Continuing Treatment for Subjects Who Have Participated on a Prior Protocol Investigating Dasatinib
Phase: PHASE2
Conditions: Multiple Indications Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
Continuing Treatment for Subjects Who Have Participated on a Prior Protocol Investigating 
Dasatinib 
 
PROTOCOL: CA180-597 
 
NCT Number: NCT02297139 
 
Document Date (Date in which document was last revised): April 19, 2016 

Page:
1
Protocol Number:
CA180597
IND Number:
NA
Ex-US
Non-IND
EUDRACT Number
2014-004278-40
Date:
20-Oct-2014
Revised Date
19-Apr-2016
Clinical Protocol CA180597
Continuing Treatment for Subjects Who Have Participated on a Prior Protocol Investigating 
Dasatinib
Revised Protocol Number: 01
Incorporates amendment(s) 01
Study Director 
Medical Monitor
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Telephone (office): 
Telephone (office): 
Fax: 
Fax: 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
Route 206 & Province Line Road
Lawrenceville, NJ 08543
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 
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 
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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, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Revised Protocol No: 01 
Date: 19-Apr-2016
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 01
19-Apr-2016
Incorporates Amendment(s) 01
Amendment 01
19-Apr-2016
This amendment: 1) adds testing for Hepatitis B virus (HBV) and 2) 
updates recommendations for methods of contraception and 
reemphasizes the need for contraception.
Original 
Protocol
20-Oct-2014
Not applicable
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SYNOPSIS
Clinical Protocol CA180597
Protocol Title:  Continuing Treatment for Subjects Who Have Participated on a Prior Protocol Investigating 
Dasatinib
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):  Subjects will receive dasatinib by oral administration at the last dose and schedule that they had been 
receiving in the previous clinical trial.  
Study Phase:  Continuation Phase 2 Roll-Over Protocol
Research Hypothesis:  No formal research hypothesis will be tested. 
Objectives:  
Primary Objective: To provide dasatinib treatment to patients who have participated on a prior protocol 
investigating dasatinib.
Secondary objective: To monitor the safety and tolerability of dasatinib. 
Study Population:  
•
Subjects who are currently receiving dasatinib therapy on another clinical trial that is ending.
•
Inclusion criteria:
a)
Participated in and completed a previous dasatinib protocol (including but not limited to CA180056, 
CA180363 or CA180227) and is deemed by the investigator to be deriving benefit from dasatinib as 
defined by the previous protocol.
b)
Receiving dasatinib at the time of signature of informed consent.
•
Exclusion criteria:
a)
All patients previously discontinued from a dasatinib study for any reason.
Study Assessments:  
•
Eligibility, safety (AEs and SAEs) and dosing assessments will be collected
•
Efficacy assessments will not be collected on study but should be performed per standard of care.   
Statistical Considerations: 
Sample Size:  Sample size is not based on statistical power considerations. This dasatinib rollover protocol will 
enroll any eligible patient including but not limited to subjects on treatment in studies CA180056, CA180363 or 
CA180227. 
Endpoints:  In this study, endpoints will include number of patients who received dasatinib and duration of 
treatment, all SAEs and AEs will be collected.
Analyses:  Data will be analyzed descriptively; details will be provided in the statistical analysis plan.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
1.4 Product Development Background ................................................................... 
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 Study............................................................................... 
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................................................. 
3.4.1.1 Medications that Prolong QT Interval ............................................ 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.2.1 H2-Agonists, PPIs, and Antacids .................................................... 
3.4.2.2 Antiplatelet Agents and Anticoagulants .......................................... 
3.4.2.3 Agents Affecting CYP3A4 ............................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
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4.10 Retained Samples for Bioavailability / Bioequivalence ................................. 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.5 Biomarker Assessments .................................................................................... 
5.6 Outcomes Research Assessments ..................................................................... 
5.7 Other Assessments ............................................................................................ 
5.8 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 ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.3.3 Exploratory Endpoint(s) .......................................................................... 
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 ....................................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research 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 ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
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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 .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 ADDITIONAL ETHICAL CONSIDERATIONS ................................ 
APPENDIX 2 COMMON CYP3A4 SUBSTRATES, INDUCERS, AND 
INHIBITORS .......................................................................................................... 
APPENDIX 3 MEDICAL CONDITIONS AND DRUGS WHICH MAY CAUSE 
QTC PROLONGATION AND TORSADE DE POINTES (NOT ALL 
INCLUSIVE) .......................................................................................................... 
APPENDIX 4 METHODS OF CONTRACEPTION ................................................... 
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1
INTRODUCTION AND STUDY RATIONALE
Dasatinib (BMS-354825) is a potent, broad-spectrum adenosine triphosphate (ATP) competitive 
inhibitor of multiple oncogenic tyrosine kinases including BCR-ABL, SRC, c-KIT, 
platelet-derived growth factor receptor, and ephrin receptor kinases.1,2 Overexpression or 
activation of these kinases plays critical roles in the etiology of various cancer types, as well as 
the malignant behavior associated with these diseases, such as unregulated proliferation and 
metastasis.  Dasatinib has been approved for treatment of adults with chronic myeloid leukemia 
(CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) 
resistant or intolerant to imatinib or newly diagnosed chronic phase CML (CP-CML).
