginning of the visit is preferred.
PRO assessments are not required and are not
applicable to patients who had a legally accepted 
representative sign the informed request at study 
entry.
EORTC-QLC-C30
At loss of 
MMR
Every 3 months
X
Health Care Resource 
Utilization Assessment
X
Every 3 months
X
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CA180406
BMS-354825
Dasatinib
Table 5.1-3:
On Treatment (Dasatinib Restart) Assessments
Procedure
Restart 
dasatinib 
treatmenta,b
On treatment with 
dasatinibb
End of study visit
Notes

Visit window is 10 days for assessment every 3 
or 6 months. 5 days for monthly assessments.

Assessments will continue throughout the 
5-year study period.
Clinical drug supplies
Every 3 months until dasatinib treatment stops. 
Dispense Study Drug
X
X
MMR = major molecular response; CCyR = complete cytogenic response; CMR= complete molecular response (MR4.5)’ Month - 30 days
a During the restart period, each assessment is counted from the day dasatinib treatment is restarted after the loss of MMR.
b All patients with loss of MMR during the off-treatment period will be restarted on dasatinib at the dose received before dasatinib was discontinued at study entry. 
Dasatinib will be continued for as long as the subject derives clinical benefit from the treatment or until the end of the study..
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Dasatinib
5.2
Study Materials
Special study 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.
The current version of the NCI CTCAE guide will be furnished by the sponsor to each site.
5.3
Safety Assessments 
Safety will be assessed throughout the study at the time points specified in the Flow Chart/Time 
and Event schedule presented in Section 5.1. Study drug toxicities will be assessed during the 
treatment periods. Adverse events will be evaluated according to the current version of the NCI 
CTCAE guide.
Baseline and on study safety assessments as described below include: physical examination, vital 
signs and performance Status (PS); assessment of signs and symptoms; ECG at baseline and if 
clinically indicated thereafter, echocardiogram (if clinically indicated), serum chemistry, and chest 
x-ray (if clinically indicated).
At baseline, signs and symptoms present within 2 weeks prior to study entry ie dasatinib 
discontinuation (regardless of relationship to current disease) will be obtained 
Physical examination will include assessment of spleen and liver size by manual palpation, weight, 
performance status and vital signs. Concomitant medications will be reported. An echocardiogram 
will be performed if clinically indicated as presented in Table 5.1-1, Table 5.1-2 and Table 5.1-3.
A 12-Lead ECG to determine baseline QTc will be done at baseline (screening) if clinically 
indicated, and at designated time points as clinically indicated. Additional ECGs will be done at 
the investigator’s discretion to ensure the subject’s safety, and in case of non-study drug treatment 
modifications with a potentially QT prolonging medication (other than the ones explicitly 
prohibited, refer to Section 3.4.1).
A 12-Lead ECG and echocardiogram will be conducted at the restart of the study drug if clinically 
indicated. 
The schedules of safety assessments to be conducted, during the off treatment period and in the 
event that dasatinib treatment is restarted after loss of MMR are presented in Table 5.1-2 and Table 
5.1-3. 
If a patient is taken off treatment due to an adverse event while on study, follow-up visits will be 
made at least every 4 weeks until all study related toxicities resolve to baseline (or CTC Grade 
1), stabilize, or are deemed irreversible.
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
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CA180406
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Dasatinib
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 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
Safety will be reported for all enrolled subjects, following discontinuation of dasatinib and during 
re-start with dasatinib. Adverse events and other symptoms will be graded according to the current 
version of the NCI CTCAE guide. Number of dose interruptions, dose reductions and treatment 
discontinuations for drug-related toxicity will be analyzed.
5.4
Efficacy Assessments
Efficacy will be assessed throughout the study at the time points specified in the Flow chart/time 
and event schedule presented in Section 5.1.
Baseline, off-treatment and restart assessments for the determination of efficacy include CBC with 
differential and PLT count, cytogenetics, and molecular analysis/Q-PCR.
Samples for mutational analysis will be drawn at baseline, and at the time of loss of MMR or any 
response failure as determined by other planned assessments, and as specified in the time and 
events schedule. Samples for mutational analysis will be drawn and stored for future exploratory 
analysis.
5.4.1
Efficacy Endpoints
Efficacy endpoints will be based on cytogenetic and molecular (Q-PCR performed in a centralized 
lab and expressed in IS) assessments at predefined intervals as specified in Table 5.1-1 to Table 
5.1-3.
5.4.1.1
Definition of Hematologic Response
A complete hematologic response (CHR) is obtained when all the following criteria are met in 
peripheral blood (PB) sampling:

WBC 10,000/mm3

Platelets <450,000/mm3

Peripheral blood basophils <5% 

No blasts or promyelocytes in peripheral blood

<5% myelocytes plus metamyelocytes in peripheral blood

No extramedullary involvement (including no hepatomegaly or splenomegaly). 
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Dasatinib
5.4.1.2
Definition of Cytogenetic Response 
Cytogenetic response (CyR) is based on the prevalence of Ph+ cells in metaphase from bone 
marrow (BM) sample. Ideally, 25 metaphases but at least 20 metaphases from a BM sample should 
be evaluated.22
The criteria for evaluation of CyR are as follows:22
Complete Cytogenetic Response (CCyR):  0% Ph+ cells in metaphase in BM
Partial Cytogenetic Response (PCyR):  1 to 35% Ph+ cells in metaphase in BM22
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
For the assessment of CCyR, FISH of blood interphase cell nuclei can substitute for bone marrow 
cell metaphases. CCyR is then defined by < 1% BCR-ABL1–positive nuclei of at least 200 
nuclei.13,14,23
5.4.1.3
Definition of Molecular Response
Molecular response will be assessed using BCR-ABL transcript levels measurement by real-time 
quantitative polymerase chain reaction (Q-PCR performed in a centralized lab and expressed in 
IS).
A major molecular response (MMR) is defined as BCR-ABL transcripts < 0.1% IS.13
CMR is defined as 0.0032% or 4.5 log reduction of BCR-ABL transcript levels MR 4.5. The 
rate of MMR is defined as the proportion of subjects who maintain MMR (BCR-ABL transcripts 
<0.1% (IS)) at 12, 24, 36, 48 and 60 months after dasatinib discontinuation, without restarting 
dasatinib at study entry. Also, the MMR rate will be estimated for the evaluable patients.
5.4.1.4
Event-free survival
Event free survival is defined as the time from the date of dasatinib treatment discontinuation to 
the date of loss of MMR. Patients who do not lose MMR will be censored on the date of their last 
molecular assessment.
5.4.1.5
Relapse (during off treatment period)
Relapse is defined as any of the following events while a subject is on study: the loss of MMR,
CCyR, CHR, or progression to advanced/blastic phase. Relapse-free survival (RFS) is defined as 
the time from dasatinib treatment discontinuation to the date of relapse. Patients who do not relapse 
will be censored on the date of their last molecular assessment.
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Dasatinib
5.4.1.6
Progression free survival
Progression-free survival (PFS) is defined as the time from dasatinib treatment discontinuation to 
the date of progression or death (due to any cause), whichever occurs first. Patients who neither 
progress nor die will be censored on the date of their last molecular assessment.
5.4.2
Progression
Any of the following events occurring while a subject is in the study, define progression.13,24
Progression is defined as Transformation to Accelerated Phase or Blast Crisis (AP/BC)
Accelerated Phase (AP)
Blasts in PB or BM 15–29%; Blast + promyelocytes 30% with blasts < 30% or ACA in Ph+ cells 
(clonal progression), or basophils in blood 20%,or platelets < 100 x 109 /L unrelated to therapy
Blastic Phase or Crisis (BP/BC)
Blasts in PB or BM 30%, or extramedullary blast cell involvement (with the exception of spleen 
and liver)
The date of progression will be defined as the date any of the above criteria is first met. Any subject 
who has not progressed will be censored on the date of the last examination.
5.4.3
Overall Survival
Overall survival (OS) is defined as the time from dasatinib treatment discontinuation to the date 
of death (due to any cause). Patients who do not die will be censored on their last known alive 
date.
5.5
Pharmacokinetic Assessments
Not applicable.
5.6
Biomarker Assessments
Not applicable.
5.7
Outcomes Research Assessments
 
 
 
 
 
 
 
 
 
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5.8
Other 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 and/or biopsies or peripheral blood (FISH) will be performed to monitor 
the subject’s response after restarting dasatinib therapy. 
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. 
An exploratory analysis identifying prognostic factors will be conducted including age, gender, 
Sokal risk group, time from diagnosis (months), time (months) in dasatinib-induced stable CMR 
(MR4.5) prior to discontinuation, occurrence of BCR-ABL blips, history of pleural effusion, and 
history of lymphocytosis (lymphocytes > 3.6 x 109L27,28). BCR ABL blips are any changes in 
residual level that do not have clinical relevance and does not imply loss of MMR. 
5.8.1
Hematology
CBC, differential and PLT will be obtained within 72 hours prior to enrollment and as indicated 
on the Time and Events Schedule. 
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For patients who are returned to treatment with dasatinib, CBC will be performed weekly during 
the first two months after restart and then monthly thereafter or as clinically indicated.  Additional 
office visits are not required; results are assessed by the investigator according to dasatinib labeling 
recommendations.  Results do not require entry into the study database, unless an abnormal result 
requires adverse event reporting.
5.8.2
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 within 72 hours prior to enrollment and as indicated 
on the Time and Events schedule. 
Only tests listed above are required to be collected and reported in the CRF.
5.8.3
Bone Marrow/Peripheral Blood (FISH).  
Bone marrow aspirates and/or biopsies or peripheral blood (FISH) will be performed for subjects 
at the loss of MMR by Q-PCR assessment. 
5.8.4
Molecular Analysis 
Q-PCR analyses to be performed in a centralized lab and expressed in International Scale units.
Patients in CMR with detectable BCR-ABL will be assessed monthly for the first year and every 
3 months thereafter. 
As defined in Section 5.8, BCR-ABL blips are any increases in BCR-ABL level that do not have 
clinical relevance (return to or below baseline without change in treatment and do not indicate loss 
of MMR.
5.8.5
Pregnancy Test
For women of child-bearing potential, a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of βHCG) is required at screening and 30 days after 
treatment discontinuation. 
If the dasatinib is restarted, a serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of βHCG) is required within 24 hours prior to restart, and monthly thereafter, and 
at the end of the study. A pregnancy test is required 30 days after the last dose of study drug.
Home pregnancy tests, furnished by the Sponsor, will be distributed to WOCBP along with the 
Pregnancy Testing Log (Appendix 1).  Patients are required to bring the log to each study visit. 
Pregnancy Testing Log data will be entered into the CRF. A home pregnancy test that is positive 
for pregnancy must be confirmed at the study site.
5.9
Results of Central Assessments
Q-PCR assessments will be performed in a central laboratory and results will be communicated to 
the investigator site on regular bases (e.g., within 2-3 weeks).
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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. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of investigational product, 
whether or not considered related to the investigational product.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and the AE.
Not related: There is not a reasonable causal relationship between study drug administration and 
the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE. 
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Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
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 
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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.
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
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at enrollment.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious 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 
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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).
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 pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
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 6.1.1 for 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. 
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7.
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
An external steering committee composed of clinicians who treat patients with CML-CP have been 
consulted throughout the development of the protocol and will participate in data analysis and 
interpretation.
In addition, 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 would 
have the remit of regularly assessing study progress at defined intervals (at least 2 times a year and 
ad-hoc as necessary), reviewing safety data including all SAEs, grade 3 and 4 AEs and 
discontinuations and examining critical efficacy endpoints (e.g. MMR, CCyR and disease 
progression) of the study.
8.
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
This is an open-label, single-arm study with no comparative objective. 
A 75% MMR rate at 12 months after dasatinib discontinuation is considered clinically relevant. 
Under such an assumption, a sample size of 74 patients will ensure a 20% width for a 95% 
confidence interval.  To accommodate an expected 5% drop-out rate, a total of 79 subjects will be 
enrolled into this trial.
8.2
Populations for Analyses

