Clinical trial NCT00820170
Conditions: Breast Cancer
Keywords: Breast Cancer DASATINIB TAXOL (PACLITAXEL) 08-122
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2009-01-01; Completion date: 2018-08-01
Enrollment: 55 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find the highest dose of dasatinib that can be safely given to a patient when the drug is given in combination with the known anticancer drug paclitaxel. Paclitaxel is an established anti-cancer drug, used in the treatment of many cancers, and it is an approved treatment for breast cancer. Dasatinib has been approved by the Food and Drug Administration for use as a single therapy in another kind of cancer, but its use in breast cancer patients, and in combination with paclitaxel is investigational.

In this study, we will test the safety of dasatinib when given at different dose levels in combination with paclitaxel. We want to find out what effects, good and/or bad, it has on the patient and on metastatic breast cancer.

Detailed description:

Arms: arm 1: The phase I portion is a standard, three-patient per cohort, dose escalation schedule will be used. Between 6 and 54 patients will likely be necessary to determine the MTD of dasatinib in combination with weekly paclitaxel.

The phase II portion of this trial has a Simon two-stage design to determine the efficacy of dasatinib when administered in combination with paclitaxel.
Interventions: intervention 1: Dasatinib and Paclitaxel
Intervention descriptions: intervention 1: A treatment cycle will consist of 28 days, according to the following schedule:

Dasatinib 120MG PO once daily, Weekly paclitaxel 80 mg/m2 given intravenously over 1 hour on day 1, 8, and 15 of a 28 day cycle.

The trial will initially test the combination of weekly paclitaxel and dasatinib given PO, once daily , continuously. In case of 2 dose-limiting toxicities (DLT) in the first cohort (0), the next cohort will test dasatinib given with a different schedule, 5 days on and 2 days off, omitting dasatinib the day prior and the day of administration of paclitaxel.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center
IRB Protocol 
IRB#: 08-122 A(17)
Amended: 06/15/15 
 
 
 
Phase I-II Study Of Dasatinib In Combination With Weekly Paclitaxel For Patients With 
Metastatic Breast Carcinoma 
CA 180 194 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: Monica Fornier, MD 
Medicine/Breast 
 
 
Co-Principal 
Investigator(s)/Department: 
Clifford Hudis, MD 
Medicine/Breast 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. New 
York, NY 10021 


Memorial Sloan-Kettering Cancer Center
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Amended: 06/15/15 
 
 
 
Investigator(s)/Department: 
Jacqueline F. Bromberg, MD, PhD 
Tiffany Traina, MD 
Maria Theodoulou, MD 
Teresa Gilewski, MD 
Larry Norton, MD 
Mark Robson, MD 
Gabriella D'Andrea, MD 
Diana Lake, MD 
Andrew Seidman, MD 
Shanu Modi, MD 
Nancy Sklarin, MD 
Maura Dickler, MD 
Chau Dang, MD 
Mary Ellen Moynahan, MD 
Patrick Morris, MD 
Heather McArthur, MD, MPH 
Sarat Chandarlapaty, MD, PhD 
Shari Goldfarb, MD 
Elizabeth Comen, MD 
Devika Gajria, MD, MPH 
Ayca Gucalp, MD 
Victoria Blinder, MD, MSc 
Jose Baselga, MD, PhD 
Selena Rota, MD 
Joshua Chaim, DO 
Svetlana Mironov, MD 
Maxine Jochelson, MD 
 
Sujata Patil 
Azeez Farooki, MD 
Martin Fleisher, MD 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
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Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Radiology 
Radiology 
Radiology 
 
Biostatistics 
Endocrinology 
Clinical Laboratories 


Memorial Sloan-Kettering Cancer Center
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Dilip Giri, MD 
Jorge Reis-Filho, MD, PhD, 
FRCPath 
Francois-Clement Bidard, MD, PhD 
Kiu Yan Charlotte Ng, PhD 
Britta Weigelt, PhD 
 
Stefan Berger, MD 
Ephraim Casper, MD 
Julie Fasano, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Philip Schulman, MD 
Steven Sugarman, MD 
Avni Desai, MD 
Marisa Siebel, MD 
Xiang Zhang, PhD 
Pathology 
Pathology 
 
Pathology 
Pathology 
Pathology 
 
Medicine/Commack 
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Medicine/Commack 
Medicine/Commack 
Medicine/Commack 
Medicine/Commack 
Cancer Biology and Genetics 


Memorial Sloan-Kettering Cancer Center
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Consenting 
Professional(s)/Department: 
Monica Fornier, MD 
Clifford Hudis, MD 
Jacqueline Bromberg, MD, PhD 
Tiffany Traina, MD 
Maria Theodoulou, MD 
Teresa Gilewski, MD 
Larry Norton, MD 
Mark Robson, MD 
Gabriella D’Andrea, MD 
Diana Lake, MD 
Andrew Seidman, MD 
Shanu Modi, MD 
Nancy Sklarin, MD 
Maura Dickler, MD 
Chau Dang, MD 
Mary Ellen Moynahan, MD 
Patrick Morris, MD 
Sarat Chandarlapaty, MD, PhD 
Heather McArthur, MD, MPH 
Shari Goldfarb, MD 
Elizabeth Comen, MD 
Devika Gajria, MD, MPH 
Ayca Gucalp, MD 
Victoria Blinder, MD, MSc 
Jose Baselga, MD, PhD 
Stefan Berger, MD 
Ephraim Casper, MD 
Julie Fasano, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Philip Schulman, MD 
Steven Sugarman, MD 
Avni Desai, MD 
Marisa Siebel, MD 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
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Medicine/Commack 
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Medicine/Commack 
Medicine/Commack 
Medicine/Commack 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 


