Conditions: Acute Myeloid Leukemia Myelodysplastic Syndromes Agnogenic Myeloid Metaplasia Myelofibrosis Hypereosinophilic Syndrome Polycythemia Vera Mastocytosis Leukemia, Myelomonocytic, Chronic
Keywords: targeted therapy leukemia Acute myeloid leukemia (AML) Myelodysplastic syndrome (MDS) Agnogenic myeloid metaplasia - myelofibrosis (MMM) Hypereosinophilic syndrome (HES) Polycythemia vera (PV) Mastocytosis CMML
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 68
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if dasatinib can help to control myeloproliferative disorders. The safety and tolerability of dasatinib will also be studied.

Detailed description:
Dasatinib is an experimental anti-cancer drug that is designed to block the function of BCR-ABL, which is the abnormal protein responsible for causing leukemia in some cells.

If you are found to be eligible to take part in this study, you will take dasatinib by mouth twice a day. If you have mastocytosis, you will take dasatinib by mouth once a day. A treatment cycle will be defined as 4 weeks (28 days) + 7 days. You will be instructed to take dasatinib in the morning (between about 6:00 a.m.-10:00 a.m.) and in the evening (between about 6:00 p.m.-10:00 p.m.).

Blood tests (about 2 - 3 teaspoons) will be done once a week for a month, then once a month for 5 years, then once every 6 months (if your doctor thinks it is needed) for the remainder of your treatment on this study. A bone marrow biopsy will be done after 1-2 months of therapy to document response.

Dasatinib will be given for as long as you are responding. You will be taken off study if the disease gets worse or intolerable side effects occur.

This is an investigational study. Dasatinib is authorized for use in research only. A total of 145 patients will take part in this study. All will be treated at MD Anderson.

Arms:
arm 1: Dasatinib 70 mg orally twice daily. arm 2: Dasatinib 70 mg orally twice daily. arm 3: Dasatinib 70 mg orally twice daily. arm 4: Dasatinib 70 mg orally twice daily. arm 5: Dasatinib 70 mg orally twice daily.

Interventions: intervention 1: Dasatinib (BMS-354825)
Intervention descriptions: intervention 1: 70 mg orally twice daily

Protocol document:
Prot_SAP_000.pdf: 
Protocol 2004-0817
July 18, 2011
Page 1
Protocol Page
Therapy of Myeloid Metaplasia-Myelofibrosis, Atypical Chronic Myeloid or 
Myelomonocytic Leukemia, C-Kit Positive Acute Myeloid Leukemia (AML) or 
High-Risk Myelodysplastic Syndrome (AML-MDS), Hypereosinophilic Syndrome, 
Polycythemia Vera, and Mastocytosis with Dasatinib (BMS-354825)
2004-0817
Core Protocol Information
Short Title 
Dasatinib as Therapy for MPDs
Study Chair: 
Hagop Kantarjian
Additional Contact:
Samuel I. Dara
Vicky H. Zoeller
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-792-7305
Unit:
428
Full Title: 
Therapy of Myeloid Metaplasia-Myelofibrosis, Atypical Chronic Myeloid or Myelomonocytic 
Leukemia, C-Kit Positive Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic 
Syndrome (AML-MDS), Hypereosinophilic Syndrome, Polycythemia Vera, and Mastocytosis 
with Dasatinib (BMS-354825)
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 03/03/2017
Version:
19
Submitted by:
Vicky H. Zoeller--5/15/2013 11:48:22 AM
OPR Action:
Accepted by:  Margie Tamez -- 5/21/2013 9:25:51 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol 2004-0817
July 18, 2011
Page 2
Protocol Body
 
Supporter:  Bristol-Myers Squibb Company


 
 
 
The University of Texas M. D. Anderson Cancer Center 
 
 
Protocol 2004-0817 
 
 
 
 
THERAPY OF MYELOID METAPLASIA-MYELOFIBROSIS, ATYPICAL CHRONIC 
MYELOID OR MYELOMONOCYTIC LEUKEMIA, C-KIT POSITIVE ACUTE MYELOID 
LEUKEMIA (AML) OR HIGH-RISK MYELODYSPLASTIC SYNDROME (AML-MDS), 
HYPEREOSINOPHILIC SYNDROME, POLYCYTHEMIA VERA, AND 
MASTOCYTOSIS WITH DASATINIB (BMS-354825) 
 
 
 
 
 
 
 
 
 
1.0 
Objectives 
2.0 
Background 
3.0 
Background Drug Information 
4.0 
Patient Eligibility 
5.0 
Treatment Plan 
6.0 
Pretreatment Evaluation 
7.0 
Evaluations During Study 
8.0 
Criteria for Response 
9.0 
Criteria for Removal from Study 
10.0 Statistical Considerations 
11.0 Reporting Requirements 
12.0 References 
 


Protocol 2004-0817 
July 11, 2011 
Page 2 of 36 
 
1.0 
 OBJECTIVES 
1) Primary Objectives:  To determine the objective response rate in patients with 
myeloid metaplasia-myelofibrosis (MMM), atypical chronic myeloid or 
myelomonocytic leukemia (CML-CMML), acute myeloid leukemia (AML) or 
high-risk myelodysplastic syndrome (MDS), hypereosinophilic syndrome 
(HES), polycythemia vera (PV), and mastocytosis to dasatinib. 
 
2) Secondary Objectives:  To evaluate duration of response and survival. 
 
2.0 
BACKGROUND 
Despite progress in leukemia therapy, most adult patients with advanced or 
refractory hematopoietic malignancies still die from their disease. No generally 
effective therapy for agnogenic myeloid metaplasia (AMM), or the other bcr-abl 
negative myeloproliferative disease (MPD) has been established.1-3 Hence, there 
is an urgent need to identify new agents for patients with these life-threatening 
diseases. 
 