Enrolled subjects: All subjects who signed an informed consent.

Evaluable subjects:  All enrolled subjects who do not have any major deviations or violations 
of the protocol.  

All enrolled subjects will be used in the tabulation of subject disposition and will be used in 
the analysis of baseline characteristics and efficacy. Also, the efficacy endpoints will be 
analyzed for the enrolled and evaluable subject populations. Safety, extent of exposure, and 
health outcome will be tabulated and analyzed for the enrolled subjects. 
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary efficacy endpoint is the proportion of subjects who maintain MMR at 12 months after 
dasatinib discontinuation without re-starting dasatinib treatment in the enrolled subjects in the 
study. In addition, the MMR rate will be estimated for the evaluable subjects. Loss of MMR is 
defined per ELN definition of progression (Section 5.4.2).24 In the event that any subject 
discontinues the study or dies prior to 12 months then these events will be considered failures and 
these patients will be included in the denominator of the proportion, following the intent to treat 
principle.  
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8.3.2
Secondary Endpoint(s)
The secondary efficacy endpoints include 

event-free survival (EFS) (defined as survival with no loss of MMR) at 12, 24, 36, 48 and 
60 months after dasatinib discontinuation 

relapse-free survival (RFS) at 6, 12, 18, 24 months and every 6 months thereafter after dasatinib 
discontinuation 

assessment of BCR-ABL kinetics for subjects who experience loss of CMR but not MMR 

assessment of BCR-ABL kinetics in subjects in CMR or less with measurable levels

the rate of transformation to AP/BC

PFS

overall survival (OS)
 
 
 
 
 
 
 
 
 
 
 
8.3.4
Safety Endpoints
Safety endpoints include the frequency and CTCAE grade of adverse events during 
discontinuation of study treatment and during treatment (re-start of dasatinib), the number of dose 
interruptions, dose reductions and treatment discontinuations for drug-related toxicity.
8.3.5
Outcome Research Endpoints
Quality of life assessments: EORTC QLQ-C30 and MDASI-CML during discontinuation of study 
treatment and during treatment (re-start of dasatinib) will be evaluated. Health care utilization 
during the discontinuation of study treatment and during treatment (re-start of dasatinib) study 
periods will also be explored and reported separately from the clinical study report.
8.4
Analyses
No formal statistical testing will be performed.  Due to the study design, some of the efficacy 
endpoints usually considered as efficacy will be considered as both efficacy and safety endpoints:  
progression of disease (per ELN guidelines) which includes transformation to AP/BC and death 
due to any reason, and risk associated with re-gaining MMR following re-start of dasatinib.
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8.4.1
Demographics and Baseline Characteristics
Summary statistics will be provided for subject disposition and baseline characteristics 
(demographics, medical history, etc.) using the enrolled subject population.
8.4.2
Efficacy Analyses
The primary efficacy analysis is to estimate the rate of MMR at 12 months after dasatinib 
discontinuation without re-starting dasatinib treatment in the enrolled subject population. The 
point estimate and Clopper-Pearson two-sided 95% confidence intervals of MMR at 12 months 
will be summarized. In the event that there are either deaths or study discontinuations prior to 
12 months, these will be considered failures and these patients will be included in the denominator 
of the proportion, following the intent to treat principle risks.
The secondary analysis including time to event endpoints: EFS, RFS, PFS, OS will be analyzed 
using Kaplan-Meier Methods at yearly intervals. Rates of transformations will be analyzed as 
binary using Clopper-Pearson methods. The estimated 25th percentile, median, and 75th percentile 
of time to EFS, RFS, PFS and OS and their respective 95% confidence intervals will be provided 
if applicable. Censoring details are provided in the Section 5.4 and will be further specified in the 
statistical analysis plan (SAP). Assessment of BCR-ABL kinetics for subjects who experience loss 
of CMR but not MMR, and assessment of BCR-ABL kinetics in subjects in CMR or less with 
measurable levels will be summarized by visit and using a spider plot.
An exploratory analysis identifying prognostic factors for maintaining MMR at 12 months after 
dasatinib discontinuation without re-starting dasatinib including age, gender, Sokal risk group, 
time from diagnosis, time in dasatinib-induced stable CMR (MR4.5) prior to discontinuation, 
occurrence of BCR-ABL before loss of remission, history of pleural effusion, and history of 
lymphocytosis will be conducted. Hazard ratios and 95% confidence intervals and P-values for 
these factors will be estimated using Cox proportional hazard model. Further details will be 
included in the SAP. Additional exploratory analyses will include estimating the rates of subjects 
who achieve molecular re-response (rMMR and rCMR) and cytogenetic re-response (rCCyR and 
rPCyR) after relapse using Kaplan-Meier method, and analyzing time to re-gaining molecular 
re-response (rMMR and rCMR) and cytogenetic re-response (rCCyR and rPCyR) after relapse 
using Kaplan-Meier and Brookmeyer-Crowley methods. 
8.4.3
Safety Analyses
All safety data will be summarized using the enrolled subjects population. Frequency and CTCAE 
grading of adverse events will be summarized during off-treatment (upon discontinuation of study 
treatment) and retreatment study periods. Number of dose interruptions, dose reductions and 
treatment discontinuations for drug-related toxicity will also be summarized. Physical 
examination, vital signs and performance status, assessment of signs and symptoms, ECG, 
echocardiogram, serum chemistry, and chest x-ray will be summarized by visit.
8.4.4
Pharmacokinetic Analyses
Not applicable.
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8.4.5
Biomarker Analyses
Not applicable. 
 
 
 
 
 
8.4.7
Other Analyses 
Not applicable.
8.5
Interim Analyses
The Sponsor will conduct continuous review and reporting of safety throughout the study as 
required by GCP and routine pharmacovigilance standards. 
In case of any progression from chronic phase to accelerated phase or blast crisis during the 
discontinuation phase, the steering committee and the internal data monitoring committee will be 
consulted and the case will be discussed to decide potential early study termination. 
An interim analysis is planned when all patients have been followed until month 12 (calculated 
from discontinuation of dasatinib). This analysis will assess specific safety and efficacy endpoints 
and will be detailed in the statistical analysis plan.
Regular reviews (at least 2 times a year and ad-hoc as necessary) of safety and efficacy data listings 
and pharmacovigilance reports will be performed. These reviews will be conducted by an internal 
data monitoring committee (IDMC) made up of representatives who are independent from the 
study team. The structure, roles, and responsibilities of the IDMC, as well as the timing of analyses, 
monitoring guidelines, and content of the reports will be detailed in the charter of the IDMC.
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
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
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 done via 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. Certain CRF pages and/or electronic files may serve as the source 
documents.
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 will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details 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. 
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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) 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

