Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) With Dasatinib (BMS-354825)
Phase: PHASE2
Conditions: Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Philadelphia Chromosome Positive, BCR-ABL1 Positive Chronic Myelogenous Leukemia
Sponsor: M.D. Anderson Cancer Center

Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) with Dasatinib (BMS-354825)  
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TABLE OF CONTENTS 
Protocol Body ..................................................................................................................  
1.0 
Objectives ......................................................................................................... 2 
2.0 
Background ....................................................................................................... 3 
2.1 
Purpose ......................................................................................................... 3 
2.2 
Historical Experience ..................................................................................... 3 
2.3 
Interferon Therapy in CML ............................................................................. 4 
2.4 
Imatinib Mesylate (STI571; Gleevec) in CML ................................................ 4 
2.5 
Dasatinib ....................................................................................................... 5 
2.6 
Proposed Therapy with Dasatinib .................................................................. 6 
2.7 
Other Biologic Endpoints ............................................................................... 6 
2.8 
Update January 2019..............................................................................................6 
3.0 
Background Drug Information ........................................................................... 7 
3.1 
Overview………………………………………………………………………   ….7 
 
3.2 
Summary of Results of Investigational Program……………………………….7 
 
3.3 
Investigational Product………………………………………………………….18 
4.0 
Patient Eligibility ......................................................................................................... 21 
5.0 
Treatment Plan ............................................................................................... 23 
5.1 
General ........................................................................................................ 23 
5.2 
Treatment Plan .......................................................................................... 234 
5.3 
Dose modifications of Dasatinib .................................................................. 24 
5.4 
Missed Doses .............................................................................................. 24 
5.5 
Duration of Therapy ..................................................................................... 24 
5.6 
Prohibited and Restricted Therapies During the Study………………………25 
6.0 
Pretreatment Evaluation ................................................................................. 26 

Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) with Dasatinib (BMS-354825)  
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7.0 
Evaluation During Study ................................................................................. 27 
8.0 
Criteria for Response ...................................................................................... 27 
9.0 
Criteria for Removal from the Study ................................................................ 28 
10.0 Statistical Considerations ................................................................................ 28 
11.0 Reporting Requirements ................................................................................. 32 
12.0 References ...................................................................................................... 34 
 
1.0 
Objectives 
Primary: 
• 
To estimate the proportion of patients with previously-untreated chronic 
phase CML attaining major molecular response by 12 months of treatment 
with dasatinib. 
Secondary: 
• To estimate the proportion of patients with Ph-positive early chronic phase 
CML achieving a complete cytogenetic response after dasatinib therapy. 
• To evaluate the durations of hematologic, cytogenetic and molecular 
response to dasatinib. 
• To define the time to progression and overall survival for patients with CML 
in early chronic phase treated with dasatinib. 
• To evaluate the toxicity profile of dasatinib in patients with CML in early 
chronic phase.  
• To evaluate the probability of developing ABL mutations for patients with 
CML in early chronic phase treated with dasatinib. 
• To analyze differences in response rates and in prognosis within different 
risk groups and patient characteristics. 
• To assess correlation between trough concentration and pleural effusion.  
• To assess the inhibition of platelet function and assess correlation between 
drug concentration and degree of platelet inhibition.  
• To assess the effect of dasatinib therapy in bone metabolism as determined 
by changes in serum alkaline phosphatase (bone specific isoenzyme), and 
trabecular bone volume. 
• To evaluate symptom burden in patients with CML receiving dasatinib 

Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) with Dasatinib (BMS-354825)  
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Exploratory Objective:  
•  To investigate the plasma/serum levels of specific miRNAs in CML patients 
receiving dasatinib as initial therapy for CML in CP.  
2.0 
Background 
2.1 
Purpose 
The basic hypothesis underlying our therapeutic programs in CML is to be 
able to achieve meaningful and long-lasting suppression of the Philadelphia 
chromosome and BCR-ABL.  Complete cytogenetic responses and major 
or complete molecular responses have been associated with improved 
survival in CML.  
2.2 
Historical Experience 
The prognosis of patients with chronic myelogenous leukemia is improving.1  
Historically, the median survival of untreated patients with CML was 19 
months from diagnosis.  In our historical experience of 303 patients with a 
diagnosis of Philadelphia-positive early chronic-phase CML referred to our 
institution within 3 months of diagnosis with minimal or no prior therapy, the 
overall median survival was 39 months.2  Patients were divided into good, 
intermediate and poor risk groups with different hazard rates and median 
survivals.2 
 
Symptoms are subjective phenomena reported by patients that indicate a 
change in normal functioning, sensation, or appearance due to disease44. 
Symptom burden is the combined impact of disease- and therapy-related 
symptoms on the ability of persons to function as they did prior to onset of 
their disease and/or therapy 45. The MD Anderson Symptom Inventory 
(MDASI) is a valid and reliable measure of symptom burden46. Recently a 
CML-specific version of the MDASI, the MDASI-CML, has been validated. 
Common symptoms of chronic myeloid leukemia (CML) and its treatment 
can significantly impair the daily functioning of patients 47. Symptoms such 
as fatigue, nausea and vomiting, diarrhea, muscle cramps, skin changes, 
and headache add to the burden of CML. Patients with serious illnesses 
often report that they would like to “return to a normal life”48. Decreasing the 
symptom burden of CML and its treatments will allow patients to function as 
normally as possible. Currently, there is little research on symptoms and 
their impact on daily functioning experienced by patients with CML to direct 
interventions that may assist patients in returning to normal.  
 
We have successfully developed IVR technology for the assessment of 
multiple symptoms using the MDASI in patients with cancer undergoing 
chemotherapy, radiation therapy, and surgery. We currently have one 
active study in a sample of patients with CML, many of whom are receiving 

Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) with Dasatinib (BMS-354825)  
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kinase inhibitor therapies, using the MDASI-CML. Initial evaluation has 
shown this to be a feasible option for patient-reported symptom burden 
assessment in this group of patients and further evaluation is ongoing. The 
patient chooses the day and the time to receive the IVR system call; the 
system calls the patient three times if necessary to complete the 
assessment. 
2.3 
Interferon Therapy in CML 
At M.D. Anderson Cancer Center, 80% of patients with early chronic phase 
Philadelphia chromosome (Ph)-positive CML treated with interferon alpha 
(IFN-α) alone or in combinations, achieved a complete hematologic 
response (CHR); 55% had a cytogenetic response, which was major and 
durable in 25%.3-5  Achieving a complete cytogenetic response was 
associated with estimated 10-year survival rates above 70% to 80%.6  In 
randomized studies and by meta-analysis, IFN-α was associated with 
significant 
survival 
prolongation 
compared 
with 
conventional 
chemotherapy.7-10  Similar associations of achieving minimal tumor burden 
and survival prolongation have been reported by these studies. The addition 
of low-dose ara-C to IFN-α may have improved outcome.11-13 
2.4 
Imatinib Mesylate (STI571; Gleevec) in CML 
Imatinib is an inhibitor of the protein-tyrosine kinases associated with Bcr-
Abl, the platelet-derived growth factor (PDGF) receptor and c-Kit.  CML 
represents an ideal disease target for imatinib, given that the Bcr-Abl kinase 
plays a dominant role in the deregulated myeloid cell proliferation which is 
the hallmark of this disease.  
Imatinib shows selectivity for the Abl protein tyrosine kinase at the in vitro, 
cellular and in vivo level.14 The compound specifically inhibits proliferation 
of Bcr-Abl expressing cells. In colony forming assays using ex vivo 
peripheral blood and bone marrow samples, imatinib shows selective 
inhibition of Bcr-Abl positive colonies from CML patients.14-16 In animal 
models, the compound shows potent anti-tumor activity against Bcr-Abl and 
v-Abl expressing cells at tolerated doses.  
In phase I studies, imatinib has demonstrated activity in all CML phases 
post IFN-α failure and in Ph-positive ALL.17,18 
Three large-scale pivotal trials of imatinib in CML chronic, accelerated and 
blastic phases have been completed.19-22 In chronic phase CML, 454 
evaluable patients who had failed IFN-α therapy were treated with imatinib 
400 mg orally daily. The CHR rate was above 90%.  The complete 
cytogenetic response rate (Ph-positive less than 35%) was 60%, including 
a complete response in 41%.  Imatinib was well-tolerated. Side effects 
included nausea, vomiting, diarrhea, skin rashes, muscle cramps, bone and 
joint aches, and liver dysfunction. Grade 3-4 toxicities requiring 
discontinuation of therapy occurred in 2% or less of patients.  Periorbital 