The transduction of signals from the extracellular milieu to the nucleus of a target 
cell (e.g., an epithelial cancer cell, a blood vessel endothelial cell or a stromal 
fibroblast) are receptor-mediated events.  It is clear, from a large body of 
research, that some of the receptors that mediate critical events in signaling 
between tumor cells and important host tissues are receptor tyrosine kinases 
(RTKs).  All of these molecules have an extracellular ligand binding domain, a 
transmembrane domain and an intracellular tyrosine kinase domain.  Upon ligand 
binding, receptors dimerize, the tyrosine kinase is activated and the receptors 
become autophosphorylated.4  The cascade triggered by RTK activation 
modulates cellular events such as proliferation, differentiation and 
morphogenesis in a positive or negative fashion.  Over the past 15 years, RTKs 
and their downstream signaling molecules have emerged as important targets for 
the development of inhibitory drugs due to their role in positive growth control.  Of 
particular interest has been the receptors platelet-derived growth factor (PDGF) 
receptors.   PDGF receptors have been shown to have defined roles in the 
autocrine stimulation of tumor cells, as well as tumor cell-host cell interactions 
such as new blood vessel growth (or “angiogenesis”) and supporting stromal 
fibroblasts.4  
 
PDGF is a pleiotropic factor that exists as a homo- or heterodimer of two 
polypeptides, the alpha- and beta-chains.
5  The PDGF ligands interact with two 
receptor subtypes, the PDGF receptor-α (PDGFRα) and PDGF receptor-β 
(PDGFRβ).  PDGF receptors are normally found in connective tissue and glia but 
are lacking in most epithelia. However, recent studies have implicated paracrine 
or autocrine PDGF loops in the growth deregulation of gliomas and sarcomas as 
well as various human epithelial tumors. Furthermore, PDGF has been 
implicated in the pathogenesis of several nonmalignant proliferative diseases, 
including atherosclerosis, restenosis following vascular angioplasty, and 
fibroproliferative disorders such as obliterative bronchiolitis.6, 7 PDGF receptors 
are expressed on tumor neovasculature and are up-regulated during tumor 


Protocol 2004-0817 
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progression.8  Furthermore, the β-receptor appears to play a role in angiogenesis 
by regulating the pericytes that surround the microvessels.9 In addition, PDGF 
receptor expression on tumor stromal fibroblasts may support tumor cell 
growth.10, 11  Thus, PDGF may influence tumor cell growth directly or indirectly, 
employing both autocrine and paracrine mechanisms.12  A large body of data 
supports a role for PDGF in the pathophysiology of a number of MPD.5, 8, 10-19 
 
C-kit and the VEGF Flk-1 receptor (also called KDR, the human homologue, or 
VEGF-R2) are closely related receptor tyrosine kinases which have arisen by 
duplication of immunoglobulin-like domains from a common ancestor.
20 C-kit is 
the cellular homolog of the v-kit retroviral oncogene. The c-kit gene product is 
expressed in hematopoietic progenitor cells, mast cells, germ cells, and some 
human tumors.21, 22 Studies with mice with inactivating mutations of c-kit or its 
ligand have demonstrated that the c-kit gene product is essential for 
maintenance of normal hematopoeisis, melanogenesis, gametogenesis, and 
growth and differentiation of mast cells. In addition to its normal role, deregulation 
of c-kit is thought to have a role in certain human tumors, including germ cell 
tumors, mast cell tumors, gastrointestinal stromal tumors, small-cell lung cancers 
(SCLCs), melanoma, breast cancer, and neuroblastoma. In a number of tumors 
types, c-kit-mediated growth has been found to occur via mutation of c-kit, which 
results in ligand-independent activation of the receptor 23-25  C-kit is essential for 
the development of normal hematopoietic cells and has been proposed to play a 
functional role in AML. In a recent investigation of 917 adult and pediatric 
patients with AML, c-kit was detected on the surface of AML blasts in 63% of the 
samples by FACS analysis.26 In recent publications, expression of c-kit was 
identified in 20 of 25 AML patients and in all of 21 cases, respectively.27, 28 c-kit is 
another member of the class III family of RTKs, characterized by an extracellular 
ligand binding region containing 5 immunoglobulin repeats, a hydrophobic 
transmembrane domain, and an intracellular kinase domain split by an insert. 
Binding of the c-kit ligand, stem cell factor (SCF), initiates a signal transduction 
cascade that includes receptor autophosphorylation and subsequent 
phosphorylation on numerous intracellular substrates. c-kit and its ligand play a 
pivotal role in normal hematopoeisis, as evidenced by naturally occurring murine 
mutations at the Sl locus, which encodes SCF, as well as in the c-kit receptor 
itself. These mutations result in varying degrees of macrocytic anemia and a loss 
of mast cells in addition to deficiencies in gametogenesis and melanogenesis. 
 
In addition to its role in normal hematopoeisis, c-kit is expressed in leukemic 
blasts in approximately 60% to 80% of patients with AML, as assessed by 
surface immunostaining using antibodies specific to c-kit or by expression of c-kit 
messenger RNA. Supporting a functional role for c-kit in AML, increased tyrosine 
phosphorylation of the receptor, as well as a proliferative response upon SCF 
stimulation, has been demonstrated in leukemic blasts in most AML cases that 
were c-kit+. The proliferative response to SCF has been shown to be synergistic 
with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin 
(IL)-3, both of which are known to promote the growth of leukemic cells in vitro.  
We have recently reported that SU5416 and SU6668,  small-molecule inhibitors 


Protocol 2004-0817 
July 11, 2011 
Page 4 of 36 
 
of RTKs such as Flk-1/KDR with structural and sequence similarity to c-kit, inhibit 
biologic functions of c-kit in MO7E cells, including ligand-induced tyrosine 
phosphorylation and proliferation.29 Additionally, both compounds induced 
apoptosis in these cells. Both SU5416 and SU6668  also inhibited SCF-induced 
phosphorylation of c-kit in blasts from several AML patients, one T-cell acute 
lymphoblastic leukemia (T-ALL) and one chronic myeloid leukemia (CML) 
patient, and also induced apoptosis in these cells.29  These results suggest that 
c-kit inhibition may provide a useful means to treat AML. 
 
Imatinib mesylate, a Bcr/Abl selective tyrosine kinase inhibitor, is the most active 
agent against CML.  Preclinical studies demonstrate similar suppression of c-kit 
and PDGF-R kinases suggesting its potential role in a wide variety of c-kit or 
PDGF-R positive tumors including gastrointestinal subcutaneous tumors (GIST).  
AML is associated with high expression of c-kit.  Other myeloproliferative 
disorders are associated with high expressions of PDGF and PDGF-R.  They are 
ideal targets for therapy with new Bcr/Abl or Abl/Src inhibitors. 
 