Several studies in adults with Ph+ leukemias and solid tumors were successful in generating a 
range of safe and effective dose schedules for the administration of dasatinib.  In CML, a Phase 1 
study provided evidence of efficacy of dasatinib as demonstrated by hematologic and cytogenetic 
responses in all disease stages.  Based on preclinical data and results from Phase 1, the dose of 
70 mg twice daily (BID) was selected for the initial Phase 2 studies. Five Phase 2 studies 
(START CA180005, -006, -013, -015 and, -017) were conducted to further assess the efficacy 
and the safety profile of dasatinib.3,4,5,6,7 Based on the Phase 1 and Phase 2 studies, dasatinib was 
approved by the US Food and Drug Administration (FDA) in June 2006 for use in subjects with 
all phases of CML and Ph+ ALL who were resistant to or intolerant of imatinib. Two Phase 3 
trials in CP-CML (CA180034), advanced phase CML and Ph+ ALL (CA180035) provided 
evidence that a lower total daily dose (100 mg) given once daily maintains the same efficacy 
with greater subject tolerability than the 70 mg BID dose.8,9 Another Phase 3 trial (CA180056)
showed statistically significant improvement in complete cytogenetic responses at 12 months 
with dasatinib compared to imatinib.10  This study led to the approval of dasatinib in the 
treatment of newly diagnosed CP-CML. 
In addition to the trials conducted in Ph+ leukemias, five BMS-sponsored Phase 1 studies and 
nine Phase 2 studies were conducted to explore the safety and efficacy across various solid tumor 
types including advanced/refractory solid tumors (CA180003, CA180021, CA180058), breast 
cancer (CA180004, CA180059, CA180088, CA180158, CA180185, CA180261), prostate cancer 
(CA180085, CA180086, CA180227), glioblastoma (CA180274), pancreatic cancer (CA180375) 
and advanced non-small cell lung cancer (CA180385). Finally, one Phase 3 study was pursued in 
metastatic castration-resistant prostate cancer, mCRPC (CA180227).11 A variety of other BMS 
and investigator-sponsored trials in hematologic malignancies and solid tumors have also been 
conducted in adults.   
The safety profile of dasatinib is mostly characterized by fluid retention and myelosuppression.  
Incidence rates of fluid retention-related events (including pleural effusion, congestive heart 
failure, pericardial effusion, and pulmonary edema), pulmonary arterial hypertension (PAH), and 
cytopenias (including neutropenia, thrombocytopenia, and anemia) continue to be of special 
interest.12 The safety data generated in subjects with solid tumors has not identified any new 
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safety risks compared to those in subjects with CML or Ph+ ALL.  Currently, dasatinib is not 
approved for the treatment of any solid tumor types in adults or in children for any indication.
1.1
  Study Rationale
This is an open-label, continuation roll-over protocol that will provide dasatinib to subjects who 
are currently receiving this therapy on another clinical trial (including but not limited to 
CA180056, CA180363 or CA180227). This study will obtain safety follow up of enrolled 
subjects after completion of other dasatinib studies. 
1.2
Research Hypothesis 
No formal research hypothesis will be tested. 
1.3
Objectives(s)
1.3.1
Primary Objectives
To provide dasatinib treatment to subjects who have participated on a prior protocol 
investigating dasatinib. 
1.3.2
Secondary Objectives
To monitor the safety and tolerability of dasatinib. 
1.4
Product Development Background
Dasatinib was first approved 28-Jun-2006 by the US FDA for the treatment of adult subjects 
with CML or Ph+ ALL who are resistant or intolerant to imatinib. Dasatinib was subsequently 
approved in other countries and is marketed worldwide for the indications below in over 
60 international countries including in the EU, Japan, and Canada. 
•
Dasatinib is indicated for the treatment of adults with chronic, accelerated, or myeloid or 
lymphoid blast phase CML with resistance to or intolerance of prior therapy including 
imatinib.
•
Dasatinib is indicated for the treatment of adults with Ph+ ALL with resistance to or 
intolerance of prior therapy. 
•
Dasatinib is indicated for the treatment of adults with newly diagnosed CP-CML. 
1.5
Overall Risk/Benefit Assessment
Dasatinib has proven therapeutic value in CML and is considered to be a standard of care. The 
safety profile of dasatinib is mostly characterized by fluid retention, gastrointestinal toxicities 
(nausea and diarrhea), fatigue and myelosuppression. The fluid retention seen was most 
commonly: pleural or pericardial effusions, superficial edema, pulmonary hypertension, and 
congestive heart failure. As referred to earlier, results of a Phase 3 (dose-optimization) study led 
to the approval of 100 mg QD dasatinib in patients with CP-CML with resistance, intolerance, or 
suboptimal response to imatinib. A 4-year follow-up of these patients confirmed 100 mg QD as 
the best-tolerated dose, with few Grade 3/4 side effects. In a Phase 3 dose-optimization study in 
patients with advanced phase CML and Ph+ ALL (median duration of treatment of 14 months 
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for AP-CML, 3 months for myeloid blast CML, 4 months for lymphoid blast CML and 3 months 
for Ph+ ALL), fluid retention (pleural effusion and pericardial effusion) was reported less 
frequently in patients treated with dasatinib 140 mg once daily than in those treated with 70 mg 
twice daily. Based on these collective data, 100 mg QD and 140 mg QD have been selected as 
the most appropriate doses in this study for CP-CML and AP-CML patients respectively. 