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain 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 will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
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. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS 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 
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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)
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.
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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)
Serious Adverse Event
Serious adverse event defined as any untoward medical 
occurrence that at any dose: results in death; is life 
threatening (defined as an event in which the subject was at 
risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it 
were more severe), requires inpatient hospitalization or 
causes prolongation of existing hospitalization; results in 
persistent or significant disability/incapacity, is a congenital 
anomaly/birth defect; is an important medical event (defined 
as a medical event(s) that may not be immediately life 
threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require intervention [eg, 
medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above). Examples of such 
events include, but are not limited to, intensive treatment in 
an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in 
hospitalization.). For reporting purposes only, BMS also 
considers the occurrence of pregnancy, overdose (regardless 
of association with an AE), and cancer as important medical 
events.
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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
BC
Blast Crisis
BCR-ABL blips
BCR-ABL kinetics in subjects who experience intermittent loss 
of CMR (MR4.5) but no loss of MMR
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
CHR
Complete Hematologic Response
cCHR
Confirmed Complete Hematological Response
CCyR
Complete Cytogenetic Response
CyR
Cytogenetic Response
CI
Confidence Interval
CML
Chronic Myeloid Leukemia
CMR
Complete Molecular Response
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
EFS
Event-free survival
eg 
Exempli Gratia (for example)
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire
ESR
Expedited Safety Report 
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Term
Definition
FSH
Follicle Stimulating Hormone 
FISH
Fluorescent-In Situ Hybridization
GCP
Good Clinical Practice
GI
Gastrointestinal 
HCG
Human Chorionic Gonadotropin
HRT
Hormone Replacement Therapy 
HU
Hydroxyurea
ICH
International Conference on Harmonization 
IDMC
Internal Data Monitoring Committee
ie 
Id Est (that is)
IEC
Independent Ethics Committee
IM
Imatinib mesylate
-IFN
Interferon-
INR 
International Normalized Ratio
IRB 
Institutional Review Board
IS
International Scale
IU 
International Unit
IV
Intravenous
K
Kalium (Potassium)
LDH
Lactate Dehydrogenase
LVEF
Left Ventricular Ejection Fraction
MCyR
Major Cytogenetic Response
mg 
Milligram
Mg 
Magnesium
M
microMolar
MMR
Major Molecular Response
MR
Molecular response
MR4.5
≤ 0.0032% (IS) or 4.5 log reduction of BCR-ABL transcript as 
determined by local standards 
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
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Term
Definition
PFS 
Progression-Free Survival
pH
-log10 Hydrogen Ion Concentration
Ph+
Philadelphia Chromosome Positive
PLT
Platelets
p.o.
Per os (by mouth)
PS
Performance Status
PTK
Protein Tyrosine Kinase
Q
Every
QD
once daily
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)
rCMR
Re-attainment of Complete Molecular Response after relapse 
rMMR
Re-attainment of Major Molecular Response after relapse
RQ-PCR
Real-time Quantitative Polymerase Chain Reaction
SAE
Serious Adverse Event
SCT
Stem cell transplant
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
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APPENDIX 1
PREGNANCY TESTING LOG
Subject Identifier:   
Protocol Number: CA180-406
Investigator:  
Site Number:
Beginning Date:
End Date:
Please fill in the information monthly and bring the log to your doctor visits
Month
(Jan, Feb, ...)
Was the test 
performed?
(Circle)
Date of Test
Day / Month / Year
*Test Results
(Circle)
Yes             No
Negative                  Positive
Yes             No
Negative                  Positive
Yes             No
Negative                  Positive
Yes             No
Negative                  Positive
Yes             No
Negative                  Positive
Yes             No
Negative                  Positive
Yes             No
Negative                  Positive
Yes             No
Negative                  Positive
Yes             No
Negative                  Positive
Yes             No
Negative                  Positive
Yes             No
Negative                  Positive
Yes             No
Negative                  Positive
* IF ANY TEST IS POSITIVE, PLEASE CONTACT YOUR DOCTOR IMMEDIATELY.
Please fill in the information monthly and bring the log to your doctor visits
  
CA180-406                               Property of BMS and Confidential                                                                 Page ___of  ___
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Guidelines of Acceptable Methods of Contraception 
NOTE: The wording below is provided as an example and may be revised based on local input 
and requests, as long as protocol requirements are maintained. 
Use of dasatinib during pregnancy can be harmful to the developing fetus (baby), potentially 
resulting in birth defects or the death of the fetus. At a minimum, you must agree to use two 
methods of contraception. One method must be highly effective (selected from Section A below) 
and the second method must be either highly effective or less effective (selected from Section B 
below):
A. HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly Effective contraception methods are as follows:
1. Progestogen only hormonal contraception associated with inhibition of ovulation.
2. Hormonal methods of contraception including oral contraceptive pills containing  
combined estrogen + progesterone, vaginal ring, injectables, implants and intrauterine 
devices (IUDs) such as Mirena
3. Nonhormonal intrauterine devices (IUDs), such as ParaGard® 
4. Bilateral tubal occlusion (also known as having tubes tied)
5. Vasectomised partner with documented azoospermia 90 days (test done to show that 
there is no sperm)  after procedure 
a.
Vasectomised partner is a highly effective birth control method provided that 
partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomised partner has received medical assessment of the surgical success.
b. If using this method of contraception, male subjects with partners who are 
WOCBP must also use condoms.
6. Intrauterine hormone-releasing system (IUS).
7. Complete abstinence
a.
Complete abstinence is defined as the complete avoidance of heterosexual 
intercourse.
b. Complete abstinence is an acceptable form of contraception for all study drugs 
and must be used throughout the duration of the study treatment plus 31 days.
c.
It is not necessary to use any other method of contraception when complete 
abstinence is elected.
d. If you choose complete abstinence, you must continue to have pregnancy tests 
monthly
B. LESS EFFECTIVE METHODS OF CONTRACEPTION
1. Diaphragm with spermicide
2. Cervical cap with spermicide
3. Vaginal sponge with spermicide
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4. Male or female condom with or without spermicide*
5. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action.
* A male and a female condom must not be used together.
C. UNACCEPTABLE METHODS OF CONTRACEPTION
1. Periodic abstinence (calendar, symptothermal, post-ovulation methods)
2. Withdrawal (coitus interruptus)
3. Spermicide only
4. Lactation amenorrhea method (LAM)
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APPENDIX 3
MEDICAL CONDITIONS AND DRUGS WHICH MAY CAUSE QTC 
PROLONGATION AND TORSADE DE POINTES (NOT ALL 
INCLUSIVE)
Refer to http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm
Patients are prohibited from taking medications listed in the Known Risk of Torsade de Pointes
Category. Caution is warranted when administering BMS-354825 to subjects taking drugs 
associated with prolongation of QTc listed in Possible Risk of Torsade de Pointes and 
Conditional Risk of Torsade de Pointes Categories. A separate study document delineating 
medications currently listed in all risk categories will be provided and updated as necessary.
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APPENDIX 4
COMMON CYP3A4 SUBSTRATES (NOT ALL INCLUSIVE)
The following lists describe medications which are common CYP3A4 substrates. This list should 
not be considered all inclusive. Consult individual drug labels for specific information on a 
compound’s propensity for metabolism by CYP3A4.
Macrolide Antibiotics:
clarithromycin
erythromycin
NOT azithromycin
Anti-arrhythmics:
quinidine
Benzodiazepines:
alprazolam
diazepam
midazolam
triazolam
Immune Modulators:
cyclosporine
tacrolimus (FK506)
HIV Antivirals:
indinavir
nelfinavir
ritonavir
saquinavir
Antihistamines:
astemizole
chlorpheniramine
terfenidine
Calcium Channel Blockers:
amlodipine
diltiazem
felodipine
lercanidipine
nifedipine
nisoldipine
nitrendipine
verapamil
HMG CoA Reductase Inhibitors:
atorvastatin
cerivastatin
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lovastatin
NOT pravastatin
Simvastatin
Steroid 6beta-OH:
estradiol
hydrocortisone
progesterone
testosterone
Others:
alfentanyl
buspirone
cafergot
caffeine
cocaine
dapsone
codeine-N-demethylation
dextromethorphan
eplerenone
fentanyl
finasteride
gleevec
haloperidol
irinotecan
LAAM
lidocaine
methadone
odanestron
pimozide
propranolol
quinine
salmetrerol
sildenafil
sirolimus
tamoxifen
taxol
terfenadine
trazodone
vincristine
zaleplon
zolpidem
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APPENDIX 5
COMMON CYP3A4 INHIBITORS (NOT ALL INCLUSIVE)
The following lists describe medications and foods which are strong to moderate inhibitors of
CYP3A4. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit CYP3A4.
Table App. 5:
CYP3A4 Inhibitors
Strong CYP3A4 Inhibitors
Moderate CYP3A4 Inhibitors
Weak CYP3A4 Inhibitors
5-fold increase in AUC
2 but < 5-fold increase in AUC
1.25 but < 2-fold increase in AUC
atazanavir, clarithromycin, 
indinavir, itraconazole, 
ketoconazole, nefazodone, 
nelfinavir, ritonavir, saquinavir, 
telithromycins
amprenavir, aprepitant, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, grapefruit juice(a), 
verapamil
cimetidine
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APPENDIX 6
COMMON CYP3A4 INDUCERS (NOT ALL INCLUSIVE)
The following lists describe medications which are common inducers of CYP3A4. This list 
should not be considered all inclusive. Consult individual drug labels for specific information on 
a compound’s propensity to induce CYP3A4.
HIV Antivirals:
efavirenz
nevirapine
Others:
barbiturates
carbamazepine
glucocorticoids
modafinil
phenobarbital
phenytoin
rifampin
St. John’s wort
troglitazone
pioglitazone
rifabutin
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APPENDIX 8
METHODS OF CONTRACEPTION
At a minimum, women of childbearing potential (WOCBP) and WOCBP who are partners of 
male subjects must agree to the use of two methods of contraception, with one method being 
highly effective and the other method being either highly effective or less effective as listed 
below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently 
and correctly. Male subjects must inform their female partners who are WOCBP of the 
contraceptive requirements of the protocol are expected to adhere to using contraception
(including condoms as the required second method) with their partner. Contraception methods 
are as follows:
1. Progestogen only hormonal contraception associated with inhibition of ovulation.
2. Hormonal methods of contraception including oral contraceptive pills containing  
combined estrogen + progesterone, vaginal ring, injectables, implants and intrauterine 
devices (IUDs) such as Mirena
3. Nonhormonal IUDs, such as ParaGard
4. Bilateral tubal occlusion
5. Vasectomised partner with documented azoospermia 90 days after procedure
Vasectomised partner is a highly effective birth control method provided that partner 
is the sole sexual partner of the WOCBP trial participant and that the vasectomised 
partner has received medical assessment of the surgical success.
If using this method of contraception, male subjects with partners who are WOCBP 
must also use condoms.
6. Intrauterine hormone-releasing system (IUS).
7. Complete abstinence
Complete abstinence is defined as the complete avoidance of heterosexual 
intercourse. (refer to Glossary of Terms)
Complete abstinence is an acceptable form of contraception for all study drugs and 
must be used throughout the duration of the study treatment (plus 5 half-lives of the 
investigational drug plus 30 days).
It is not necessary to use any other method of contraception when complete 
abstinence is elected.
Subjects who choose complete abstinence must continue to have pregnancy tests, as 
specified in Section 6.4
Acceptable alternate methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete abstinence.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the subject.
LESS EFFECTIVE METHODS OF CONTRACEPTION
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1. Diaphragm with spermicide
2. Cervical cap with spermicide
3. Vaginal sponge with spermicide
4. Male or female condom with or without spermicide*
5. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action.
* A male and a female condom must not be used together.
UNACCEPTABLE METHODS OF CONTRACEPTION
1) Periodic abstinence (calendar, symptothermal, post-ovulation methods)
2) Withdrawal (coitus interruptus)
3) Spermicide only
4) Lactation amenorrhea method (LAM)
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SAP_001.pdf: 
Official Title of Study:  
Open-Label Single Arm Phase 2 Study Evaluating Dasatinib Therapy Discontinuation In Patients 
With Chronic Phase Chronic Myeloid Leukemia (CP-CML) With Stable Complete Molecular 
Response (CMR) DASFREE 
 