In this study, we propose to evaluate the efficacy of dasatinib, dual Abl/Src 
inhibitors in c-kit positive and PDGF-R expressing (myeloproliferative) disorders 
in a time-efficient approach.  Some of these disorders have responded to imatinib 
including HES, mastocytosis, PV, and to lesser extent AML and MMM. 
 
• Polycythemia vera (PV):  This is a MPD involving excessive proliferation of 
the erythroid series, producing erythrocytosis, high Hb/Ht levels, vessel 
stasis, splenomegaly, and transformation to AML and other MPD.  Response 
rate to PV after failure on hydrea and IFN-α to imatinib is about 50%. 
• Hypereosinophilic syndrome (HES):  This is an MPD of the eosinophils 
causing eosinophilia, skin rashes, organ infiltration, heart failure, CVAs and 
multi-organ failure (liver, kidney).  The median survival range reported is 1-4 
years.  There is no effective therapy for HES.  Patients with HES treated with 
imatinib 100mg daily had a 50% response rate.  In our studies 5/9 patients 
with HES responded to imatinib.  The efficacy of imatinib in HES has been 
confirmed in at least one other study.  
• Responses in mastocytosis have been reported recently in 4 of 9 patients 
treated. In addition, patients with atypical CML or CMML with PDGF-R fusion 
genes have been reported to have significant activity with imatinib.  
 
2.1 
Update of May 3, 2006 
As of this date, 20 patients with mastocytosis have been treated for a 
median of 39 days (range 6 – 147).  Fifteen patients have been treated for 
more than one month.  So far, by protocol criteria responses are:  major 
response – 2, partial response – 6, clinical benefit – 4, for an overall 
response of 12/15 = 80%. 
 
Preclinical studies suggest that high levels of dasatinib may be more 
effective against mastocytosis lines.  Following discussion with Bristol-
Myers and other investigators, it was felt that a single dose (SD) daily of 


Protocol 2004-0817 
July 11, 2011 
Page 5 of 36 
 
dasatinib (140 mg SD as opposed to 70 mg BID) may prove more 
effective.  We propose to treat an additional 25 patients with mastocytosis 
with 140 mg SD orally daily.  The statistics will be the same as for the first 
cohort of 25 patients.  This would allow enough patients to evaluate 
efficacy:toxicity in order to design the FDA pivotal approval trial for 
mastocytosis. 
 
2.2 
Update as of July 8, 2011 
Two patients with mastocytosis remain on study for over 5 years with 
symptom control and stability of the disease.  The update reflects current 
monitoring practice in patients on long term therapy. 
 
3.0 
BACKGROUND DRUG INFORMATION 
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 the 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 
(CA180002) was conducted to determine the safety profile, tolerability, and 
pharmacokinetics of dasatinib in patients 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 reporters of the 
mechanism of action.  CA180005, was designed to further evaluate the anti-
tumor activity and safety of dasatinib in patients with imatinib-refractory, 
accelerated phase CML. 
 
3.1 
Summary of Results of Investigational Program  
Additional background information on preclinical pharmacology, toxicology 
and pharmacokinetics may be found in the Investigator Brochure.32 
 
3.1.1 Preclinical Antitumor Activity  
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 kinases/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 PDGFb receptor (28 
nM). Dasatinib is much more potent than imatinib against several 
important tyrosine kinases, as outlined in Table 1 below. 
 
Table 1  Comparative Potency of Dasatinib vs. Imatinib 


Protocol 2004-0817 
July 11, 2011 
Page 6 of 36 
 
Mesylate 
 
Kinase 
Fold more potent 
 
than Imatinib (based on IC50) 
BCR-ABL 
260 
C-kit  
8 
PDGFb  
60 
SRC  
>1000 
 
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 217 nM 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 mM)33
  
independently established by 
investigators at M.D. Anderson Cancer Center from the sensitive 
parent line by continuous exposure of K562 cells to high 
concentration 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 clinical 
resistance to imatinib mesylate was demonstrated in three CML cell 
lines established from patients who failed imatinib mesylate 
therapy. These cells remained highly sensitive to the cell-killing 
effects of dasatinib.34  Table 2 shows the IC50 of dasatinib 
compared to the IC50  of imatinib in these three cell lines.  
 
Table 2  IC50 of Dasatinib and Imatinib mesylate in three patient 
cell lines 


Protocol 2004-0817 
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Page 7 of 36 
 
 
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. 
 
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-off). 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 
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.  
 
3.1.2 Preclinical Toxicology  
Additional information related to the preclinical toxicology of 
dasatinib is available in the Investigator 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; 


Protocol 2004-0817 
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there were 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 
inhibition is best typified by antiplatelet agents such as the 
GPIIb/IIIa antagonists, integrelin and 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   
 


Protocol 2004-0817 
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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 rat 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.  
 
3.1.3  Preclinical Pharmacokinetics  
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.  
 
Distribution.  Dasatinib is highly bound (> 91%) to proteins in 
mouse, rat, dog, monkey, and human sera, and its blood to plasma 
concentration ratio ranges from 1.1 in rat to 1.8 in human.38 The 
average steady-state volume of distribution 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.  
 
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, 


Protocol 2004-0817 
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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.  
 
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 elimination of 
dasatinib is by metabolism.38 
 
 
Pharmacokinetic Drug Interactions.  Caution is warranted when 
administering dasatinib to patients taking drugs that are highly 
dependent on CYP3A4 for metabolism and have a narrow 
therapeutic 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 
mM) and a weak inhibitor of CYP1A2 and CYP2D6 (IC50 of > 100 
mM), CYP2C9 (IC50 of 63 mM) and CYP2C19 (IC50 of 32 mM). 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 (see 
Section 5.3.2).   
 
3.2 
Rationale 
The selective effect of imatinib against Bcr-Abl, c-kit, PDGFR, and other 
recently discovered kinases (e.g. FIP1 L1- PDGR R in HES) explains its 
efficacy, not only in Ph-positive CML and ALL, but also perhaps in other 
hematologic cancers including HES, mastocytosis, PV (response rates of 
50%), and to a lesser extent in MMM and AML. 
 
Dasatinib is a dual Abl/Src inhibitor.  In preclinical models and in Phase I 
studies in CML, it appears to be far more potent than imatinib.  The 
potency of dasatinib in some models is 260 fold more than imatinib 
against Bcr-Abl, 8 fold more against c-kit, 60 fold more against PDGFR, 
and > 1,000 fold against Scr.  Thus, it is reasonable to investigate in 
clinical trials the potential activity of dasatinib in hematologic cancers in 
which these kinases might be operative.  These include AML-MDS, 


Protocol 2004-0817 
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atypical CML and CMML, HES, PV, mastocytosis, and MMM.  This is the 
purpose of this study. 
 
