Clinical trial NCT02011945
Conditions: Chronic Myeloid Leukemia
Sponsor: Bristol-Myers Squibb
Start date: 2014-02-07; Completion date: 2018-12-26
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find a dose of Nivolumab that can be safely added to Dasatinib in patients with Chronic Myeloid Leukemia.

Detailed description:

Arms: arm 1: dasatinib 100 mg QD(CP) or 140 mg QD (AP) arm 2: Nivolumab 1 mg/kg q 2 weeks + dasatinib 100 mg QD (CP) or 140 mg QD (AP) arm 3: Nivolumab 3 mg/kg q 2 weeks + dasatinib 100 mg QD (CP) or 140 mg QD (AP)
Interventions: intervention 1: Dasatinib intervention 2: Nivolumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_001.pdf: 


Clinical Protocol
CA180373
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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 
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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Document
Date of Issue
Summary of Change
Administrative 
Letter 02
30-Jan-2015
The objective of the administrative letter is to provide clarification 
regarding a recent change made to the protocol section 4.3.1.1 through 
Amendment 5 and Revised Protocol 02. In the section 4.3.1.1, the clause 
requiring interruption for dasatinib-related DLT was deleted but the 
intent of this deletion was not to remove the requirement to interrupt 
dasatinib for DLT.
Revised 
Protocol 02
01-Oct-2014
Incorporates Amendment 05
Amendment 05
01-Oct-2014
 
 
 
 
 
 
 
 
 
 
 
 
 
Administrative 
Letter 01
22-Jan-2014
The objective of the administrative letter is to correct a typo in the 
pharmacogenetics blood sample amendment number 01.
Revised 
Protocol 01
23-Oct-2013
Incorporates Amendment 03
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SYNOPSIS
Clinical Protocol CA180373
Protocol Title: A Phase 1B Dose Escalation Study to Investigate the Safety, Tolerability and Preliminary Efficacy 
for the Combination of Dasatinib (BMS-354825) plus Nivolumab (BMS-936558) in Patients with Chronic Myeloid 
Leukemia (CML)
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): 
Dasatinib Dose and Schedule:
Dasatinib will be administered at standard doses appropriate for the phase of CML.  The dasatinib (starting) dose 
will be as per the current dasatinib prescribing information for these patient populations: 100 mg daily for CML-CP 
and 140 mg for CML-AP.  
Nivolumab Dose and Schedule:
The starting dose for this trial of 1 mg/kg every 2 weeks is tolerable as a single agent and is within the range that has 
shown anti-tumor activity in solid tumors.  The maximum nivolumab dose in this trial is 3 mg/kg every 2 weeks.  
A dose de-escalation of nivolumab to 0.3 mg/kg maybe investigated, depending on the safety profile at 1 mg/kg.
Study Duration:
Study duration per subject is defined as a maximum of 3 years. Subjects will receive a maximum 2 years of 
treatment with dasatinib and nivolumab or until treatment failure or intolerance- whichever comes first. In the 
absence of disease progression or intolerance, subjects may receive up to a maximum of one additional year of 
dasatinib alone following cessation of nivolumab.
At the end of the study duration, BMS will not continue to supply study drug to subjects/investigators unless BMS 
chooses to extend the study. The investigator should ensure that the subject receives appropriate standard of care to 
treat the condition under study.
Study Phase: Phase 1B
Research Hypothesis: The combination of dasatinib and nivolumab will be safe, well tolerated and provide 
preliminary evidence of efficacy in subjects with previously treated CML-CP and CML-AP.
Objectives:  
Primary Objective:
The primary objective is to assess the safety and tolerability for the combination of dasatinib and nivolumab in 
patients with chronic phase (CP) or accelerated phase (AP) CML, in order to select a Phase 2 dose. The assessment 
of safety and tolerability will be based on:

Dose limiting toxicities (DLTs)

Incidences of adverse events (AEs) and serious adverse events (SAEs), during the DLT period, the full 
treatment period of the subjects with the combination therapy, and during the expansion phase,

Frequencies of abnormal clinical laboratory tests (summarized by worst toxicity grade).
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This is a phase 1B trial with an escalation and expansion cohort investigating the combination of dasatinib and 
nivolumab in subjects with CML-CP and CML-AP, who are progressing on, resistant to, suboptimally responding 
to, or intolerant of prior treatment with any Tyrone Kinase Inhibitors (TKI) (except dasatinib in case of prior 
intolerance).
Adult patients, both male and female with a confirmed diagnosis of CML will be enrolled. Two or more prior TKI 
therapies for CML are allowed, therefore, patients with resistance or suboptimal response per inclusion criteria 
remain eligible regardless of other intervening treatments. 
To further characterize safety and efficacy an expansion cohort will be enrolled. Between 21 and 33 treated subjects 
will be enrolled at the dose selected for expansion (ie, 0.3 mg/kg, 1.0mg/kg or 3.0 mg/kg nivolumab), in 
combination with dasatinib 100 mg QD /140 mg QD, (as applicable for CP and AP-CML, respectively), based on 
the safety profile observed in the escalation phase.  
Study Population:  
Key Inclusion Criteria:

Confirmed diagnosis of chronic myeloid leukemia (CML), in chronic phase (CP) or accelerated phase (AP): 
a)
With historically documented either cytogenetic Ph+ cells on BMA or molecular results from peripheral 
blood 
b)
2 prior TKI therapies for CML
c)
Meeting one of the following criteria:
i)
Progression, resistance or suboptimal response to most recent prior Abl-kinase inhibitor (imatinib, 
nilotinib ponatinib, bosutinib or dasatinib)
ii)
Intolerance to most recent prior TKI (other than dasatinib) at the lowest possible effective dose

ECOG Performance Status (PS) Score 0 - 1

Toxicity of any prior therapy must have returned to Grade 0 - 1 (Grade 2 for hematologic) or be considered 
irreversible.
Key Exclusion Criteria:

Known dasatinib-resistant Abl-kinase mutations (eg, T315I or T315A) (test results not required)

Blast phase CML: Subjects cannot be (or have been within prior 6 months) in blast phase defined as 30% 
blasts in peripheral blood (PB) or in Bone Marrow Aspirates (BMA) and/or extramedullary disease other than 
hepatosplenomegaly

Prior intolerance to dasatinib, defined as Grade 2 adverse event requiring discontinuation

Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to 
receive protocol therapy, including:
a)
Known pleural or pericardial (s) effusion at baseline
b)
Clinically-significant gastrointestinal disease, digestive dysfunction or surgery that would compromise 
absorption of dasatinib or the administration of dasatinib by mouth (eg, uncontrolled nausea or 
malabsorption syndrome)
c)
Thromboembolic disease requiring ongoing anticoagulation or deep vein thrombosis that is not adequately 
controlled
d)
Clinically-significant coagulation or platelet function disorder (other than related to thrombocytopenia), eg, 
von Willebrand’s disease
e)
A history of pulmonary arterial hypertension

Uncontrolled or significant cardiovascular disease, including any of the following:
a)
Myocardial infarction within 6 months of enrollment date
b)
Uncontrolled angina or congestive heart failure within 3 months of enrollment date
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c)
Left ventricular ejection fraction (LVEF) < 40%
d)
Significant cardiac conduction abnormality, including
i)
History of clinically-significant ventricular arrhythmia (such as ventricular tachycardia, ventricular 
fibrillation, or Torsades de Pointe)
ii)
History of second or third degree heart block (except for second degree type 1 is not excluded)
iii) Prolonged QTc/f interval > 450 msec on baseline ECG (unless a cardiac pacemaker is present).
Study Assessments:
The safety and tolerability of the combination dasatinib and nivolumab will be assessed continuously during the 
study and for 100 days post last dose of nivolumab and for 30 days post last dose of dasatinib. 
Efficacy will be assessed by hematological assessment, cytogenetic assessment and molecular assessment 
Pharmacokinetics, anti-drug antibody and biomarkers samples will be collected at several timepoints.
Statistical Considerations: 
Sample Size:  
Dose Escalation Phase
The sample size at each of the 3 dose levels in the dose escalation phase of this study depends on observed toxicity 
and posterior inference. Twenty-four (24) subjects are expected to be treated during the dose escalation phase. There 
may be more than 24 subjects treated due to replacement, or less than 24 subjects treated due to toxicity at the 
lowest dose level. The number of subjects was derived by simulation. The simulation results from mTPI with totals 
of 24 and 36 subjects suggest that a sample size of 24 subjects is appropriate for the dose escalation phase. 
Additional subjects however, may be enrolled to dose level 2 if 24 subjects were treated at dose level 1 and 
escalation to dose level 2 is suggested either by decision rule or by investigators following careful review of study 
data. In that case the dose escalation phase may include 36 or 48 subjects.
Dose Expansion Phase
The total number of subjects treated in this study depends on the number of subjects treated in the escalation phase, 
but is expected to be at least 45 and to be below 70. In the dose expansion phase subjects will initiate treatment with 
the dose assessed to be the maximum tolerated dose among the three proposed doses. In the dose escalation phase 
and the dose expansion phase combined approximately 45 subjects will be treated at that dose. Administration of 
nivolumab in combination with dasatinib in 45 subjects will provide 90% probability of observing at least one 
occurrence of any adverse event that would occur with a 5% incidence in the population from which the sample is 
drawn.
Endpoints:  
Primary Endpoint(s)
The primary objective is to assess the safety and tolerability for the combination of dasatinib and nivolumab in 
patients with chronic phase or accelerated phase CML, in order to select a Phase 2 dose. The assessment of safety 
and tolerability will be based on:

Dose limiting toxicities

Incidences of adverse events

Incidences of serious adverse events

Frequencies of clinical laboratory tests by worst toxicity grade.
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1.3
Objectives(s)
1.3.1
Primary Objectives
The primary objective is to assess the safety and tolerability for the combination of dasatinib and 
nivolumab in subjects with chronic phase (CP) or AP CML, in order to select a Phase 2 dose. 
The assessment of safety and tolerability will be based on:

Dose limiting toxicities (DLTs) as defined in Section 3.1.3.1,

Incidences of adverse events (AEs) and serious adverse events (SAEs), during the DLT 
period, the full treatment period of the subjects with the combination therapy, and during the 
expansion phase,