NCT Number: NCT01850004 
 
Document Date (Date in which document was last revised):  13-July-2018 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
OPEN-LABEL SINGLE ARM PHASE 2 STUDY EVALUATING DASATINIB THERAPY 
DISCONTINUATION IN PATIENTS WITH CHRONIC PHASE CHRONIC MYELOID 
LEUKEMIA (CP-CML) WITH STABLE COMPLETE MOLECULAR RESPONSE (CMR) 
DASFREE
PROTOCOL(S) CA180406
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3 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT .....................................1 
2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................5 
1 
6 
2 
STUDY DESCRIPTION ..............................................................................................7 
2.1 
Study Design .................................................................................................................7 
2.2 
Treatment Assignment ..................................................................................................8 
2.3 
Blinding and Unblinding ..............................................................................................8 
2.4 
Protocol Amendments ..................................................................................................9 
3 
OBJECTIVES .............................................................................................................10 
3.1 
Primary .......................................................................................................................10 
3.2 
Secondary ...................................................................................................................10 
3.3 
10 
4 
ENDPOINTS ..............................................................................................................11 
5 
SAMPLE SIZE AND POWER ..................................................................................11 
6 
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES .......................................................................................................11 
6.1 
Study Periods ..............................................................................................................11 
6.2 
Treatment Regimens ...................................................................................................12 
6.3 
Populations for Analyses ............................................................................................12 
6.4 
Subgroups for Analyses ..............................................................................................12 
7 
STATISTICAL ANALYSES .....................................................................................13 
7.1 
General Methods .........................................................................................................13 
7.2 
Analysis Visits ............................................................................................................14 
7.3 
Study Conduct ............................................................................................................15 
7.4 
Study Population .........................................................................................................15 
7.4.1 
Subject Disposition .....................................................................................................15 
7.4.2 
Protocol Deviations ....................................................................................................16 
7.4.3 
Demographic and Baseline Characteristics ...............................................................17 
7.5 
Medical History ..........................................................................................................17 
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7.6 
Extent of Exposure .....................................................................................................18 
7.6.1 
18 
7.7 
Efficacy .......................................................................................................................18 
7.7.1 
Primary Efficacy Endpoint .........................................................................................21 
7.7.1.1 
Primary Analysis ........................................................................................................21 
7.7.2 
Secondary Efficacy Endpoints ....................................................................................21 
7.7.2.1 
Secondary Analysis .....................................................................................................21 
7.7.3 
23 
7.7.3.1 
Exploratory Analysis ..................................................................................................24 
7.8 
Safety ..........................................................................................................................25 
7.8.1 
Adverse Events ............................................................................................................25 
7.8.2 
Adverse Events of Special Interest ..............................................................................26 
7.8.3 
Electrocardiograms, Echocardiograms and Chest X-rays .........................................27 
7.8.4 
Clinical Laboratory Evaluations ................................................................................27 
7.8.4.1 
Hematology .................................................................................................................27 
7.8.4.2 
Serum Chemistry .........................................................................................................27 
7.8.5 
Vital Signs ...................................................................................................................27 
7.8.6 
Physical Examination .................................................................................................27 
7.8.7 
Pregnancy ...................................................................................................................27 
7.9 
28 
7.10 
 
 
 
 
28 
8 
INTERIM ANALYSIS ...............................................................................................29 
8.1 
General Information ....................................................................................................29 
8.1.1 
Statistical Approaches ................................................................................................29 
9 
CONVENTIONS ........................................................................................................29 
10 
CONTENT OF REPORTS .........................................................................................30 
11 
31 
APPENDIX 1 
SUMMARY OF DOSE REDUCTION GUIDELINES ............................32 
APPENDIX 2 
34 
APPENDIX 3 
STUDY ASSESSMENTS AND PROCEDURES .....................................37 
 
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LIST OF TABLES
Table 2.2-1: 
Product Descriptions....................................................................................8
Table 2.4-1: 
Protocol Amendments..................................................................................9
Table 7.2-1: 
Analysis of Study Visits for Molecular Response .....................................14 
Table 7.2-2: 
Analysis of Study Visits for Safety Endpoints and PRO...........................14
Table 7.7.2.1-1: 
Time-to-Event Censoring...........................................................................22 
LIST OF FIGURES
Figure 2.1-1: 
Study Design Schematic ..............................................................................8
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Schedule of Analyses: 
The primary analysis will be performed   when the primary endpoint, MMR status at 12 months 
after dasatinib discontinuation is available to be evaluated for all the enrolled subjects.  
In addition to primary analysis, an interim analysis is planned when 30 patients have been followed 
for 12 months after discontinuation of dasatinib. This analysis will assess specific safety and 
efficacy endpoints and will be detailed in the statistical analysis plan. 
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Regular reviews of safety and efficacy data listings and pharmacovigilance reports will be 
performed. These reviews will be conducted by an internal data monitoring committee (IDMC) 
made up of representatives who are independent from the study team. The structure, roles, and 
responsibilities of the IDMC, as well as the timing of analyses, monitoring guidelines, and content 
of the reports will be detailed in the charter of the IDMC. 
This regular review will be repeated at 6 months intervals until the final analysis is conducted 
when all patients have been followed for 5 years. 
2 
STUDY DESCRIPTION 
2.1 
Study Design 
This is an open-label, single-arm study in adult patients with CP-CML who have received dasatinib 
treatment for a minimum of 2 years at the time of enrollment and have confirmed dasatinib-induced 
complete molecular remission (defined as  4.5-log reduction of BRC-ABL transcript as 
determined by local standards) ongoing for at least 1 year immediately prior to study enrollment. 
Prospective patients will be prescreened to confirm dasatinib-induced CMR stable for a minimum 
of nine months. CMR must be documented by at least three assessments, 2-6.5 months apart 
conducted at a local lab. Once stable CMR is confirmed at prescreening, patients are eligible for 
the study sponsored molecular analyses conducted via the central lab. If the first study sponsored 
molecular analysis assessment confirms CMR, the assessment will be repeated after three months. 
Patients are eligible for enrollment if both assessments from the central lab confirm CMR (MR4.5). 
Once all eligibility criteria are met, patients will be enrolled and dasatinib will be discontinued. 
Patients will be monitored for maintenance of MMR (BCR-ABL transcripts < 0.1% IS). In case of 
loss of MMR, dasatinib treatment will be resumed at the dose level the patient was receiving before 
dasatinib was discontinued at study entry. Patients who have restarted treatment due to loss of 
MMR will remain on treatment for the duration of the study. Dose escalations and adjustments in 
case of toxicities are permitted as described in Section.4.3.1 (Dose Adjustments) of the protocol. 
A rise of PCR > 0.0032% (4.5 log reduction) on international scale (IS) after discontinuation of 
dasatinib should not trigger dasatinib re-initiation, if the BCR-ABL transcripts remain below 0.1% 
on IS. All patients on study will be followed for 5 years after enrollment. The study will end 5 
years after the first visit of the last enrolled patient. 
The study design schematic is presented in Figure 2.1-1. 
 
 
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Figure 2.1-1: 
Study Design Schematic 
 
2.2 
Treatment Assignment 
This is an open-label, single arm study. Patients will be identified according to the standard trial 
procedure of each site. 
Study drugs include Investigational Medicinal Products (IMP) and can consist of the following: 
All products, active or placebo, being tested or used as a comparator in a clinical trial. See Table 
2.2-1 for product description. 
Table 2.2-1: 
Product Descriptions 
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 
 