3.2.1 Phase I Experience: CA180002  
Also refer to recent publications39,40,41,42 and the most current 
revision of the Investigator Brochure32.  
 
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 
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. 


Protocol 2004-0817 
July 11, 2011 
Page 12 of 36 
 
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% 


Protocol 2004-0817 
July 11, 2011 
Page 13 of 36 
 
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 
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% 


Protocol 2004-0817 
July 11, 2011 
Page 14 of 36 
 
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. 
Efficacy 


Protocol 2004-0817 
July 11, 2011 
Page 15 of 36 
 
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) 
 
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   


Protocol 2004-0817 
July 11, 2011 
Page 16 of 36 
 
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, 30 tabs/bottle 
BMS-354825-03 
 
 
50 mg film coated tablets, 30 tabs/bottle 
 
3.3.3 Handling and Dispensing of Investigational Product  
It is recommended that investigational product should only be handled by 
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 lot numbers, dosing start dates and the number of tablets for each 
dosage strength must be recorded on the drug accountability pages of the 
Case Report Form. The subject must be instructed to return all unused 
study medications in the provided packaging at each subsequent visit.  
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 


Protocol 2004-0817 
July 11, 2011 
Page 17 of 36 
 
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 
the investigational pharmacy, in accordance with the environmental 
conditions (temperature, light and humidity) as determined by the supplier 
and defined in the Investigator 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 supplier 
• 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 Destruction of Investigational Product  


Protocol 2004-0817 
July 11, 2011 
Page 18 of 36 
 
 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 
Patients > 18 years old who meet the following eligibility criteria: 
 
4.1 
Patients must have one of the following hematopoietic malignancies: 
1) C-kit positive (10% or more bone marrow or peripheral blood 
mononuclear cells positive by flow) acute myeloid leukemia (AML 
excluding acute promyelocytic leukemia) or myelodysplastic syndrome 
(MDS) of the following types: 
• Refractory-relapse AML-MDS including those who fail to achieve 
CR after the first cycle of induction 
• Second or subsequent AML-MDS refractory-relapse 
• Newly diagnosed AML-MDS patients over 60 years of age with 
karyotype other than t(15:17), inv16, t(8:21), who do not want 
chemotherapy.  Patients with MDS who do not want chemotherapy 
as initial treatment, or who are not eligible for the treatments of 
higher priority. 
2) Ph negative MPD including chronic myelomonocytic leukemia (CMML)  
3) Agnogenic myeloid metaplasia – myelofibrosis (MMM) 
4) Hypereosinophilic syndrome (HES) 
5) Polycythemia vera (PV) 
6) Mastocytosis 
 
4.2 
Serum bilirubin less than 2mg%, serum creatinine less than 2mg% unless 
abnormality is considered due to hematologic malignancy by investigator. 
 
4.3 
ECOG Performance Status < 3. 
 
4.4 
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. 
4.5 
Women of pregnancy potential must practice an effective method 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) (defined as not post-menopausal for 12 months or no previous 
surgical sterilization) must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an 
unintentional pregnancy.  In addition, men enrolled on this study should 


Protocol 2004-0817 
July 11, 2011 
Page 19 of 36 
 
understand the risks to any sexual partner of childbearing potential and 
should practice an effective method of birth control.  Women and men 
must continue birth control for the 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. 
4.6 
Inclusion of women and minorities: As per NIH policy, women and 
members of  minorities will be included in this protocol as they are 
referred in the relevant populations.  There are no exclusions of women or 
minorities based on the study objectives.   
 
4.7 
NYHA Class < 3 
 
4.8 
Cardiac Symptoms patients meeting the following criteria are not eligible:  
• 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: 
1. 
Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease) 
2. 
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: 
3. 
quinidine, procainamide, disopyramide 
4. 
amiodarone, sotalol, ibutilide, dofetilide 
5. 
erythromycins, clarithromycin 
6. 
chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide 
7. 
cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, 
domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, 
lidoflazine. 
 
5.0  
TREATMENT PLAN 
5.1  
General 
All patients should be registered with the Data Management Office PDMS 
system. Dasatinib will be supplied by Bristol-Myers Squibb Company.  
Patients will be assigned an identifying number once registered.   


Protocol 2004-0817 
July 11, 2011 
Page 20 of 36 
 
 
5.2  
Treatment Plan 
Patients will receive therapy according to the suggested guidelines below. 
Individual variations in the initiation of therapy, WBC count at start of 
therapy, individual doses are acceptable as indicated by patients condition 
and physicians judgment.   
 
5.2.1 WBC reduction: hydroxyurea may be used during the first month of 
therapy for control of WBC or other indications.  Use beyond the 
first month will have to be discussed with the PI and the reason 
clearly documented. 
 
5.2.2 Treatment Administration  
Dasatinib will be administered continually at an oral dose of 70 mg 
twice daily.  A treatment cycle will be defined as 4 weeks (28 days), 
+ 7 days.  Patients will be instructed to take Dasatinib in the 
morning (between approximately 6:00 a.m. - 10:00 a.m.) and in the 
evening (between approximately 6:00 p.m. - 10:00 p.m.).  
Patients preferably should not take H2 blockers.  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. 
Patients should avoid taking CYP3A4 inhibitors such as:  
acetaminophen, aldrin, alfentanil, amiodarone, astemizole, 
benzphetamine, budesonide, carbamazepine, cyclophosphamide, 
cyclosporin, dapsone, digitoxin, diltiazem, diazepam, erythromycin, 
ethinylestradiol, etoposide, flutamide, hydrogxyarginine, 
ifosphamide, imipramine, lansoprazole, lidocaine, loratadine, 
losartan, lovastatin, midazolam, nifedipine, omeprazole, quinidine, 
paclitaxel, rapamycin, retinoic acid, steroids (e.g., cortisol), 
tacrolimus (FK 506), tamoxifene, teniposide, terfenadine, 
tetrahydrocannabinol, theophylline, toremifene, triazolam, 
troleandomycin, verapamil, warfarin, zatosetron, or zonisamide.  If 
necessary, they should be taken at least 2 hours away from 
dasatinib dose. 
If a scheduled dose is missed or dosing is interrupted for toxicity or 
for any other reason, these doses should be omitted. Patients will 
ideally be treated with dasatinib until disease progression, 
unacceptable toxicity, the Investigator and the patient feel that it is 
in the best interest of the patient to discontinue treatment, 
withdrawal of patient's consent, or for reasons outlined in Sections 
5.2.4 and 5.6.  
 