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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA........................................................................ 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 7 
3.0 
BACKGROUND AND RATIONALE ....................................................................................... 8 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .......................................................... 28 
4.1 
DESIGN ........................................................................................................................ 28 
4.2 
INTERVENTION ......................................................................................................... 28 
5.0 THERAPEUTIC/DIAGNOSTIC AGENTS ................................................................................... 32 
5.1 
DASATINIB………………………………………………………………………….30 
5.2 
STORAGE, HANDLING AND DISPENSING OF DASATINIB…………………..31 
5.3 
DRUG ORDERING AND ACCOUNTABILITY…………………………………....31 
5.4 
DASATINIB ACCOUNTABILITY………………………………………………….32 
5.5 
DESTRUCTION OF DASATINIB…………………………………………………..32 
5.6 
PACLITAXEL…………………………………………………………...…………...32 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................. 36 
6.1 
SUBJECT INCLUSION CRITERIA............................................................................ 36 
6.2 
SUBJECT EXCLUSION CRITERIA........................................................................... 36 
7.0 
RECRUITMENT PLAN........................................................................................................... 43 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 43 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................ 44 
9.1 
PHASE I STUDY……………………………………………………………………..42 
9.2 
PHASE II STUDY……………………………………………………………………44 
9.3 
CORRELATIVE STUDIES………………………………………………………….45 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ................................................ 50 
11.0 
TOXICITIES/SIDE EFFECTS ................................................................................................. 54 
11.1 
DASATINIB TOXICITY…………………………………………………………….51 
11.2 
PACLITAXEL TOXICITY…………………………………………………………..53 
11.3 
CHEMOTHERAPY DELAY………………………………………………………...53 
11.4 
DOSE MODIFICATION FOR PACLITAXEL……………………………………...53 
11.5 
DOSE MODIFICATION FOR DASATINIB………………………………………..54 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT....................... 58 
12.1 
PRIMARY ENDPOINT………………………………………………………………55 
12.2 
SECONDARY ENDPOINTS…………...……………………………………………55 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ........................................................................ 59 
14.0 
BIOSTATISTICS ..................................................................................................................... 60 
15.0 
RESEARCH PARTICIPANT REGISTRATION & RANDOMIZATION PROCEDURES .. 62 
15.1 
RESEARCH PARTICIPANT REGISTRATION......................................................... 62 
16.0 
DATA  MANAGEMENT......................................................................................................... 62 
16.1 
DATA AND SAFETY MONITORING ....................................................................... 62 
16.2 
REGULATORY DOCUMENTATION……………………………………………...60 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................... 63 
17.1 
PRIVACY ..................................................................................................................... 63 
17.2 
SERIOUS ADVERSE EVENT (SAE) REPORTING.................................................. 63 


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17.3 
SAFETY REPORTS ..................................................................................................... 64 
18.0 
INFORMED CONSENT PROCEDURES ............................................................................... 67 
19.0 
REFERENCE(S)....................................................................................................................... 67 
20.0 
APPENDICES .......................................................................................................................... 71 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This trial is phase I-II study of dasatinib in combination with weekly paclitaxel for patients with 
advanced and metastatic breast carcinoma. 
 
The phase I component of the study will be open to all patients with metastatic breast carcinoma, 
regardless of ER/PR/HER2 status and number and type of prior regimens. 
 
The phase II component will be open to patients with HER2 negative metastatic breast carcinoma, 
with 0-2 prior chemotherapeutic regimen for metastatic disease. Patients with ER/PR positive disease 
will be allowed to enter the study. 
 
 
Dasatinib  [SPRYCEL®]  is  a  potent,  broad  spectrum  ATP-competitive  inhibitor  of  5  critical 
oncogenic tyrosine kinase/kinase families: BCR-ABL, SRC, c-KIT, PDGF receptor β (PDGFRβ), and 
ephrin (EPH) receptor kinases, each of which has been linked to multiple forms of human 
malignancies. (1) 
 
Drug discovery and non-clinical pharmacology studies showed that dasatinib: 
 
 
Kills BCR-ABL dependent leukemic cell lines, including a number that are resistant to imatinib 
due to kinase domain mutations or overexpression of SRC family kinases and is effective against 
all imatinib-resistant kinase domain mutations tested to date, except T315I 
 
Inhibited proliferation of cancer cell lines that express activated SRC or c-KIT 
 
Potently inhibits VEGF-stimulated proliferation and migration in HUVECs 
 
Has potent bone anti-resorptive activity 
 
 
More specifically, recent data showed that dasatinib selectively inhibits growth of basal-type 
/ER/PR/HER2 negative breast cancer cell lines growing in vitro. 
 
Two phase II trials are currently ongoing to assess activity and safety of single agent dasatinib in 
patients with metastatic breast carcinoma ER/PR/HER2 negative (CA 180059) and ER/PR positive or 
HER2 positive (CA 180088). 
 
The combination of chemotherapy and dasatinib is currently being studied in patients with 
malignancies. This study will aim at defining the maximum tolerated dose (MTD), for the 
combination of weekly paclitaxel and dasatinib. 
 
Once established the MTD, the phase II portion of the study will aim at defining efficacy and safety 
of the combination in patients with HER2 negative metastatic breast carcinoma. 


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Efficacy endpoints will include overall response rate based upon RECIST response criteria, clinical 
benefit (CR+PR+SD > 6 months), time to tumor progression, progression free survival and duration 
of response. Toxicity will be evaluated in terms of a toxicity rate; the type, frequency, severity, 
timing and relationship of each toxicity will be determined as per the NCI Common Toxicity Criteria, 
version 
3. 
(Common 
Terminology Criteria for Adverse Events (CTCAE). Available at 
http://ctep.cancer.gov/forms/CTCAEv3.pdf) 
 
 
Eligible patients must have pathologically confirmed breast cancer, which is known to be metastatic 
or locally advanced. Patients must have at least one site of measurable disease using RECIST criteria 
(Appendix E). 
 
In the Phase I portion of the study, a standard three patient per cohort dose escalation scheme will be 
used, treating between 6 and 54 patients with dasatinib and a fixed dose of weekly paclitaxel. 
Dasatinib will be dose-escalated to determine the MTD using a standard, three-patient per cohort dose 
escalation schedule.  Between 6 and 54 patients will be required to determine the MTD of dasatinib. 
There will be no intrapatient dose escalation. The starting dose of dasatinib is 70 mg DAILY, given 
continuously (Dose level 0). Two dose reductions levels have been included, if necessary.  It is 
expected that the maximum of 54 patients will be enrolled in less than one year, between the two 
centers.  All patients within a cohort will be observed for toxicity for 4 weeks (1 cycle) prior to 
entering patients at the next dose level. 
 