2.3 
Blinding and Unblinding 
Not applicable. 
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3 
OBJECTIVES 
3.1 
Primary 
The primary objective of this study is to assess the rate of MMR, defined as the proportion of 
patients who maintain MMR (BCR-ABL transcripts < 0.1% on IS) at 12 months after dasatinib 
discontinuation, without re-starting dasatinib treatment. 
3.2 
Secondary 
The secondary objectives of this study are to assess the following: 
 Event-free survival (EFS) (defined as no loss of MMR) at 12, 24, 36, 48 and 60 months after 
dasatinib discontinuation 
 Relapse-free survival (RFS) at 6, 12, 18, 24 months after dasatinib discontinuation and every 
6 months thereafter. 
 Assessment of BCR-ABL kinetics in those patients who experience loss of CMR (MR4.5) but 
no loss of MMR (BCR-ABL kinetics are any changes in residual level that do not have clinical 
relevance). 
 Assessment of BCR-ABL kinetics in patients who are in CMR (MR4.5) where transcript levels 
are still measurable. 
 Rate of transformation to AP/BC. 
 Progression free survival (PFS). 
 Overall survival (OS). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4 
ENDPOINTS 
Primary Efficacy Endpoints: 
The primary efficacy endpoint is the proportion of patients who maintain MMR at 12 months after 
dasatinib discontinuation without re-starting dasatinib treatment in the enrolled patients in the 
study. 
Secondary Efficacy Endpoints: 
The secondary efficacy endpoints include: 
 EFS at 12, 24, 36, 48 and 60 months after dasatinib discontinuation 
 RFS at 6, 12, 18, 24 months and every 6 months thereafter after dasatinib discontinuation. 
 Assessment of BCR-ABL kinetics for patients who experience loss of CMR but not MMR. 
 Assessment of BCR-ABL kinetics in patients in CMR with measurable levels. 
 The rate of transformation to AP/BC 
 PFS 
 OS 
Safety endpoints include incidence of AEs, serious AEs, AEs leading to discontinuation, and death 
as well as marked abnormalities in clinical laboratory tests, vital sign measurements, ECGs, and 
physical examinations. 
Quality of life assessments: EORTC QLQ-C30 and MDASI-CML during discontinuation of study 
treatment and during treatment (re-start of dasatinib) will be evaluated. Health care utilization 
during the discontinuation of study treatment and during treatment (re-start of dasatinib) study 
periods will also be explored and reported separately from the clinical study report. 
5 
SAMPLE SIZE AND POWER 
This is an open-label, single-arm study with no comparative objective.  
A 75% MMR rate at 12 months after dasatinib discontinuation is considered clinically relevant. 
Under such an assumption, a sample size of 74 patients will ensure a 20% width for a 95% 
confidence interval.  To accommodate an expected 5% drop-out rate, a total of 79 patients will be 
enrolled into this trial. 
6 
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES 
6.1 
Study Periods 
All patients in the study will be followed for 5 years after enrollment.  The study will end 5 years 
after the first visit of the last enrolled patient.  The study will consist of 3 study periods: on-
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treatment during the screening period; off-treatment (upon discontinuation of dasatinib); and on-
treatment study periods.   
The on-treatment during screening period is defined as the period between the date of informed 
consent and the day prior to the start date of dasatinib discontinuation.  The off-treatment period 
is defined as the period between the start date of dasatinib discontinuation and the date when a 
patient start losing MMR, or the last date in the study, whichever occurs first. For patients who 
restarted dasatinib, the on-treatment after restarting dasatinib is defined as the period between the 
date dasatinib is restarted and the last date in the study. 
The study design schematic is presented in (Figure 2.1-1). 
6.2 
Treatment Regimens 
All enrolled patients will discontinue dasatinib at baseline visit. Patients will be identified 
according to the standard trial procedure of each site. 
6.3 
Populations for Analyses 
 Enrolled patients: All patients who signed an informed consent and meet study eligibility 
criteria and are discontinued from dasatinib. 
 Evaluable patients:  All enrolled subjects who have at least one BCR-ABL assessment.   
All enrolled patients will be used in the tabulation of subject disposition and will be used in the 
analysis of baseline characteristics and efficacy.  Also, the efficacy endpoints will be analyzed for 
evaluable subject population.  Safety, and health outcome will be tabulated and analyzed for the 
enrolled patients. Extent of exposure will be summarized in the enrolled patients who restarted 
dasatinib. 
6.4 
Subgroups for Analyses 
Efficacy will be described for each of the following subgroups:  
 Patients in CMR (MR4.5)  ≤ 24 months prior to dasatinib discontinuation are those patients 
who achieve a sustained CMR (≤0.0032% (IS) or ≥4.5 log reduction of BCR-ABL transcript 
levels as determined by local standards) for a duration of up to and including 24 months 
calculated from the date patients achieve CMR for the first time up to the date of baseline visit. 
 Patients in CMR (MR4.5)  > 24 months prior to dasatinib discontinuation are those patients 
who achieve a sustained CMR for a duration superior to 24 months calculated from the date 
patients achieve CMR for the first time up to the date of baseline visit. 
 Patients with first versus patients with second or third line of therapy. 
 Patients with Dasatinib as second or third line of therapy due to Resistance vs due to 
Intolerance. 
Subgroups of patients with resistance and intolerance to 2nd or 3rd line of therapy (i.e., imatinib, 
nilotinib, ponatinib or bosutinib) will be defined as follows:  
 If patient has "disease progression" or "inadequate response" entered under “Reason for 
Therapy Action” box in the “Previous and Concomitant Therapies for CML” electronic case 
report form (eCRF) page this will be counted as resistance; 
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 It will be counted as intolerance if patient has "side effects", or "Other: side effect", or 
"hematologic side effect", or "non-hematologic side effect", or “musculoskeletal side effect", 
or "non-hematologic adverse event" entered under “Reason for Therapy Action” box in the 
“Previous and Concomitant Therapies for CML” eCRF page.   
If an instance of resistance is recorded, no matter if a second event of intolerance is recorded, this 
patient is considered as a resistant subject.  
Subgroups of patients with dasatinib as first line or second/third line treatment will be defined 
based on the information collected at study entry through the “Previous and Concomitant 
Therapies for CML” eCRF page.  
 Patients with dasatinib as first line treatment are those patients that responded “Yes” to the 
question “Did subject take previous or current therapies?” and have only dasatinib or Sprycel 
recorded under “Therapy” will be considered under the subgroup of patients with dasatinib as 
first line treatment. If the patient has at least one record with Imatinib, or Gleevec, or Glivec, 
or Tasigna, or Nilotinib or Ponatinib or Bosutinib under “Therapy” then such patient will not 
be included in the subgroup of patients with dasatinib as first line of treatment. 
 Patients with dasatinib as second/third line treatment are those patients that responded “Yes” 
to the question “Did subject take previous or current therapies?” and have either Imatinib, or 
Gleevec, or Glivec, or Tasigna, or Nilotinib or Ponatinib or Bosutinib recorded under 
“Therapy” with a start date and end date of therapy prior to date of study entry (i.e. date 
informed consent form signed) will be considered under the subgroup of patients with dasatinib 
as second/third line treatment. Hydrea or Hydroxyurea are not to be considered as prior 
therapies. 
7 
STATISTICAL ANALYSES 
SAS® Version 9.2 or higher will be used for statistical analyses, tabulations, and graphical 
presentations.  
7.1 
General Methods 
In the analysis 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. 
Summary statistics will consist of the number and percentage of patients in each category for 
discrete variables, and the sample size, mean, median, standard deviation (SD), minimum and 
maximum for continuous variables.   
All mean and median values will be formatted to one or more decimal place than the measured 
value.  Standard deviation values will be formatted to two or more decimal places than the 
measured value.  Minimum and maximum values will be formatted to the same decimal place as 
the measured value.  All percentages will be rounded to one decimal place.  The number and 
percentages of responses will be presented in the form XX (XX.X), where the percentage is in the 
parentheses. 
All analysis and summary tables will have the analysis population sample size (i.e., number of 
patients) in the column heading. All listings will be sorted for presentation in order of subject 
identification and date of procedure or event. 
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Confidence intervals (CIs) will be presented as 2-sided 95% CIs unless specified differently for a 
given analysis.
Baseline value will be defined as the last assessment conducted on or prior to visit 1 (baseline 
visit).
7.2
Analysis Visits
For binary outcome of molecular response, study visits will be analyzed on the basis of the events 
schedule specified in the study protocol (Section 5.1), allowing a little variance in actual practice. 
Subjects who remained MMR up to 12 months need to keep BCR-ABL transcripts < 0.1% IS for 
at least 345 days. The detail for each analysis visit is specified in Table 7.2-1
Table 7.2-1:
Analysis of Study Visits for Molecular Response
Nominal Visits
Target Day from 
Off Treatment
Remains MMR up to 
Nominal Visit
6 Months
165 days
>= 160 days
12 Months
350 days
>= 345 days
24 Months
730 days
>= 715 days
36 Months
1095 days
>= 1080 days
48 Months
1460 days
>= 1445 days
60 Months
1825 days
>= 1810 days
Subjects who remained MR4.5 will be analyzed in the same method. 
Safety endpoints and patients reported outcomes (PRO) are evaluated in either 3 months or 6 
months interval. They will be analyzed by analysis visits based on the events schedule specified 
in the study protocol (Section 5.1). Please note that if subjects’ measurements were done just 1 
day later than the dasatinib discontinuation date, it will be still included in defining baseline. The 
detail of each analysis visit is specified in Table 7.2-2
Table 7.2-2:
Analysis of Study Visits for Safety Endpoints and PRO
Nominal Visits
Target Day from Off 
Treatment
Analysis Visit Window
Baseline
On or prior to dasatinib 
discontinuation
<= start day of dasatinib discontinuation +1
3 Months
90 days
3 – 100 days
6 Months
180 days
101 – 190 days
9 Months
270 days
191 – 280 days
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Table 7.2-2:
Analysis of Study Visits for Safety Endpoints and PRO
Nominal Visits
Target Day from Off 
Treatment
Analysis Visit Window
Every 3 Months 
thereafter
Months*30 days
((Months – 3)*30 + 11) 
– (Month*30 + 10) days
Restart Baseline
On or prior to restarting 
dasatinib
<= restart day
3 Months after 
restarting dasatinib
90 days since restarting 
dasatinib
(Restart day + 1)
– (Restart day + 99) days
6 Months after 
restarting dasatinib
180 days since restarting 
dasatinib
(Restart day + 100) 
– (Restart day + 189) days 
9 Months after 
restarting dasatinib
270 days since restarting 
dasatinib
(Restart day + 190)
– (Restart day + 279) days
Every 3 Months 
thereafter
(Restart Visit Number –
1)*90 days since restarting 
dasatinib
((Restart Visit Number – 2)*90 + 11) –
(Restart Visit Number – 1)*90 + 10) days
If more than one result for a parameter is obtained in an analysis visit window, the result with the 
data closest to the target day of the scheduled visit will be used. In the event of 2 observations 
equidistant to the target day, the later of the observations will be used. In case there are two 
observations collected at the same day, the worse value will be used.
7.3
Study Conduct
All patients with any relevant protocol deviations or violations will be identified.  All protocol 
deviations will be listed and summarized in the study report. The relevant protocol deviations are 
listed in Section 7.4.2 below.
7.4
Study Population
7.4.1
Subject Disposition
The total number of patients enrolled into the study will be presented.  The screen failures and 
reasons for screen failures will be summarized by frequency and percentage of the total number of 
subjects screened.
The number and percentage of patients who restarted treatment, reasons for restarting treatment, 
and patients who discontinued study drug after restarting treatment will be presented for the on-
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treatment study period and total number of patients enrolled into the study. Reasons for restarting 
treatment will be summarized for all patients with the following categories: 
 Failure to maintain MMR levels of BCR-ABL lower than 0.1% on IS 
 Loss of CHR 
 Loss of CCyR 
 Other 
The number and percentage of patients who discontinued the study will be summarized during off-
treatment period (upon discontinuation of dasatinib), the on-treatment period, and total number of 
patients enrolled into the study.  Reasons for discontinuation from the study will be summarized 
for all patients with the following categories: 
 Disease progression 
 Adverse Events (AEs) related to study drug 
 Death 
 AE unrelated to study drug 
 Subject request to discontinue treatment 
 Subject withdrew consent 
 Lost to follow-up 
 Maximum clinical benefit 
 Poor/non-compliance 
 Subject no longer meets study criteria 
 Administrative reason by Sponsor 
 Other 
Finally, summary statistics for the distribution of time after dasatinib discontinuation will be 
presented for the total number of patients enrolled, subjects that reached at least 6 and 12 months 
after discontinuation of dasatinib.  Number of patients enrolled will also be presented for each site. 
A by-patient listing of study disposition in the enrolled population will be provided. 
7.4.2 
Protocol Deviations 
Each patient’s data will be examined for protocol deviations.  The relevant protocol deviations will 
be summarized for the enrolled population.  Relevant protocol deviations will be programmatically 
determined from the clinical database.  The following relevant protocol deviations will be 
summarized: 
 Violation of inclusion criteria (only 2.a and 2.b) 
 Violation of exclusion criteria (only 1.b, 1.c, and 1.e) 
 Molecular labs never done 
 Molecular labs done late 
 No treatment restart after loss of MMR 
 