5.2.2.1 For patients with mastocytosis, dasatinib will be given at 
140 mg single dose (SD) daily.  H1 and H2 blockers are 
allowed.  If worsening symptoms occur in the first week 
(histamine release), steroids are allowed e.g. prednisone 


Protocol 2004-0817 
July 11, 2011 
Page 21 of 36 
 
40-80 mg daily x 7. 
 
5.2.3  Dose Modifications and Escalations  
Patients will be monitored continuously for adverse events (toxicity) 
while on study therapy. Patients will be instructed to notify their 
physician immediately for any and all toxicity. Patients will continue 
to receive therapy as long as they have not had disease 
progression and all non-hematologic toxicities thought to be related 
to dasatinib are < CTC Grade 1 or have returned to baseline 
(except alopecia and fatigue), and ANC >˜1000/mm 3. Potassium 
and magnesium must continue to be within normal limits, and total 
serum calcium or ionized calcium must be greater than the lower 
limits of normal.  
 
For any dose interruptions (as described below), initiation of 
additional therapy may be delayed for a maximum of 21 days to 
allow recovery from any toxicity.  
 
Dose Escalations for Resistance or Progression.  The dose 
modification levels are specified in Table 7.  Patients who show 
evidence of progressive disease after starting treatment with 
dasatinib may have their dose increased to 100 mg twice daily 
upon agreement between the Investigator and the Medical 
Monitor/drug supplier. Patients who do not achieve response within 
8 weeks of initiation of therapy may also escalate their dose to 100 
mg twice daily starting with the 3rd cycle of therapy as long as 
toxicity does not cause discontinuation of therapy.  Patients who 
achieve response on 70 mg twice daily and subsequently progress 
while on therapy may also escalate their dose to 100 mg twice 
daily.  Patients who progress during 100 mg twice daily dosing will 
discontinue therapy.   Patients with mastocytosis who do not 
respond may be treated at 200 mg SD daily. 
 
Dose Modifications for Non-Hematologic Toxicity.  Criteria for 
dose reductions and discontinuation of therapy for some specific 
non-hematologic toxicities are described in Table 8.  Guidelines for 
dose reductions and discontinuation from therapy due to other non-
hematologic toxicities are as follows:  
 
• If a patient has CTC Grade 2 non-hematologic toxicity (except 
alopecia or fatigue) thought to be at least possibly related to 
dasatinib, treatment should be interrupted until the toxicity 
decreases to < Grade 1 or to baselines levels. Therapy will then 
be reinitiated at the original dose. There should be no attempt to 
make up for doses omitted due to toxicity. If the same Grade 2 
non-hematologic toxicity recurs upon retreatment with the 
original dose, treatment will again be interrupted until the toxicity 


Protocol 2004-0817 
July 11, 2011 
Page 22 of 36 
 
decreases to < Grade 1 or returns to baselines levels. Therapy 
with dasatinib will then be reinitiated at the next dose reduction 
level.  If the same Grade 2 non-hematologic toxicity recurs 
despite this dose reduction, a second dose reduction is 
permitted.  Additional therapy following a second dose reduction 
vs. discontinuation of the patient from further protocol therapy 
will be discussed and agreed upon by the Investigator.  Therapy 
can be permitted to continue with a Grade 2 non-hematologic 
toxicity if continuing treatment of the patient’s cancer is thought 
to outweigh the risk of the toxicity and the toxicity does not 
progress to Grade 3.  This will only be applicable after two 
attempts of dose reduction. 
 
• Patients who experience CTC Grade 3 non-hematologic toxicity 
thought to be at least possibly related to dasatinib, will have 
their treatment interrupted until the toxicity decreases to < 
Grade 1 or to baseline levels. Therapy with dasatinib will then 
be reinitiated at the next dose reduction level. If the same Grade 
3 non-hematologic toxicity recurs despite this dose reduction, a 
second dose reduction is permitted. Additional therapy following 
a second dose reduction vs. discontinuation of the patient from 
further protocol therapy will be discussed and agreed upon with 
the Investigator. There should be no attempt to make up for 
doses omitted due to toxicity.   
 
• Patients who experience a CTC Grade 4 non-hematologic 
toxicity thought to be at least possibly related to dasatinib will 
generally not receive additional protocol therapy and be 
removed from study. Additional therapy following a resolution in 
this Grade 4 toxicity to < Grade 1 or to baselines levels will only 
be given with at least a 1 dose level reduction, if the Investigator 
agree that it is in the best interest of the patient to receive 
additional therapy with dasatinib (for example, if this or other 
patients have demonstrated a response to therapy).  
 
Table 7: Dose Modification Levels  
Dose Level 
Dose (mg) twice 
daily (BID) 
Single dose 
(SD) daily (mg) 
Escalation 1 
100 
200 
Starting Dose 
70 
140 
Reduction 1 
50 
100 
Reduction 2 
40 
80 
Reduction 3 
20 
40 
 
However, for an individual patient, dose reductions and 
discontinuations may be more conservative than indicated in the 


Protocol 2004-0817 
July 11, 2011 
Page 23 of 36 
 
above scheme (i.e., dose reduce or discontinue at a lower grade 
of non-hematologic toxicity) based on the clinical judgment of 
the Investigator. With the expanded NCI CTCAE Version 3, 
some Grade 2 toxicities may require dose reductions after the 
first occurrence. Also, patients experiencing some Grade 3 
organ toxicities (e.g., renal, cardiac, CNS) judged to be related 
to study therapy should be discontinued from therapy. Patients 
with a QTc >530 msec with both the Bazett and Fridericia 
corrections must be discontinued from the study. Patients who 
have any evidence of serious bleeding or hemorrhage (e.g., 
cutaneous, GI, etc) must be discussed with the Investigator for 
possible dose adjustment or to have therapy discontinued.  
 
• Abnormalities of LDH, alkaline phosphatase, glucose, albumin, 
calcium, phosphorus, uric acid, magnesium, electrolytes will be 
noted and corrected but will not mandate changes in dasatinib 
doses. 
 