Dasatinib at both doses has a well described safety profile with most subjects experiencing 
Grade 1 - 2 AE that can be managed with dose interruptions and/or reductions.
The safety data generated in subjects with solid tumors and pediatric subjects have not identified 
any new safety risks, the safety profile is consistent with that observed with the hematological 
malignancies. Therefore, subjects that appear to be deriving benefit from the continued treatment 
of dasatinib with acceptable toxicity may continue treatment, even though no definitive efficacy 
has been demonstrated in solid tumor program. 
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.
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 Harmonisation (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 
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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 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
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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 study is an open-label, continuation roll-over study of dasatinib for subjects who are 
currently receiving dasatinib therapy on another clinical trial that is ending. There is no target 
number of subjects to be enrolled in this study. It is estimated that ≤50 subjects will be enrolled
Each subject will continue to receive dasatinib at the last dose and schedule received on the 
previous study. Safety and tolerability information will be collected through laboratory testing 
and adverse event reporting (adverse events will be assessed by the CTCAE version 4.0). 
Subjects will continue on study until the Investigator deems that the subject is not benefiting 
from treatment.  Reasons for discontinuation from study may include progression of disease, 
unacceptable toxicity or subject withdrawal/discontinuation from the study. The study will 
continue until all subjects have discontinued study medication or until all subjects are treated for
up to 2 years.  
All subjects will be followed for a minimum of 30 days after the last dose of study drug therapy.
If study related toxicities are present at the End of Treatment visit, additional follow-up visit(s) 
are required until all study related toxicities resolve to baseline or to CTC Grade 1, stabilize or 
are deemed irreversible.
3.2
Post Study Access to Study
At the end of the study/Period, treatment with study drug for up to 2 years after enrollment, BMS 
will not continue to provide BMS supplied 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.
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3.3
Study Population
The study population includes subjects who are currently receiving dasatinib therapy on another 
dasatinib clinical trial that is ending.
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects able to provide written informed consent
2. Target Population
a) Participated in and completed a previous dasatinib protocol (including but not limited to 
CA180056, CA180363 or CA180227) and is deemed by the investigator to be deriving 
benefit from dasatinib as defined by the previous protocol. 
b) Receiving dasatinib at the time of signature of informed consent
c) Subject Re-enrollment:  This study does not permit the re-enrollment of a subject who 
has discontinued the study as a pre-treatment failure.
3. Age and Reproductive Status
a) Males and Females, ages 18 and older
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study, dasatinib plus 30 days (duration of ovulary cycle) for a total of 
30 days post-treatment completion. 
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug, dasatinib 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% when used consistently and correctly.
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dasatinib
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 
described in Appendix 4.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) All patients previously discontinued from a dasatinib study for any reason
2. Medical History and Concurrent Diseases
a) Any serious or uncontrolled medical disorder or active infection that would impair the 
ability of the subject to receive protocol therapy
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.
3. Physical and Laboratory Test Findings
Not applicable
4. Allergies and Adverse Drug Reaction
a) History of allergy to dasatinib
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated 
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Dementia or serious psychiatric condition that may compromise the informed consent 
process and increase the risks associated with study participation.
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, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40 mIU/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
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level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement 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
3.4.1
Prohibited and/or Restricted Treatments
Continued co-administration of additional anticancer therapy, other than prohibited therapies 
below, is allowed as per previous protocol. No additional anticancer therapy may be started on 
study. 
3.4.1.1
Medications that Prolong QT Interval
Medications associated with QT interval prolongation that are prohibited while subjects are on 
active therapy with dasatinib during 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.
Ideally, subjects enrolled in this study should not begin taking other medications known to 
prolong the QT interval. A website and further information on medications known to prolong the 
QT interval is found in Appendix 3. However, should the investigator believe that beginning 
therapy with a potentially QT prolonging medication (other than the ones listed above which are 
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.
3.4.2
Other Restrictions and Precautions
Restricted therapies are not prohibited, but are not recommended; therefore, the following are 
permitted with caution if clearly medically indicated.
3.4.2.1
H2-Agonists, PPIs, and Antacids
The concomitant use of dasatinib and a histamine (H2) antagonist (eg, famotidine), proton pump 
inhibitor [PPI (eg, omeprazole)], or aluminium hydroxide/magnesium hydroxide (eg, Maalox®) 
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may reduce the exposure to dasatinib. Thus, H2 antagonists and PPIs are not recommended (but 
are not prohibited) and aluminium hydroxide/magnesium hydroxide products should be 
administered at least 2 hours before or after dasatinib.