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and leg edema and fluid retention were frequent at imatinib doses of 600 to 
1000 mg orally daily. 
An open-label, multicenter, randomized phase III study (International 
Randomized Interferon vs. STI571 [IRIS]) has been conducted in patients 
with newly diagnosed Ph+ CML.23  This study compared treatment with 
either single-agent Imatinib or a combination of IFN plus cytarabine (Ara-
C), and allowed for crossover for lack of response, loss of response or 
toxicity. A total of 1106 patients have been randomized from 177 centers in 
16 countries, 553 to each arm. The major cytogenetic response rate for 
patients treated with Imatinib was 83% (68% complete) compared to 20% 
with IFN and ara-C (7% complete). With the follow-up currently available, 
the 4-year estimated rate of free of progression was over 90% with 
imatinib.24  High-dose imatinib 400 mg orally BID has improved the early 
incidences of complete cytogenetic and molecular remissions.  Its impact 
on long-term prognosis remains to be determined.25,26 This study also 
demonstrated the significance of achieving a molecular response. 
Evaluating the response at 12 months from the start of therapy, patients that 
had achieved a complete cytogenetic response and at least a 3-log 
reduction in transcript levels compared to a standardized baseline value had 
a 98% probability of progression-free survival at 42 months, compared to 
90% those with complete cytogenetic response but less than a 3-log 
reduction in transcript levels. The corresponding figure for patients without 
a complete cytogenetic response was 75%.24,27 Thus, in the modern era, 
achieving a major molecular response at 12 months of therapy has become 
an important goal of therapy. With standard therapy with imatinib, only 20% 
to 35% of patients achieve a major molecular response by 12 months and 
it would be advantageous to have as many patients as possible reach this 
goal at least by 12 months. 
2.5 
DASATINIB 
Dasatinib is a potent inhibitor of the BCR-ABL, c-KIT, and SRC family of 
kinases. Pre-clinical data suggests that dasatinib is 100-300-fold more 
potent inhibitor of BCR-ABL kinase activity than imatinib. In addition, it 
inhibits the phosphorylation of BCR-ABL carrying most of the mutations 
clinically relevant in CML patients who have failed imatinib, and inhibits the 
proliferation of cells transfected with these mutated variants of BCR-ABL.28 
Dasatinib has been investigated in phase I studies on patients with CML 
who were resistant, refractory or intolerant to imatinib. As of September 28, 
2004, 58 patients have been treated. Both twice daily and once daily 
administration schedules have been investigated, revealing comparable 
dosing interval exposures. The maximum daily dose administered was 180 
mg daily (this dose was only investigated as a single dose). A dose of 70 
mg twice daily or 140 mg daily has been well tolerated in all stages of the 
disease and surpasses the dose at which most responses were observed. 
Overall, hematologic and non-hematologic toxicities have been tolerable 
and no MTD has been reached. Sustained hematologic responses have 

Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) with Dasatinib (BMS-354825)  
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been achieved in over 70% of patients, and cytogenetic responses in over 
40% of patients.29,30 
2.6 
Proposed Therapy with Dasatinib 
In this study we propose to treat patients with early chronic phase CML with 
dasatinib.  Due to its higher in vitro potency, we hypothesize that dasatinib 
may be more effective than imatinib in achieving early (i.e., at 12 months) 
molecular responses in patients with early chronic phase CML.  
The endpoints of therapy in early chronic phase will be to achieve a PCR 
ratio of < 0.05%, which is the equivalent to a 3-log reduction based on our 
methodology. We will also evaluate the cumulative overall incidence of 
complete cytogenetic response.  In early chronic phase CML, BCR-
ABL/ABL ratios <0.05% after 12 months of therapy occur in 20% to 35% of 
patients.  The goal of therapy would be to improve this to at least 50%. We 
will treat 100 patients in a randomized phase II study, and they will be 
divided into two arms treated with different dose schedules (same total 
dose).  Based on the current accrual rate of 50 patients/year with a minimum 
follow up of 1 year, we estimate that the study could be completed in 3 
years. 
2.7 
Other Biologic Endpoints 
In addition to the endpoints mentioned above, we would like to investigate 
any predictors of response. For this purpose, we will collect cells from 
patients to be treated in this clinical trial and they will be directly exposed to 
dasatinib for short-term incubation (1-2 days) and markers of cell response 
will be assessed using a novel direct high-throughput quantitative real-time 
PCR assay, without further purification. Monitored will be transcript levels 
of a panel of apoptotic genes, the bcr-abl transcript as well as several 
transcriptional targets of bcr-abl activation. We will also use a quantitative 
multiplex assay for detecting levels of phosphorylated bcr-abl targets in 
clinical samples. 
 
2.8 
Update January 2019 
 
Ninety-four patients remain on study for a median of 9 years (range 4-13).  
All patients have achieved a complete cytogenetic remission and 98% 
achieved a major molecular remission with 77% in complete molecular 
remission. 
 
There are no emerging long term toxicities and all patients are on a stable 
dose of dasatinib. 
 
The study primary objective has been met as have several of the secondary 
objectives. The focus is now on the secondary objectives of duration of 
cytogenetic and molecular remission and time to progression and survival.   
 

Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) with Dasatinib (BMS-354825)  
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This amendment reflects a change to the current standard for monitoring 
patients on tyrosine kinase inhibitor therapy in long term cytogenetic and 
molecular remission. 
3.0 
Background Drug Information 
 
3.1 
Overview 
 
 
 
Dasatinib, at a dose of 70 mg orally twice a day, with continuous daily 
dosing, has activity, as defined by hematologic response, in all phases of 
CML refractory to imatinib. 
 
 
Dasatinib is a potent, orally active inhibitor of the BCR-ABL, c-KIT, and SRC 
family of kinases, which play critical roles in oncogenesis and persistence 
of malignant phenotypes.  In preclinical studies, dasatinib has been shown 
to be a more potent inhibitor of BCR-ABL and c-KIT than imatinib 
mesylate.31  Dasatinib is also active in patient-derived CML cells that are 
resistant to imatinib mesylate, and an in vivo xenograft model of imatinib-
resistant CML.  A Phase I study (CA18002) was conducted to determine the 
safety profile, tolerability, and pharmacokinetics of dasatinib in subjects with 
CML who have primary or acquired hematologic resistance to or intolerance 
of imatinib mesylate.  This study has provided preliminary evidence of 
efficacy of this compound as demonstrated by hematologic and cytogenetic 
responses and pharmacodynamic support of the mechanism of action.  
CA180013 was designed to further evaluate the anti-tumor activity and 
safety of dasatinib in subjects with imatinib-resistant, chronic phase 
Ph+CML. 
 
3.2 
Summary of Results of Investigational Program 
 
 
 
Additional background information on preclinical pharmacology, toxicology 
and pharmacokinetics may be found in the Investigator Brochure.32 
 
3.2.1 Preclinical Antitumor Activity 
 
 
 
3.2.1.1  
In Vitro Molecular Studies 
 
 
 
Dasatinib competes with ATP for the ATP-binding site in 
the kinase domain of selected protein tyrosine kinases 
(PTKs) and has been shown to inhibit at least five protein 
tyrosine kinase/kinase families:  SRC family kinases (IC50:  
SRC = 0.55 nM, LCK = 1.1 nM, YES = 0.41 nM, FYN = 0.2 
nM); BCR-ABL (3 nM); c-KIT (22 nM); EPHA2 (17 nM); 
and the PDGFβ receptor (28 nM).  Dasatinib is much more 

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potent than imatinib mesylate against several important 
tyrosine kinsases, as outlined in the table below: 
 
 
 
Comparative Potency of Dasatinib vs Imatinib 
Mesylate 
Kinase 
Fold more potent than Imatinib 
(based in IC50) 
BCR-ABL 
260 
c-KIT 
8 
PDGFβ 
60 
SRC 
> 1000 
 
3.2.1.2 
Cellular Studies 
 
Dasatinib inhibits the BCR-ABL kinase with an in vitro IC50 
of 3 nM, a potency that was 260-fold greater than that of 
imatinib mesylate (IC50 = 790 nM).  In cellular assays, 
Dasatinib killed or inhibited the proliferation of all BCR-
ABL dependent leukemic cell lines tested to date.  
Dasatinib also demonstrated undiminished antitumor 
activity against several preclinically- and clinically-derived 
models of imatinib mesylate resistance.  In the 
K562/imatinib mesylate/R model (derived from continuous 
exposure 
of 
K562 
cells 
to 
clinically 
achievable 
concentration of imatinib mesylate), imatinib mesylate was 
6-fold less effective than in the parent K562 line (IC50 of 
1288 nM and 217nM in the resistant and parental cell lines, 
respectively), while dasatinib remained approximately 
equally active against both cell lines (IC50 of 0.7 nM (vs. 
the parent line) and 1.03 nM (vs. the resistant line)).  The 
mechanism by which K562/imatinib mesylate/R became 
resistant to imatinib mesylate is not fully understood, but 
molecular studies demonstrated that the resistant cells 
show 5 to 6 fold overexpression of the FYN tyrosine 
kinase, a member of the SRC kinase family.  Direct 
sequencing of the ABL portion of BCR-ABL gene failed to 
reveal any mutations. 
 