• Dose adjustments may be made at the discretion of the treating 
physician for patients on therapy >5 years.  The lowest dose is 
20mg, the highest dose is 140mg.  Occasional missed doses of 
therapy will not be considered as protocol violations/deviations. 
 
Table 8:  Dose Modifications for Non-Hematologic Toxicity 
 
Toxicity 
Dasatinib 
Grade 3 nausea/vomitinga (1st or 2nd event )  
Decrease current dose by 1 dose level.  
Grade 3 nausea/vomitinga (3rd event)  
Off studyb  
Grade 3 diarrhea a (1st or 2nd event)  
Decrease current dose by 1 dose levela  
Grade 3 diarrhea a (3rd event)  
Off studyb 
Grade 4 non-hematologic toxicities  
Off studyb  
Grade 2 neuropathy (motor or sensory)  
Decrease current dose by 1 dose level  
> ˜Grade 3 neuropathy (motor or sensory)  
Off studyb  
QTc > 530 msec (both Bazett and Fridericia)  
Off studyb  
> Grade 3 cardiac troponin I  
Off study  
Cardiac troponin T > ULN  
*** c  
> Grade 2 CK or CK-MB > ULN  
*** c  
> Grade 2 AST, ALT  
*** c 
> Grade 2 bilirubin  
*** c  
Any evidence of bleeding  
*** c  
 
a Despite adequate/maximal medical intervention and/or prophylaxis. 
b Unless Investigator agree that continued therapy at a reduced dose is in the best 
interest of the patient as in the case of responding patients. 
c To be adjusted as medically indicated after discussion with Investigator. 


Protocol 2004-0817 
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Page 24 of 36 
 
 
Hematologic Toxicity 
Neutropenia  
There should be no dose modifications or treatment interruption for 
neutropenia during the first 14 days of therapy. If Grade 4 
neutropenia (ANC < 500/mm3) occurs after 14 days of treatment, a 
bone marrow aspirate and biopsy may be performed. If marrow 
cellularity is < 10%, study drug must be held until ANC > 1000/mm3, 
at which time treatment may be resumed at full dose. If Grade 4 
neutropenia persists, a repeat bone marrow aspirate and biopsy 
may be performed to assess the cellularity and percentage of 
blasts. If Grade 4 neutropenia recurs after resuming trial treatment, 
study drug will be held until ANC > 1000/mm3, at which time study 
drug will be resumed at 1 dose level lower. If Grade 4 neutropenia 
occurs again, a second dose reduction should be tried.  Further 
dose reductions versus discontinuing the patient from study drug 
for further episodes of grade 4 neutropenia will be decided by the 
Investigator. The above procedures will continue to apply if the 
patient receives additional treatment.  
 
If marrow cellularity is > 10% and/or contains > 30% blasts, 
treatment will be continued (or restarted if it has been withheld 
because of marrow hypocellularity and/or granulocytopenia). If 
Grade 4 neutropenia persists for an additional week, a bone 
marrow aspirate and biopsy may be repeated and the above criteria 
applied. If Grade 4 neutropenia persists for an additional two weeks 
(i.e., a total of 4 weeks), study drug will be withheld (regardless of 
the bone marrow appearances) until ANC >1000/mm3, at which 
time treatment will be resumed at full dose. If Grade 4 neutropenia 
recurs, study drug will again be withheld until ANC > 1000/mm3 at 
which time study drug will be resumed at 1 dose level lower. If 
Grade 4 neutropenia occurs again a second dose reduction should 
be tried.  For additional grade 4 neutropenia, further dose 
reductions versus discontinuing the patient from study drug will be 
decided by the Investigators. The above procedures will continue to 
apply if the patient receives additional treatment.  
 
Patients with AML and MDS may start with low counts due to their 
basic disease.  In them, dose interruptions/adjustments will not be 
considered if myelosuppression is attributed to disease. 
 
There should be no dose modifications for thrombocytopenia 
without an associated bleeding complication. Patients may be 
supported with platelet transfusions as needed.  
 
Febrile Neutropenia  
There will be no dose modification or treatment interruption for 


Protocol 2004-0817 
July 11, 2011 
Page 25 of 36 
 
fever associated with neutropenia unless the neutropenia leads to 
dose reduction or interruption as defined above (under 
Neutropenia), or unless the patient has signs and symptoms of 
sepsis considered related to dasatinib.  
 
Bleeding  
Patients who have any evidence of bleeding or hemorrhage of any 
grade (e.g., skin, GI, etc.) must be discussed with the principal 
investigator for possible dose adjustment or to have therapy 
discontinued.  
 
5.2.4 Discontinuation of Therapy  
Study therapy MUST be immediately discontinued for the following 
reasons:  
 
• Any clinical adverse event, laboratory abnormality or 
intercurrent illness which, in the opinion of the investigator, 
indicates that continued treatment with study therapy is not in 
the best interest of the subject  
• Pregnancy  
 
5.2.5 Treatment Compliance  
Trained medical personnel will dispense dasatinib to patients. 
Treatment compliance will be monitored by drug accountability, as 
well as recording dasatinib administration using patient diaries. 
Drug accountability may also be reported verbally by the patient to 
the research team.  This information will be recorded in the medical 
record. 
 
5.3 
Prohibited and Restricted Therapies During the Study  
 
5.3.1 Prohibited Therapies  
No other therapy for the treatment of CML, with the exception of 
anagrelide hydrochloride for the treatment of elevated platelet 
counts and hydroxyurea will be permitted while the patient is on 
study. 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 treating physician after 
discussion with the PI. 
 
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  


Protocol 2004-0817 
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Page 26 of 36 
 
• cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, 
domperidone, halofantrine, levomethadyl, pentamidine, 
sparfloxacin, lidoflazine.  
 
Except for anagrelide and hydroxyurea, patients are prohibited from 
taking medications that directly inhibit platelet function (i.e., aspirin, 
dipyridamole, epoprostenol, eptifibatide, clopidogrel, cilostazol, 
abciximab, ticlopidine, ) or anticoagulants (warfarin, heparin/low 
molecular weight heparin [e.g., danaparoid, dalteparin, tinzaparin, 
enoxaparin]) while on study therapy. Low-dose warfarin for 
prophylaxis to prevent catheter thrombosis, and heparin-flushes for 
IV lines is permitted.  
 