Once the MTD for dasatinib has been identified, additional patients will be enrolled into the Phase II 
portion of the study to determine the efficacy and safety of dasatinib at the MTD when administered 
in combination with weekly paclitaxel.  Efficacy will be measured in terms of response rate assessed 
after 2 cycles of therapy.  Simon’s two-stage optimal design will be used to test the null hypothesis of 
a 15% response rate against the alternative of a 30% response rate.  Setting both the Type I and Type 
II errors at 10%, 23 patients will initially enter the study.  If there are 3 or fewer responses observed, 
the study will be terminated early and declared to have a negative result.  If 4 or more responses are 
observed, enrollment will be extended to 55 patients.  If > 12 responses are observed among the 55 
patients, the study will be considered to have a positive result and this regimen would be considered 
worthy of further testing.  For this design, the probability of early termination is 54% if the true 
response probability is < 10%.  Upon completion of the study, the true response rate will be estimated 
via the observed response rate and an exact confidence interval will be constructed. 
 
 
The maximum of 55 patients possible for the Phase II portion of this study is estimated to take one 
year to accrue with an anticipated enrollment of 5 patients per month between the two centers. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
The primary objectives of this trial are: 
 
Phase I Portion: To determine the MTD of dasatinib when administered in combination with 
a fixed dose of weekly paclitaxel. 


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Phase II Portion: To estimate efficacy (objective response rate; ORR; complete response
 
 
(CR) + partial response (PR)) of dasatinib when administered in combination with weekly paclitaxel 
at the MTD established during the phase I portion of this trial. 
 
The secondary objectives of this trial are: 
 
Phase I Portion: 
 
1.   To obtain preliminary data on the therapeutic activity of dasatinib when administered in 
combination with weekly paclitaxel. 
 
Phase II Portion: 
 
1.   To obtain safety and tolerability of dasatinib when administered in combination with weekly 
paclitaxel; 
2.   To estimate secondary efficacy endpoints of this combination including clinical benefit 
(CR+PR+SD > 6 months), time to tumor progression (TTP), progression free survival (PFS) 
and duration of response. 
3.   To obtain exploratory tumor biomarker data: assays of p-SRC, VEGFR2 and 
Collagen Type IV in plasma, obtained at baseline and after 2 cycles of treatment (8 
weeks), will be performed by enzyme-linked immunosorbent assay. 
4.   To perform analysis of mRNA expression on the tumor specimens, for a gene expression 
profiling of the responders versus non-responders, in order to identify potential predictors of 
response to dasatinib. If differentially interesting candidates emerge, immunohistochemistry 
assays including EphA2, IGFBP2, caveolin and phospho-caveolin and other potential 
predictive markers and SFK substrates as available will also be performed. 
5.   To collect circulating tumor cells (CTC) at baseline and after 2 cycles of treatment (8 
weeks); 
 
3.0       BACKGROUND AND RATIONALE 
 
3.1 
Metastatic Breast Cancer 
 
Cancer of the breast is one of the most common life-threatening malignancies occurring in women. In 
2007, an estimated 178,480 new cases of invasive breast cancer will be diagnosed in the United 
States and despite advances in early detection, surgery and adjuvant therapy, a significant number of 
women are expected to die of metastatic breast cancer. (2) Unlike early stage breast cancer, metastatic 
breast cancer is generally not curable with currently available therapy. (3) To date, the five-year 
survival rate for women with distant metastases is only 21%, underscoring the need for more 
efficacious therapeutic options for the advanced stages of this disease.  When metastatic disease is 
diagnosed, the goals of treatment are multiple, including cure (<5%), palliation of symptoms and 
improved survival. Hormonal therapy is usually the first-line treatment of choice for those women 
with hormone receptor-positive cancer but eventually nearly all patients develop hormone refractory 


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disease.  For  these  women,  and  for  those  with  hormone  receptor-negative  disease,  cytotoxic
 
 
chemotherapy is utilized. 
Today there are several classes of cytotoxic treatment available to patients with metastatic disease 
(eg, anthracyclines, taxanes, fluoropyrimidines, vinca alkaloids, topoisomerase inhibitors). A 
treatment paradigm of sequential single agent therapy is practiced in this disease of chronicity. 
 
Newly introduced hormonal, cytotoxic and biologically targeted agents are hoped to improve upon 
the modest survival advantage with systemic therapy for these women. 
 
3.2 
Dasatinib 
 
 
Dasatinib [SPRYCEL®] is a potent, broad spectrum ATP-competitive inhibitor of 5 critical oncogenic 
tyrosine kinase/kinase families: BCR-ABL, SRC, c-KIT, PDGF receptor β (PDGFRβ), and ephrin 
(EPH) receptor kinases, each of which has been linked to multiple forms of human malignancies. (1) 
 
Drug discovery and nonclinical pharmacology studies showed that dasatinib: (4) 
 
 
Kills BCR-ABL dependent leukemic cell lines, including a number that are resistant to imatinib 
due to kinase domain mutations or overexpression of SRC family kinases and is effective against 
all imatinib-resistant kinase domain mutations tested to date, except T315I 
     Inhibited proliferation of cancer cell lines that express activated SRC or c-KIT 
     Potently inhibits VEGF-stimulated proliferation and migration in HUVECs 
     Has potent bone anti-resorptive activity 
 
3.2.1 
Pre-clinical Anti-tumor Activity: In Vitro Molecular Studies 
 
Dasatinib potently inhibits: SRC kinases, BCR-ABL, c-KIT, PDGFRβ and EPHA and was less potent 
against 16 other unrelated protein tyrosine kinases (PTKs) and serine/threonine kinases. Imatinib is 
less potent against several key enzymes: for example, Dasatinib was 260-, 8-, 60-, and >1000-fold 
more potent than imatinib versus BCR-ABL, c-KIT, PDGFR, and SRC kinases, respectively.2 
 
In  vitro,  dasatinib  was  active  in  leukemic  cell  lines  representing  variants  of  imatinib  mesylate 
sensitive and resistant disease. dasatinib inhibited the growth of chronic myeloid leukemia (CML) 
and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions 
of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase 
domain  mutations,  activation  of alternate signaling pathways  involving  the SRC  family kinases 
(LYN, HCK), and multi-drug resistance gene overexpression. (1) 
 
Dasatinib inhibits the BCR-ABL kinase with an in vitro IC50 of 3 nM, a potency 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 anti-tumor activity against several preclinically- and clinically-derived 
models of imatinib mesylate resistance. Evidence that SRC family kinase over expression may play a 
role in clinical resistance to imatinib mesylate was demonstrated in three CML cell lines established 


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from patients who failed imatinib mesylate therapy. These cells remained highly sensitive to the 
cell-killing effects of dasatinib. 
 