 
 
A second imatinib mesylate-resistant K562 subline 
(designated K562-R; IC50 > 10 µM)33 independently 
established by investigators at M.D. Anderson Cancer 
Center from the sensitive parent line by continuous 
exposure of K562 cells to high concentrations of imatinib 
mesylate revealed overexpression of LYN, another 
member of the SRC family tyrosine kinases.  Evidence that 
SRC family kinase overexpression may play a role in 

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clinical resistance to imatinib mesylate was demonstrated 
in three CML cell lines established from subjects who 
failed imatinib mesylate therapy.  These cells remained 
highly sensitive to the cell-killing effects of dasatinib.34  The 
table below shows the IC50 of dasatinib compared to the 
IC50 of imatinib mesylate in these three cell lines. 
 
 
 
IC50 of Dasatinib and Imatinib Mesylate in three 
subject cell lines 
Cell line 
IC50   
Dasatinib 
IC50        
Imatinib Mesylate 
WDT-1 
5 nM 
> 10000 nM 
WDT-2 
0.02 nM 
150 nM 
WDT-3 
0.05 nM 
500 nM 
 
 
These results demonstrate that dasatinib is effective in 
reducing the proliferation or survival of both imatinib 
mesylate-sensitive and resistant cells, and its inhibitory 
activity is not solely dependent on BCR-ABL. 
3.2.1.3 
In Vivo Studies 
The activity of dasatinib against CML cells in vitro was 
reproduced in vivo against several human CML xenograft 
models grown subcutaneously (SC) in scid mice.  Against 
K562 xenografts, dasatinib was curative over a 20-fold 
dose range (2.5 – 50 mpk) when it was administered orally 
(PO), once-a-day for 10 days (QD x 10), with a 2-day break 
following every 5 days of treatment (5-days-on, 2-days-of).  
Imatinib mesylate, administered on an optimized dosing 
regimen (three-times-a-day, every day for 10 consecutive 
days) failed to elicit significant cures at its maximum 
tolerated dose (MTD) of 150 mg/kg/administration, 
although it did not produce significant growth delay. 
 
 
Against the K562/imatinib mesylate/R CML model that had 
acquired resistance to imatinib mesylate, dasatinib 
produced equally impressive activity similar to that seen in 
the K562 model.  At doses of 50, 30, or 15 mg/kg/adm, 
using an identical treatment schedule as described above, 
dasatinib was curative in 100% of the treated animals.  In 
contrast, at its optimal dose and schedule (150 mpk TID x 
10 days), imatinib mesylate was inactive. 
 
3.2.2 Preclinical Toxicology 
 
Additional information related to the preclinical toxicology of 

Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) with Dasatinib (BMS-354825)  
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dasatinib is available in the Investigator’s Brochure32 and a BMS 
report 35. 
 
Principal repeat-dose drug-related toxicities were manifested in the 
GI, hematopoietic (bone marrow), and lymphoid systems of rats and 
in the GI and lymphoid systems of monkeys.  GI, bone marrow, and 
lymphoid toxicities were considered the major causes of morbidity 
and death in rats. 
 
Systemic exposure to dasatinib increased with increasing dose; 
there was no apparent sex-related differences.  For rats, systemic 
exposure (AUC) decreased with repeated administration ~12 to 47% 
at dasatinib doses of ≥ 79.2 mg/m2.  For monkeys, there were no 
apparent differences in systemic exposure with repeated dosing. 
 
In an in vitro receptor and ion-channel ligand binding assay, dasatinib 
had no significant inhibitory effect on any of the 42 different receptors 
and ion channels investigated. 
 
Safety pharmacology of dasatinib was evaluated by in vitro 
cardiovascular assays and in vivo single and repeat-dose toxicity 
studies.  Dasatinib in vitro activity in the HERG/IKr and Purkinje-fiber 
assays indicated a moderate liability for prolongation of cardiac 
ventricular repolarization (QT interval) in the clinic.  However, there 
were no dasatinib -related changes observed in electrocardiograms, 
nervous system function, respiratory and heart rate or sounds, blood 
pressure, or arterial oxygen saturation in single-dose, 10-day, or 1-
month oral toxicity studies in monkeys. 
 
Because dasatinib inhibits LCK, it could potentially cause 
immunosuppression by virtue of its effects on T-cell proliferation and 
activation.  At doses that are efficacious in xenografts, dasatinib had 
no immunosuppressive effects in a preclinical model of solid organ 
transplantation that assesses graft rejection as the endpoint.  By 
contrast, dasatinib suppressed T-cell proliferation or activation in 
mixed-lymphocyte reaction assays at doses that are efficacious in 
xenografts.  However, the introduction of a 2-day drug holiday 
ameliorated this toxicity. 36 
 
Dasatinib was tested for effects on in vitro platelet function and found 
to inhibit platelet aggregation induced by ADP and collagen to a 
greater extent than what would be expected by single pathway 
inhibitors such as clopidogrel or aspirin.   Further effects were an 
inhibition of shear-induced adhesion of human platelets and a 
reduction in clot strength.  This profile of broad-spectrum platelet 

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inhibition is best typified by antiplatelet agents such as the GPIIb/IIIa 
antagonists, integrelin ad abciximab. 
 
Finally, modulation of SRC kinase activity could also affect 
osteoclast morphology and function and bone remodeling.  Dasatinib 
was shown to have a potent inhibitory activity in vitro in the rat fetal 
bone resorption assay with IC50 of 2.0 nM, and in vivo when 
administered 
subcutaneously 
in 
the 
acute 
thyro-
parathyroidectomized rat model at 10 mg/kg.  This effect could 
potentially result in an increase in bone mineral density and a 
phenotype analogous to osteopetrosis.37 
 
In conclusion, single or repeated oral administration of dasatinib 
principally affected the GI (including hepatic), hematopoietic, and 
lymphoid systems in rats and monkeys.  Other prominent effects 
after single oral administration of dasatinib included renal and 
cardiac toxicity in rats at lethal doses, and cutaneous hemorrhage in 
monkeys.  Dasatinib can also effect the immune system and bone 
turnover.  These nonclinical studies identified significant target-organ 
toxicities of dasatinib and established 180 mg/m2 as the single-dose 
rate STD10 and 79.2 mg/m2 as the 1-month repeat-dose rat STD10.  
These results suggest that the repeat-dose toxicity of dasatinib is 
less than additive, which is consistent with the modest decrease in 
systemic exposure observed in the rat after repeated dosing.  In 
monkeys, a single dose of 180 mg/m2 (equivalent to the rat single 
dose STD10) and a repeat dose of 60 mg/m2 (approximately 75% of 
the rat repeat-dose STD10) were generally well tolerated, providing a 
basis for the selection of the starting dose of dasatinib in CA180002, 
the first-in-human Phase I dose-escalation study. 
 
3.2.3 Preclinical Pharmacokinetics 
 
3.2.3.1 
Absorption 
 
The extent of oral absorption of dasatinib varied among 
species.38  The oral bioavailability ranged from 15.2% in 
monkeys to 34% in dogs, with the average oral 
bioavailability in mice and in rats being 16 and 27%, 
respectively. 
 
3.2.3.2 
Distribution 
 
Dasatinib is highly bound (>91%) to proteins in mouse, rat, 
dog, monkey, and human sera, and its blood to plasma 
concentration ration ranges from 1.1 in rat to 1.8 in 
human.38  The average steady-state volume of distribution 

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of dasatinib in the mouse, rat, dog, and monkey is 4.2, 6.3, 
4.7, and 3.5 L/kg, respectively.  These values are greater 
than the total body water volume of each of these species, 
indicating extensive extravascular distribution across 
species. 
 
3.2.3.3 
Metabolism 
 
 
 
The metabolic stability of dasatinib in mouse, rat, dog, 
monkey and human hepatocytes predicts a moderate 
clearance in all five species. 
 
 
 
Incubations with recombinant human cytochrome P450 
isozymes suggest that dasatinib is primarily metabolized 
by the CYP3A4 enzyme.  Many other enzymes, however, 
appear capable of metabolizing dasatinib, including 
CYP1A1, 2C9, 2E1, FMO3, 1B1, 2B6,  2A6, 2C8, and 4A1.  
It is unknown at this time what contributions these 
enzymes may have to the total metabolic clearance of 
dasatinib. 
 