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. 
 
5.3.2 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 


Protocol 2004-0817 
July 11, 2011 
Page 27 of 36 
 
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. 
 
5.4 Non-therapy Precautions and Restrictions  
Based on preclinical data, dasatinib may increase the likelihood of 
bleeding. Hence, patients undergoing surgical procedures, including 
dental procedures should be instructed to inform their other doctors of this 
potential increase in bleeding. 
 
5.5 
The above are general guidelines to changes in therapy.  However, 
individual variations including dose escalations or reductions as indicated 
by patients condition and physicians judgment, are allowed, if felt to be 
needed to optimize therapy. Discuss dose schedule reductions with 
Principal Investigator in difficult cases. 
 
5.5 Duration of Therapy 
Patients may continue on therapy indefinitely until disease progression or 
unacceptable toxicity. 
 
6.0 
PRETREATMENT EVALUATION 
 
6.1 
Screening Procedures 
 
To be conducted within 28 days prior to enrollment, except where noted.  
 
• Patient or legally authorized representative must sign the IRB 
approved Informed Consent Form prior to any protocol-specific  
procedures being performed. 
 
• Within 14 days prior to enrollment: CBC, differential, platelets, 
serum chemistry (albumin, bilirubin, LDH, SGPT, creatinine, calcium, 
potassium, magnesium). 
 
• Within 4 weeks prior to enrollment:  Bone marrow aspirate 
with/without biopsy.  Cytogenetics if not done within 12 months. 
 
• Extra-medullary disease: assessment to document extent of disease. 
This may include CT scan of the abdomen/pelvis, CT or x-ray of the 
chest, ultrasound of the liver/spleen or abdomen, bone marrow scan 
plus additional staging as appropriate for each patient. 


Protocol 2004-0817 
July 11, 2011 
Page 28 of 36 
 
• Patients with AML-MDS will be screened for c-kit positivity which 
should be > 10% positive. 
• Within 2 weeks:  EKG. 
• Within 1 week:  Pregnancy test. 
 
7.0 
EVALUATION DURING STUDY 
7.1 
CBC weekly x 4; then every 2-4 weeks on study. 
 
7.2 
Serum chemistries (see 6.1) every 2 weeks x 2 then every month on 
study. 
 
7.3 
Bone marrow aspirate to document CR.  Repeat cytogenetics post CR if 
abnormal before therapy.  (Patients with no bone marrow involvement on 
pre-treatment evaluation do not need to have any subsequent bone 
marrow studies.) 
 
7.4 
Laboratory Correlative Studies (optional) – to be performed on all patients 
whenever possible and if patient consents to additional studies.  Not all 
samples will be collected in all patients at all points. 
 
The laboratory correlative studies to be conducted may include: 
 
• Blast and medullary levels of c-Kit and PDGF –R pretreatment, at CR 
and at failure as indicated. 
 
• C-kit and PDGF-R levels of phosphorylation pretreatment, at CR and 
at failure as indicated. 
7.5 
One EKG between Day 4 and Day 8 of cycle 1. 
 
7.6 
After 5 years of therapy, lab tests are recommended every 6 months and 
are at the discretion of the treating physician. 
 
8.0 
CRITERIA FOR RESPONSE 
From experience with imatinib in similar patients, responses take an average of 3 
to 4 months to occur.   
 
Patients will be evaluated for response. 
 
All patients who receive any dasatinib will be considered evaluable for efficacy 
analyses.  The following criteria will be utilized to judge response. 
 
8.1 
AML, MDS 
Complete Remission (CR):   Normalization of the peripheral blood and 
bone marrow with 5% or less blasts; normo- or hypercellular marrow; ANC 
> 1.0 x 109/L, and platelet count >100 x 109/L. 


Protocol 2004-0817 
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Page 29 of 36 
 
 
Partial Remission:  As per Complete Remission except for the presence of 
6-25% marrow blasts, but reduction by > 50%. 
 
CR marrow:  As per Complete Remission but platelet count < 100 x 109/L. 
 
All other responses are considered failures. 
 
8.2 
MMM and CMML 
Complete Response:  Absence of signs or symptoms of the disease.   
WBC between 1 to 10 x 109/L with no peripheral blasts, promyelocytes, or 
myelocytes and with normalization of bone marrow (< 5% blasts in 
normocellular or hypercellular marrow) for at least 4 weeks. 
 
Resolution of pretreatment cytopenias: 
 
• ANC ≥ 1.0 x 109/L without G-CSF or GM-CSF 
• Hgb ≥ 12.0 gm/dl (≥11.0 gm/dl for females) without erythropoietin or 
transfusion support. 
• PLT  ≥ 100 x 109/L without growth factor or transfusion support. 
 
Resolution of pretreatment leukocytosis and/or thrombocytosis: 
 
• WBC ≤ 10 x 109/L without peripheral blasts, promyelocytes, or 
myelocytes 
• PLT ≥ 100 x 109/L but less than 450 x  109/L 
 
Partial Response:   Improvement of two or more of the following:    
ANC:  
• Increase by 100% and to above 109/L for neutropenia 
• WBC between 1-10 x 109/L with persistence of immature cells (blasts, 
promyelocytes, myelocytes, metamyelocytes) for pretreatment 
leukocytosis. 
 
Hemoglobin:  
• Increase by 2 gm/dL if it was below 10 gm/dL 
• Decrease in transfusion requirements by at least 50% (decrease in 
frequency and/or volume) 
 
Platelet Count:  
• below that level prior to therapy 
• Persistent thrombocytosis > 450 x 109/L but < 50% of pretreatment 
 
Marrow Blasts:  
• Reduction of marrow blasts to 5% or less if it was above 10% in 
normocellular or hypercellular marrow 


Protocol 2004-0817 
July 11, 2011 
Page 30 of 36 
 
 
Organomegaly:  
• Reduction in splenomegaly and/or hepatomegaly by 50% of 
pretreatment dimensions (measured as length below the left costal 
margin on palpation) confirmed by imaging in difficult cases 
 
 
All other responses are considered failures. 
 
8.3 
PV 
CR=normalization of Hb/Ht without need for phlebotomies and 
disappearance of all signs or symptoms of disease 
 
PR=reduction of Hb by ≥ 2g/dl; reduction of splenomegaly by ≥ 50%. 
 