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 cells, dasatinib inhibited c-SRC, and other kinases in the SRC kinase family (including LCK, YES, 
FYN) at sub-nanomolar concentrations. Dasatinib inhibited the cellular SRC 
autophosphorylation in several cancer cell lines that highly express c-SRC, including the 
human prostate carcinoma cells PC3 and MDA-PCa-2b, and the human colon carcinoma 
cells WiDr and SW-480. 
 
The concentrations required to inhibit SRC autophosphorylation in these cells (15 - 135 nM) 
approximate those needed for inhibition of cellular proliferation (range = 17 - 845 nM, 
median = 35 nM, n = 10). 
 
Dasatinib demonstrated potent antiproliferative activity for VEGF- or bFGF-dependent 
human umbilical vein endothelial cells (HUVEC). An IC50 of 43 nM against 
VEGF-stimulated growth and of 248 nM under bFGF-driven growth conditions was 
demonstrated. Dasatinib also inhibited HUVEC cell migration with IC50 of < 5 nM in a 
standard in vitro cell migration assay (Boyden chamber). 
 
SRC kinase plays a major role in osteoclast function. In short-term in vitro studies, dasatinib 
was a potent inhibitor of bone resorption. Dasatinib also potently inhibits KIT, the receptor 
tyrosine kinase for the natural cognate ligand stem-cell factor (SCF), also known as Steel 
factor (SLF); constitutive activation of KIT is a critical oncogenic contributing factor to the 
malignant phenotype of the sarcoma known as Gastrointestinal Stromal Tumor (GIST). 
In an in vitro biochemical assay, dasatinib inhibited KIT with an IC50 of 22 nM, while the IC50 
for imatinib mesylate was 169 nM, an 8-fold difference. 
 
In three small cell lung cancer cell lines (NCI-H59, H526 and H187) that are dependent on 
SCF for proliferation, dasatinib inhibited SCF-driven proliferation with IC50 in the range of 
114 - 220 nM. In the same study, the IC50 for imatinib mesylate was 1150 - 2270 nM, a 
difference in potency of about 10-fold. The concentration range of dasatinib required to 
inhibit KIT phosphorylation in cells (10 - 1000 nM) was in agreement with that needed for 
inhibiting cellular proliferation. 
 
3.2.2 Preclinical Toxicology 
 
 
Single or repeated oral administration of dasatinib principally affected the gastro-intestinal (GI) tract, 
including the liver, the 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 


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doses, and cutaneous hemorrhage in monkeys.  Dasatinib can also affect the immune system and bone 
turnover. 
 
 
 
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, respirations 
and heart rate, blood pressure, or arterial oxygen saturation in single-dose, 10-day, or 1-month oral 
toxicity studies in monkeys. 
 
Dasatinib was found to exhibit a profile of broad-spectrum platelet inhibition best typified by anti- 
platelet 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. This effect could potentially result in an increase in bone mineral density and a 
phenotype analogous to osteopetrosis.(4) 
 
 
3.2.3 In Vivo Studies of Dasatinib in Breast Cancer 
 
An artificial Src-driven cell line “mamSRC” was developed which is sensitive to 
dasatinib in vitro with IC50 = 3.2 nM; sensitivity in vivo was striking: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Of 35 breast cancer cell lines, 11 were sensitive in vitro to dasatinib (defined as IC50 
< 1µM); as will be indicated in Section 3.5.1, these were predominantly those of basal-like 
subtype. Well-tolerated regimens of oral dasatinib, typically administered BID on a 5-day 


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per week schedule to immunodeficient mice bearing xenograft tumors, provided growth 
inhibition of 32 - 87%, depending on the cell line. Additional studies are in progress. 
 
 
 
3.2.4 Results of Clinical Investigations 
 
Dasatinib was initially developed in patients with imatinib-resistant or –intolerant CML. A 
Phase I trial CA180002 was completed (see Section 3.2.7.1) and identified 70 mg twice 
daily (BID) as a safe starting dose for CML patients. (5) Subsequent Phase II trials were 
performed in all phases of imatinib-resistant and imatinib-intolerant CML to assess the 
efficacy and safety of dasatinib. (9-13) Data were submitted for regulatory 
review, leading to approval of dasatinib in the U.S. Two randomized phase III studies 
(CA1800034 and CA1800035) were performed to compare efficacy and safety of daily vs 
BID schedules in all phases of CML and of total daily dose in chronic phase CML . 
Two Phase I trials are in progress in patients with recurrent or progressive solid tumors, one 
(CA180003) using a BID and one (CA180021) using a daily schedule. 
 
3.2.5 Pharmacokinetics of Dasatinib 
 
The pharmacokinetics of dasatinib have been evaluated in 229 healthy subjects and in 137 patients 
with leukemia (CML or Ph+ALL) from a Phase I clinical study (CA180002). (4) 
 
Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) 
following oral administration. dasatinib exhibits dose proportional increases in AUC and linear 
elimination characteristics over the dose range of 15 mg to 240 mg/day. The overall mean terminal 
half-life of dasatinib is 3–5 hours. (1) 
 
Data from a study of 54 healthy subjects administered a single, 100-mg dose of dasatinib 30 minutes 
following consumption of a high-fat meal resulted in a 14% increase in the mean AUC of dasatinib. 
The observed food effects were not clinically relevant. 
 
In patients, dasatinib has an apparent volume of distribution of 2505 L, suggesting that the drug is 
extensively distributed in the extravascular space. Binding of dasatinib and its active metabolite to 
human plasma proteins in vitro was approximately 96% and 93%, respectively, with no concentration 
dependence over the range of 100–500 ng/mL. (1) 
 
Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. 
CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. Flavin- 
cotaining monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferase (UGT) 
enzymes are also involved in the formation of dasatinib metabolites. In human liver microsomes, 
dasatinib was a weak time-dependent inhibitor of CYP3A4. 
 
The exposure of the active metabolite, which is equipotent to dasatinib, represents approximately 5% 
of the dasatinib AUC. This indicates that the active metabolite of dasatinib is unlikely to play a major 
role in the observed pharmacology of the drug. Dasatinib also had several other inactive oxidative 
metabolites. 