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A by-patient listing of patients with all protocol deviations will be provided.   
The inclusion and exclusion criteria are described in Sections 3.3.1 and 3.3.2., respectively, in the 
protocol.  
7.4.3 
Demographic and Baseline Characteristics 
The demographic and baseline characteristics will be summarized for the enrolled population.   
The following demographic and baseline characteristics will be summarized: 
 Age (years) 
 Gender 
 Race 
 Performance status (Eastern Cooperative Oncology Group -  ECOG) 
 Prior Interferon-α (IFN)  
 Sokal 
 Time from diagnosis to dasatinib discontinuation 
 Time in MR 4.5 before dasatinib discontinuation 
 Last Dose of Dasatinib received prior to discontinuation 
The above demographic and baseline characteristics will also be summarized separately for those 
patients who lose MMR and patients who do not lose MMR. 
Finally, the number and percentage of treatment restart status in patients with the loss of MMR 
will the summarized.  A detailed summary of treatment restart status will be reported to include 
the number of patients with loss of MMR, the number of patients who restart along with reasons 
and did not restart treatment along with reasons, number of patients who restarted treatment and 
regained MMR/CMR(MR4.5) (separately), and time to regain MMR/CMR(MR4.5) (separately), 
and number patients who restarted treatment and did not regain MMR, and time from restart date 
to latest visit date (<=6 months, >6 months). For those patients who restarted dasatinib treatment 
and regained MMR/CMR(MR4.5), time to regain MMR/CMR(MR4.5) will be calculated as 
follows: 
 Time to regain MMR(months) = [(date regained MMR – date restarted dasatinib treatment)+1] 
/ 30.4375 
 Time to regain CMR(MR4.5) (months) = [(date regained CMR(MR4.5) – date restarted 
dasatinib treatment)+1] /30.4375 
The reasons for restarting/not restarting treatment will be taken from the dasatinib treatment restart 
status page of the CRF. 
7.5 
Medical History 
A summary of relevant medical history/current medical conditions will be summarized by system 
organ class (SOC), coded according to the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA).   
A by-patient listing of medical history in the enrolled population will be provided. 
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7.6
Extent of Exposure
Dasatinib dose adjustments are allowed during the restart of treatment with the study drug for 
patients losing MMR.  In the case of loss of MMR during the off treatment period, dasatinib 
treatment will be resumed at the dose the patient received before dasatinib was discontinued at 
study enrollment.  Dose adjustments for response and toxicity are presented in Table 4.3.1 of the 
protocol.
Dose reduction is defined as when the dose assigned after restarting dasatinib is at a lower dose 
level than the assigned dose at the previous visit. 
Dose interruption is defined as omission of dosing on at least 2 consecutive study days during the 
on-treatment study periods.  If a patient does not resume dosing, then this will not be considered a 
dose interruption and will be considered a treatment discontinuation.
Treatment discontinuation is defined as when a patient discontinues dasatinib after restarting 
dasatinib due to loss of MMR.
Dose interruptions or reductions for dasatinib related AEs occurring on study during the on-
treatment periods are described in APPENDIX 1.
Treatment exposure and dose reductions and interruptions will be summarized as follows during
the on-treatment study period (patients who restart dasatinib):

Number of doses administered and duration (months) of exposure

Number and percentage of patients with at least 1 dose reduction, number of dose reductions,
and reasons (adverse event or other) for reduction

Number and percentage of patients with at least 1 dose interruption, number of dose 
interruptions

Number and percentage of patients with a treatment discontinuation
A summary of each patient’s exposure will be presented in a listing.
7.6.1
Concomitant Medications
Medications reported on the Concomitant medications CRF pages will be code to therapeutic drug 
classes and generic drug names using the latest version of the WHO drug dictionary.
Concomitant medications are defined as medications that were either initiated before enrollment 
during the screening period, or initiated during the restart of dasatinib when the study drug will be 
administered until the end of the study.
A summary showing the number and percentage of patients who took concomitant medications 
will be presented by therapeutic drug class and generic drug name for the enrolled population. 
A by-patient listing of concomitant medications will be provided.
7.7
Efficacy
This section describes the efficacy analyses for the study. No formal statistical testing will be 
performed. Summary statistics will be provided for efficacy data using the enrolled subject 
population. The efficacy endpoints will also be analyzed for the evaluable subject population.
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Screening/baseline, off-treatment (Dasatinib discontinued), and on-treatment (Dasatinib restart) 
assessments for the determination of efficacy include complete blood count (CBC) with 
differential and platelet (PLT) count, cytogenetics (if clinically indicated), and molecular analysis
(qualitative polymerase chain reaction [Q-PCR]). Samples for mutational analysis will be drawn 
at baseline (and stored for future exploratory analysis), and at the time of loss of MMR or any
response failure after reinitiating dasatinib as determined by other planned assessments, and as 
specified in the time and events schedule. 
Efficacy endpoints will be based on molecular (Q-PCR performed in a centralized lab and 
expressed in IS) assessments done throughout the study at the time points specified in the flow 
chart/time and events schedule presented in APPENDIX 3. Other relevant complementary efficacy 
endpoints will be based on hematologic and cytogenetic response.
The following definitions are to be taken into account for the efficacy analyses:
Hematologic Response - a complete hematologic response (CHR) is obtained when all the 
following criteria are met in peripheral blood (PB) sampling:

WBC ≤10,000/mm^3

Platelets <450,000/mm^3

Peripheral blood basophils <5%

No blasts or promyelocytes in peripheral blood

<5% myelocytes plus metamyelocytes in peripheral blood

No extramedullary involvement (including no hepatomegaly or splenomegaly).
If a subject failed on any of criteria above on or after progression, he would be considered as loss 
of CHR. 
Cytogenetic response (CyR) - is based on the prevalence of Ph+ cells in metaphase from bone 
marrow (BM) sample. The criteria for evaluation of CyR are based on the percentage of Ph+ cells 
in metaphase and are specifically categorized as follows (with ideally 25 metaphases, but at least 
20 metaphases from a BM sample evaluated 5):

Complete Cytogenetic Response (CCyR): 0% Ph+ cells in metaphase in BM

Partial Cytogenetic Response (PCyR): 1 to 35% Ph+ cells in metaphase in BM5

Minor CyR: 36 to 65% Ph+ cells in metaphase in BM

Minimal CyR: 66 to 95% Ph+ cells in metaphase in BM

No CyR: 96 to 100% Ph+ cells in metaphase in BM

Major Cytogenetic Response (MCyR) is defined as CCyR plus PCyR.
For the assessment of CCyR, if Ph+ cells in metaphase from the BM sample data using 
conventional cytogenetic assessment are not available, fluorescence in situ hybridization (FISH)
of blood interphase cell nuclei can substitute for bone marrow cell metaphases. The same 
categorizations will be applied, except CCyR according to FISH will be defined by < 1% BCR-
ABL1–positive nuclei of at least 200 nuclei.6 7 8
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Molecular response (MR) - will be assessed using BCR-ABL transcript levels measurement by 
real-time quantitative polymerase chain reaction (Q-PCR performed in a centralized lab and 
expressed in IS).

MMR is defined as BCR-ABL transcripts < 0.1% IS6.

CMR is defined as ≤ 0.0032% or 4.5 log reduction of BCR-ABL transcript levels MR4.5.

The rate of MMR is defined as the proportion of subjects who maintain MMR at 12, 24, 36, 
48 and 60 months after dasatinib discontinuation, without restarting dasatinib at study entry. 
Also, the MMR rate will be estimated for the evaluable patients.
Event-free survival (EFS) - is defined as the time from the date of dasatinib treatment 
discontinuation to date of loss of MMR. 
The rate of EFS at 12, 24, 36, 48 and 60 months will be estimated from the Kaplan-Meier (KM) 
curve.
Relapse (during off-treatment period) - is defined as any of the following events while a subject 
is on study: 

loss of MMR,

loss of CCyR, 

loss of CHR, 

or progression to advanced/blastic phase. 
Relapse-free survival (RFS) is defined as the time from dasatinib treatment discontinuation to the 
date of relapse. RFS rate will be estimated from the KM curve at 6, 12, 18, and 24 months and 
every 6 months thereafter. Subjects who do not relapse will be censored on the date of their last
molecular assessment.
Progression – is defined by any of the following events occurring while a subject is in the study:6
9.

Accelerated Phase (AP): 
o
Blasts in PB or BM 15–29%; 
o
Blast + promyelocytes ≥ 30% with blasts < 30% or ACA in Ph+ cells (clonal 
progression), or basophils in blood ≥ 20%, or platelets < 100 x 109 /L unrelated to
therapy.

Blastic Phase or Crisis (BP/BC): Blasts in PB or BM ≥ 30%, or extramedullary blast cell 
involvement (with the exception of spleen and liver).