8.4 
HES 
CR=disappearance of eosinophilia (≤ 10%) and disappearance of signs 
and symptoms of disease. 
 
PR=reduction of eosinophilia by ≥ 50%; reduction of organomegaly by ≥ 
50%. 
 
8.5 
Mastocytosis 
Major Response:  Complete resolution of at least one clinical finding [C-
Finding(s)] and no progression in other C-Findings. 
a. Complete remission = with disappearance of mast cell infiltrates in 
affected organs, decrease of serum tryptase levels to <20 ng/ml, and 
disappearance of SM-associated organomegaly. 
b. Incomplete remission = with decrease in mast cell infiltrates in affected 
organs and/or substantial decrease of serum tryptase level and/or 
visible regression of organomegaly. 
c. Pure clinical response  = without decrease in mast cell infiltrates, 
without decrease in tryptase levels, and without regression of 
organomegaly. 
 
Partial Response:  Incomplete regression of one or more C-Finding(s) 
without complete regression and without progress in other C-Findings. 
a. Good partial response:  > 50% regression 
b. Minor response:  ≤ 50% regression 
 
 
No Response:  C-Finding(s) persistent or progressive. 
a. Stable disease:  C-Finding-parameters show constant range 
b. Progressive disease:  one or more C-Finding(s) show progression 
 
9.0 
CRITERIA FOR REMOVAL FROM STUDY 
9.1 
Patients who develop progressive disease with no response to 
optimization of therapy through increases of treatment doses and duration.   
 


Protocol 2004-0817 
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Page 31 of 36 
 
9.2 
Unacceptable severe (grade 3-4) toxicity despite dose optimization. 
 
9.3 
Patient request 
 
9.4 
Death 
 
9.5 
Non-compliance with the treatment schedule. 
 
10.0  STATISTICAL CONSIDERATIONS 
This is an open-label, phase II study in which patients with any of these possible 
hematopoietic malignancies will be treated with dasatinib.  
 
The primary objective for the study is to determine the activity of dasatinib when 
given to patients in the following patient groups:  
 
1. 
C-kit positive AML-MDS 
2. 
Atypical CML or CMML 
3. 
HES 
4. 
PV 
5. 
Mastocytosis 
6. 
Myelofibrosis – myeloid metaplasia 
 
Safety and tolerability of dasatinib in these patient groups will be assessed.  An 
assessment of biological activity of dasatinib in these patient groups will be 
performed, using a variety of laboratory correlative studies, including gene and 
protein expression; blast, plasma, and medullary levels of significant growth 
factors; receptor tyrosine kinase levels and phosphorylation status; and 
measurements of apoptosis of hematopoietic malignant cells. cells.   
 
10.1 Sample Size Considerations 
Because dasatinib has a unique mechanism of action, a response rate as 
low as 10% is of interest for further investigation. A minimum-maximum 
total of 14-25 patients will be entered in each diagnostic group, for a total 
of 145 patients on the trial. This sample size will yield an 82% posterior 
credibility interval for PR (probability of response) of width approximately 
0.16. 
 
If, for example, 3/25 (12%) responses are observed, the 82% posterior 
credibility interval will range from 2% to 18%, formally:   
 
 
Pr  .02 < PR < .18   3 / 25  responses
[
] = 0.82 .  
 
For each group, there will be one interim analysis after 14 patients have 
been evaluated. The trial will terminate if no responses have been 
observed. This is based on a Bayesian criterion to stop if: 
 


Protocol 2004-0817 
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Page 32 of 36 
 
Pr  PR > 0.1  data 
[
] < 0.10,  assuming a  beta .2,  1.8
(
) prior on P
R. 
 
Using these guidelines, simulation results indicate the following 
probabilities of early termination for several possible true rates of 
response: 
 
True Response Rate 
Prob. early termination 
.01 
.05 
.10 
.20 
.30 
.87 
.49 
.23 
.04 
.01 
 
As a further measure to guard against exposure of patients to an agent 
with minimal activity, the aggregate response rate (CR+PR) will be 
reviewed periodically.  If response rates of less than or equal to 1 in 26 
patients, less than or equal to 2 in 42 patients, or less than or equal to 3 in 
55 patients are observed, this would be evidence that the probability of 
<10% activity among this group of diseases is > 90%.  Any decision 
regarding early termination of the study would take into account all 
findings in the individual disease groups.  An objective response refers to 
the cumulative responses (e.g. CR + PR + improved) for each disease 
category. 
 
The secondary objectives include analysis for the duration of response 
and survival.  Response duration is from date of first response until 
relapse.  Survival is from start of therapy.  They will be done using the 
Kaplan-Meier estimators, the log-rank tests and the Cox-Cox-proportional 
hazards models. For correlative studies, the analysis for continuous 
variables will be done using thet- tests, linear regression models, etc. The 
analysis for categorical variables will be done using the chi-square tests 
and the logistic regression models.  
 
11.0 REPORTING REQUIREMENTS 
 
11.1 Reporting requirements will be as per institutional guidelines (Appendix 
C).  Exceptions will include: 
 
 
•  Grade 3-4 myelosuppression 
11.2 Adverse events related to study conditions 
The SAE reporting period will begin with the signing of the informed 
consent. 
AEs should be followed to resolution or stabilization, and reported as 
SAEs if they become serious.  This also applies to patients experiencing 
AEs that cause interruption or discontinuation of investigational product, or 


Protocol 2004-0817 
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Page 33 of 36 
 
those experiencing AEs that are present at the end of their participation in 
the study.  Such patients should receive post-treatment follow-up as 
appropriate.  If an ongoing AE changes in its severity or in its perceived 
relationship to study drug, a new AE entry for the event should be 
completed. 
11.3 Handling of Serious Adverse Events (SAEs) 
Drug toxicities will evaluated according to CTC version 3 (appendix B).  
Reporting of adverse events will be according to M. D. Anderson 
Guidelines for AE Reporting (Appendix C).  
 
Serious adverse events will be delivered to Clinical Research Compliance 
and will be submitted to the FDA by the safety coordinator according to 21 
CFR 312.32. 
 
Investigator Communication with Drug Company 
All SAEs should be faxed to Bristol-Myers Squibb at:  Global 
Pharmacovigilance Bristol-Myers Squibb Company, fax number 609-818-
3804. 
 
11.4  Toxicities of this agent are well described.  Only drug related unexpected 
serious adverse events will be recorded and reported. 
 
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