 
 
The biotransformations of dasatinib in mouse, rat, dog, 
monkey, and human liver microsomes and hepatocytes 
are qualitatively similar.  The major metabolites isolated 
from liver microsomal and hepatocyte incubations from 
human non-clinical donors consist of three hydroxylated 
isomers, a bis-oxygenated metabolite, an N-dealkylated 
metabolite, 
a 
carboxylic 
acid 
metabolite, 
and 
a 
dehydrogenation product.  Two additional metabolites, a 
glucuronic acid conjugate, and a sulfate conjugate, were 
isolated from the plasma, urine or bile of bile-duct 
cannulated rats treated with the compound. 
 
3.2.3.4 
Elimination 
 
Following an intravenous dose of 10 mg/kg of dasatinib to 
bile-duct cannulated rats, the percent of the dose excreted 
in the urine and bile at the end of 9 hours was 0.8 and 
9.6%, respectively, implying that the major route of 
administration of dasatinib is by metabolism.38 
 
3.2.3.5 
Pharmacokinetic Drug Interactions 
 
Caution is warranted when administering dasatinib to 
subjects taking drugs that are highly dependent on 
CYP3A4 for metabolism and have a narrow therapeutic 

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index.38  Systemic exposures to these medications could 
be increased while receiving dasatinib.  In in vitro studies, 
dasatinib is a strong inhibitor of the human CYP3A4 (IC50 
of 1.9 µM) and a weak inhibitor of CYP1A2 and CYP2D6 
(IC50 of > 100 µM), CYP2C9 (IC50 of 63 µM) and CYP2C19 
(IC50 of 32 µM).  Until information regarding exposure-
toxicity and exposure-response relationships are available 
with dasatinib, concomitant CYP3A4 inhibitors and 
inducers should be avoided, if possible, since they could 
alter the systemic exposure to dasatinib.  Incubations with 
recombinant human cytochrome P450 isozymes suggest 
that dasatinib is primarily metabolized by the CYP3A4 
enzyme.   
 
3.2.4 Phase I Experience:  CA180002 
 
Also refer to recent publications39,40,41,42 and the most current 
revision of the Investigator Brochure.32 
 
The phase I dose escalation study was conducted in two major 
hematologic malignancy referral centers in the U.S. This study 
allowed inter- and intra-subject dose escalation. Pharmacokinetics 
(PK) were evaluated during the first month of treatment. The first 
patient was enrolled in November 2003.  As of April 2005, 84 
subjects have been enrolled: 40 in chronic phase CML, 10 in 
accelerated phase CML, 24 in myeloid blast phase CML, 5 in 
lymphoid blast phase CML and 5 in Ph+ ALL. 
 
Chronic phase CML subjects were initially treated with a QD 5 days 
on/2 days off schedule and later the protocol was amended to include 
BID 5 days on/2 days off and BID continuous daily dosing (CDD) 
schedules.  A total of 40 subjects have enrolled in doses ranging from 
15 - 180 mg QD and 25 - 70 mg BID on the 5 days on/2 days off 
schedule and 70 - 90 mg BID on the CDD schedule.  All 44 subjects 
with advanced phase disease were enrolled in dose cohort ranging 
35 - 120 mg BID CDD. 
 
Chronic Phase CML 
Of the 40 chronic phase CML subjects, 53% were male and 47% 
were female.  The median age was 61 years.  The median duration 
of CML was 8 years (range 1-17).  Eighty percent were clinically 
resistant to imatinib and 20% were intolerant.  Intolerance included 
hepatotoxicity, 
rash 
or 
avascular 
necrosis 
that 
required 
discontinuation of imatinib.  Most subjects had received > 600 
mg/day of imatinib (65%).  Only 38% previously had a major 
cytogenetic response to imatinib.  Seventy-four percent were found 

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to have a mutation in the BCR-ABL protein that has been reported in 
the literature to confer resistance to imatinib.  The median duration 
of follow-up on study for chronic phase CML subjects was 14 months.  
Of the 40 subjects in chronic phase 36 remain on study as of April 
2005. 
 
Safety 
Hematologic adverse events are shown below.  Myelosuppression 
and thrombocytopenia were common but reversible and easily 
managed with drug interruption.   
 
 
 
Non-hematologic events included mild elevations in transaminases 
and creatinine that were asymptomatic, diarrhea, paresthesias and 
headache.  One case of grade 3 pleural effusion was noted on the 
BID dosing schedule and was managed with thoracentesis and 
diuretics.  The subject continues on study treatment.  There were 2 
episodes of grade 3 GI hemorrhage.  There were no episodes of QTc 
prolongation over 500 msec and no reported cardiac symptoms 
related to prolonged QT intervals. 
 
Table 2: 
Non-hematologic Adverse Events 
Adverse event 
Grade 1–2  
n (%) 
Grade 3–4  
n (%) 
Elevated ALT 
11 (28) 
0 (0) 
Elevated creatinine 
9 (23) 
1 (3) 
Diarrhea 
7 (18) 
0 (0) 
Paresthesia 
4 (10) 
0 (0) 
Headache 
4 (10) 
0 (0) 
Nausea 
2 (5) 
0 (0) 
Peripheral edema 
2 (5) 
0 (0) 
Pleural effusion 
1 (3) 
1 (3) 
GI hemorrhage  
0 (0) 
2 (5) 
 
Table 1: 
Hematologic Adverse Events 
 
ANC 
Hemoglobin 
Platelets 
Grade 3 
23% 
25% 
18% 
Grade 4 
15% 
8% 
10% 

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Efficacy 
Out of the 40 subjects, 39 had been followed for at least 3 months 
for the first bone marrow and cytogenetic evaluation on the protocol.  
The hematologic and cytogenetic response rates are shown below. 
 
Table 3: 
Chronic Phase CML: Treatment Response 
 
Number of patients (N=39) 
Resistant (N=31) Intolerant (N=8) 
CHR – n (%) 
26 (84) 
8 (100) 
CyR – n (%)  
Complete (CCyR)  
Partial (PCyR)  
Overall  
9 (29)  
2 (6) 
16 (52)*  
4 (50)  
1 (13) 
7 (88) 
*Includes 2 patients with no previous cytogenetic response to 
imatinib 
CHR = complete hematologic response; CyR = cytogenetic 
response  
CCyR = 0% Ph+; PCyR = 1–35% Ph+; minor CyR = 35–65% Ph+  
Overall CyR = CCyR + PCyR + minor CyR + minimal CyR 
 
Complete hematologic responses were seen in 87% of the evaluable 
subjects.  The overall cytogenetic response rate was 59%.  
Cytogenetic and hematologic responses were also examined in 
patients sub grouped according to mutational status, resistance 
versus intolerance and BID versus QD dosing.  No differences in 
response were observed between the different dose regimens.  
However, hematologic and cytogenetic responses were higher in 
imatinib intolerant compared to imatinib resistant subjects. 
 
Advanced Phase CML and Ph+ ALL 
There were 10 accelerated phase CML, 29 blast phase CML and 5 
Ph+ ALL subjects enrolled in CA180-002 as of April 2005.  There 
were 59% male and 41% female.  The median age for accelerated 
phase CML subjects was 64 and for blast phase CML/Ph+ ALL 
subjects it was 53.  Median duration of CML for accelerated phase 
CML was 3 years and for blast phase CML/Ph+ ALL it was 3 years.  
Clinical resistance to imatinib was reported in 84% of subjects and 

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mutations in BCR-ABL that have been reported to confer resistance 
to imatinib were noted in 55% of subjects at study entry.  Previous 
complete hematologic response with imatinib was noted in 70% 
patients entered.  Twenty-five percent of subjects had grade 3-4 
neutropenia before beginning dasatinib.  The median duration of 
follow-up on study for advanced subjects was 5 months.  Of the 44 
subjects in advanced phase CML/ALL, 17 subjects remain on trial as 
of April 2005. 
 
Safety 
Grade 3-4 hematologic toxicity was common but could be managed 
with dose interruption and reduction. 
 
 
 
 
Table 4: 
Advanced 
Phase 
CML/Ph+ 
ALL: 
Grade 
3-4 
Hematologic Adverse Events 
 
ANC 
Hemoglobin 
Platelets 
Accelerated phase (N=10) 
70% 
80% 
80% 
Blast phase CML/ALL (N=34) 
91% 
74% 
76% 
 
Grade 3-4 non-hematologic adverse events included pleural 
effusions, pericardial effusions, diarrhea and rectal hemorrhage.  
Two subjects had grade 3-4 tumor lysis syndrome. 
 