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Dasatinib is a time-dependent inhibitor of CYP3A3. At clinically relevant concentrations, dasatinib 
does not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 2E1. Dasatinib is not an inducer of human 
CYP enzymes. (1) 
Elimination is primarily via the feces. Following a single oral dose of [14C]-labeled dasatinib, 
approximately 4% and 85% of the administered radioactivity was recovered in the urine and feces, 
respectively, within 10 days. Unchanged dasatinib accounted for 0.1% and 19% of the administered 
dose in urine and feces, respectively, with the remainder of the dose being metabolites. (1) 
 
 
3.2.6 Pharmacodynamics of Dasatinib 
 
Src phosphorylation was studied in peripheral blood mononuclear cells (PBMC) and 
xenograft tumors (prostate cancer cell line PC3) of mice. Phospho-Src inhibition was 
> 90% both in PBMC and in tumor at doses ≥ 15 mg/kg, and correlated closely with 
tumor growth inhibition. 
 
Doses of ~200 mg provide plasma concentrations in human subjects comparable to 
15 mg/kg in mouse (Cmax ~150 - 200 ng/mL). The in vitro dose-response curve for 
phospho-Src inhibition is the same in PBMC of human and mouse. In human PBMC, 
60 - 80% inhibition of phospho-Src persisted for at least 6 - 8 hours after doses of 
≥ 70 mg; inhibition of tumor SFKs has not been measured in humans. 
 
3.2.6.1 
Somatic Mutations and Response to Dasatinib-Paclitaxel Drug 
Combination 
 
In lung cancers models and patients, activating somatic mutations of the Discoidin Domain Receptor 
2 (DDR2) gene were shown to be both oncogenic and associated with high sensitivity to dasatinib as 
single agent (Hammerman et al, Cancer Discov 2011). DDR2 is receptor tyrosine kinase that binds 
collagen as its endogenous ligand and is mutated in about 3% of squamous cell lung carcinomas. A 
paralog gene, DDR1, also exists. DDR2 mutations have been shown to be present in breast cancer at 
a frequency of 1 to 2%, according to data from The Cancer Genome Atlas (TCGA). 
 
Somatic  genomic  analyses,  based  on  next-generation  sequencing  (NGS)  techniques  applied  to 
archival breast cancer tissue samples and/or on plasma (circulating tumor DNA) can unravel the 
somatic mutation(s) associated with sensitivity to the tested treatment regimen. This approach can be 
used not only to investigate the existence of both known (e.g. DDR2) mutations, but also for the 
identification of novel mutations related to sensitivity or resistance to a given therapy. 
 
3.2.7 Experience in CML 
 
Dasatinib has been administered to more than 2000 subjects, the majority with CML 
refractory or intolerant to imatinib. Dasatinib’s activity has been investigated in eight 
Phase 1 studies (CA180009, CA180016, CA180019, CA180020, CA180022, CA180032, 
CA180037, and CA180002) and five Phase 2 studies (CA180005, CA180006, 


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CA180013, CA180015, and CA180017) that supported the approved indication and 
dosage of dasatinib at 70 mg BID in subjects with CML or Ph+ ALL.(4) Two Phase 3 
studies (CA1800034 and CA180035) were designed to compare alternate doses and 
administration schedules in imatinib resistant or intolerant subjects with chronic, 
accelerated, or blast phase CML or Ph+ ALL. 
 
 
Four single-arm multicenter studies were conducted to determine the efficacy and safety of dasatinib 
in patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) 
resistant to or intolerant of treatment with imatinib. All patients were treated with dasatinib 70 mg 
BID on a continuous basis. The median durations of treatment was between 2.8 - 5.6 months. 
 
The primary efficacy endpoint in chronic phase CML was major cytogenetic response (MCyR), 
defined as elimination (complete cytogenetic response, CCyR) or substantial diminution (by at least 
65%, partial cytogenetic response) of Ph+ hematopoietic cells. The primary endpoint in accelerated 
phase, myeloid blast phase, and lymphoid blast phase CML, and Ph+ ALL was major hematologic 
response (MaHR), defined as either a complete hematologic response or no evidence of leukemia as 
defined in the table below. 
 
Additional information from all these studies may be found in the Investigator Brochure and 
in FDA-approved drug labeling. (4) 


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Table 1: 
Efficacy in Dasatinib Clinical Studies in CML and Ph+ ALL (All Treated Populations)a 
 
Hematologic Response Ra
Chronic 
(n=186) 
Accelerated 
(n=107) 
Myeloid 
Blast 
(n=74) 
Lymphoid 
Blast 
(n=42) 
Ph+ ALL 
(n=36) 
b 
te   (%) 
MaHR (95% CI) 
n/a 
59 (49–68) 
32 (22–44) 
31 (18–47) 
42 (26–59) 
CHR (95% CI) 
90 (85–94) 
33 (24–42) 
24 (15–36) 
26 (14-42) 
31 (16–48) 
NEL (95% CI) 
n/a 
26 (18–36) 
8 (3–17) 
5 (0.6–16) 
11 (3.1–26) 
Cytogenetic Respon c 
se  (%) 
MCyR (95% CI) 
45 (37–52) 
31 (22–41) 
30 (20–42) 
50 (34–66) 
58 (41–74) 
CCyR (95% CI) 
33 (26–40) 
21 (14–30) 
27 (17–39) 
43 (28–59) 
58 (41–74) 
a 
Numbers in bold font are the results of primary endpoint. 
b 
Hematologic response criteria (all responses confirmed after 4 weeks): 
Major hematologic response: (MaHR) = complete hematologic response (CHR) + no evidence of leukemia (NEL). 
CHR (chronic CML): WBC  institutional ULN, platelets <450,000/mm3, no blasts or promyelocytes in peripheral blood, <5% myelocytes 
plus metamyelocytes in peripheral blood, basophils in peripheral blood  institutional ULN, and no extramedullary involvement. 
CHR (advanced CML/Ph+ ALL):  WBC  institutional ULN, ANC 1000/mm3, platelets ≥100,000/mm3, no blasts or promyelocytes in 
peripheral blood, bone marrow blasts 5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood 
institutional ULN, and no extramedullary involvement. 
NEL: same criteria as for CHR but ANC 500/mm
3 and <1000/mm3, and/or platelets 20,000/mm
3 and 100,000/mm
3. 
c 
Cytogenetic response criteria: complete (0% Ph+ metaphases) or partial (>0%–35%). MCyR (0%–35%) combines both complete and partial 
responses. 
 
n/a = not applicable. 
 
3.2.7.1 Safety of Dasatinib in Clinical Studies in CML and Ph+ ALL 
 
The data presented in Table 2 reflect exposure to dasatinib in 2182 patients with leukemia in clinical 
studies (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice 
daily). The median duration of therapy was 11 months (range 0.03–26 months). 
 