3.4.2.2
Antiplatelet Agents and Anticoagulants
Caution should be exercised if subjects are required to take medications that inhibit platelet 
function (ie, anticoagulant and antiplatelet agents). Further, anticoagulants should be avoided in 
the setting of Grade 3 or 4 thrombocytopenia, while subjects are on active dasatinib treatment.
Based on pre-clinical and 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. As a precaution treatment with 
dasatinib should not be given 24 hours prior to and after such procedures.
3.4.2.3
Agents Affecting CYP3A4
Dasatinib is predominantly metabolized by the CYP3A4 pathway. Strong and moderately-potent 
inhibitors of CYP3A4 should be avoided in combination with dasatinib if not clearly indicated, 
as they may increase dasatinib concentrations unpredictably. Substantial quantities of grapefruit, 
pomegranate and Seville (blood) orange juices may also inhibit CYP3A4. Refer to Appendix 2 
for a list of agents affecting the CYP enzyme system.
CYP3A4 inducers (eg, rifampicin) may decrease the concentration of dasatinib and should be 
used with caution when administered concurrently. Alternative agents with less enzyme-inducing 
potential should be considered if anticonvulsant therapy is indicated.
There is no restriction on agents metabolized by CYP3A4, but other CYP3A4 substrates known 
to have a narrow therapeutic index (eg, cyclosporine) should be administered with caution in 
subjects receiving dasatinib.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects will continue on study until progression or unacceptable toxicity or until subject 
withdrawal/discontinuation from the 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
•
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
•
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
•
Disease progression which, in the investigator’s opinion, precludes the subject’s 
continued participation in the study
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•
In the opinion of the investigator, continued participation in the study is not in the best 
interest of the subject
•
QTcF value > 530 msec
•
Subject eligible and willing to undergo stem cell transplant. 
•
Non-compliance by the subject with the requirements of the protocol, treatment or 
monitoring
•
Two years after being enrolled in this study, or until the subject can obtain dasatinib from 
a government sponsored or private health program, whichever comes first. 
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue study drug 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 drug 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.
3.6
Post Study Drug Study Follow up
All subjects will be followed for a minimum of 30 days after the last dose of study drug therapy.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug 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.
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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
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
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Table 4-1:
Study Drugs for CA180597
Product Description / 
Class and Dosage 
Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging/ Appearance
Storage Conditions
(per label)
Dasatinib Film-coated 
Tablet
20 mg
30 tablets per bottle
Open Label
film coated tablets, 
biconvex, round, white to 
off-white in appearance 
with “20” or 
“BMS”debossed on one 
side and “527” on the 
other side
15° to 25°C
(59° to 77°F)
Dasatinib Tablet
50 mg
30 tablets per bottle
Open Label
film coated tablets, 
biconvex, oval, white to 
off-white in appearance 
with “50” or “BMS” 
debossed on one side and 
“528” on the other side
15° to 25°C
(59° to 77°F)
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4.1
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. 
Dasatinib 20 mg and 50 mg film-coated tablets (see description in Table 4-1).
4.2
Non-investigational Product
Other medications used as support for preventative, diagnostic, or therapeutic reasons, as 
components of the standard of care for a given diagnosis, may be considered as 
non-investigational products. 
Not applicable for this study. 
4.3
Storage 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.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) 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).
4.4
Method of Assigning Subject Identification
Each site will be assigned a new site number by BMS at the start of the study. 
Once a subject has been confirmed as eligible by the investigator, a subject number will be 
assigned by the site. The site will assign the subject numbers sequentially for that site, starting 
with the number 
. 
This unique subject number and the newly assigned site number must be recorded on the CRF 
and on all further documentation and correspondence referring to this particular subject. 
The protocol and subject number from the prior BMS dasatinib protocol, under which the subject 
was receiving dasatinib prior to enrollment in the current protocol, will also be recorded on the 
screening CRF pages.
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Once informed consent has been obtained, the investigator (or designee) will register the subject 
by transmitting a copy of the completed enrollment worksheet (registration form) by facsmile 
(fax) or email to the number/email address listed on the cover page. The following information is 
required for registration. 
4.5
Selection and Timing of Dose for Each Subject
Dasatinib will be administered at the last dose and schedule received on the previous study. 
Subjects may adjust the time they take dasatinib as long as they take the drug approximately 
every 24 hours. Dasatinib tablets should be taken once per day at the same time with or without 
food. Dose modifications for dasatinib should be made when dasatinib related toxicity is 
suspected (outlined below in Table 4.5-1).
Table 4.5-1:
Dose Modification Guidance for Dasatinib Related Toxicities
Toxicity
Action to be taken with dasatinib
Grade 3 drug-related hematologic 
toxicity 
Interrupt until ANC ≥1.0 x 109/L and platelets ≥50 x 109/L.
Resume treatment with dasatinib at the original starting dose if 
recovery occurs in ≤7 days. 
If > 7 days, resume dasatinib at dose level 80 mg QD. For second 
episode, resume at dose level 50 mg QD.
Grade 4 drug-related hematologic 
toxicity 
Interrupt until ANC ≥1.0 x 109/L and platelets ≥50 x 109/L.