Frequencies of abnormal clinical laboratory tests (summarized by worst toxicity grade).
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1.5
Overall Risk/Benefit Assessment
Dasatinib has proven therapeutic value in CML and is considered to be a standard of care. 
Dasatinib will be administered at the approved doses and schedule for CML-CP and CML-AP. 
The safety profile of dasatinib is mostly characterized by fluid retention, GI toxicities (nausea & 
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 CML-CP with resistance, intolerance, or suboptimal 
response to imatinib. A four-year follow-up (between 24 and 48 months) 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 for CML-AP, 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 CML-CP and CML-AP patients 
respectively; these dasatinib doses are used in this trial, but if a lower dasatinib dose is clinically 
indicated in an otherwise-eligible patient, then it may be allowed with agreement of BMS 
monitor. 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. 
Myelosuppression is common at initiation of dasatinib treatment in patients with resistant CML 
(see Section 1.4.2), attributable to control of the Abl-driven clone; it will therefore not be 
considered a DLT. In light of potential benefit from dasatinib, furthermore, a DLT will not 
require discontinuation from study therapy.
In CA180323, a previous Phase I study of dasatinib in a similar population, most patients with 
CML-BP at study entry were not able to complete the DLT period; for this reason, they are 
excluded from this trial. However, patients with prior history of CML-BP (> 6 months prior to 
enrollment) may be DLT-evaluable and are eligible.
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 
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of pregnancy prevention and the implications of an unexpected pregnancy during treatment with 
dasatinib.
Nivolumab has documented efficacy in a variety of solid tumors and will be administered at 
doses within the known tolerable range using a q2 week schedule. In multiple nivolumab trials, 
treatment-related AEs were reported for most subjects including treatment-related AEs of 
Grade 3 or 4. Some of the most frequently reported AEs, regardless of causality, included: 
fatigue, nausea, proteinuria, constipation, back pain, dry mouth, vomiting, rash and dyspnea. 
Additional events of interest include diarrhea and increase in thyroid stimulating hormone. 
Treatment-related SAEs of hypothyroidism, colitis, anemia and pneumonitis (including fatal) 
have been reported, however there was no dose-related pattern with regard to the incidence, 
severity, or relationship of AEs. Common laboratory abnormalities that were considered related 
to nivolumab that have been reported include decreases in CD4 counts, lymphopenia, increases 
in C-reactive protein and decrease in lymphocyte counts.
AEs reported in a trial of metastatic RCC subjects treated with nivolumab 2 mg/kg in 
combination with sunitinib (n = 6) or pazopanib (n = 10)42 are of particular interest since this is a 
combination study with a TKI. A review of the data at the last interim analysis (03-Jul-2012) 
indicated that the AEs/SAEs were comparable to that reported in RCC subjects treated with 
nivolumab monotherapy. Although a Grade 3 SAEs of abdominal pain and syncope was reported 
in one subject treated with nivolumab + pazopanib and one additional ungraded SAE was 
reported as “early bowel obstruction” for a second subject in the same treatment group, neither 
were considered related to study treatment. 
Drug-related AEOSIs with potential immune-related etiologies, that were reported in nivolumab 
trials include: pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis, among others. 
AEOSIs including hepatic, gastrointestinal and respiratory were managed with treatment
interruption and administration of corticosteroids, and were generally completely reversible. 
Endocrine AEOSIs were managed with replacement therapy. Several subjects in these categories 
successfully reinitiated treatment with nivolumab. Drug-related pneumonitis has been shown to 
occurred in less than 3% of all subjects treated with nivolumab with Grade 3~4 pneumonitis 
reported in < 1%, most of who presented with NSCLC No clear relationship between the 
occurrence of pneumonitis and tumor type, dose level, or the number of doses received was 
noted. Early grade pneumonitis was generally reversible with treatment discontinuation and 
corticosteroid administration. In 3 subjects, infliximab and/or mycophenolate were utilized for 
additional immunosuppression, with unclear effectiveness. There were 3 (1%) drug-related 
deaths, due to pneumonitis.
Because of the potential for the development of nivolumab-related AEs including AEOSI, 
management algorithms have been developed to assist investigators in assessing and managing 
the following groups of AEs: Endocrinopathy, Gastrointestinal, Hepatic, Neurological. 
Pulmonary, Renal, and Skin. These algorithms are found in the Nivolumab IB and in 
Appendix 2 of this protocol.
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The combination of dasatinib and nivolumab has not been previously studied. Due to the 
possible overlap in toxicities between dasatinib and nivolumab, as outlined above, several safety 
precautions to mitigate risk have been implemented in this trial which, are outlined below:

Several doses of nivolumab will be investigated however; the first subjects will be treated 
with a dose of 1 mg/kg, which is 1/10th the maximal dose studied in other nivolumab trials.

Enrollment will initially be limited to 6 subjects in dose level 1 and potentially for other dose 
levels as appropriate. Data from these 6 subjects will be evaluated and all 6 subjects must 
have completed the DLT evaluation period (described in Section 3.1.3.1) before initiating 
combination treatment of subsequent subjects into the cohort. This will limit the number of 
subjects exposed to the combination prior to understanding potential overlapping toxicities. 

An mTPI design is used in this trial, using a low predefined target DLT rate (~ 11%) that will 
allow for nivolumab dose escalation only if acceptable tolerability is observed. 

Algorithms are provided for the management of nivolumab AEs, and dose modification 
guidelines are provide for dasatinib for management of AEs with recommendations on study 
drug interruption, dose reduction and discontinuation.
Finally, there is a low potential risk of pharmacokinetic interactions between the drugs given 
their different elimination pathways (liver vs kidney). Dasatinib is primarily metabolized by liver 
enzyme CYP3A4, whereas nivolumab as an IgG antibody, the majority of its elimination occurs 
via intracellular catabolism, following fluid-phase or receptor mediated endocytosis. PK data for 
nivolumab are needed in this study population, but (as dasatinib PK is well-characterized) 
intensive dasatinib PK sampling is not warranted.
The potential benefits of nivolumab with or without dasatinib in subjects with CML is unknown
as to date no trials in Ph+ leukemias have been conducted. However, responses to nivolumab 
monotherapy have been observed in both solid tumors and subjects with other hematological 
malignancies such as non-Hodgkin’s lymphoma and multiple myeloma (Nivolumab IB 
version 12 
and 
data 
on 
file).In 
addition 
(and 
as 
previously 
mentioned), 
other 
immunomodulatory-like therapies (SCT and DLI) have a known curative potential in CML which 
points to CML’s responsiveness to T-Cell mediated immunity. Hence there is potential for a 
novel immune-targeted therapy such as nivolumab to add to the benefit of dasatinib in CML 
patients previously treated with a TKI by helping to overcoming TKI resistance, deepening 
responses and potentially prolonging a treatment free-interval.
In conclusion, in subjects with CML-CP and CML-AP with relapsed, refractory or 
suboptimal-responding disease there is an acceptable risk/benefit profile and appropriate 
safeguards to initiate a Phase 1 trial with the combination of dasatinib and nivolumab.
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 
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underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
are clearly and fully informed about the purpose, potential risks, and other critical issues 
regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
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. 
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2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a phase 1B trial with an escalation and expansion cohort investigating the combination of 
dasatinib and nivolumab in subjects with CML-CP and CML-AP, who are progressing on, 
resistant to, sub-optimally responding to, or intolerant of prior treatment with any TKI (except 
dasatinib in case of prior intolerance).
Adult subjects, both male and female with a confirmed diagnosis of CML will be enrolled. Two 
or more prior TKI therapies for CML are allowed; therefore, subjects with resistance or 
suboptimal response per inclusion criteria remain eligible regardless of other intervening 
treatments. 
Cohorts of subjects will be treated with escalating doses of nivolumab as described in the 
treatment plan below. All subjects are treated until progression/treatment failure 
(see Section 5.4.2) or intolerance for a maximum of up to 2 years with dasatinib and nivolumab 
combination and up to 1 additional year with dasatinib alone. Subjects stopping nivolumab prior 
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to two years will be able to receive one additional year with dasatinib alone, from the date of 
nivolumab cessation.
The proportion of subjects with CML-CP and CML-AP is not known in advance. However it is 
not the intention to separate these subjects into different cohorts for the purposes of a safety 
evaluation. The Study Team (Principal Investigators and Sponsor representatives) will determine 
accrual schedule and timing of cohort escalation and dose for expansion based on all available 
information. Decisions will be based primarily on safety data for the first 6 weeks of combined 
treatment (Weeks 3 - 8 inclusive) in subjects with both CML-CP and AP but all relevant 
experience, including interruption or discontinuation for toxicity after the DLT period and AEs 
during subsequent treatment, will be considered. Approximately 24 - 48 subjects will be required 
for escalation phase. Subsequently, 21 - 33 additional subjects will be treated in an expansion 
phase at the selected dose.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Additional cohorts will be enrolled either at the same dose, at 3 mg/kg (dose level 2), or at 
0.3 mg/kg (dose level -1) as per mTPI decision rules (see Table 3.1.3-2).
Dose levels are defined as in Table 3.1.3-1 below.
Table 3.1.3-1:
Dose Levels for Dose-escalation of Nivolumab in Combination with 
Dasatinib
Dose Level
Nivolumab (mg/kg)
Dasatinib (mg)
-1a
0.3
100/140
1
1
100/140
2
3
100/140
a Subjects will only be enrolled at dose level -1 if de-escalation is required from dose level 1.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3.1.3-2:
Dose Assignment Decision Rules Based on Observed Dose 
Limiting Toxicities and the mTPI Method
Number of DLTs
Number of Subjects Treated at Current Dose
12
24
0
E
E
1
S
E
2
S
S
3
D(U)
S
4
D(U)
S
5
D(U)
D(U)
6
D(U)
D(U)
At completion of the escalation phase, the MTD will be assessed based on the estimate derived 
from the mTPI method (the dose for which the difference between the estimated toxicity and the 
target toxicity is smallest among the doses tested). The toxicity probabilities needed for the 
above comparison to the target toxicity probability will be estimated based on toxicity outcomes 
during the DLT period observed on all patients evaluated in the dose escalation phase, utilizing 
an isotonic regression procedure.43 The MTD is the maximum tolerated dose among the doses 
tested.
3.1.3.1
Dose Limiting Toxicity
DLT will be determined based on the incidence and intensity of drug related adverse events 
(AEs). The following drug-related AEs (whether related to one or both agents) occurring during 
the first 6 weeks of combined treatment with both dasatinib plus nivolumab (ie, Weeks 3 to 8, 
inclusive) would be considered DLTs:

Grade 4 hematologic AE lasting > 7 days despite appropriate medical intervention, except as 
noted below;

Grade 3 or Grade 4 nonhematologic AE irrespective of duration;

Grade 2 nonhematologic AE lasting > 7 days despite appropriate medical intervention 
(exception: asymptomatic laboratory values of Grade 2 which do not require medical 
intervention);

Any toxicity managed by discontinuation of nivolumab;
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
Grade 2 AE not controlled by medical intervention and requiring dasatinib treatment 
interruption for > 28 consecutive days;

Grade 2 AE not controlled by medical intervention and requiring missing 2 consecutive 
doses of nivolumab.
Cytopenias (especially absolute neutrophil count [ANC] and platelets) are common and expected 
when patients with TKI-pretreated resistant CML begin dasatinib treatment. These are related to 
rapid control of Abl-driven myeloproliferation in the setting of reduced normal hematopoietic
progenitors. Therefore Grade 4 hematologic AEs attributable to disease and dasatinib are not 
considered DLT.
Criteria for dose delay during the DLT period are outlined in Section 4.3.1.
3.1.4
Expansion Cohorts
To further characterize safety and efficacy an expansion cohort will be enrolled. Between 21 and 
33 treated subjects will be enrolled at the dose selected for expansion (ie, 0.3 mg/kg, 1.0 mg/kg 
or 3.0 mg/kg nivolumab), in combination with dasatinib 100 mg QD /140 mg QD, (as applicable 
for CP and AP-CML, respectively), based on the safety profile observed in the escalation phase.
In the dose expansion phase, subjects will initiate treatment with the dose selected in the 
escalation phase of the trial based on the totality of the data, including AEs during subsequent 
treatment or related to dose escalation. The dose in the expansion phase will be no higher than 
the MTD, or Dose Level 2 if no MTD is identified. In the dose escalation phase and the dose 
expansion phase combined approximately 45 subjects will be treated. Clinical safety monitoring 
of subjects enrolled during this additional cohort expansion portion of the study will be similar to 
that conducted during the dose-escalation portion of the study. If the overall safety profile of the 
study drugs is less favorable than that initially observed in the escalation phase, then further 
enrollment to the expansion cohort will be interrupted and a decision whether or not to continue 
dosing will be based on discussions of the observed aggregate (acute and chronic) toxicities 
between the study Investigators and the Sponsor. An expanded mTPI toxicity monitoring table 
provided in Appendix 3 of the protocol may also be used as an additional resource to facilitate 
decisions related to subject accrual during cohort expansion. An agreement will be reached as to 
whether a lower dose should be examined, or whether any additional treatment guidelines should 
be implemented prior to enrollment of additional subjects. 
3.2
Post Study Access to Therapy
Study duration per subject is defined as a maximum of 3 years. Subjects will receive a maximum 
2 years of treatment with dasatinib and nivolumab or until treatment failure or intolerance-
whichever comes first. In the absence of disease progression or intolerance, subjects may receive 
up to a maximum of one additional year of dasatinib alone following cessation of nivolumab.
At the end of the study duration, BMS will not continue to supply study drug to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the subject receives appropriate standard of care to treat the condition under study.
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3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/EC approved written informed consent form 
in accordance with regulatory and institutional guidelines. This must be obtained before 
the performance of any protocol related procedures that are not part of normal subject 
care
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study
2. Target Population
a) Confirmed diagnosis of CML, in chronic phase (CP) or accelerated phase (AP):
i)
With historically documented either cytogenetic Ph+ cells on Bone Marrow Aspirates 
(BMA) or molecular results from peripheral blood
ii) 2prior TKI therapies for CML
iii) Meeting one of the following criteria:
(1) Progression, resistance or suboptimal response to most recent prior Abl-kinase 
inhibitor (imatinib, nilotinib, ponatinib, bosutinib or dasatinib)-(see Appendix 4)
(2) Intolerance to most recent prior TKI (other than dasatinib) at the lowest possible 
effective dose.
A subject is defined as being intolerant to prior TKI (other than dasatinib) if he or she had 
a Grade 3 toxicity considered at least possibly related to that TKI at the dose which led 
to discontinuation of therapy. Subjects intolerant to prior dasatinib (experiencing a grade 
2 adverse event requiring discontinuation) are excluded.
b) Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been treated) after 
obtaining agreement from the BMS Central Medical Monitor prior to re-enrolling a 
subject. If re-enrolled, the subject must be re-consented.
c) ECOG Performance Status (PS) Score 0 - 1 (see Appendix 5)
d) Toxicity of any prior therapy must have returned to Grade 0 - 1 (Grade 2 for 
hematologic) or be considered irreversible.
3. Age and Reproductive Status
a) Males and Females, ages 18 years 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
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d) WOCBP must agree to follow instructions for method(s) of contraception from the time 
of enrollment for the duration of treatment with study drug dasatinib plus time required
for the study drug nivolumab to undergo approximately five half lives plus 30 days 
(duration of ovulatory cycle) for a total of 5 months post-treatment completion of 
nivolumab and 30 days post treatment completion of dasatinib.
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 
time required for the investigational drug nivolumab to undergo approximately five 
half-lives plus 90 days (duration of sperm turnover) for a total of 7 months post-
treatment completion of nivolumab and 90 days post treatment completion of dasatinib.
f)
Male subjects whose partners are WOCBP must use condoms, including male subjects 
who are azoospermic. WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements but still must undergo pregnancy testing as 
described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP 
on the use of highly effective methods of contraception. Highly effective methods of 
contraception have a failure rate of < 1% per year when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one 
method being highly effective and the other method being either highly effective or less 
effective as listed in appendix 9.
3.3.2
Exclusion Criteria
1. Target Disease Exclusions
a) Known dasatinib-resistant Abl-kinase mutations (eg, T315I or T315A) (test results not 
required to start therapy)
b) Blast phase CML: Subjects cannot be (or have been within prior 6 months) in blast phase 
defined as 30% blasts in peripheral blood (PB) or in BMA and/or extramedullary 
disease other than hepatosplenomegaly
2. Medical History and Concurrent Diseases
a) Prior intolerance to dasatinib, defined as Grade 2 adverse event requiring
discontinuation
b) Any serious or uncontrolled medical disorder or active infection that would impair the 
ability of the subject to receive protocol therapy, including:
i)
Known pleural or pericardial (s) effusion at baseline
ii) Clinically-significant gastrointestinal disease, digestive dysfunction or surgery that 
would compromise absorption of dasatinib or the administration of dasatinib by 
mouth (eg, uncontrolled nausea or malabsorption syndrome)
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iii) Thromboembolic disease requiring ongoing anticoagulation or deep vein thrombosis 
that is not adequately controlled
iv) A history of pulmonary arterial hypertension
c) Uncontrolled or significant cardiovascular disease, including any of the following:
i)
Myocardial infarction within 6 months of enrollment date
ii) Uncontrolled angina or congestive heart failure within 3 months of enrollment date
iii) Left ventricular ejection fraction (LVEF) < 40%
iv) Significant cardiac conduction abnormality, including
(1) History of clinically-significant ventricular arrhythmia (such as ventricular 
tachycardia, ventricular fibrillation, or Torsades de Pointe) 
(2) History of second or third degree heart block (except for second degree type 1 is 
not excluded) 
(3) Prolonged QTc/f interval > 450 msec on baseline ECG (unless a cardiac 
pacemaker is present)
d) History of significant bleeding disorder unrelated to CML, including:
i)
Diagnosed congenital bleeding disorders (eg, von Willebrand’s disease)
ii) Diagnosed acquired bleeding disorder within one year (eg, acquired anti-factor VIII 
antibodies).
e) Prior malignancy active within the previous 3 years except for locally curable cancers 
that have been apparently cured, such as basal or squamous cell skin cancer, superficial 
bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
f)
Subjects with active, known or suspected autoimmune disease. (Note: Subjects with 
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition 
only requiring hormone replacement, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll.) 
g) A serious uncontrolled medical disorder or active infection which would impair the 
ability of the subject to receive protocol therapy or whose control may be jeopardized by 
the complications of this therapy.
i) Although subjects with acute hepatitis B virus (HBV) infection or who are HBsAg 
positive are excluded, subjects who are positive for anti-HBc only 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
a) Positive test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or 
chronic infection
b) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS)
c) Grade 3 peripheral blood count deficiency, ie:
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i)
ANC < 1,000 cells/mm3
ii) Platelet count < 50,000 cells/mm3
iii) Hemoglobin < 8 g/dL (transfusion-support permitted)
d) Laboratory abnormalities (per CTCAE v 4.03):
i)
Serum sodium, potassium or calcium (ionized or corrected for albumin) or phosphate 
below ILLN (Institutional lower limit of normal)
ii) Baseline magnesium Grade 2
iii) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2.5 X 
institutional upper limit of normal (IULN). Total bilirubin > 2.0 X ULN (unless 
Gilbert syndrome has been diagnosed)
iv) Creatinine clearance < 40 mL/min (measured or calculated by Cockroft-Gault 
formula).
e) Oxygen saturation < 92% (by pulse oximetry).
4. Allergies and Adverse Drug Reaction
a) History of allergy to dasatinib 
b) History of grade 4 anaphylactic reaction to monoclonal antibody therapy or known 
hypersensitivity reactions to drugs formulated with polysorbate 90)
5. Sex and Reproductive Status
a) Subjects who are pregnant or breastfeeding or likely to become pregnant.
b) Men whose partner is unwilling or unable to avoid pregnancy
6. Prohibited Treatments and/or Therapies
a) Prior therapies for CML are permitted with the following restrictions 
i)
Investigational agent must be 28 days before first dasatinib dose (Note: regardless 
of approval status, imatinib, nilotinib, ponatinib, bosutinib and dasatinib are not 
considered investigational)
ii) Standard chemotherapy or TKI treatment except dasatinib must be discontinued 
7 days before first dasatinib dose (no interruption for ongoing dasatinib)
b) Subjects currently taking QT prolonging agents strongly associated with Torsades de 
Pointes (see Section 3.4.1.2) 
c) Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti CTLA-4 
antibody (or any other antibody or drug specifically targeting T-cell costimulation or 
checkpoint pathways)
d) Prior organ allograft or allogeneic bone marrow transplantation must have been > 1 year 
before enrollment, and only if there is no history of Grade 3 rejection or GVHD at any
time, there have been no signs of rejection nor GVHD for > 6 months before enrollment, 
and there is no ongoing therapy for GVHD.
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3.4.1.2
Medications that Prolong QT Interval
Medications associated with QT interval prolongation are prohibited while subjects are on 
therapy with dasatinib, including:

Anti-arrhythmics: quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, 
dofetilide, bepridil

CNS agents: propofol, chlorpromazine, droperidol, haloperidol, thioridazine, pimozide, 
citalopram, escalitopram, haloperidol, methadone, levomethadyl

Antibiotics: fluconazole, chloroquine, halofantrine, ciprofloxacin, erythromycin, 
clarithromycin, azithromycin, levofloxacin, sparfloxacin, pentamidine 

Other: cocaine (topical), cisapride, domperidone, astemizole, terfenadine 
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 6. 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.
3.4.1.3
Use of Growth Factors during the DLT Evaluation Period
Growth factors such as G-CSF/GM-CSF or epo-compounds (eg, erythropoietin or darbepoetin) 
are not permitted during the 6-week DLT evaluation period for subjects enrolled in the 
escalation phase as these may mask potential DLT. There are no restrictions on growth factors 
outside this period (see Section 3.4.3.2 for further guidance).
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. 
 