The majority of dasatinib-treated patients experienced adverse reactions at some time. Drug was 
discontinued for adverse reactions in 9% of patients in chronic phase CML, 10% in accelerated phase 
CML, 15% in myeloid blast phase CML, and 8% in lymphoid blast phase CML or Ph+ ALL. In a 
Phase 3 dose-optimization study in patients with chronic phase CML, the rate of discontinuation for 
adverse reaction was lower in patients treated with 100 mg once daily than in patients treated with 70 
mg twice daily (4% and 12%, respectively). 
 
The most frequently reported adverse reactions (reported in ≥20% of patients) included fluid retention 
events, diarrhea, headache, skin rash, nausea, hemorrhage, fatigue, and dyspnea. 
 
The most frequently reported serious adverse reactions included pleural effusion (9%), pyrexia (3%), 
pneumonia (3%), infection (2%), febrile neutropenia (4%), gastrointestinal bleeding (4%), dyspnea 
(3%), sepsis (1%), diarrhea (2%), congestive heart failure (2%), and pericardial effusion (1%). 


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All adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of the 
patients in dasatinib clinical studies are shown in Table 2. (4) 
 
 
Table 2: 
Adverse Reactions Reported in ≥10% of All Patients (All 
Grades) in Clinical Studies 
Preferred Term 
All Patients 
(n=2182) 
Chronic 
a 
Phase 
(n=1150) 
Accelerated 
Phase 
(n=502) 
Myeloid 
Blast Phase 
(n=280) 
Lymphoid 
Blast Phase 
and 
Ph+ ALL 
(n=250) 
All 
Grades 
Grades 
3/4 
Grades 
3/4 
Grades 
3/4 
Grades 
3/4 
Grades 
3/4 
Percent (%) of Patients 
Fluid Retention 
37 
8 
6 
7 
13 
7 
Superficial localized edema 
20 
<1 
<1 
1 
1 
<1 
Pleural effusion 
22 
5 
4 
5 
10 
6 
Other fluid retention 
10 
3 
3 
3 
6 
2 
Generalized edema 
3 
<1 
<1 
1 
<1 
1 
Congestive heart 
b 
failure/cardiac dysfunction 
2 
1 
2 
<1 
2 
1 
Pericardial effusion 
3 
1 
1 
1 
2 
0 
Pulmonary edema 
2 
1 
1 
1 
1 
1 
Ascites 
<1 
<1 
0 
0 
1 
<1 
Pulmonary hypertension 
1 
<1 
<1 
0 
1 
1 
Diarrhea 
31 
3 
3 
4 
5 
4 
Headache 
24 
1 
1 
1 
1 
2 
c 
Skin Rash 
22 
1 
1 
1 
1 
1 
Nausea 
22 
1 
1 
1 
2 
2 
Hemorrhage 
21 
6 
2 
11 
12 
8 
Gastrointestinal bleeding 
7 
4 
1 
8 
9 
5 
CNS bleeding 
1 
<1 
0 
<1 
<1 
2 
Fatigue 
21 
2 
2 
3 
1 
2 
Dyspnea 
20 
4 
5 
4 
5 
2 
Musculoskeletal Pain 
14 
1 
2 
1 
1 
<1 
Pyrexia 
13 
1 
1 
2 
3 
1 


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Table 2: 
Adverse Reactions Reported in ≥10% of All Patients (All 
Grades) in Clinical Studies 
Preferred Term 
All Patients 
(n=2182) 
Chronic 
a 
Phase 
(n=1150) 
Accelerated 
Phase 
(n=502) 
Myeloid 
Blast Phase 
(n=280) 
Lymphoid 
Blast Phase 
and 
Ph+ ALL 
(n=250) 
All 
Grades 
Grades 
3/4 
Grades 
3/4 
Grades 
3/4 
Grades 
3/4 
Grades 
3/4 
Percent (%) of Patients 
Vomiting 
13 
1 
1 
1 
1 
2 
Abdominal Pain 
10 
1 
1 
<1 
1 
2 
a The chronic phase data include patients prescribed any dose of SPRYCEL. 
 
b Includes left ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, 
diastolic dysfunction, ejection fraction decreased, and ventricular failure. 
c Includes erythema, erythema multiforme, exfoliative rash, generalized erythema, heat rash, milia, rash, rash erythematous, 
rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, 
skin irritation, systemic lupus erythematosus rash, urticaria vesiculosa, and rash vesicular. 
 
In the Phase 3 dose-optimization study in patients with chronic phase CML, the median duration of 
therapy was approximately 12 months (range <1-20 months). Selected adverse reactions are shown 
by dose regimen in Table 3. (4) 
 
 
 
Table 3: 
Selected Adverse Reactions Reported in Phase 3 Dose- 
Optimization Study (Chronic Phase CML) 
Preferred Term 
100 mg daily 
(n=165) 
140 mg daily
a 
(n=163) 
50 mg BID
a 
(n=167) 
70 mg BID
a 
(n=167) 
All 
Grades 
Grades 
3/4 
All 
Grades 
Grades 
3/4 
All 
Grades 
Grades 
3/4 
All 
Grades 
Grades 
3/4 
Percent (%) of Patients 
Diarrhea 
23 
1 
26 
3 
26 
3 
25 
4 
Fluid Retention 
24 
2 
33 
4 
27 
4 
32 
5 
Superficial localized edema 
14 
0 
14 
1 
14 
0 
16 
0 
Pleural effusion 
10 
2 
20 
2 
16 
3 
18 
2 
Generalized edema 
2 
0 
3 
0 
0 
0 
1 
0 
Congestive heart 
b 
failure/cardiac dysfunction 
0 
0 
2 
1 
1 
1 
4 
2 


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Table 3: 
Selected Adverse Reactions Reported in Phase 3 Dose- 
Optimization Study (Chronic Phase CML) 
Preferred Term 
100 mg daily 
(n=165) 
140 mg daily
a 
(n=163) 
50 mg BID
a 
(n=167) 
70 mg BID
a 
(n=167) 
All 
Grades 
Grades 
3/4 
All 
Grades 
Grades 
3/4 
All 
Grades 
Grades 
3/4 
All 
Grades 
Grades 
3/4 
Percent (%) of Patients 
Pericardial effusion 
1 
1 
4 
1 
2 
1 
2 
1 
Pulmonary edema 
0 
0 
0 
0 
1 
0 
2 
1 
Pulmonary hypertension 
0 
0 
0 
0 
0 
0 
1 
1 
Hemorrhage 
10 
1 
12 
1 
9 
2 
14 
2 
Gastrointestinal bleeding 
1 
1 
2 
0 
4 
2 
4 
2 
a Not a recommended starting dosage of Sprycel for chronic phase CML. 
 
b Includes left ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, 
diastolic dysfunction, ejection fraction decreased, and ventricular failure. 
 