Resume treatment with dasatinib at dose level 80 mg QD if recovery 
occurs in ≤7 days. For second episode, reduce dose to dose level 
50 mg QD. 
Grade 1 pleural effusion
Interrupt until resolved and resume at same dose level. For second 
episode, reduce to dose level 80 mg QD.
Grade ≥2 pleural effusion
Interrupt until resolved and then resume at dose level 80 mg QD. For 
second episode, resume at dose level 50 mg QD. 
Grade ≥3 LFTs
Interrupt until ≤Grade 1or baseline and resume dasatinib. 
QTc/f > 500 msec, confirmed by 
repeat ECG. 
Interrupt until Grade ≤1, 
Eliminate drugs that prolong QTc/f, Supplement K, Mg;
Consider monitored rechallenge.
NOTE: Subject should be discontinued in the event of QTc/f 
> 530 msec.
LVEF Grade 2 (or decrease by > 10% 
from baseline), confirmed by repeat 
Echo
Interrupt until ≤Grade 1 or baseline and resume dasatinib at same 
dose. For second episode, reduce to dose level 80 mg QD. 
If Grade ≥3, reduce to dose level 80 mg QD.
Other Grade 3 - 4 non hematologic 
event (eg, vomiting) despite adequate 
medical intervention
Hold until ≤Grade 1 or baseline and resume at dose level 80 mg QD
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4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.8
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.
4.9
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 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, 
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and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
Arrangements for the return of study drug will be made by the responsible Study Monitor.
4.10
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, 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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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA180597)
Procedure
Screeninga
During 
Treatment 
Visit 1
Every 6 
months
Every 12 
months
End of 
Treatment 
Visit X
30 Days 
Follow-Up 
Phone Call 
Visit
Notes
Eligibility Assessments
Informed consent
X
Inclusion/Exclusion Criteria
X
Medical History
X
Safety Assessments
Physical Examination
Xb
X
X
Vital Signs
Xb
X
X
Heart rate, blood pressure, 
temperature, weight, 
respiratory rate
Serious Adverse Event 
Assessment
X
X
Adverse Events Assessment & 
Concomitant Medication
X
X
Serum Chemistry
Xb
X
X
BUN, creatinine, ALT, AST, 
total bilirubin
CBC with differential and 
platelets
Xb
X
X
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Table 5.1-1:
Screening Procedural Outline (CA180597)
Procedure
Screeninga
During 
Treatment 
Visit 1
Every 6 
months
Every 12 
months
End of 
Treatment 
Visit X
30 Days 
Follow-Up 
Phone Call 
Visit
Notes
Pregnancy Test
<-------->
Monthly
Need to be done monthly. 
Home pregnancy test kits 
provided to WOCBP subjects 
to perform pregnancy test 
between visits and record
result in log book
For WOCBP only
Review Contraception 
requirements
X
X
Hepatitis B serologic testing
X
See Note
Hepatitis B surface antigen 
(HBsAg) and antibody to 
Hepatitis B core antigen (also 
known as total hepatitis B core 
antibody; anti-HBc
The test has to be done at 
screening or once during the 
study (for subjects already 
treated)
Study Drug
Dispense Study Drug
X
X
a Screening visit will take place the same day as Visit 1.
b Record information from EoT visit of parent study on CRF
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5.1.1
Retesting During Screening or Lead-in Period
Not applicable.
5.2
Study Materials
The following will be distributed to the sites: 
•
Dasatinib Investigator Brochure (current version 14, updated when available).
•
Clinical supplies.
•
Pregnancy tests log.
The site will provide materials for tests performed locally (ie, clinical laboratory tests).
5.3
Safety Assessments
The schedule of study visits, assessments and procedures is provided in Table 5.1-1. Informed 
consent must be obtained prior to any study required procedures that would not have been 
performed as part of normal subject care (Section 2.3). While collection of safety laboratory data 
will only occur 6 months, subject should receive routine monitoring for safety and efficacy as per 
standard of care. In addition, for WOCBP, monthly pregnancy testings need to be performed.
HBV Serology
Although subjects with acute 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
Imaging Assessment for the Study
Not applicable.
5.4
Efficacy Assessments
Efficacy assessments will not be collected on study but should be performed per standard of care. 
5.5
Biomarker Assessments
Not applicable.
5.6
Outcomes Research Assessments
Not applicable.
5.7
Other Assessments 
Not applicable.
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5.8
Results of Central Assessments
Not applicable.
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 study drug 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 study drug, whether or not considered related to the study 
drug.
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.)
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Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE. 
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).
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).
−
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols).
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited 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). The preferred method for SAE data 
reporting collection is through the eCRF.  The paper SAE/pregnancy surveillance forms are only 
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intended as a back-up option when the eCRF system is not functioning.  In this case, the paper 
forms are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number:  Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, 
the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to 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 initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
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 
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•
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 study drug, 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 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours and in accordance with 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.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1. 
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.).
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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. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
Sample size is not based on statistical power considerations. This dasatinib rollover protocol will 
enroll any eligible subject including but not limited to subjects on treatment in studies 
CA180056, CA180363 or CA180227.