 
 
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3.5
Discontinuation of Subjects from Treatment
3.5.1
During Combination Therapy Period (During Escalation or Expansion 
Phase)
Subjects MUST discontinue both dasatinib and nivolumab for any of the following reasons:

Subject’s request to stop study treatment
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
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject 

Pregnancy

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

QTc Fridericia value > 500 msec, if confirmed on repeat ECG

Treatment Failure while receiving active study therapies (see Section 5.4.2).
Outside of the DLT period, subjects MUST discontinue nivolumab only for any of the following 
reasons:

Subject’s request to stop nivolumab 

Any drug-related adverse event requiring nivolumab discontinuation as described in 
Appendix 2 including the following, if related to nivolumab:

Grade 4 hematologic AE lasting > 7 days despite appropriate medical intervention

Grade 4 nonhematologic AE irrespective of duration

Grade 3 nonhematologic AE lasting > 7 days despite appropriate medical intervention 
(exception: asymptomatic laboratory values of Grade 3 which do not require medical 
intervention, and alopecia will not require discontinuation), unless requiring immediate 
discontinuation per Appendix 2.

Grade 3-4 hypersensitivity reaction
Please see Table 5.1-3 for procedures on continuing dasatinib monotherapy after discontinuation 
from nivolumab therapy.
3.5.2
During Dasatinib Monotherapy Phase
Subjects MUST discontinue dasatinib 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 

Pregnancy

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

QTc Fridericia value > 500 msec, if confirmed on repeat ECG

Treatment Failure while receiving active study therapies (see Section 5.4.2).
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All subjects who discontinue investigational product should comply with protocol specified 
follow-up procedures as outlined in Section 5. 
The only exception to this requirement is when a subject withdraws consent for all study 
procedures including post-treatment study follow-up or loses the ability to consent freely (ie, is 
imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or physical 
illness).
If study treatment is discontinued prior to the subject’s completion of the study, the reason for 
the discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Treatment Study Follow up
Subjects who discontinue study treatment should continue to be followed for safety assessments 
as described in Table 5.1-2 and Table 5.1-3.
Subjects who discontinue dasatinib from Day 1 to Day 14 must perform the dasatinib alone 
Follow-up visit within 30 days (7 days) from the last dose of dasatinib.
Combination Period
During the combination period, subjects who discontinue both dasatinib and nivolumab must 
perform the Follow-up visits 1 & 2 for nivolumab toxicities. The Follow-up visit 1 should be 
performed 35 days (7 days) from the last dose of nivolumab. The Follow-up visit 2 must be 
performed 80 days (7 days) from the Follow-up visit 1. 
Dasatinib Monotherapy Period
Subjects who discontinue nivolumab but continue on dasatinib alone beyond Month 4 visit
should not perform the follow-up visits 1 & 2 for nivolumab toxicities. The assessments 
performed during these visits are identical to those performed during the dasatinib alone Month 1 
and Month 4 visits. 
However, subjects who discontinue dasatinib alone before Month 1 visit must perform two 
follow-up visits for assessment of nivolumab toxicities: Follow-up visit 1 approximately 35 days 
(7 days) from the last dose of nivolumab and a Follow-up visit 2 approximately 80 days 
(7 days) from the first follow-up visit. 
Subjects who discontinue dasatinib alone after Month 1 and prior to Month 4 visits must also 
have a follow-up visit for nivolumab toxicities assessment approximately 100 days (7 days) 
from the last dose of nivolumab. 
Finally, subjects that discontinue dasatinib alone treatment after Month 4 visit must have a 
follow-up visit for dasatinib toxicities assessment performed 30 days (7 days) from the last 
dose of dasatinib.
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3.6.1
Withdrawal of Consent
Subjects who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4
TREATMENTS
Study drugs include both Non-investigational (NIMP) and Investigational Medicinal Products 
(IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial. 

Study required premedication, and 

Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, background therapy, rescue medications)

Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
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4.1
Study Treatments
Table 4.1-1:
Product Description: Open Label Period
Product Description 
and Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Appearance
Storage Conditions
(per label)
Dasatinib Tablet
20 mg
30 tablets per bottle / 
open label
NA
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° - 25°C
(59° - 77°F)
Dasatinib Tablet
50 mg
30 tablets per bottle / 
open label
NA
Film coated tablets, 
biconvex, round, white 
to off-white in 
appearance with “50” 
or “BMS” debossed on 
one side and “528” on 
the other side
15° - 25°C
(59° - 77°F)
Nivolumab Injection
10 mg/mL
10 mL 
(100 mg/vial)
Booklet label 
6 vials per carton
Booklet label
Clear to opalescent, 
colorless to pale yellow 
liquid, light (few) 
particulates may be 
present
2°- 8° C 
(36° - 46°F)
Protect from light
Protect from freezing
Medications used to treat infusion-related reactions should be sourced by the investigative sites if available and permitted by local 
regulations.
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4.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is/are: 

nivolumab 10 mg/mL

dasatinib tablets, 20 mg and 50 mg.
 
 
 
. 
4.1.3
Handling and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets). Study medication should be stored in a 
secure area according to local regulations. Storage facilities for investigational agents must be 
substantially constructed, securely locked and access restricted to prevent theft or diversion, and 
as applicable by local regulations.
For supportive care therapies product, if marketed product is utilized, it should be stored in 
accordance with the package insert, summary of product characteristics (SmPC), or similar.
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations.
Please refer to Section 9.2 for investigational product record retention and Section 4.6 for return 
and destruction instructions.
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Dasatinib
Dasatinib should be stored at 59F to 77F (15C to 25C). The investigator (or assigned 
designee, eg, study pharmacist) will dispense the proper number of each strength tablet to the 
subject to satisfy dosing requirements for 4 weeks, or longer if appropriate (eg, during dasatinib 
monotherapy). The label ID number or batch number, date and amount dispensed for each 
dosage strength must be recorded on the drug accountability pages. The subject must be 
instructed to return all unused study medications in the provided packaging at each subsequent 
visit.
Please refer to the current version of the dasatinib Investigator Brochure and/or pharmacy 
reference sheets for complete storage, handling, and dispensing information for dasatinib.
Nivolumab
Nivolumab vials must be stored at a temperature of 2°C to 8°C and should be protected from 
light and freezing. If stored in a glass front refrigerator, vials should be stored in the carton. 
Recommended safety measures for preparation and handling of nivolumab include laboratory 
coats and gloves.
For details on prepared drug storage and use time of nivolumab under room temperature/light 
and refrigeration, please refer to the BMS-936558 (nivolumab) Investigator Brochure section for 
“Recommended Storage and Use Conditions” and/or pharmacy reference sheets. 
Nivolumab is to be administered as a 60-minute IV infusion. At the end of the infusion, flush the 
line with a sufficient quantity of normal saline.
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% NaCl, or 5% dextrose solution) will 
not be supplied by the sponsor and should be purchased locally if permitted by local regulations.
Please refer to the current version of the BMS-936558 (nivolumab) Investigator Brochure and/or 
pharmacy reference sheets for complete storage, handling, dispensing, and infusion information.
 
 
 
 
4.3
Selection and Timing of Dose for Each Subject
Dasatinib
Dasatinib is administered from Day 1 for 2 weeks (14 days) prior to starting of nivolumab dosing 
(see below). 
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The starting dose of dasatinib is 100 mg QD for subject with CML-CP and 140 mg QD for 
subjects with CML-AP. In selected cases, a starting dose of dasatinib lower than 100 mg QD for 
CML-CP and 140 mg QD for CML-AP can be allowed with written agreement from the BMS 
Central Medical Monitor.
Dasatinib dosing must be held on the day of PK trough determinations for dasatinib until after 
PK predose samples for dasatinib have been drawn, as appropriate. 
On the Day 29, when both dasatinib and nivolumab samples are drawn, dasatinib dosing must be 
immediately before nivolumab infusion is begun in order to accurately evaluate PK. 
Dasatinib 50 mg and/or 20 mg tablets should be administered as two/four tablets taken once per 
day at the same time with or without food. Dose modifications are permitted and are outlined 
below in Section 4.3.2.
In the event of adverse event or intolerance, subjects may adjust the time of the day they take 
dasatinib as long as they take the drug approximately every 24 hours, except the days where PK 
samples are drawn for dasatinib.
Nivolumab
Nivolumab will be administered as an IV infusion beginning on treatment Day 15 and then every 
two weeks (3 days) for up to 2 years. Subjects may be dosed no less than 11 days from the 
previous dose of drug.
Nivolumab infusion should begin right after administration of dasatinib, as described above, 
whenever possible.
In the escalation phase, multiple dose levels of nivolumab will potentially be explored (see Table 
4.3-1). 
Table 4.3-1:
Nivolumab Dose Level
Dose Levels
Dose of Nivolumab Intravenous, q2 wks
-1
0.3 mg/kg
1
1 mg/kg
2
3 mg/kg
Dosing calculations should be based on body weight. Dose should be recalculated if weight has 
changed more than 5%. All doses should be rounded to the nearest milligram. However, 
nivolumab doses may be rounded down to the nearest 100 mg (vial size) if the difference is 
10 mg; at 3 mg/kg, this applies to subjects 67 - 70 kg or 100 - 103 kg.
There will be no dose modifications allowed, except as specified in Section 4.3.3.
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4.3.1
Dose Interruption or Delay
4.3.1.1
Dasatinib Interruption
Interruption of dasatinib administration is at investigator discretion. Depending on the nature of 
the AE, dasatinib should be interrupted for drug-related AE of Grade 2 or laboratory 
abnormality of Grade 4. Omitted/skipped doses should not be made up. Please refer to 
Section 4.3.2.
Dasatinib interruption is required for a dasatinib-related DLT (see Section 3.1.3.1, Dose Limiting 
Toxicity) and must follow the same instructions under Section 4.3.2, Dose Modifications.
Subjects must be re-treated within 28 days from the previous dose during the DLT period. 
Following the DLT period subjects may be allowed to remain on therapy following delays 
> 28 days after discussion and agreement with the BMS Central Medical Monitor.
Please refer to Table 5.1-3 for procedures on continuing dasatinib monotherapy after 
discontinuation from combination study therapy.
4.3.1.2
Nivolumab Dose Delay
Nivolumab administration should be delayed for the following drug-related AEs:

Any Grade 2 non-skin AE, except that

Grade 2 fatigue or laboratory abnormalities do not require delay, however
For a subject with baseline AST, ALT, or total bilirubin within normal limits, delay 
dosing for drug-related Grade 2 values

Any Grade 3 skin AE, or Grade 3 laboratory abnormality, with the following exceptions:

Grade 3 lymphopenia or leukopenia does not require dose delay.

If a subject has Grade 1 baseline AST, ALT, or total bilirubin, delay dosing for 
drug-related Grade 3 toxicity

Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Please refer to Appendix 2 for algorithms pertaining to nivolumab concerning the management 
of drug related adverse events. If the criterion to resume treatment is met, the subject should 
restart treatment at the next scheduled timepoint per protocol.
Consultation between the Investigator of record and the BMS Central Medical Monitor is 
mandatory prior to resuming nivolumab dosing after nivolumab delay. The BMS Central 
Medical Monitor may decide on nivolumab delay that supercedes the guidance in Appendix 2.
Subjects must be re-treated within 28 days from the previous dose during the DLT period. 
Following the DLT period subjects may be allowed to remain on therapy following delays 
> 28 days after discussion and agreement with the BMS Central Medical Monitor.
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4.4
Blinding/Unblinding
Not applicable: this is an open-label trial. 
4.5
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF
4.6
Destruction and Return of Study Drug
4.6.1
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS 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 BMS 
Study Monitor to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible BMS 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.
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4.6.2
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible BMS Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
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5.2
Study Materials

NCI CTCAE version 4.03

Dasatinib Investigator Brochure

Nivolumab Investigator Brochure

Pharmacy Binder

Laboratory manuals for collection and handling of blood (including biomarkers, PK and 
ADA) and tissue specimens

Site manual for operation of Interactive Voice Response System

Manual for entry of local laboratory data

Pregnancy Surveillance Forms

Pregnancy Log.
5.3
Safety Assessments
At screening, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG Performance Status, vital signs, 
chest x-ray, 12-lead ECG, echocardiogram, pregnancy testing for WOCBP, and oxygen 
saturation by pulse oximetry at rest and after exertion and should be performed within 28 days of 
first dasatinib dose. Pre-treatment medications will be collected from within 14 days prior to first 
treatment through the study treatment period (see Table 5.1-1). 
Screening local laboratory assessments should be done within 14 days of first dose of dasatinib 
include: CBC with differential and platelets, AST, ALT, direct bilirubin (reflex only), alkaline 
phosphatase, creatinine, BUN, uric acid, glucose, albumin, sodium, potassium, chloride, calcium, 
magnesium, phosphorus, lipase, amylase, TSH, urinalysis, HBV surface Ag, anti-HBc and HCV 
Ab or HCV RNA.
During the combination treatment period, pregnancy testing for WOCBP must be performed 
within 24 hours prior to the first dose of dasatinib, within 24 hours prior to first nivolumab 
infusion, at Day 15, Day 29, and every 4 weeks thereafter, at the combination EOT visit and at 
the Follow-Up visits 1 & 2 for nivolumab toxicities. During the dasatinib monotherapy period, 
pregnancy testing for WOCBP must be performed monthly and at the Dasatinib Alone EOT 
Visit. 
During the combination treatment period, vital signs and weight should be assessed at Day 1 and 
every 2 weeks thereafter. During the dasatinib monotherapy period, vital signs and weight should 
be assessed at Month 1, 4, 6, and at the Dasatinib Alone EOT visit. Vital signs should also be 
taken as per institutional standard of care prior to, during and after dosing. ECOG Performance 
status should be assessed as described in the Table 5.1-2 and Table 5.1-3.
On study local laboratory assessments should be done as described in the Table 5.1-2 and Table 
5.1-3, and should include the same hematology and chemistry laboratory tests done at screening. 
Additional measures including non-study required laboratory tests should be performed as 
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clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme elevations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline or are deemed irreversible.  
Screening for anti-HBc should be done for subjects not previously tested. 
Vital signs include BP, HR, respiratory rate, and temperature. A complete physical exam 
includes observation of general appearance and examination of HEENT, neck, cardiovascular, 
lungs, 
abdomen, 
lymph 
nodes, 
genitourinary, 
extremities, 
neurological, 
skin, 
and 
musculoskeletal. A brief physical includes heart and lung and other body systems as indicated.
Oxygen saturation by pulse oximetry should be obtained prior to each dosing and at any time a 
subject has any new or worsening respiratory symptoms. The start and stop time of the 
nivolumab infusion should be documented. A reading at rest and on exertion should be obtained 
at each time point. The extent of the exertion should be based on the judgment of the 
investigator, but should remain consistent for each individual subject throughout the study. If the 
subject’s status changes, the investigator can alter the extent of exertion based on their medical 
judgment. If a subject shows changes on pulse oximetry or other pulmonary related signs 
(hypoxia, fever) or symptoms (eg, dyspnea, cough, fever) consistent with possible pulmonary 
adverse events, the subject should be immediately evaluated to rule out pulmonary toxicity. An 
algorithm for the management of suspected pulmonary toxicity can be found in Appendix 2.
Adverse events will be assessed continuously during the study and for at least 100 days post last 
dose of nivolumab and for 30 days post last dose of dasatinib. Adverse events will be coded 
using the most current version of MedDRA and reviewed for potential significance and clinical 
importance. Adverse events will be evaluated according to the NCI CTCAE Version 4.03 dated 
14-Jun-2010. Subjects should be followed until all treatment-related adverse events have 
recovered to baseline or are deemed irreversible by the investigator.
Some of the previously referred to assessments may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
HBV Serology
Although subjects with acute hepatitis B virus (HBV) infection or who are HBsAg positive are  
excluded, subjects who are positive for anti-HBc only 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.  Subjects not previously tested for anti-
HBc should be tested while on study.  They may remain on study regardless of the result but 
follow guidance above if they test positive.
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5.3.1
Imaging Assessment for the Study
Not applicable
5.4
Efficacy Assessments
Efficacy will be assessed by hematological assessment, cytogenetic assessment and molecular 
assessment See Table 5.1-2 and Table 5.1-3 for the schedule of assessments. Detailed 
instructions for processing and shipment of blood samples will be provided in a separate 
Procedure Manual at the time of study initiation. 
Mutation analysis will be performed as applicable in case of loss of response or treatment failure 
and at the end of treatment visit. 
The definitions of response and treatment failure provided below should be used when 
determining an individual subject’s response and treatment failure to treatment and in making 
treatment decisions. Response and treatment failure definitions are provided below as they may 
require one or more actions on the part of the investigator and/or site staff.
These assessments can be performed with visit a window of 7 days.
5.4.1
Molecular Response Assessment
Molecular response will be assessed by BCR-ABL transcript levels measurement using qPCR. 
5.4.1.1
Definition of Major Molecular Response (MMR)
MMR is defined as 3-log reduction in BCR-ABL transcripts or a ratio of 0.1% on the 
International Scale (IS).
5.4.1.2
Definition of Molecular Response4.5 (MR4.5)
A molecular response 4.5 (MR4.5) is defined as 4.5-log reduction in BCR-ABL transcripts or a 
ratio of 0.00316% on the International Scale (IS). 
5.4.2
Definitions of Treatment Failure Requiring Discontinuation of Study 
Treatment
Any of the following events occurring while a subject is continuously on study therapy would 
define treatment failure and would require withdrawal of the subject from treatment. Subjects 
should be on the maximum tolerated dose (as determined by the investigator) before 
criteria for treatment failure is considered. Please refer to the dose escalation section 
(Section 4.3.3) for more details. 
The date of treatment failure will be defined and documented as the date any of the below 
criteria is first met. 
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Table 5.4.2-1:
Definitions of Treatment Failure Requiring Discontinuation of 
Study Treatment
Type of Treatment 
Failure
Definition
Confirmation
Loss of Cytogenetic 
Response a
Loss of Complete 
Cytogenetic 
Response (CCyR) 
or Partial 
Cytogenetic 
Response (PCyR)
An increase in the Ph+ bone 
marrow cells by at least 30% from 
the subject’s nadir
Loss of Hematologic 
Response
Increasing WBC:
Doubling of WBC to > 20.0 x 
109/L [> 20,000/mm3]
Confirmed at least 28 days 
apart in a subject who 
never achieved a 
confirmed Complete 
Hematologic Response 
(CHR).
Loss of CHR:
Defined as any one of the 
following:
WBC count that rises to > 20.0 x 
109/L (> 20,000/mm3)
Platelet count that rises to > 600 x 
109/L (> 600,000/mm3)
Appearance of extramedullary 
disease not present at baseline 
including hepatosplenomegaly by 
palpation or other extramedullary 
involvement proven by biopsy
Appearance of > 5% myelocytes + 
metamyelocytes in the peripheral 
blood
Appearance of blasts or 
promyelocytes in the peripheral 
blood.
Confirmed at least 28 days 
apart, unless associated 
with progression to 
accelerated or blast phase 
CML.
Progression
Criteria for 
accelerated phase 
are met for subject 
enrolled in CP or 
who attain CP 
during the study
As per Investigator decision
NA
Criteria for blast 
phase are met at 
any time
30% blasts in peripheral blood or 
in bone marrow aspirates and/or
extramedullary disease other than 
hepatosplenomegaly
NA
a Cytogenetic evaluation except at baseline and EOT is not mandatory, but may be performed if deemed necessary.
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6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered an investigational 
(medicinal) product and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of investigational product, 
whether or not considered related to the investigational product.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual 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).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason)

admission for administration of anticancer therapy in the absence of any other SAEs
6.1.1
Serious Adverse Event Collection and Reporting
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 100 days of discontinuation of nivolumab dosing and 30 days of dasatinib dosing. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg, a 
follow-up skin biopsy). 
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.
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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 

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of study exposure, including during at 
least 5 half lives after product administration, the investigator must immediately notify the BMS 
(or designee) Medical Monitor of this event and complete and forward a Pregnancy Surveillance 
Form to BMS (or designee) within 24 hours of awareness of the event and in accordance with the 
SAE reporting procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug, after a thorough 
discussion of benefits and risk with the subject.
Protocol required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
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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 of 
awareness of the event 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
All occurrences of overdose must be reported as SAEs (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
1) ALT (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
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8.2
Populations for Analyses

All Enrolled Subjects: All subjects who signed the informed consent form.