 
3.2.7.2 Laboratory Abnormalities 
 
Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 
neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML or Ph+ 
ALL than in chronic phase CML (Table 4). Myelosuppression was reported in patients with normal 
baseline laboratory values as well as in patients with pre-existing laboratory abnormalities. 
 
In patients who experienced severe myelosuppression, recovery generally occurred following dose 
interruption or reduction; permanent discontinuation of treatment occurred in 1% of patients. 
 
Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia and 
hypophosphatemia were reported in patients with all phases of CML but were reported with an 
increased frequency in patients with myeloid or lymphoid blast phase CML and Ph+ ALL. Elevations 
in transaminase or bilirubin were usually managed with dose reduction or interruption. Patients 
developing Grade 3 or 4 hypocalcemia during the course of dasatinib therapy often had recovery with 
oral calcium supplementation.  In the Phase 2 randomized study, the frequency of Grade 3 or 4 
neutropenia, thrombocytopenia, and anemia was 63%, 56%, and 19%, respectively, in the dasatinib 
group and 39%, 14%, and 8%, respectively, in the imatinib group.  The frequency of Grade 3 or 4 
hypocalcemia was 4% in the dasatinib group and 0% in the imatinib group. Laboratory abnormalities 
reported in the Phase 3 dose-optimization study in patients with chronic phase CML are shown in 
Table 5. 


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Table 4: 
CTC Grades 3/4 Laboratory Abnormalities in Clinical 
Studies 
a 
Chronic Phase 
(n=1150) 
Accelerated 
Phase 
(n=502) 
Myeloid Blast 
Phase (n=280) 
Lymphoid Blast 
Phase and Ph+ 
ALL (n=250) 
Percent (%) of Patients 
Hematology Parameters 
Neutropenia 
46 
68 
80 
78 
Thrombocytopenia 
41 
71 
81 
78 
Anemia 
18 
55 
75 
45 
Biochemistry Parameters 
Hypophosphatemia 
10 
12 
19 
20 
Hypocalcemia 
2 
7 
16 
11 
Elevated SGPT (ALT) 
1 
3 
6 
7 
Elevated SGOT (AST) 
1 
1 
4 
5 
Elevated Bilirubin 
1 
1 
4 
5 
Elevated Creatinine 
1 
2 
3 
1 
a The chronic phase data include patients prescribed any dose of SPRYCEL. 
 
CTC grades: neutropenia (Grade 3 ≥0.5–1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombocytopenia (Grade 3 ≥10–50 × 109/L, 
Grade 4 <10 × 109/L); anemia (hemoglobin ≥65–80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of 
normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 x ULN); elevated SGOT or 
SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN); hypocalcemia (Grade 3 <7.0-6.0 mg/dL, Grade 4 <6.0 mg/dL); 
hypophosphatemia (Grade 3 <2.0-1.0 mg/dL, Grade 4 <1.0 mg/dL). 
 
 
 
Table 5: 
CTC Grades 3/4 Laboratory Abnormalities in Phase 3 
Dose-Optimization Study (Chronic Phase CML) 
100 mg daily 
(n=165) 
140 mg daily
a 
(n=163) 
50 mg BID
a 
(n=167) 
70 mg BID
a 
(n=167) 
Percent (%) of Patients 
Hematology Parameters 
Neutropenia 
34 
43 
46 
43 
Thrombocytopenia 
22 
40 
34 
38 
Anemia 
10 
19 
18 
17 
Biochemistry Parameters 


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Table 5: 
CTC Grades 3/4 Laboratory Abnormalities in Phase 3 
Dose-Optimization Study (Chronic Phase CML) 
100 mg daily 
(n=165) 
140 mg daily
a 
(n=163) 
50 mg BID
a 
(n=167) 
70 mg BID
a 
(n=167) 
Percent (%) of Patients 
Hypophosphatemia 
8 
6 
7 
7 
Hypocalcemia 
2 
3 
1 
2 
Elevated SGPT (ALT) 
0 
1 
1 
1 
Elevated SGOT (AST) 
1 
1 
0 
0 
Elevated Bilirubin 
1 
2 
0 
1 
Elevated Creatinine 
0 
1 
0 
1 
a Not a recommended starting dosage of SPRYCEL for chronic phase CML. 
 
CTC grades: neutropenia (Grade 3 ≥0.5–1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombocytopenia (Grade 3 ≥10–50 × 109/L, 
Grade 4 <10 × 109/L); anemia (hemoglobin ≥65–80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of 
normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 x ULN); elevated SGOT or 
SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN); hypocalcemia (Grade 3 <7.0-6.0 mg/dL, Grade 4 <6.0 mg/dL); 
hypophosphatemia (Grade 3 <2.0-1.0 mg/dL, Grade 4 <1.0 mg/dL). 
 
 
 
3.2.8 Phase I-II experience in Solid Tumors 
 
In  a  Phase  I  study  (CA180003)  conducted  by  Bristol  Myers  Squibb  (BMS),  dasatinib  was 
administered on a BID schedule to 42 subjects with refractory solid tumor. As of 10-Feb-2006, 33 
subjects were treated for a full 4 weeks for evaluation of dose-limiting toxicities (DLTs). This study 
explored 8 dose levels with 2 different dosing schedules. The first schedule assessed 5 days of 
dasatinib followed by 2 days off-drug each week, and the second schedule assessed continuous daily 
dosing that was added in Amendment #3 (7-Mar-2005). In the 5 days on/2 days off schedule, the 
following dose levels were explored: 35 mg BID, 50 mg BID, 70 mg BID, 90 mg BID, 120 mg BID 
and 160 mg BID. Of the six subjects enrolled and evaluable for DLT determination at the dose level 
of 90 mg BID given on a continuous daily schedule, two episodes were considered possibly to 
represent DLT reported by 2 subjects. These were recurrent Grade 2 rash in 1 subject and removal 
from study for Grade 2 nausea and vomiting and lightheadedness in the other subject. Given the 
otherwise acceptable tolerability of this dose level with toxicities that are medically manageable with 
a maximum severity of Grade 2, further escalation to the next dose level of 120 mg BID continuous 
daily schedule is currently under investigation. No further escalation above 160 mg BID was explored 
on this schedule because, as per protocol, this represents the maximum tolerated dose (MTD). (4) 
 