8.2
Populations for Analyses
The following dataset will be used in this study: 
−
All treated subjects: all subjects who received at least one dose of dasatinib.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
Number of subjects who received dasatinib treatment and duration of treatment will be collected. 
8.3.2
Secondary Endpoint(s)
In this study, all SAEs and AEs will be collected. 
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8.3.3
Exploratory Endpoint(s) 
Not applicable.
8.4
Analyses
Detailed analysis description will be provided in the statistical analysis plan. Analysis will be 
conducted when all subjects have discontinued the study. 
8.4.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be tabulated for all treated subjects by disease 
type. Analysis by dose will be performed if deemed appropriate. 
8.4.2
Efficacy Analyses
Not applicable.
8.4.3
Safety Analyses
Analysis of safety data will be performed on all treated subjects by disease type. Analysis by 
dose will be performed if deemed appropriate. Data will be analyzed descriptively. Adverse 
events and other symptoms will be graded according to the NCI. Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 
8.4.4
Pharmacokinetic Analyses
Not applicable.
8.4.5
Biomarker Analyses
Not applicable.
8.4.6
Outcomes Research Analyses
Not applicable.
8.4.7
Other Analyses 
Not applicable.
8.5
Interim Analyses
Not applicable.
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. 
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If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:
•
IRB/IEC for review and approval/favorable opinion
•
BMS
•
Regulatory Authority(ies), if required by local regulations.
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a 
schedule of on-site visits for targeted review of study records. 
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. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
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When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
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.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product 
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.
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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 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 single site protocol, the Principal Investigator for the site will sign the clinical study 
report.
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
Complete Abstinence
If one form of contraception is required, Complete 
Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Female subjects must continue to have
pregnancy tests.  Acceptable alternate methods of highly 
effective contraception must be discussed in the event that 
the subject chooses to forego complete abstinence.
If two forms of contraception is required, Complete 
abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as 
complete avoidance of heterosexual intercourse is an 
acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle 
of the patient. This does not mean periodic abstinence (e.g., 
calendar, ovulation, symptothermal, profession of abstinence 
for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of 
contraception. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence
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11
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ALL
Acute Lymphoblastic Leukemia
ALT
alanine aminotransferase
AP
Accelerated Phase
AST
aspartate aminotransferase
BID, bid
bis in die, twice daily
BMS
Bristol-Myers Squibb
BP
blast phase
BUN
blood urea nitrogen
C
Celsius
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
cm
centimeter
CRF
Case Report Form, paper or electronic
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
CYP
cytochrome p-450
D/C
discontinue
dL
deciliter
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
F
bioavailability
FDA
Food and Drug Administration
g
gram
GCP
Good Clinical Practice
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Term
Definition
h
hour
HR
heart rate
HRT
hormone replacement therapy
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IU
International Unit
K+
potassium
kg
kilogram
L
liter
LDH
lactate dehydrogenase
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
mmHg
millimeters of mercury
μg
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
PO
per os (by mouth route of administration)
QC
quality control
QD, qd
quaque die, once daily
RBC
red blood cell
SAE
serious adverse event
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Term
Definition
SOP
Standard Operating Procedures
sp.
species
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
T-HALF
Half life
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
x g
times gravity
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12
REFERENCES
1
Preclinical pharmacology of dasatinib, a SRC protein kinase inhibitor. Bristol-Myers Squibb 
Company; 2003. Document Control No. 930003300.
2
Further studies on the preclinical pharmacology of dasatinib (BMS-354825), a multi-targeted 
tyrosine kinase inhibitor. Bristol-Myers Squibb Company. Document Control No. 
930012327.
3
BMS-354825, Bristol-Myers Squibb Interim Clinical Study Report for Study CA180005, 
Dec 2005. BMS Document Control No. 9300013100.
4
BMS-354825, Bristol-Myers Squibb Interim Clinical Study Report for Study CA180006, 
Dec 2005. BMS Document Control No. 9300013152.
5
BMS-354825, Bristol-Myers Squibb Interim Clinical Study Report for Study CA180013, 
Dec 2005. BMS Document Control No. 9300013195.
6
BMS-354825, Bristol-Myers Squibb Interim Clinical Study Report for Study CA180015, 
Dec 2005. BMS Document Control No. 9300011891.
7
BMS-354825, Bristol-Myers Squibb Interim Clinical Study Report for Study CA180017, 
Dec 2005. BMS Document Control No. 9300011560.
8
Clinical study report for Study CA180034: A randomized two-by-two, multicenter, 
open-label phase 3 study of BMS-354825 administered orally at a dose of 50 mg or 70 mg 
twice daily or 100 mg or 140 mg once daily in patients with chronic phase Philadelphia 
chromosome or BCR-ABL positive chronic myelogenous leukemia who are resistant or 
intolerant to imatinib mesylate. Six-month Clinical Study Report. Bristol-Myers Squibb 
Company; 2007. Document Control No. 930020746.