All Treated Subjects: All subjects who received at least 1 dose of dasatinib.

Escalation Phase Evaluable Subjects: All subjects who completed the escalation phase or 
experienced DLTs.

Pharmacokinetic Data Set: All available PK data from subjects who received dasatinib and 
nivolumab.

ADA Data Set: All available ADA data from subjects with CML who received dasatinib and 
nivolumab and have at least 1 post-treatment ADA measurement.

Biomarker Data Set: All available biomarker data from the subjects who received dasatinib.
Analyses of safety, extent of exposure, pharmacokinetics, biomarkers, efficacy, and ADA will be 
based on all treated subjects. Determination of the MTD among the 3 candidate dose levels at 
completion of the escalation phase will be based on the Escalation Phase evaluable subjects.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary is to assess the safety and tolerability for the combination of dasatinib and 
nivolumab in subjects with chronic phase or accelerated phase CML, in order to select a Phase 2 
dose. The assessment of safety and tolerability will be based on:

Dose limiting toxicities

Incidences of adverse events

Incidences of serious adverse events

Frequencies of clinical laboratory tests by worst toxicity grade.
8.3.2
Secondary Endpoint(s)
The secondary endpoints are based on MMR and MR4.5:

MMR and MR4.5 rates at 6, 12, 24, and 36 months

Time to, and duration of, MMR and MR4.5.
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8.4.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized by dose level and disease state at 
study entry (CP/AP CML) using descriptive statistics.
8.4.2
Efficacy Analyses
MMR and MR4.5 rates at 6, 12, 24, and 36 months will be provided by dose level and disease 
state at study entry with their corresponding 2-sided 95% exact (Clopper and Pearson) 
confidence intervals. Time to event and duration of event will be analyzed using Kaplan-Meier 
methodology. Median time to event and median duration will be presented with their 95% 
confidence intervals derived with the method of Brookmeyer and Crowley.48
8.4.3
Safety Analyses
All recorded adverse events will be listed and tabulated by system organ class, preferred term, 
treatment arm, dose level and disease state at study entry and coded according to the most 
current version of MedDRA. Vital signs and clinical laboratory test results will be listed and 
summarized by dose level and disease state at study entry. Any significant physical examination 
findings and results of clinical laboratory test will be listed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
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them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. 
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb 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 
investigational product (those supplied by BMS) is maintained at each study site where study 
drug are inventoried and dispensed. Records or logs must comply with applicable regulations and 
guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS
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
retain samples for bioavailability/bioequivalence, if applicable 

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form .For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool.
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected considering the following criteria:

External Principal Investigator designated at protocol development

Study Steering Committee chair or their designee
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
Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or 
country)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study must adhere to the publication requirements set forth in the 
clinical trial agreement (CTA) governing [Study site or Investigator] participation in the study. 
These requirements include, but are not limited to, submitting proposed publications to BMS at 
the earliest practicable time prior to submission or presentation and otherwise within the time 
period set forth in the CTA.
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10
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the investigator 
or BMS as related to the investigational product
Unexpected Adverse Reaction
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg, 
Investigator Brochure for an unapproved investigational 
product)
Serious Adverse Event
Serious adverse event defined as any untoward medical 
occurrence that at any dose: results in death; is life 
threatening (defined as an event in which the subject was at 
risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it 
were more severe), requires inpatient hospitalization or 
causes prolongation of existing hospitalization; results in 
persistent or significant disability/incapacity, is a congenital 
anomaly/birth defect; is an important medical event (defined 
as a medical event(s) that may not be immediately life 
threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require intervention [eg, 
medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above). Examples of such 
events include, but are not limited to, intensive treatment in 
an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in 
hospitalization.). For reporting purposes only, BMS also 
considers the occurrence of pregnancy, overdose (regardless 
of association with an AE), and cancer as important medical 
events.
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11
LIST OF ABBREVIATIONS
Term
Definition
ADA
Anti-drug antibody
ADL
Activities of Daily Living
AE
adverse event
AEOSIs
Drug-related adverse events of special interests
AIDS
Acquired immunodeficiency syndrome
ALL
acute lymphoblastic leukemia
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AP
accelerated phase
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
-HCG
beta-human chorionic gonadotrophin
BID, bid
bis in die, twice daily
BMS
Bristol-Myers Squibb
BP
Blastic Phase
BP
blood pressure
BSA
Body Surface Area
BUN
blood urea nitrogen
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca++
calcium
CBC
complete blood count
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Term
Definition
CCyR
Complete Cytogenetic Response
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CHMP
Committee for Medicinal Products for Human Use
CHR
Complete Hematologic Response
CI
confidence interval
C1-
chloride
CL
clearance
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CML
Chronic myeloid leukemia
CP
chronic phase
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.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
CTCAE
Common Toxicity Criteria
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
D
day
DEHP
di(2-ethylhexyl)phthalate
DILI
drug induced liver injury
dL
deciliter
DLI
donor lymphocyte infusion
DLT
Dose limiting toxicity
ECG
electrocardiogram
ECHO
ECOG
Eastern Cooperative Oncology Group
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Term
Definition
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EFS
event free survival
eg
exempli gratia (for example)
ELISA
Enzyme-linked immunosorbent assay
EOI
End Of Infusion
EOT
End of Treatment
EPH
ephrin
F
bioavailability
F
Fahrenheit
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
FU
Follow-up
g
gram
GCP
Good Clinical Practice
h
hour
HBV
hepatitis B virus
HCG
human chorionic gonadotrophin
HCV
hepatitis C virus
HEENT
Hear, ears, eyes, nose and throat
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
HU
hydroxyurea
IB
Investigator brochure
ICF
Informed Consent
ICH
International Conference on Harmonisation 
ID
number
ie
id est (that is)
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Term
Definition
IEC
Independent Ethics Committee
IFN
Interferon alpha
IL
interleukin
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
I-O
Immuno Oncology
IRB
Institutional Review Board
ITIM
immunoreceptor tyrosine inhibitory motif
ITSM
immunoreceptor tyrosine based switch motif
IU
International Unit
IUD
intrauterine devices
IULN
institutional upper limit of normal
IV
intravenous
IVIG
intravenous immuno globulin
IVRS
Interactive Voice Response System
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
potassium
kg
kilogram
L
liter
LFT
Liver function test
LGL
Large granular lymphocyte
LVEF
Left ventricular ejection fraction
Mg
magnesium
mg
milligram
min
minute
mL
milliliter
MLR
mixed lymphocyte reaction
mmHg
millimeters of mercury
MMR
major molecular response
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Term
Definition
MR
molecular response
MRD
minimal residual disease
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
NSCLC
Non-small cell lung cancer
ORR
Overall Response Rate
OS
overall survival
PCyR
Partial Cytogenetic Response
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamics
PDGF
Platelet-derived growth factor beta
PD-L1
Programmed cell death 1 ligand 1
PFS
Progression-free survival
PH
Philadelphia chromosome
PK
pharmacokinetics
PO
Per os, by mouth
PPI
Proton pump inhibitor
PPK
preliminary population PK
PS
Performance Status
PVC
polyvinyl chloride
QC
quality control
QD, qd
quaque die, once daily
qPCR
Real-time polymerase chain reaction
RCC
renal cell carcinoma
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Term
Definition
RECIST
Response Evaluation Criteria In Solid Tumors
RR
respiratory rate
SAE
serious adverse event
SCT
stem cell transplant
SD
standard deviation
SHP
src homology phosphatase
SmPC
Summary of product characteristics
SOP
Standard Operating Procedures
sp.
species
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
TCR
T-cell receptor
TGF-beta
Transforming growth factor beta
T-HALF
Half life
TID, tid
ter in die, three times a day
TKIs
tyrosine kinase inhibitors
Tmax, TMAX
time of maximum observed concentration
T3
triiodotyronine
TR_Cmax
Cmax treatment ratio
TSH
Thyroid-stimulating hormone
ULN
Upper Limit Normal
W
washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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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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SAP_000.pdf: 
Statistical Analysis Plan for 
 
Official Title of Study 
A PHASE 1B DOSE ESCALATION STUDY TO INVESTIGATE THE SAFETY, 
TOLERABILITY AND PRELIMINARY EFFICACY FOR THE COMBINATION OF 
DASATINIB (BMS-354825) PLUS NIVOLUMAB (BMS-936558) IN PATIENTS WITH 
CHRONIC MYELOID LEUKEMIA (CML) 
 