Table 5: 
Advance Phase CML/Ph+ ALL: Grade 3-4 
Non-Hematologic Adverse Events 
 
Accelerated 
Phase CML 
Blast Phase 
CML/Ph+ ALL 
Pleural effusion 
0% 
12% 
Pericardial effusion 
0% 
6% 
Tumor lysis syndrome 
0% 
6% 
Diarrhea 
0% 
3% 
Rectal hemorrhage 
0% 
3% 
Dyspnea 
0% 
3% 
Pneumonia 
10% 
0% 
Sinusitis 
10% 
0% 
Elevated total bilirubin 
0% 
6% 
Elevated creatinine 
0% 
3% 
There were no QTc prolongation greater than 500 msec and no 
cardiac symptoms related to prolonged QT. 

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Efficacy 
A major hematologic response was noted in 80% of accelerated 
phase and 69% of blast phase/ALL subjects.  Overall cytogenetic 
response was 40% in accelerated phase and 56% in blast phase/ALL 
subjects. 
 
 
 
 
Table 6: 
Advanced Phase CML/Ph+ ALL: Responses 
 
Accelerated 
Phase CML 
Blast Phase 
CML/Ph+ ALL 
Major Hematologic 
Response 
80% 
69% 
CHR 
50% 
28% 
NEL 
30% 
41% 
Overall CyR 
40% 
56% 
CCyR 
30% 
19% 
PCyR 
10% 
16% 
Major HR is defined as bone marrow blasts <5%, and has two 
subgroups: CHR and NEL  
CHR = complete hematologic response (<5% blasts in bone marrow 
and return of peripheral blood to normal parameters) 
NEL = no evidence of leukemia (same as CHR, but without 
hematopoietic recovery of the peripheral blood parameters) 
Dose schedule 
Recently, a randomized trial comparing 4 different schedules of 
administration of dasatinib in patients with resistance or intolerance 
to imatinib has been completed and the results are being submitted 
for publication. Patients were randomized to receive 1 of 4 different 
dose schedules: 50 mg twice daily, 100 mg once daily, 70 mg twice 
daily (the standard dose at the time), or 140 mg once daily43. The 
results are summarized in the following table: 
Table 7. Dasatinib dose optimization in patients with CML in CP after 
imatinib failure: 
 
 

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Parameter 
Percentage 
p  
value 
100mg 
QD 
N=166 
50mg 
BID 
N=166 
140mg 
QD 
N=163 
70mg 
BID 
N=167 
MCyR 
64 
58 
62 
58 
NS 
CCyR 
46 
46 
47 
50 
NS 
Progression 
10 
13 
14 
18 
0.032 
Anemia 
10 
18 
19 
17 
0.105 
Neutropenia 
34 
46 
43 
43 
0.123 
Thrombocytopenia 
22 
34 
40 
38 
0.003 
Pleural effusion 
10 
16 
20 
18 
NS 
Interruption 
58 
66 
69 
71 
0.047 
Reduction 
33 
45 
54 
57 
<0.001 
Based on these results, the standard dose for patients with CML in 
CP after imatinib failure was changed by the FDA to 100mg once 
daily. In view of this we plan to close the 50mg twice daily dose arm 
and continue accrual only with the 100mg once daily arm. 
3.3 
INVESTIGATIONAL PRODUCT  
Investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in the study, whether blinded or 
unblinded.  
 
3.3.1 Investigational Product Identification  
The following investigational product, Dasatinib, will be supplied by Bristol-
Myers Squibb Pharmaceutical Research Institute in two different strengths:  
 
Dasatinib 20 mg film coated tablets, biconvex, round, white to off-white in 
appearance with “20” debossed on one side and “527” on the other side.  
Dasatinib 50 mg film coated tablets, biconvex, oval, and white to off-white 
in appearance with “50” debossed on one side and “528” on the other side.  
 
3.3.2 Packaging and Labeling   
Dasatinib will be labeled in open-label fashion per site requirements. 
 
BMS-354825 will be labeled in open-label fashion.  
 
Study Drug  
 
Packaging 
BMS-354825-03 
 
20 mg film coated tablets, 60 tabs/bottle 
BMS-354825-03 
 
50 mg film coated tablets, 60 tabs/bottle 
 
3.3.3 Handling and Dispensing of Investigational Product  
It is recommended that investigational product should only be handled by 

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the subject. While the risk for dermal exposure is considered minimal, it is 
recommended that only the study subject handle the study medication. In 
particular, pregnant women or women who are breastfeeding should not 
handle the study drug. Also children who are not study participants should 
not handle the drug. If caregivers must handle or come in contact with the 
drug, it is advised that protective gloves be worn.  
 
Bristol-Myers Squibb will be responsible for assuring that the quality of 
Dasatinib is adequate for the duration of the trial.  
 
Investigational product should be stored in a secure area, at 59°F to 77°F 
(15°C to 25°C).  
 
The Investigator (or assigned designee, i.e., study pharmacist) will dispense 
the proper number of each strength tablet to the subject to satisfy dosing 
requirements for the study.  The containers provided to the subject should 
be labeled with proper instructions for use. Subjects should be instructed to 
return all unused drug to the site in the same container. Re-supplies can be 
obtained by completing the SRC re-supply request form and fax to 203-677-
6489 or submit the electronic copy to srcsupply@bms.com.  These re-
supply requests need to be submitted at-least 2 weeks before the expected 
delivery date. 
 
Drug re-supply will be provided at the Investigator’s request at least two 
weeks before needed.  
 
The subject must be instructed to return all unused study medications in the 
provided packaging at each subsequent visit.   Returned drugs from patients 
will be destroyed at MD Anderson Cancer Center. 
 
The Investigator must be satisfied the subject returned or accounted for all 
unused medication before additional medication is dispensed. If the number 
of tablets used is substantially different from the number of tablets 
dispensed, the subject must be counseled on how study therapy should be 
taken. If such deviations persist, the Investigator may consider 
discontinuing the subject for non-compliance.  
 
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.  
 
The Investigator should ensure that the investigational product is stored in 
accordance with the environmental conditions (temperature, light and 
humidity) as determined by the Sponsor and defined in the Investigator 

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Brochure or SmPC/reference label.  
 
3.3.4 Investigational Product Records at Investigational Sites  
It is the responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site where 
investigational product is inventoried and disposed. 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  
 
• Amount transferred to another area/site for dispensing or storage.  
 
• Label ID number or batch number and use date or expiry date  
 
• Dates and initials of person responsible for each investigational 
product inventory entry/movement  
 
• Amount dispensed to and returned by each subject, including unique 
subject identifiers  
• Non-study disposition (e.g., lost, wasted, broken)  
 
• Amount returned to Sponsor  
 
• Amount destroyed at study site, if applicable  
 
• Retain samples sent to third party for bioavailability/bioequivalence, 
if applicable  
 
Investigational product dispensing record/inventory logs and copies of 
signed packing lists must be maintained at the investigational site. Batch 
numbers for dasatinib must be recorded in the drug accountability records.  
 
3.3.5 Return and Destruction of Investigational Product  
 
3.3.5.1 Return of Investigational Product  
Upon completion or termination of the study, all unused and/or 
partially used investigational product must be returned to BMS 
unless BMS specifically states (in writing) at that time the 
investigational product can be destroyed by MD Anderson Cancer 
Center. 
 
All investigational products returned to BMS must be accompanied 
by the appropriate documentation and be clearly identified by 
protocol number and study site number on the outermost shipping 

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container. Returned supplies should be in the original containers. 
Empty containers should not be returned to BMS. 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.  The return of unused 
investigational products should be arranged by the responsible 
Investigator at the site.   
 