9
Final clinical study report for Study CA180035: A randomized, twoarm, multicenter, 
open-label Phase III study of BMS-354825 administered orally at a dose of 70 mg twice 
daily or 140 mg once daily in subjects with chronic myeloid leukemia in accelerated phase or 
in myeloid or lymphoid blast phase or with Philadelphia chromosome positive acute 
lymphoblastic leukemia who are resistant or intolerant to imatinib mesylate. Two-year 
Clinical 
Study 
Report. 
Bristol-Myers 
Squibb 
Company; 
2008. 
Document 
Control No. 930029431.
10 Clinical study report for Study CA180056: An open-label, randomized, multicenter Phase III 
trial of dasatinib (SPRYCEL®) vs. standard dose imatinib (400 mg) in the treatment of 
subjects with newly diagnosed chronic phase Philadelphia chromosome positive chronic 
myeloid 
leukemia. 
Bristol-Myers 
Squibb 
Company; 
2010. 
Document 
Control No. 930041803.
11 Final clinical study report for Study CA180227: A randomized double blind Phase 3 trial 
comparing docetaxel combined with dasatinib to docetaxel combined with placebo in 
castration-resistant prostate cancer. Bristol-Myers Squibb Company; 2013. Document 
Control No. 930070027.
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12 BMS-354825 Investigator Brochure, Version #14. Princeton, NJ: Bristol-Myers Squibb; 
2005. Report No.: BMS Document Control No. 930003494.
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APPENDIX 1
ADDITIONAL ETHICAL CONSIDERATIONS
1
INFORMED CONSENT PROCEDURES
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. Prior to the beginning of the study, the investigator must have the 
IRB/IEC’s written approval/favorable opinion of the written informed consent form and any 
other information to be provided to the subjects.
The investigator must provide the subject, or, in those situations where consent cannot be given 
by subjects, their legally acceptable representative with a copy of the consent form and written 
information about the study in the language in which the subject is most proficient. The language 
must be non-technical and easily understood. The investigator should allow time necessary for 
subject or subject's legally acceptable representative to inquire about the details of the study, then 
informed consent must be signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. The 
subject or legally acceptable representative should receive a copy of the signed informed consent 
and any other written information provided to study subjects prior to subject's participation in the 
study.
1.1
Subjects Unable to Give Written Informed Consent
1.1.1
Minors
For minors, according to local legislation, one or both parents or a legally acceptable 
representative must be informed of the study procedures and must sign the informed consent 
form approved for the study prior to clinical study participation. (In the event that the parents or 
legal guardians are unable to read, then an impartial witness should be present during the entire 
informed consent discussion). Whenever feasible, minors who are judged to be of an age of 
reason must also give their written assent by signing and dating the completed informed consent. 
All local laws, rules and regulations regarding informed consent of minors must be followed.
1.1.2
Subjects Experiencing Acute Events or Emergencies
A legally acceptable representative or legal guardian must provide informed consent when 
consent of the subject is not possible prior to clinical study participation, eg, for subjects 
experiencing an acute medical event such as myocardial infarction or stroke. Informed consent of 
the subject must additionally be obtained if they become capable of making and communicating 
their informed consent during the clinical study. All local laws, rules and regulations regarding 
informed consent of adult subjects incapable of giving informed consent must be followed.
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1.1.3
Mentally Impaired or Incapacitated Subjects
Investigators (or whoever required by local regulations) should determine whether or not a 
mentally impaired or incapacitated subject is capable of giving informed consent and should sign 
a statement to that effect. If the subject is deemed mentally competent to give informed consent, 
the investigator should follow standard procedures. If the subject is deemed not to be mentally 
competent to give informed consent, a fully informed legal guardian or legally acceptable 
representative can be asked to give consent for, or on behalf of, the subject. All local laws, rules 
and regulations regarding informed consent of mentally impaired or incapacitated subjects must 
be followed.
Patients who are involuntarily hospitalized because of mental illness must not be enrolled in 
clinical studies
1.1.4
Other Circumstances
Subjects who are imprisoned or involuntarily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness must not be enrolled in clinical studies. 
In circumstances where a subject’s only access to treatment is through enrollment in a clinical 
study, eg, for subjects in developing countries with limited resources or for subjects with no 
marketed treatment options, the investigator must take special care to explain the potential risks 
and benefits associated with the study and ensure that the subject is giving informed consent.
When a subject may be in a dependent relationship with the investigator, a well-informed 
physician who is not engaged in the clinical study and is completely independent of the 
relationship between the subject and investigator should obtain the subject’s informed consent.
1.1.5
Illiterate Subjects
If the subject, or, in those situations where consent cannot be given by the subject, their legally 
acceptable representative is unable to read, a reliable and independent witness should be present 
during the entire informed consent discussion. The choice of the witness must not breach the 
subject’s rights to confidentiality. A reliable independent witness is defined as one not affiliated 
with the institution or engaged in the investigation. A family member or acquaintance is an 
appropriate independent witness. After the subject or legally acceptable representative orally 
consents and has signed, if capable, the witness should sign and personally date the consent form 
attesting that the information is accurate and that the subject, or, in those situations where 
consent cannot be given by subjects, their legally acceptable representative has fully understood 
the content of the informed consent agreement and is giving true informed consent.  