Death
The date of progression will be defined as the date any of the above criteria is first met. Any subject 
who has not progressed will be censored on the date of the last examination.
Progression-free survival (PFS) - is defined as the time from dasatinib treatment discontinuation 
to death (due to any cause) or accelerated phase, or blast crisis. Patients who neither progress nor 
die will be censored on the date of their last molecular assessment.
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Overall survival (OS) - is defined as the time from dasatinib treatment discontinuation to the date 
of death (due to any cause). Patients who do not die will be censored on their last known alive 
date. 
7.7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects who maintain MMR (MMR rate) at 12 
months after dasatinib discontinuation without re-starting dasatinib treatment in the enrolled 
subjects in the study. In addition, the MMR rate will also be estimated for the evaluable subjects. 
Loss of MMR is defined per European Leukemia Net (ELN) definition of progression (Section 
7.6).  
7.7.1.1 
Primary Analysis 
The primary efficacy analysis is to estimate the rate of MMR at 12 months after dasatinib 
discontinuation without re-starting dasatinib treatment in the enrolled subject population. MMR 
rate at 12 months and at 6, 24, 36, 48 and 60 months will be summarized by point estimate and 
Clopper-Pearson two-sided 95% confidence intervals, for the enrolled subject population and the 
evaluable subject population. Summaries will also be produced for subjects with first line of 
therapy, and subjects with second/third line of therapy. The summaries for subjects with 
second/third line of therapy will include two additional columns split between resistance vs 
intolerance. This will be performed using PROC FREQ with BINOMIAL under options. In the 
event that any subject discontinues the study or dies prior to analysis timepoint (such as 6, 12... 
months) then these events will be considered failures and such patients will be included in the 
denominator of the proportion. 
7.7.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
 EFS at 12, 24, 36, 48 and 60 months after dasatinib discontinuation; 
 RFS at 6, 12, 18, 24 months and every 6 months thereafter after dasatinib discontinuation; 
 Assessment of BCR-ABL kinetics for subjects who experience loss of CMR but not MMR; 
 Assessment of BCR-ABL kinetics in subjects in CMR with measurable levels; 
 The rate of transformation to AP/BC; 
 PFS; 
 OS. 
7.7.2.1 
Secondary Analysis 
The secondary analysis including EFS rate at 12, 24, 36, 48 and 60 months (including number of 
subjects with event free at 12, 24, 36, 48 and 60 months, and event free survival rate at 12, 24, 36, 
48 and 60 months with 95% CI), RFS rate at 6, 12, 18, 24 months and every 6 months thereafter 
after dasatinib discontinuation (including number of subjects with relapse free at 6, 12, and 18 
month, and relapse free survival rate at 6,12, and 18 months with 95% CI), PFS rate, OS rate, and 
transformation rate will be estimated using Kaplan-Meier and Brookmeyer-Crowley method. This 
will be performed using PROC LIFETEST with METHOD=KM and CONFTYPE=LINEAR.  
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Time from dasatinib discontinuation to loss of MMR (including descriptive statistics for time in 
days from dasatinib discontinuation to loss of MMR, percentage of patients who were in 
CMR(MR4.5) at the time of discontinuation and remain in CMR(MR4.5) , percentage of patients 
who were in CMR(MR4.5)  at the time of discontinuation and lost CMR but keep MMR, and 
percentage of patients keeping CMR(MR4.5)  at 12 months after discontinuation), and the rate of 
transformation to AP/BC/late chronic phase of CML will be summarized using descriptive 
statistics. These summaries will be produced for the enrolled subject population, the evaluable 
subject population, subjects with first line of therapy, and subjects with second/third line of 
therapy. The summaries for subjects with second/third line of therapy will include two additional 
columns split between resistance vs intolerance. 
Kaplan-Meier plots will also be presented for EFS, RFS, PFS, and OS. A forest plot will also be 
produced for RFS, EFS, PFS, OS, and proportion of subjects who maintain MMR at 12 months. 
The estimated 25th percentile, median, and 75th percentile of time to EFS, RFS, PFS and OS and 
their respective 95% confidence intervals will be provided if applicable.  
As specified under Section 7.6 of the statistical analysis plan (SAP), censoring will occur if: 
Table 7.7.2.1-1: 
Time-to-Event Censoring 
Time-to-Event Endpoint 
Event/Censoring 
Event/Censoring Date 
EFS  
1) Event 
Date of Loss of MMR 
 
2.1) Censoring 
Date of Discontinuation (if subjects 
maintain MMR but discontinue 
study) 
 
2.2) Censoring 
Last Molecular Measurement Date 
(if subjects maintain MMR) 
 
2.3) Censoring 
Visit 1 Date (if subjects do not have 
any post-baseline BCR-ABL 
assessments) 
RFS 
1) Event 
Date of Relapse (earliest date of 
loss of MMR, loss of CCyR, loss of 
CHR, or progression) 
 
2.1) Censoring 
Date of Discontinuation (if subjects 
maintain MMR, CCyR, CHR, and 
have no progression but discontinue 
study) 
 
2.2) Censoring 
Last Molecular Measurement Date  
(if subjects  maintain MMR, CCyR, 
CHR, have no progression and do 
not discontinue study) 
 
2.3) Censoring 
Visit 1 Date (if subjects have no 
post-baseline relapse-related 
Central Lab Assessments done after 
Visit 1 Date) 
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Table 7.7.2.1-1: 
Time-to-Event Censoring 
Time-to-Event Endpoint 
Event/Censoring 
Event/Censoring Date 
PFS 
1) Event 
Date of Progressive Disease, Date 
of Death 
Note: Date of Progressive Disease 
includes date of events progression 
to accelerated phase, or blast crisis 
as defined under Section 7.6. 
 
2.1) Censoring 
 Last Molecular Measurement Date 
(if subjects have no progression and 
no death) 
 
2.2) Censoring 
Visit 1 Date (if subjects have no 
post-baseline progression 
assessment and no death reported) 
OS 
1) Event 
Date of Death 
 
2) Censoring 
Date of Last Known Alive (if 
subjects have no death reported) 
Transformation to AP/BC 
1) Event 
Accelerated Phase, or blast crisis 
phase of CML 
 
2 Censoring 
Last Molecular Measurement Date 
(if subjects did not develop 
Accelerated Phase, or blast crisis 
phase) 
 
Note: Time-to-Event for each Endpoint (EFS, RFS, PFS, OS) will be calculated using the dates in 
the table above and the following equation: Time-to-EFS/RFS/PFS/OS (months) = [(Date of 
event/censoring – Date of Last Dasatinib Discontinuation before Study Enrollment) +1] / 30.4375  
Assessment of BCR-ABL kinetics for subjects who experience loss of CMR but not MMR, and 
assessment of BCR-ABL kinetics in subjects in CMR(MR4.5) with measurable levels will be 
summarized by visit using descriptive statistics. These summaries will be produced for the enrolled 
subject population, the evaluable subject population, subjects with first line of therapy, and 
subjects with second/third line of therapy. The summaries for subjects with second/third line of 
therapy will include two additional columns split between resistance vs intolerance. 
A plot (spider or waterfall plot) will also be presented for BCR-ABL level over time for subjects 
who restarted treatment and it will display percent of BCR-ABL / ABL (IS) versus study months 
relative to latest dasatinib discontinuation date before study entry.  
Time to loss of MMR, re-gaining MMR, re-start of treatment, and time of re-gaining of 
CMR(MR4.5) will also be displayed on a swimming lane plot using different geometrical figures 
to distinguish between them. 
 
 
 
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7.8 
Safety 
The purpose of this section is to describe the safety analyses for the study. All summaries of safety 
data will be conducted using the enrolled population, following discontinuation of dasatinib and 
during re-start with dasatinib.   
7.8.1 
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 will be summarized in the off-treatment, on-treatment screening and on-treatment after 
restarting dasatinib periods. 
AEs of special interest during the off-treatment and on-treatment (during screening and after 
restarting dasatinib periods will be summarized by worst NCI CTCAE grade, AEs of special 
interest categories, and MedDRA system organ class and preferred terms.  If a subject experiences 
multiple AEs under the same preferred term (system organ class), then the subject will be counted 
only once for that preferred term (system organ class). 
Treatment-related AEs, defined as an adverse event which was considered to be related will be 
summarized during the on-treatment after restarting dasatinib period.  If a subject experiences 
multiple occurrences of the same AE with different relationship to study medication categories, 
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the subject will be counted once, as a relationship category of treatment-related.  In the event the 
relationship to study drug is 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 according to NCI CTCAE, Version 4.0.  If a subject 
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.” 
Tables summarizing the number of patients experiencing AEs and patient incidence for AEs will 
be generated for each of the following: 
 Overall summary of AEs 
 All AEs by worst CTCAE grade category  
 Treatment-related AEs by worst CTCAE grade category 
 Serious AEs 
 Treatment-related serious AEs 
 AEs with action taken as study drug withdrawn 
 AEs leading to study discontinuation 
 AEs with fatal outcome. 
The worst NCI CTCAE for treatment-related AEs will also be summarized for the number of dose 
interruptions, dose reductions and treatment discontinuations. Adverse events due to intolerance 
of study treatment will also be summarized.   
Corresponding by-patient data listings for adverse events will be provided in on-treatment 
screening, off-treatment, and on-treatment after restarting dasatinib periods. 
7.8.2 
Adverse Events of Special Interest  
The following AEs of special interest will consist of any: 
 Musculoeskeletal disorders 
 Connective tissue disorders 
 Vascular disorders 
The following summaries will be provided for AEs of special interest: 
 AEs of special interest by preferred terms 
 AEs of special interest by worst CTCAE grade  
 AEs of special interest with action taken as study drug withdrawn 
 AEs of special interest with action taken as study treatment reduced, interrupted, or 
discontinued. 
In addition, withdrawal syndrome after dasatinib discontinuation will be summarized. Subjects 
who need treatment after withdrawal syndrome will be listed.   
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7.8.3 
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 during off-treatment and on-treatment study periods.  
Echocardiogram and chest x-ray measurements will be documented at baseline and during off-
treatment and on-treatment study periods only if clinically indicated.   
Electrocardiograms (ECGs), echocardiogram, and chest x-ray measurements will be summarized 
by visit during off-treatment and on-treatment periods. 
Corresponding by-patient listings for ECGs, echocardiogram, and chest x-rays will be provided. 
7.8.4 
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. 
7.8.4.1 
Hematology 
The worst NCI CTCAE grade for white blood cell (WBC) counts, absolute neutrophil counts 
(ANC), basophils (% and absolute), platelet counts, and hemoglobin will be summarized during 
off-treatment (upon discontinuation of dasatinib) and on-treatment study periods.  
A summary of hematology lab results and changes from baseline by visit during off-treatment and 
on-treatment study periods may also be needed. 
7.8.4.2 
Serum Chemistry 
The worst NCI CTCAE grade for AST (SGOT), ALT (SGPT), total bilirubin, and serum creatinine 
will be summarized during off-treatment (upon discontinuation of dasatinib) and on-treatment 
study periods. 
A summary of serum chemistry lab results and changes from baseline by visit during off-treatment 
and on-treatment study periods may also be needed.     
7.8.5 
Vital Signs 
Vital sign measurements (systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, 
and temperature) will be summarized by visit during the off-treatment and on-treatment study 
periods. 
A by-patient listing of vital sign measurements will be provided. 
7.8.6 
Physical Examination 
Physical examination parameters will be summarized by visit during the off-treatment and on-
treatment study periods. 
7.8.7 
Pregnancy 
 A by-patient listing of pregnancy test results will be provided. 
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.
8
INTERIM ANALYSIS
8.1
General Information
An IDMC will be convened with experts not otherwise involved with the study team.  During the 
course of the study, the IDMC will conduct regular reviews (at least 2 times per year and ad-hoc 
as necessary) of safety data and efficacy data listings and pharmacovigilance reports.  Operational 
details for the IDMC, as well as the timing of analyses, monitoring guidelines, and content of the 
reports will be detailed in the IDMC charter.
8.1.1
Statistical Approaches
There will be an interim analysis when 30 patients have been followed until month 12 (calculated 
from discontinuation of dasatinib). This analysis will focus on specific efficacy endpoints such 
asMMR, time from discontinuation to loss of MMR, deep molecular response, EFS and other 
endpoints for the enrolled population.  In addition, standard safety data will be presented.
The interim analysis will be performed using the data collected by the cutoff date for the interim 
analysis.  All patients enrolled prior to the cutoff date will be included in the interim analysis and 
all data up to the cutoff date will be summarized or listed.
9
CONVENTIONS
Unless specified otherwise, the following conventions will be used for imputing partial 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 month are missing, “July 1” will be used to replace the missing day and 
month.