NCT02011945 
 
30-June-2015 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A PHASE 1B DOSE ESCALATION STUDY TO INVESTIGATE THE SAFETY, 
TOLERABILITY AND PRELIMINARY EFFICACY FOR THE COMBINATION OF
DASATINIB (BMS-354825) PLUS NIVOLUMAB (BMS-936558) IN PATIENTS WITH 
CHRONIC MYELOID LEUKEMIA (CML)
PROTOCOL(S) CA180373
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2
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT.....................................1
TABLE OF CONTENTS.................................................................................................................2
LIST OF TABLES...........................................................................................................................4
2
STUDY DESCRIPTION..............................................................................................6
2.1
Study Design.................................................................................................................6
2.2
Treatment Assignment..................................................................................................7
2.3
Blinding and Unblinding ..............................................................................................7
3
OBJECTIVES...............................................................................................................8
3.1
Primary .........................................................................................................................8
3.2
Secondary .....................................................................................................................9
4
ENDPOINTS ................................................................................................................9
4.1
Efficacy Endpoints........................................................................................................9
4.1.1
Molecular Response......................................................................................................9
4.2
Safety Endpoints.........................................................................................................11
5
SAMPLE SIZE AND POWER ..................................................................................11
5.1
Efficacy Endpoints......................................................................................................11
5.1.1
Molecular Response....................................................................................................11
5.2
Safety Endpoints.........................................................................................................13
5.3
Other Endpoints..........................................................................................................13
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES.......................................................................................................13
6.1
Study Periods..............................................................................................................13
6.1.1
Baseline.......................................................................................................................13
6.1.2
On-study......................................................................................................................13
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3
6.2
Treatment Regimens...................................................................................................13
6.3
Populations for Analyses ............................................................................................14
7
STATISTICAL ANALYSES.....................................................................................14
7.1
General Methods.........................................................................................................14
7.2
Interim Analysis..........................................................................................................14
7.3
Study Population.........................................................................................................15
7.3.1
Subject Disposition.....................................................................................................15
7.3.5
Pre-treatment Clinical Complaints.............................................................................15
7.3.6
Baseline Examinations................................................................................................16
7.4
Extent of Exposure .....................................................................................................16
7.5
Efficacy.......................................................................................................................18
7.5.1
Molecular Response....................................................................................................18
7.5.5
Other Efficacy.............................................................................................................19
7.6
Safety..........................................................................................................................20
7.6.1
Maximum Tolerated Dose / Recommended Phase 2 Dose.........................................20
7.6.2
Adverse Events............................................................................................................20
7.6.3
Clinical laboratory Evaluations .................................................................................20
7.6.4
Electrocardiogram......................................................................................................21
7.6.5
Echocardiogram .........................................................................................................21
7.6.6
Deaths.........................................................................................................................22
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7.6.7
Vital Signs...................................................................................................................22
LIST OF TABLES
Table 2.1-1:
Dose Levels for Dose-escalation of Nivolumab in Combination 
with Dasatinib..............................................................................................7
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2
STUDY DESCRIPTION
2.1
Study Design
This is an open-label non-randomized Phase Ib trial investigating the combination of dasatinib 
and nivolumab in CML subjects with chronic phase (CML-CP) or accelerated phase (CML-AP), 
who are progressing on, resistant to, sub-optimally responding to, or intolerant to prior treatment 
with any TKI (except dasatinib in case of prior intolerance).
The study consists of an escalation and an expansion phase. Dose levels are defined by the 
nivolumab dose (see Table Table 2.1-1). All subjects are treated until progression/treatment 
failure or intolerance for a maximum of up to 2 years with dasatinib and nivolumab combination 
and up to 1 additional year with dasatinib alone. 
In the escalation phase, safety and tolerability will be assessed in cohorts of up to 12 subjects 
using a modified toxicity probability interval (mTPI) design1. This method is expected to more 
accurately estimate the maximum tolerated dose (MTD) among a set of proposed doses than 
designs like 3 + 3 or 6 + 6 (when the same cohort size is used). The mTPI method uses a set of 
decision rules guided by posterior inference and requires the definition of a target toxicity rate 
and an equivalence interval (EI), in which any dose is considered sufficiently close to the true 
MTD as to be selected as the estimated MTD. Dose-limiting toxicity (DLT) will be assessed for 
CML-CP and CML-AP in a pooled fashion. Approximately 24 - 48 subjects will be required for 
the escalation phase (see Section 5). Subjects who do not complete the DLT period for reasons 
other than dose-limiting toxicities will be replaced.
The Study Team (Principal Investigators and Sponsor representatives) will determine accrual 
schedule and timing of cohort escalation and dose for expansion based on all available 
information. Refer to protocol Section 3.1.3 for the criteria for dose escalation. Decisions will be 
based primarily on safety data for the first 6 weeks of combined treatment (Weeks 3 - 8 
inclusive) in subjects with both CML-CP and AP but all relevant experience, including 
interruption or discontinuation for toxicity after the DLT period and AEs during subsequent 
treatment, will be considered. Refer to protocol Section 3.1.3.1 for the definition of DLT. At 
completion of the escalation phase, the MTD will be assessed based on the estimate derived from 
the mTPI method (the dose for which the difference between the estimated toxicity and the target 
toxicity is smallest among the doses tested). 
Subsequently, 21 - 33 additional subjects will be treated in an expansion phase at a dose selected 
during the escalation phase (recommended Phase 2 dose), in order to achieve a total of 45 - 68 
subjects (see Section 5). If the overall safety profile of the study drugs is less favorable than that 
initially observed in the escalation phase, then further enrollment to the expansion cohort will be 
interrupted and a decision whether or not to continue dosing will be based on discussions of the 
observed aggregate (acute and chronic) toxicities between the study Investigators and the 
Sponsor. 
Dasatinib is administered once-daily (QD) starting in Week 1 (Day 1) at 100mg po QD in 
subjects with CML-CP and at 140mg po QD in those with CML-AP. In selected cases, a lower 
starting dose of dasatinib could be allowed. Subjects will receive dasatinib alone during 
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Weeks 1 - 2 of this study. Nivolumab will be administered as an IV infusion beginning on 
treatment Day 15 (Week 3) and then every two weeks (3 days). In the escalation phase, DLT 
assessment will occur during the first 6 weeks of combination therapy (Weeks 3-8, inclusive).
Dose levels are defined as in Table Table 2.1-1 below.
Table 2.1-1:
Dose Levels for Dose-escalation of Nivolumab in Combination with 
Dasatinib
Dose Level
Nivolumab (mg/kg)
Dasatinib (mg)
-1
0.3
100/140
1
1
100/140
2
3
100/140
Initially, subjects will be treated at DL 1. DL -1 is provided in case DL 1 is not tolerated and 
dose reduction would be needed for subsequent subjects. 
2.2
Treatment Assignment
Not applicable (open label study).
2.3
Blinding and Unblinding
There are currently 6 approved amendments. The history of protocol amendments including the 
dates and changes to the protocol are summarized below.

Amendment 1 (11-Jul-2013, all sites): The objective of this amendment was to permit the 
collection and storage of blood samples for use in future exploratory pharmacogenetic 
research. 

Amendment 2 (12-Sep-2013, all German sites): This amendment was written in response to a 
request from the German Health Authorities to ensure that HIV positive subjects are 
excluded from the study in Germany.

Amendment 3 (23-Oct-2013, all sites): The main objective of this amendment was to 
implement recommendations received from the United State Food and Drug Administration 
(FDA). These recommendations were mainly to have 2 prior TKI therapies for CML prior 
to entering the trial and to include all non-hematologic Grade 3 or greater adverse events 
(AE) irrespective of duration in the definition of DLT. The pharmacokinetic and anti-drug 
antibody sampling schedules were amended as well as the analysis section (to add report of 
immunogenicity and neutralizing antibodies analyses). In addition, the method to assess the 
selected dose for the expansion phase, the MTD, as well as some inclusion or exclusion 
criteria, and the time and event schedule were corrected or clarified. 

Amendment 4 (07-Feb-2014, all French sites): The main objective of this amendment was to 
implement recommendations received from the French Health Authorities. The major 
changes resulting from this amendment were the exclusion of subjects with suboptimal 
response during or intolerance to the last prior TKI, to consider possible pulmonary arterial 
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hypertension (PAH) at cardiac evaluations and to change slightly the QTcF (Fridericia 
correction) level at which dasatinib must be discontinued.

Amendment 5 (01-Oct-2014, all sites): The main objectives of this amendment were to 
clarify some eligibility criteria, to update the DLT definition (by excluding Grade 4 
hematologic AEs attributable to disease and dasatinib, as cytopenia is very common in TKI-
pretreated CML patients with hematologic progression who are starting dasatinib), to remove 
most dasatinib PK sampling, and to allow a starting dose of dasatinib lower than 
100mg/140mg daily for CML-CP/AP in select cases. In addition, edits to provide 
consistency, clarification, correction, simplification of time and events schedules or fix 
typographical errors were made.

Amendment 6 (15-Apr-2015, all sites): Escalation to nivolumab 3mg/kg will be permitted for 
subjects receiving a nivolumab dose of 1mg/kg (n = 9, at time of this Amendment) after 
9 months on study. 
Now that Dose Level 2, nivolumab 3mg/kg, is open to enrollment, this option becomes 
appropriate. The minimum of 9 months treatment at 1mg/kg will assure that safety data is 
adequate at this dose. This change will permit subjects to escalate under the following 
conditions:

Only subjects with clear evidence that their disease is not responding at 1mg/kg 
nivolumab could be escalated. There is evidence that nivolumab efficacy is dose-
dependent, with different thresholds for different tumors.

Only subjects with very good tolerance of 1mg/kg (i.e., have no clinically-significant 
nivolumab-related AEs of any grade) after > 9 months on study could be escalated. No 
DLTs were observed among the 12 evaluable subjects treated at nivolumab dose of 
1mg/kg. Subjects who have tolerated 1mg/kg are expected to tolerate 3mg/kg equally 
well.
3
OBJECTIVES
3.1
Primary
The primary objective is to assess the safety and tolerability for the combination of dasatinib and 
nivolumab in subjects with CP or AP CML, in order to select a Phase 2 dose. The assessment of 
safety and tolerability will be based on:

Dose limiting toxicities (DLTs) as defined in Section 3.1.3.1 of the protocol,

Incidences of adverse events (AEs) and serious adverse events (SAEs), during the DLT 
period, the full treatment period of the subjects with the combination therapy, and during the 
expansion phase,

Frequencies of abnormal clinical laboratory tests (summarized by worst toxicity grade).
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3.2
Secondary
The secondary objectives are based on Major Molecular Response (MMR) and Molecular 
Response 4.5 (MR4.5):

MMR and MR4.5 at 6, 12, 24, and 36 months

To evaluate time to and duration of MMR and MR4.5.
).
 