1.2
Update of Informed Consent
The informed consent and any other information provided to subjects, or, in those situations 
where consent cannot be given by subjects, the subject's legally acceptable representative, should 
be revised whenever important new information becomes available that is relevant to the 
subject's consent, and should receive IRB/IEC approval/favorable opinion prior to use. The 
investigator, or a person designated by the investigator should fully inform the subject or the 
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subject's legally acceptable representative 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. 
During a subject's participation in the study, any updates to the consent form and any updates to 
the written information will be provided to the subject.
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APPENDIX 2
COMMON CYP3A4 SUBSTRATES, INDUCERS, AND 
INHIBITORS
The following lists describe medications which are common CYP3A4 substrates, inducers and 
inhibitors. These lists should not be considered all inclusive. Consult individual medication 
labels for specific information on a compound’s propensity for metabolism by CYP3A4. For 
medication/compounds you do not find in this appendix, please look at the following website to 
determine if they may be processed through the CYP3A4 pathway (in case of any doubts, 
discussion with the BMS Medical Monitor is strongly encouraged). Refer to: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla
beling/ucm093664.htm or http://medicine.iupui.edu/clinpharm/ddis/table.aspx
Common CYP3A4 Substrates (not all inclusive)
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Anti-arrhythmics:
quinidine
Antihistamines:
astemizole
chlorpheniramine
terfenidine
Benzodiazepines:
alprazolam
diazepam
dronedarone
midazolam
triazolam
Calcium Channel 
Blockers:
amlodipine
diltiazem
felodipine
lercanidipine
nifedipine
nisoldipine
nitrendipine
verapamil 
Immune Modulators:
Cyclosporine
sirolimus
tacrolimus (FK506)
Macrolide 
Antibiotics:
clarithromycin
erythromycin
telithromycin
NOT: zithromycin  
HIV Antivirals:
darunavir
indinavir
lopinavir
maraviroc
nelfinavir
ritonavir
saquinavir
tipranavir
HMG CoA Reductase 
Inhibitors:
atorvastatin
cerivastatin
lovastatin
NOT: pravastatin 
NOT: Simvastatin
Steroid 6beta-OH:
budesonide
estradiol
fluticasone
hydrocortisone
progesterone
testosterone
Others:
Alfentanyl
aripiprazole
aprepitant
boceprevir
buspirone
cafergot
caffeine
cilostaxol
cisapride
cocaine
conivaptan
dapsone
docetaxel
domperidone
codeine-N-
demethylation
darifenacin
dexamethasone
dextromethorphan
dihydroergotamine
eletriptan
eplerenone
ergotamine
everolimus
fentanyl
finasteride
gleevec
haloperidol
irinotecan
LAAM
Lidocaine
lurasidone
methadone
nateglinide
odanestron
pimozide
propranolol
quinine
quetiapine
risperidone
salmetrerol
sildenafil
sorafinib
tamoxifen
taxol
tolvaptan
torisel
trazodone
vardenafil
vincristine
zaleplon
ziprasidon
zolpidem
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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, boceprevir, 
clarithromycin, 
conivaptan, grapefruit 
juice,(a) indinavir, 
itraconazole, 
ketoconazole, mibefradil , 
nefazodone, nelfinavir, 
posaconazole, ritonavir, 
saquinavir, telaprevir, 
telithromycins, 
voriconazole
amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, 
diltiazem, erythromycin, 
fluconazole, fosamprenavir, 
blood orange juice, 
pomegranate juice, 
grapefruit juice,a verapamil
Alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, 
cimetidine, cyclosporine, 
fluoxetine, fluvoxamine, 
ginkgo,b goldenseal,b
isoniazid, nilotinib,
Oral contraceptives, 
ranitidine, ranolazine, 
tipranavir/ritonavir, 
zileuton
a The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and is preparation 
dependent.  Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation 
was used (eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was 
used (eg, low dose, single strength).
b Herbal product.
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Common CYP3A4 Inducers (not all inclusive)
HIV Antivirals:
Efavirenz 
nevirapine
Others: 
Amprenavir
Aprepitant
armodafinil
barbiturates
bosentan
carbamazepine
echinacea
etravirine
glucocorticoids
modafinil
nafcillin
phenobarbital
phenytoin
rifabutin
rifampin
rufinamide
St. John’s wort
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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 Category 1: Drugs with Risk of Torsade 
de Pointes. Caution is warranted when administering BMS-354825 to subjects taking drugs 
associated with prolongation of QTc listed in Category 2: Drugs with Possible Risk of Torsade 
de Pointes. A separate study document delineating medications currently listed in Categories 1 
and 2 will be provided and updated as necessary.
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APPENDIX 4
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. WOCBP and female partners of male subjects, who are WOCBP, are expected to 
use one of the highly effective methods of contraception listed below. Male subjects must inform 
their female partners who are WOCBP of the contraceptive requirements of the protocol and 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 MirenaÒ
3. Nonhormonal IUDs, such as ParaGardÒ 
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.
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LESS EFFECTIVE METHODS OF CONTRACEPTION
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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