3.3.5.2 Destruction of Investigational Product  
If investigational product is to be destroyed on site, it is 
Investigators responsibility to ensure that arrangements have been 
made for the disposal, written authorization has been granted by 
BMS, procedures for proper disposal have been established 
according to applicable regulation and guidelines and institutional 
procedures, and appropriate records of the disposal have been 
documented.  The unused investigational products can only be 
destroyed after appropriate instruction by BMS. 
4.0 
Patient Eligibility 
4.1 
Diagnosis of Ph-positive or Bcr-Abl positive CML in early chronic phase 
CML (i.e., time from diagnosis ≤ 12 months). Except for hydroxyurea, 
patients must have received no or minimal prior therapy, defined as <1 
month (30 days) of prior IFN-α (with or without ara-C) and/or an FDA 
approved TKI. 
4.1.1 Clonal evolution defined as the presence of additional chromosomal 
abnormalities other than the Ph chromosome has been historically 
been included as a criterion for accelerated phase. However, 
patients with clonal evolution as the only criterion of accelerated 
phase have a significantly better prognosis, and when present at 
diagnosis may not impact the prognosis at all. Thus, patients with 
clonal evolution and no other criteria for accelerated phase will be 
eligible for this study. 
4.2 
Age >16 years (Age > 18 years to participate in optional symptom burden 
assessment) 
4.3 
ECOG performance of 0-2. 
4.4 
Adequate end organ function, defined as the following: total bilirubin <1.5x 
ULN, SGPT <2.5x ULN, creatinine <1.5x ULN. 
4.5 
Patients must sign an informed consent indicating they are aware of the 
investigational nature of this study, in keeping with the policies of the 
hospital. 
4.6 
Reliable telephone access to receive calls from an interactive voice 
response system (IVR) (only applicable to patients who will participate in 

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optional symptom burden assessment). 
 
4.7 
Exclusions: 
a. 
NYHA cardiac class 3-4 heart disease 
 
b. 
Cardiac Symptoms:  Patients meeting the following criteria are not 
eligible unless cleared by Cardiology:  
• 
Uncontrolled angina within 3 months 
• 
Diagnosed or suspected congenital long QT syndrome 
• 
Any history of clinically significant ventricular arrhythmias 
(such as ventricular tachycardia, ventricular fibrillation, or 
Torsades de pointes).  
• 
Prolonged QTc interval on pre-entry electrocardiogram (> 
450 msec) on both the Fridericia and Bazett’s correction. 
• 
Uncontrolled hypertension. 
• 
History of significant bleeding disorder unrelated to cancer, 
including: 
Diagnosed congenital bleeding disorders (e.g., von 
Willebrand’s disease) 
Diagnosed acquired bleeding disorder within one year (e.g., 
acquired anti-factor VIII antibodies) 
• 
Patients currently taking drugs that are generally accepted to 
have a risk of causing Torsades de Pointes including: 
1. 
 
quinidine, procainamide, disopyramide 
2. 
 
amiodarone, sotalol, ibutilide, dofetilide 
3. 
 
erythromycins, clarithromycin 
4. 
 
chlorpromazine, haloperidol, mesoridazine, 
thioridazine, pimozide cisapride, bepridil, droperidol, 
methadone, arsenic, chloroquine, domperidone, halofantrine, 
levomethadyl, pentamidine, sparfloxacin, lidoflazine. 
 
c. 
Patients with active, uncontrolled psychiatric disorders including:  
psychosis, major depression, and bipolar disorders. 
 
d.  
Women of pregnancy potential must practice 2 effective methods of 
birth control during the course of the study, in a manner such that 
risk of failure is minimized.  Prior to study enrollment, women of 
childbearing potential (WOCBP) must be advised of the importance 
of avoiding pregnancy during trial participation and the potential risk 
factors for an unintentional pregnancy.  Postmenopausal women 
must be amenorrheic for at least 12 months to be considered of non-
childbearing potential.  Women must continue birth control for the 

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duration of the trial and at least 3 months after the last dose of study 
drug.   
 
Pregnant or breast-feeding women are excluded. 
 
All WOCBP MUST have a negative pregnancy test prior to first 
receiving investigational product.  If the pregnancy test is positive, 
the patient must not receive investigational product and must not be 
enrolled in the study. 
 
4.8 
Patients in late chronic phase (i.e., time from diagnosis to treatment 
>12 months), accelerated or blast phase are excluded.   
The definitions of CML phases are as follows:   
a. Early chronic phase: time from diagnosis to therapy ≤ 12 months 
 
Late chronic phase: time from diagnosis to therapy > 12 months 
b.  Blastic phase: presence of 30% blasts or more in the peripheral 
blood or bone marrow.   
c. Accelerated phase CML: presence of any of the following 
features:   
• Peripheral or marrow blasts 15% or more 
• Peripheral or marrow basophils 20% or more  
• Thrombocytopenia < 100 x 109/L unrelated to therapy 
• Documented extramedullary blastic disease outside liver or 
spleen 
d.  Clonal evolution defined as the presence of additional 
chromosomal abnormalities other than the Ph chromosome has 
been historically been included as a criterion for accelerated 
phase. However, patients with clonal evolution as the only 
criterion of accelerated phase have a significantly better 
prognosis, and when present at diagnosis may not impact the 
prognosis at all. Thus, patients with clonal evolution and no other 
criteria for accelerated phase will be eligible for this study. 
5.0 
Treatment Plan 
5.1 
General 
All patients should be registered with the Data Management Office PDMS 
system.  
5.2 
Treatment Plan 
Patients will receive dasatinib therapy according to the suggested 

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guidelines below. Individual minor variations in the initiation of therapy, 
WBC count at start of therapy, are acceptable as indicated by patient 
condition and physician judgment.   
5.2.1 CML debulking: patients may receive hydroxyurea for debulking 
before and during the first 6 weeks of therapy. Patients who cannot 
take hydroxyurea may receive other agents such as 6-
mercaptopurine (6-MP) and 6-thioguanine (6-TG).   
5.2.2 Therapy:  Patients will receive dasatinib at a dose of 100 mg orally, 
once daily. 
5.2.3 Dose adjustments:  Dose adjustments will be allowed at the 
discretion of the treating physician.   
 
Dose modifications will be made according to the Dasatinib 
package insert. 
5.3 
Dose modifications of Dasatinib 
General guidelines include the following: 
a) 
Non-Hematologic Toxicity 
Recommended management of non-hematologic toxicity sis allowed 
per the discretion of the treating physician. 
b) 
Hematologic Toxicity 
Recommended management of hematologic toxicity is allowed per 
the discretion of the treating physician. 
c) 
Modifications of dose schedules are allowed per the discretion of the 
treating physician.  
5.3.1 Patients currently enrolled receiving BID schedule may be converted 
to a once daily schedule if it is considered in the best interest of the 
patient.  Dose adjustments can be done according to the once daily 
schedule thereafter. 
5.3.2 Dose Escalations 
Dose escalations are allowed at the discretion of the treating 
physician for loss of or failure to achieve major molecular remission. 
Maximum dose is 100mg daily. 
5.4 
Occasional missed doses will not be considered a deviation.  Missed dosed 
of ≥ 2 weeks will be considered a protocol deviation. 
5.5 
Duration of Therapy 
Total duration of therapy will be 15 to 18 years.  Subsequent changes of 
duration of treatment will depend on the earlier analyses of data.  Consider 
holding therapy if BCR-ABL is undetectable continuously over 2 years. 

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5.6 
Prohibited and Restricted Therapies During the Study 
 
5.6.1  Prohibited Therapies  
 
No other therapy for the treatment of CML, with the exception of 
anagrelide hydrochloride for the treatment of elevated platelet counts 
(> 700,000/mm3), and hydroxyurea for WBC greater than 
50,000/mm3, will be permitted while the patient is on study. The 
exception will be the use of agents for management of minimal 
residual disease on clinical trial such as Azacitidine (as per protocol 
2011-0254) or Ruxolitinib (protocol 2012-0697) provided patients are 
experiencing no unacceptable toxicity with dasatinib and meet all 
eligibility criteria for these trials.  These include adequate response 
to dasatinib, a minimum of 18 months on therapy with dasatinib, 
adequate organ function as defined in those studies, and a stable 
dose of dasatinib.  Hydroxyurea use should be limited to 
approximately 4 weeks duration whenever possible. Use of 
anagrelide and hydroxyurea, as well as colony-stimulating factors 
(e.g., G-CSF, GM-CSF, etc) and erythropoietin, is permitted at the 
discretion of the investigator.  
 
Medications associated with QT prolongation that are prohibited on 
this study include:  
• quinidine, procainamide, disopyramide  
• amiodarone, sotalol, ibutilide, dofetilide  
• erythromycins, clarithromycin  
• chlorpromazine, 
haloperidol, 
mesoridazine, 
thioridazine, 
pimozide  
• cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, 
domperidone, 
halofantrine, 
levomethadyl, 
pentamidine, 
sparfloxacin, lidoflazine.  
 
Caution should be exercised if patients are required to take 
medications that inhibit platelet function or anticoagulants.  It is 
recommended that antiplatelet agents or anticoagulants are avoided 
in setting of Grade 3 or 4 thrombocytopenia. 
 