 
4
ENDPOINTS
The primary endpoint is to assess the safety and tolerability for the combination of dasatinib and 
nivolumab in subjects with CML-CP or CML-AP, in order to select a Phase 2 dose. The 
assessment of safety and tolerability will be based on:

Dose limiting toxicities

Incidences of adverse events

Incidences of serious adverse events

Frequencies of clinical laboratory tests by worst toxicity grade.
Timing of evaluation of the efficacy and safety endpoints is detailed in Tables 5.1-1, 5.1-2 and 
5.1-3 of the protocol.
4.1
Efficacy Endpoints
Efficacy will be assessed by molecular assessment, cytogenetic assessment, and hematological 
assessment. 
4.1.1
Molecular Response
Molecular response will be assessed using BCR-ABL transcript levels measurement by real-time 
quantitative polymerase chain reaction (RQ-PCR). The assay will be run in a centralized 
laboratory and data will be expressed on the international scale (IS)2.
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4.2
Safety Endpoints
Beside the evaluations used to address the primary endpoint (see Section 4), safety endpoints 
include deaths, SAEs and AEs, laboratory evaluations, electrocardiograms (ECG), 
echocardiograms, and reasons off treatment.
 
 
5
SAMPLE SIZE AND POWER
The primary endpoint is to assess the safety and tolerability for the combination of dasatinib and 
nivolumab in subjects with CML-CP or CML-AP, in order to select a Phase 2 dose. The 
assessment of safety and tolerability will be based on:

Dose limiting toxicities

Incidences of adverse events

Incidences of serious adverse events

Frequencies of clinical laboratory tests by worst toxicity grade.
Timing of evaluation of the efficacy and safety endpoints is detailed in Tables 5.1-1, 5.1-2 and 
5.1-3 of the protocol.
5.1
Efficacy Endpoints
Efficacy will be assessed by molecular assessment, cytogenetic assessment, and hematological 
assessment. 
5.1.1
Molecular Response
Molecular response will be assessed using BCR-ABL transcript levels measurement by real-time 
quantitative polymerase chain reaction (RQ-PCR). The assay will be run in a centralized 
laboratory and data will be expressed on the international scale (IS)2.

A major molecular response (MMR) is defined as a ratio BCR-ABL/ABL 0.1% on the 
international scale (i.e., at least 3 log reduction from a standardized baseline value). 
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5.2
Safety Endpoints
Beside the evaluations used to address the primary endpoint (see Section 4), safety endpoints 
include deaths, SAEs and AEs, laboratory evaluations, electrocardiograms (ECG), 
echocardiograms, and reasons off treatment.
 
 
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
6.1.1
Baseline

Baseline AEs will be defined as AEs with an onset date prior to but not including the first 
day of dasatinib treatment in study CA180373.

For all other evaluations (ECOG, laboratory evaluations, extramedullary assessments, ECGs, 
pulse oximetry, vital signs, etc.) baseline will be defined as evaluations with an onset date on 
or prior to the first day of dasatinib treatment in study CA180373.
6.1.2
On-study

On-study AEs will be defined as AEs with an onset date on or after the first day of treatment. 
For subjects off treatment, AEs will be counted as on-study if the event occurred within 
100 days of the last dose of nivolumab or within 30 days of the last dose of dasatinib, 
whichever is later.

For all other evaluations (ECOG, laboratory evaluations, extramedullary assessments, ECGs, 
pulse oximetry, vital signs, etc.) on-study will be defined as evaluations taken after the first 
day of treatment. For subjects off treatment, on-study evaluations will also be within 
100 days of the last dose of nivolumab or within 30 days of the last dose of dasatinib, 
whichever is later.
6.2
Treatment Regimens
Treatment regimen will be represented by the assigned starting dose level defined by the 
nivolumab dose (Table Table 2.1-1) or reported as DAS if subject did not start nivolumab 
dosing.
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6.3
Populations for Analyses
The following populations will be used in this study:

All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the Interactive Voice Response System (IVRS).

All Treated Subjects: All enrolled subjects who received at least one dose of dasatinib. 

Molecular Response-evaluable Subjects: All treated subjects without a MMR at study entry. 

DLT-evaluable Subjects: All treated subjects who completed the DLT phase (i.e., received 
study treatment for at least 8 weeks, to Day 57) or experienced DLT. 
Determination of an MTD, if any, will be based on AEs in DLT-evaluable subjects. Except 
where indicated, all other analyses will be based on All Treated Subjects population.
7
STATISTICAL ANALYSES
7.1
General Methods
Descriptive summaries of continuous and other numeric variables will at least consist of the 
following summary statistics: median, minimum and maximum values. Categorical variables will 
be summarized by frequencies and percentages. Unless otherwise indicated, percentages in tables 
will be column percentages, using the total number of observations in the population as the 
denominator. Percentages will be rounded to one decimal place, and thus may not always add up 
to exactly 100%.
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) system organ classes and preferred terms. AEs and laboratory tests will be 
graded using the National Cancer Institute - Common Toxicity Criteria for Adverse Event (NCI-
CTCAE) Version 4.03 dated 14-Jun-2010 criteria. Laboratory results will be presented using the 
United States standard units.
Subjects in 1mg/kg nivolumab cohort who will escalate to 3mg/kg nivolumab will be reported in 
the 1mg/kg nivolumab dose level cohort.
7.2
Interim Analysis
An interim analysis will be performed at the time the last subject in the escalation phase 
completes the DLT period, i.e. when that subject has been observed for a minimum of 8 weeks. 
The interim analysis will provide preliminary safety and efficacy information on the treatment 
combination; the list of outputs to be produced for the interim analysis will be specified in the 
Data Presentation Plan.
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7.5
Efficacy
All efficacy tables and listings will be displayed by disease state at study entry (CML-CP 
without prior dasatinib, CML-CP with prior dasatinib, CML-AP) and dose level. 
The exact two-sided 95% confidence intervals (CI) around a rate will be computed using the 
method of Clopper and Pearson3. For variables summarized with the Kaplan-Meier product limit 
method4, the CI around the median time or duration will be computed using the method of 
Brookmeyer-Crowley5.
7.5.1
Molecular Response
MMR and MR4.5 rates as well as 95% exact CI at 6, 12, 24, and 36 months will be tabulated 
using the All Treated Subjects population. As some subjects may have entered the study with a 
MMR, the analysis on MMR rates will be repeated using the Molecular Response-evaluable 
Subjects population.
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Time to MMR and to MR4.5 will be estimated using the Kaplan-Meier product limit method and 
median time will be reported along with 95% CI using the All Treated Subjects population.
Duration of MMR and of MR4.5 will be estimated using the Kaplan-Meier product limit method 
and median time will be reported along with 95% CI using the Treated Subjects with a MMR (or 
a MR4.5) population. 
Response variables will be listed using the All Treated Subjects population.
 
 
 
 
 
 
 
 
 
 
 
 
 
7.5.5
Other Efficacy
A listing with peripheral hematology (WBC, ANC, platelets, blasts, promyelocytes, myelocytes,
metamyelocytes, and basophils, bone marrow (number of metaphases, metaphase positive 
values, and blast) and extramedullary disease (any and spleen or liver) by subject and assessment 
date will be provided using the All Treated Subjects population. 
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7.6
Safety
Analyses of safety (tables and listings) will be based on the All Treated Subjects population (All 
Enrolled Subjects for the SAE and death listings), and will be displayed by disease state at study 
entry (CML-CP without prior dasatinib, CML-CP with prior dasatinib, CML-AP), dose level and 
overall.
 
 
 
 
7.6.2
Adverse Events
The following summaries will be provided by worst toxicity grade on-study (0, 1, 2, 3, 4, and 5):

On-study AEs,

On-study drug-related AEs, 

On-study SAEs, 

On-study drug-related SAEs, 

On-study AEs leading to discontinuation, 

On-study drug-related AEs leading to discontinuation.
Listing of AEs, SAEs and AEs leading to discontinuation will be provided. 
The following will be provided by dose level (disease state pooled): 

On-study non-serious AEs reported for at least 5% subjects within any dose level,

Standard analyses on multiple AEs:

Exposure adjusted adverse event summary,

Frequency of unique adverse events summary, and

Listing of unique events.
7.6.3
Clinical laboratory Evaluations
Summary of laboratory tests consisting of shift tables in CTC toxicity grading from baseline to 
worst grade on-study (0, 1, 2, 3, and 4) will be provided.  
The following laboratory tests will be considered for tabulation:

Hematology: WBC, neutrophil (ANC), platelets, hemoglobin

Serum chemistry for liver function: alkaline phosphatase (ALP), alanine aminotransferase
(ALT), aspartate aminotransferase (AST), total bilirubin 
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
Serum chemistry for renal function: creatinine

Other serum chemistry: calcium (low and high), magnesium (low and high), phosphorus, 
potassium (low and high), sodium (low and high), amylase and lipase. 
Listing of all laboratory data will be provided. 
Because of the combination with nivolumab, the following laboratory abnormalities (vs. lower 
limit of normal, LLN or upper limit of normal, ULN) will be tabulated and listed by dose level 
(disease state pooled):

Liver specific tests in relation to potential drug induced liver injury (DILI): 

ALT or AST > 3xULN, > 5xULN, > 10xULN or > 20xULN; 

Total bilirubin > 2xULN; 

Concurrent (within one day) ALT or AST elevation > 3xULN and total bilirubin > 
2xULN;

Concurrent (within 30 days) ALT or AST elevation > 3xULN and total bilirubin > 
2xULN..

Thyroid specific test  (TSH) > ULN:

Any,

With TSH ULN at baseline,

With at least one FT3/FT4 test value < LLN,

With all other FT3/FT4 test values LLN,

With FT3/FT4 test missing.

Thyroid specific test  (TSH) > 2*ULN:

Same categories as above.

Thyroid specific test  (TSH) < LLN:

Any,

With TSH LLN at baseline,

With at least one FT3/FT4 test value > ULN,

With all other FT3/FT4 test values ULN,

With FT3/FT4 test missing.
7.6.4
Electrocardiogram
Frequency distribution of maximal QTc(F) intervals and QTc(F) changes from baseline 
(> 30msec, > 60msec, etc.) will be tabulated. A listing of ECG parameters (e.g., HR, QTc(F)) 
will be provided.
7.6.5
Echocardiogram
A listing of echocardiogram parameters will be provided.
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