If a date is completely missing, no imputation is needed.  The date will be considered missing.
For dasatinib start date:
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 If only the day of the month is missing, the last day of the month will be used to replace the 
missing day. 
 If the day and month are missing or the date is completely missing, no imputation is needed.  
The date will be considered missing. 
For adverse events: 
 If only the day 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. 
10 
CONTENT OF REPORTS 
The complete list of analyses contributing to the clinical study report is given in the Data 
Presentation Plan. 
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APPENDIX 3 
STUDY ASSESSMENTS AND PROCEDURES 
Table 11-2: 
Screening and Baseline Assessments 
Procedure 
Screening 1 
Screening 2 
Visit 1 
(Baseline) 
Notes 
 Visit 1 window is open until all entry criteria are 
satisfied unless otherwise specified. 
 Screening 2: 90 days  10 days after Screening 1. 
Eligibility Assessments 
 
 
 
 
Informed Consent 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
Serum chemistry and CBC with diff, platelets: Visit 1 only, 
within 72 hrs prior to study entry  
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. 
Results must be recorded on the CRF. 
See Study Protocol Section 5.3 for recommendations 
regarding subjects with positive HBV serology. 
Medical History 
X 
 
X 
 
Pregnancy Test 
X 
 
X 
At screening  
Review Contraception 
Requirements 
X 
 
X 
Review contraception requirements presented in Study 
Protocol Section 3.3.1 and Appendix 8 with both WOCBP 
and male subjects. 
Safety Assessments 
 
 
 
 
Physical Examination, vital 
signs and Performance Status 
(PS)/Sokal (or Hasford) score 
 
 
X 
 
Assessment of signs and  
symptoms 
 
 
X 
 
Concomitant medications 
 
 
X 
 
Adverse event assessment 
 
 
X 
 
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Table 11-2: 
Screening and Baseline Assessments 
Procedure 
Screening 1 
Screening 2 
Visit 1 
(Baseline) 
Notes 
 Visit 1 window is open until all entry criteria are 
satisfied unless otherwise specified. 
 Screening 2: 90 days  10 days after Screening 1. 
ECG 
 
 
X 
 
Echocardiogram 
 
 
X 
Only if clinically indicated  
Serum chemistry 
 
 
X 
Within 72 hrs prior to study entry.  
Chest X-ray 
 
 
X 
Chest X-ray only if clinically 
indicated, or there is evidence of 
shortness of breath. 
Efficacy-related Laboratory 
tests  
 
 
 
 
CBC with diff, platelets 
 
 
X 
Within 72 hrs prior to study entry. 
 
 
 
 
 
Mutational analysis 
 
 
X 
Blood sample to be stored and analyzed later if 
mutations are detected in other assessments during the 
study 
Molecular analysis (Q-PCR) 
X 
X 
 
Q-PCR labs will be performed in a centralized lab and 
expressed on an international scale (IS) 
 
Screening 2 molecular analysis (90 days after Screening 
1 assessment) is required to confirm CMR (MR4.5). 
Patient-reported Outcomes 
 
 
 
 
(MDASI)-CML symptom-
burden assessment 
 
 
X 
Patient must complete the PROs during the study visit: 
at the beginning of the visit is preferred. 
 
PRO assessments are not required and are not 
applicable to patients who had a legally accepted 
representative sign the informed request at study entry. 
 
EORTC-QLC-C30 assessment 
 
 
X 
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Table 11-2: 
Screening and Baseline Assessments 
Procedure 
Screening 1 
Screening 2 
Visit 1 
(Baseline) 
Notes 
 Visit 1 window is open until all entry criteria are 
satisfied unless otherwise specified. 
 Screening 2: 90 days  10 days after Screening 1. 
Health Care Resource 
Utilization Assessment 
 
 
X 
 
Clinical Drug Supplies 
 
 
Dasatinib will be discontinued after all screening criteria are met and 
baseline assessments are completed. 
 
 
 
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Table 11-3: 
On Study Assessment: Off Treatment (Dasatinib Discontinued) Assessments 
 
Procedure 
Off Treatmenta,b 
 
Notes 
 Visit window is  10 days for assessment 
every 3 or 6 months.  5 days for monthly 
assessments.  
 Assessments will continue throughout the 5 
year study period.  
Safety Assessments 
 
 
Physical Examination, vital signs and Performance 
Status (PS) 
Every 3 months 
 
Assessment of signs and symptoms  
Every 3 Months 
 
Adverse event assessment 
Every 3 Months 
If a pt is taken off study due to AE, follow-up 
visits are required q 4 weeks until toxicities 
resolve to baseline or Grade ≤1, stabilize, or 
are deemed irreversible. 
Concomitant medications 
Every 3 Months 
 
ECG 
As clinically indicated 
 
Echocardiogram 
As clinically indicated 
 
Serum chemistry 
Every 3 months  
 
HBV Serology 
Only once for subjects not previously tested 
within 1 year prior to Visit 1. 
HBV serology test results must be recorded in the 
CRF. 
See Section 5.3 for recommendations for subjects 
with positive HBV serology. 
Chest X-ray 
As clinically indicated 
 
Pregnancy test 
X 
One month after discontinuation of dasatinib. 
Review Contraception Requirements 
X 
Review contraception requirements presented 
in Section 3.3.1 and Appendix 8 with both 
WOCBP and male subjects 
 
 
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Table 11-3:
On Study Assessment: Off Treatment (Dasatinib Discontinued) Assessments
Procedure
Off Treatmenta,b
Notes
 Visit window is  10 days for assessment 
every 3 or 6 months.  5 days for monthly 
assessments. 
 Assessments will continue throughout the 5 
year study period.
Efficacy Assessments
CBC with diff, platelets
Every 3 months
CBC may be done more frequently if 
clinically indicated.
Cytogenetics
At loss of MMR.b
Bone marrow aspirate/biopsy or peripheral 
blood (FISH) will be performed within 4 
weeks of loss of MMR. For adequate 
cytogenetic results, peripheral blood (FISH) 
should ideally be performed when the ANC > 
500/mm3
Molecular analysis/Q-PCR
Year 1: Monthly  
Year 2-5: Every 3 months (see note for 
exceptions) 
Q-PCR analyses to be performed in a 
centralized lab and expressed in International 
Scale units
Exceptions to Years 2-5, 3 monthly assessment

Subjects with BCR-ABL kinetics who 
experience the first episode of intermittent 
loss of CMR (MR4.5) (“blips” but no 
MMR loss), will have Q-PCR levels 
measured monthly for 3 months after the 
event. If MMR is maintained, Q-PCR
levels will continue to be measured every 3 
months.
Mutational analysis
X
Mutational Analysis will be conducted any 
time there is loss of MMR, loss of CCyR or 
Loss of CHR. Samples to be drawn and stored 
for future exploratory analysis.
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Table 11-3: 
On Study Assessment: Off Treatment (Dasatinib Discontinued) Assessments 
 
Procedure 
Off Treatmenta,b 
 
Notes 
 Visit window is  10 days for assessment 
every 3 or 6 months.  5 days for monthly 
assessments.  
 Assessments will continue throughout the 5 
year study period.  
Patient-reported outcomes 
 
 
(MDASI) CML symptom burden assessment 
Every 6 months and at loss of MMRb 
Patient must complete the PROs during the 
study visit: at the beginning of the visit is 
preferred. 
PRO assessments are not required and are not 
applicable to patients who had a legally 
accepted representative sign the informed 
request at study entry. 
EORTC-QLC-C30 
Every 6 months and at loss of MMRb 
Health Care Resource Utilization Assessment 
Every 3 months 
Health care resource utilization will be 
assessed at each visit. 
MMR = major molecular response; CCyR = complete cytogenic response; CMR= complete molecular response (MR4.5); Month = 30 days 
a During the off-treatment period, each assessment time point is counted from Visit 1, the day dasatinib was discontinued. 
b Patients with loss of MMR during the off-treatment period will be restarted on dasatinib at the dose received before dasatinib was discontinued at study entry. 
See Study protocol Table 5.1-3 for study assessments at dasatinib restart and during treatment with dasatinib. 
 
 
 
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