Ideally, subjects enrolled in this study should not be taking and not 
begin taking medications known to prolong the QT interval.  
However, should the Investigator believe that beginning therapy with 
a potentially QT prolonging medication (other than the ones explicitly 
prohibited) is vital to an individual subject’s care, the Investigator 
must check that the subject’s prior on-therapy ECG has not shown a 
QTcF ≥ 480 msec or an increase in QTc ≥ 60 msec over the baseline 
value.  Additional ECG(s) will be done one week later or more at the 
Investigator’s discretion to ensure the subject’s safety. 

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5.6.2 Restricted Therapies  
Caution is warranted when administering dasatinib to subjects taking 
drugs that are highly dependent on CYP3A4 for metabolism and 
have a narrow therapeutic index.  Systemic exposures to these 
medications could be increased while receiving dasatinib.  In in vitro 
studies, dasatinib is a strong inhibitor of the human CYP3A4 enzyme 
and a weak inhibitor of CYP1A2, CYP2D6 and CYP2C19. dasatinib 
shows time-dependent inhibition of CYP3A4; however, there 
appears to be a low probability for drug-drug interactions due to 
metabolism-dependent CYP3A4 inactivation.  Results from an in 
vitro hPXR trans-activation study suggest that dasatinib has little 
potential to induce CYP3A4 through the activation of hPXR. 
 
Until information regarding exposure-toxicity and exposure-response 
relationships is available with dasatinib, concomitant CYP3A4 
inhibitors and inducers should be avoided, if possible, since they 
could alter the systemic exposure to dasatinib.  Incubations with 
recombinant human CYP450 isozymes suggest that dasatinib is 
primarily metabolized by the CYP3A4 enzyme.  Many other enzymes 
appear capable of metabolizing dasatinib, including CYP1A1, 2C9, 
2E1, FMO3, 1B1, 2B6, 2A6, 2C8, and 4A1; however, it is unknown 
at this time what contributions these enzymes may have to the total 
metabolic clearance of dasatinib. 
 
In vitro solubility data indicate that dasatinib may have decreased 
solubility and absorption at pH > 4.  Until further data are available, 
subjects should try to avoid taking proton pump inhibitors and H2 
antagonists.  Short-acting antacid agents may be taken, but it is 
recommended that these not be taken from 4 hours before to 4 hours 
after dosing of dasatinib. 
6.0 
Pretreatment Evaluation  
6.1 
A complete history and physical examination including performance status. 
6.2 
CBC, platelet count and differential (differential not required if WBC < 0.5 x 
109/L), total bilirubin, SGPT (or SGOT), HBV screening, and creatinine 
within 1 week. 
6.3 
Bone marrow aspirate for morphology and cytogenetics or FISH (if not done 
within 3 months). 
6.4 
EKG within 2 weeks 
6.5 
Pregnancy test (blood or urine) for female patients of childbearing potential 
within 7 days before initiation of study drug dosing 
6.6 
Peripheral blood and bone marrow for correlative studies (optional*).  Not 
all optional samples may be collected. 

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6.7 
Peripheral blood or bone marrow for quantitative PCR (QPCR) 
6.8 
Platelet aggregation study and PK (optional*) 
6.9 
miRNA analysis (optional): one single blood sample (5cc) will be collected 
only by EDTA or citrate (Dr. Calin's lab at MD Anderson Cancer Center). 
6.10 Serum alkaline phosphatase (bone-specific isoenzyme) (optional*). 
6.11 Bone marrow biopsy for trabecular bone volume (optional*). Will not be 
done if a repeat bone marrow is required for this purpose only.  
6.12 MDASI-CML and single item quality of life (QOL) rating completed by 
patient (optional*).  
* Missed collection of any of the optional procedures will not be considered a 
protocol deviation or violation. 
7.0 
Evaluation During Study  
7.1 
Physical exam and evaluation of toxicity (clinic visit or telephone interview) 
every 3 months (±1 month) for the first year then recommended every 6 to 
12 months at the discretion of the treating physician.   
7.2 
CBC, platelet, differential every 1-2 weeks for 4 weeks, every 4-6 weeks 
until 1 year from the start of therapy, then every 3-4 months until 2 years, 
then at the discretion of the treating physician.  
7.3 
Bone marrow aspirate with cytogenetics or FISH every 3-4 months in year 
1, then at the discretion of the treating physician. 
7.4 
Total bilirubin, SGPT or SGOT, and creatinine every 2-4 weeks for 1 month 
then every 4-6 weeks until 1 year from the start of therapy, then every 3-4 
months until 2 years, then at the discretion of the treating physician. 
7.5 
EKGs to be done approximately every 3 months until month 12 from the 
start of therapy then at the discretion of the treating physician. 
7.6 
Adherence to the prescribed therapy will be verified by diary or verbally by 
patient interview (Appendix D) 
7.7 
Peripheral blood or bone marrow for quantitative PCR (QPCR) every 3-4 
months for 1 year then every 6-12 months until 2 years on therapy then 
every year (+/- 3 months). 
8.0 
Criteria for Response 
8.1 
Complete Hematologic Remission (CHR) - normalization for at least 4 
weeks of the bone marrow (less than 5% blasts) and peripheral blood with 
WBC < 10 x 109/L and no peripheral blasts, promyelocytes or myelocytes.  
This is in addition to disappearance of all signs and symptoms of the 
disease.  
Partial Hematologic Response (PHR) = CHR except for persistence of 
immature cells (myelocytes, metamyelocytes), or splenomegaly < 50% of 

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pretreatment, or thrombocytosis >450x109/L but <50% of pretreatment. 
8.2 
Complete hematologic remission will further be classified according to 
suppression of the Philadelphia chromosome (Ph) by cytogenetics (FISH if 
cytogenetic analysis not informative, e.g., insufficient metaphases) 
a) 
No cytogenetic response - Ph positive 100% of pretreatment value 
b) 
Minor cytogenetic response - Ph positive 35-90% of pretreatment 
value 
c) 
Partial cytogenetic response - Ph positive 1-34% of pretreatment 
value 
d) 
Complete cytogenetic response - Ph positive 0% 
* Major cytogenetic response = complete + partial (Ph positive <35%) 
8.3 
Molecular response  
 
a) 
Major (MMR): BCR-ABL/ABL ratio < 0.05% 
 
b)  
Complete: Undetectable BCR-ABL, confirmed by nested PCR 
9.0 
Criteria for Removal from the Study 
9.1 
Patients who develop accelerated disease features (except clonal evolution 
if it is the only criterion for accelerated phase) or blastic phase with no 
response to optimization of therapy as defined under 5.2 and 5.3.  
9.2 
Failure to achieve CHR after 3 months of therapy. 
9.3 
Unacceptable severe (grade 3-4) toxicity despite dose optimization 
9.4 
Patient request 
9.5 
Physician’s decision when judged to be in the best interest of the patient 
9.6 
Other – recurrent and irremediable lack of adherence to treatment plan, 
recurrent and consistent protocol violations, etc. 
10.0 Statistical Considerations 
 
The new trial is a phase II study of BMS354825 to assess Time to first Molecular 
Response prior to 12 months (MMR) in patients with early phase chronic CML.  Two 
endpoints will be monitored, the probability of MMR by 12 months, and the 12 month 
toxicity rate.  The goal of this study is to determine if the compound has activity with 
respect to the MMR while maintaining an acceptable toxicity rate.  MMR will be measured 
every 3 months (a total of 4 assessments within one year of therapy.  Because of the 
discrete nature of the measurements, continuous time models would be inappropriate.  
As such we use an ordinal sequential model with discrete time hazards to define the 
likelihood.  
Yr,k be an ordinal outcome  associated with the kth treatment arm which can take on 
values 1,…, J and represents (for a given patient) either the visit at which MMR was first 
observed or the last follow-up visit (which ever is less).  Let dr be a censoring indicator 

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where dr=0 means that the patient was not censored and dr =0 indicates the patient was 
censored.  Note that (ignoring censoring for the moment) the discrete time hazard for the 
jth interval is equal to 
 
,
Pr(
)
Pr(
|
)
Pr(
)
r
r j
r
r
r
Y
j
p
Y
j Y
j
Y
j
=
=
=
≥
=
≥
 
Moreover note that 
,
Pr(
)
Pr(
)
Pr(
1)
1
Pr(
)
Pr(
)
r
r
r
r j
r
r
Y
j
Y
j
Y
j
p
Y
j
Y
j
≥
−
=
≥
+
−
=
=
≥
≥
 
 
The above identity allows us to exploit a recursive relationship between the hazard 
function during period j and the probability of response beyond period j via 
,
(1
)Pr(
)
Pr(
1)
r j
r
r
p
Y
j
Y
j
−
≥
=
≥
+
 
Since Pr(Yr>1)=1 we have that  
 
 
 
 
,2
Pr(
2)
1
r
r
Y
p
≥
= −
 
 
 
 
 
,2
Pr(
3)
(1
)Pr(
2)
r
r
r
Y
p
Y
≥
=
−
≥
 
 
 
 
 
 
 
 
 
 
,
1
Pr(
)
(1
)Pr(
1)
r
r j
r
Y
j
p
Y
j
−
≥
=
−
≥
−
 
This allows us to express the contribution to the likelihood of an event that occurs in the 
jth interval as  
1
,
,
1
Pr(
,
0)
(1
)
j
r
r
r j
r h
h
Y
j d
p
p
−
=
=
=
=
−
∏
 
The contribution to the likelihood for a censored observation (i.e., the discrete time 
survival function) having maximum followup in the jth interval is  
1
,
1
Pr(
,
1)
(1
)
j
r
r
r h
h
Y
j d
p
−
=
=
=
=
−
∏
 
The likelihood for toxicity events can be constructed in a similar manner.   
 
For the kth arm, we assume (a priori) that each 
,r j
p
  (for j=1,…, 4) follows a 
beta(0.03,0.97) distribution and each
,t j
p
 (for j=1,…, 4)  follows a beta(.5,.5) distribution. 
For purposes of trial monitoring we assume independence between toxicity and response.  

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Let the 12 month MMR response rate in the kth arm be 
4
,
1
1
(1
)
r
r h
h
p
π
=
= −
−
∏
  and denote 
the 12 month toxicity rate as 
4
,
1
1
(1
)
t
t h
h
p
π
=
= −
−
∏
.   
 
While the trial is ongoing, the kth arm will be declared unacceptable for completion if 
 
Pr(
0.50 |
)
.975
r
data
π <
>
  or  
 
 
 
Pr(
0.10 |
)
.90
t
data
π >
>
 or  
A maximum of n=75 patients will be treated per arm.  The stopping rules for response will 
be applied 52 weeks after the first patient accrues to the study (and every 13 weeks 
thereafter) while the toxicity rules will be applied 13 weeks after the first patient accrues 
to the study (and every 13 weeks thereafter).  An arm that is not declared unacceptable 
for completion will be completed.  At the end of the trial we will calculate, for any 
completed arms 
 
,
Pr(
0.50 |
)
.975
r k
data
π
<
>
   
The following Table shows the scenarios studied using the above design.  In this 
simulation we assume that, on average between 2 or 3 patients accrue to the study every 
month.  Also recall that 33% of the patients have already accrued to the study.  Thus, the 
simulation results presented below combine fixed observed data with future as yet 
unobserved data.  Each virtual trial was simulated (1000 simulations per scenario), and 
the tables summarize the design’s average behavior given the already accrued data.   
 
 
Scenario 
Toxicity Rate* 
 
MMR*  
Prob of 
Stopping Before 
75 patients 
accrue to study 
Expected Sample 
Size Enrolling to 
Study 
Scenario 1 
0.25 
0.80 
0.206 
73.29 
Scenario 2 
0.05 
0.30 
0.454 
70.11 
Scenario 3 
0.05 
0.80 
0.003 
74.90 
Scenario 4 
0.25 
0.30 
0.555 
69.50 
*Rates for future patients (already accrued patients have already been 
observed) 
 
 
10.1 Updated Statistical Design 
 
To date, 33 patients have been treated with the 50mg BID dose schedule, 
now discontinued, and 56 patients have been treated with the 100mg QD 

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dose schedule, for a total of  89. Under the current design, which has target 
total sample size 100, 11 additional patients would be treated using the 
100mg QD schedule, giving a subtotal of 56+11 = 67. Under the proposed 
design with target total sample size 150, 61 additional patients would be 
treated using the 100mg QD schedule, giving a subtotal of 56+61 = 117. 
Assuming a non-informative beta(0.5, 0.5) prior on Pr(MMR12) = probability 
of major molecular response at 12 months, the trial’s primary endpoint, and 
assuming  that the currently observed rate of 76% for MMR12 persists, 
under the current design if 51/67 (76%) MMR12’s were observed in the 
100mg QD dose schedule patients then a posterior 95% credible for 
Pr(MMR12) would be [0.650 – 0.851]  which has a width of 0.205.  Under 
the proposed design with 50 more patients, if 89/117 (76%) MMR12’s were 
observed in the 100mg QD dose schedule patients then a posterior 95% 
credible for  Pr(MMR12) would be [0.678 – 0.831]  which has a width of 
0.153.  Consequently, in terms of reliability of estimation, 50 additional 
patients would provide a 25% reduction in the width of a posterior 95% 
credible interval for Pr(MMR12). Similarly, substantial improvements in 
statistical reliability would be obtained for estimates all other parameters of 
interest, 
including 
the 
probability 
of 
complete 
cytogenetic 
response,  distribution of response duration, Kaplan-Meier estimates of 
progression-free and overall survival time distributions, and toxicity rates. 
 
10.2  Statistical Considerations for MDASI and QoL   
 
Continuous variables (e.g., age, hematology values) will be summarized 
using the mean (s.d.) or median (range).  Frequency tables will be used to 
summarize categorical variables.  Logistic regression will be used to assess 
the impact of patient, disease, and treatment characteristics on symptom 
severity and interference. Correlations of symptom severity and therapy 
adherence (from research nurse records) will be determined. 
11.0 Reporting Requirements  
 
11.1 Serious adverse events and unanticipated events will be reported as per 
institutional policy and as noted below.   
 
Information on adverse events and concomitant medications will recorded 
in the medical record. 
 
11.3 Serious Adverse Event Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, 
in the view of either the investigator or the sponsor, it results in any of the 
following outcomes: 
 
• Death 

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• A life-threatening adverse drug experience – any adverse experience 
that places the patient, in the view of the initial reporter, at immediate 
risk of death from the adverse experience as it occurred. It does not 
include an adverse experience that, had it occurred in a more severe 
form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered a serious adverse drug 
experience when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
 
• Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should be 
reported as an SAE if deemed appropriate by the Principal Investigator 
or the IND Sponsor, IND Office. 
• All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in “The University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”. Unless stated otherwise in the protocol, all SAEs, expected or 
unexpected, must be reported to the IND Office, regardless of attribution 
(within 5 working days of knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related 
to the study drug, must have a written report submitted within 24 hours 
(next working day) of knowledge of the event to the Safety Project 
Manager in the IND Office.  
• Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB.  
• Serious adverse events will be captured from the time of the first 
protocol-specific intervention, until 30 days after the last dose of drug, 
unless the participant withdraws consent. Serious adverse events must 
be followed until clinical recovery is complete and laboratory tests have 
returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event.  
• Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the 

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IND Office. This may include the development of a secondary 
malignancy.  
 
Reporting to FDA: 
 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor 
(Safety Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal 
Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s 
guidelines, 
and 
Institutional 
Review 
Board 
policy. 
 
 
Investigator Communication with Supporting Companies: 
 
For reporting purposes, BMS also considers the occurrences of 
pregnancy or overdose (regardless of adverse outcome) as events 
which must be reported as important medical events. 
 
Adverse events classified as “serious” require expeditious handling and 
reporting to BMS to comply with regulatory requirements.  
 
All serious AEs whether related or unrelated to investigational product, 
must be immediately reported to BMS (or designee) by confirmed 
facsimile transmission.  If only limited information is initially available, 
follow-up reports are required.  The original SAE form must be kept on 
file at the study site. 
 
All SAEs should simultaneously be faxed to Bristol-Myers Squibb at: 
Global Pharmacovigilance 
Bristol-Myers Squibb Company 
Fax Number:  609-818-3804 
 
Collection of complete information concerning SAEs is extremely 
important.  Thus, follow-up information which becomes available as the 
SAE evolves, as well as supporting documentation (e.g., hospital 
discharge summaries and autopsy reports), should be collected 
subsequently, if not available at the time of the initial report, and 
immediately sent using the same procedure as the initial SAE report. 
 
11.4 Overdose 
An overdose is defined as the accidental or intentional ingestion of any dose 
of a product that is considered both excessive and medically important.  For 
reporting purposes, BMS considers an overdose, regardless of adverse 
outcome, as an important medical event (see Serious Adverse Events). 
 

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11.5 Reporting of AE Information Following Study Completion 
Collection of safety information following the end of investigational product 
administration is important in assisting in the identification of possible 
delayed toxicities or withdrawal effects.  In BMS trials, all SAEs must be 
collected which occur within 30 days of discontinuation of dosing or 
completion of the patient’s participation in the study if the last scheduled 
visit occurs at a later time.  In addition, the Investigator should notify BMS 
of any SAE that may occur after this time period which they believe to be 
certainly, probably or possibly related to investigational product. 
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