The preliminary safety results from CA180003 demonstrate that no severe clinical toxicity has been 
encountered. Dasatinib did not induce significant myelosuppression in this patient population 
Gastrointestinal symptoms including nausea and vomiting were reported in most subjects, fatigue was 


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reported in 17 subjects (40%) and rash in 9 subjects (21%). Edema, lethargy and headache were 
uncommon, and appear to be dose-related. Additionally, the incidence and severity of fluid retention 
and of pleural effusion, in particular, appear to be less in subjects with solid tumors than in those with 
leukemia receiving comparable doses of dasatinib. There were 4 subjects with drug-related AEs 
leading to discontinuation; none of these events were related to myelosuppression or fluid retention. 
(4) 
 
In another Phase I study (CA180021), dasatinib was administered on a daily schedule to 24 subjects 
with solid tumors in a drug-drug interaction and multi-ascending dose (MAD) study at doses up to 
180 mg. This ongoing study investigated the effect of ketoconazole, a potent inhibitor of CYP3A4, on 
the PK of dasatinib (Segment 1) and the effect of dasatinib on pharmacodynamic markers in subjects 
with advanced solid tumors that are refractory to standard therapies or for which no standard therapy 
exists (Segment 2). 
 
Segment 1 includes 18 subjects, of which 16 subjects were treated with dasatinib as of 2-Jan-2006. 
Segment 2 includes approximately 30 additional subjects, of which 14 subjects were treated with 
dasatinib as of 2-Jan-2006. A total of 4 deaths, all related to disease progression, were reported. There 
were 4 subjects with drug-related AEs leading to discontinuation: 1 subject with Grade 1 amnesia, 1 
with Grade 2 pleural effusion, 1 with Grade 3 dehydration, and 1 subject with Grade 3 dysphagia and 
Grade 3 dehydration.  Hypocalcemia, GI symptoms and skin rash have been mild and infrequent. (4) 
 
To date, the safety profile in solid tumor subjects has been similar to that in CP CML subjects with 
the exception of severe myelosuppression, which has not been observed in solid tumor subjects and is 
considered related to efficacy against the leukemia as noted above, and severe bleeding which is 
secondary to thrombocytopenia in most instances. (4) 
 
Two phase II trials are currently ongoing to assess activity and safety of single agent dasatinib in 
patients with metastatic breast carcinoma ER/PR/HER2 negative (CA 180059) and ER/PR positive or 
HER2 positive (CA 180088). Starting dose of dasatinib is 100 mg BID with continuous dosing, 
which was considered to be safe, based on data from the phase I experience. 
In the ongoing Phase II trials however, suboptimal tolerance was observed at the dose of 100 mg 
BID, in terms of gastro-intestinal toxicity including nausea and vomit, and fluid retention, including 
pleural and pericardial effusions, prompting reduction to 70 mg BID with continuous dosing as 
starting dose. (Bristol Myers Squibb, data on file). 
 
3.3 
Paclitaxel 
 
Paclitaxel is a taxane originally derived from the bark of the of the Pacific yew tree 
(Taxus brevifolia) and is one of the most active agents against breast cancer. Paclitaxel 
binds to the dimeric tubulin preventing microtubule disassembly by stabilizing 
microtubules so that the spindle cannot be dismantled. This microtubule disruption halts 
mitosis, interferes with other critical interphase functions and subsequently leads to cell 
death. (6) 


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Taxanes (docetaxel and paclitaxel) like many chemotherapy drugs are known to have 
anti-angiogenic activity. Paclitaxel has been shown to inhibit endothelial cell 
proliferation, migration and tubule formation at concentrations lower than required to 
induce tumor cell kill. (7) In vivo testing demonstrated that murine microvasculature 
was significantly decreased by treatment with paclitaxel. 
 
Taxanes are indicated in several cancers but the most impressive activity of the taxanes has 
been seen in patients with ovarian and breast cancers. In metastatic breast cancer, 
paclitaxel is often indicated after failure of anthracycline based combination chemotherapy. 
The weekly schedule of paclitaxel has been proven to offer the best efficacy/tolerability ratio, 
when compared to the q 3-weekly schedule in randomized trials. (8) . 
 
As monotherapy, paclitaxel showed to induce response rates ranging from 20 - 50 % in 
earlier studies in breast cancer patients. (8,9) However, more recent randomized trials have 
reported more modest response rates, in the range of 14-16%, likely due to the fact that 
nowadays patients are receiving overall more chemotherapy in the adjuvant setting, and the 
overall likelihood of response to therapy in the metastatic setting might result diminished. 
(10, 11) 
 
Neutropenia and neuropathy are the two most common significant toxicities of paclitaxel. 
The onset of neutropenia usually occurs on days 8 to 10, with recovery generally 
complete by days 15 to 21 in every 3 week dosing regimens at doses of 175 to 200 mg/m2 
over 3 or 24 hours intravenous infusion. More frequent administration schedules, 
particularly weekly treatment with doses of 80 to 100 mg/m2, are associated with less 
severe neutropenia and equivalent antitumor activity in a number of cancers, when 
compared to the every 3 week schedule. In the CALGB 9840 study (weekly paclitaxel 
given as 1-hour infusion v standard 3-hour infusion of paclitaxel every third week in the 
treatment of metastatic breast cancer, with trastuzumab for HER2 positive patients) the 
administration of paclitaxel in the weekly schedule caused less grade 3 neutropenia 
compared to the every 3 week administration regimen (8% v 15%, p = 0.013), but more 
grade 3 sensory/motor neuropathy (23/8% v 12/4%, p = 0.001/0.04). (8) 
 
3.4 
Study Rationale: Dasatinib in Combination with Paclitaxel 
 
 
Taxanes, including paclitaxel, are very active agents in the treatment of breast cancer, and have 
shown clinical benefit both in the metastatic and adjuvant setting. (8, 12) The combination of taxanes 
with biologic agents is particularly appealing in the treatment of breast cancer and has shown 
significant results in a number of clinical trials. (13, 14) 
 
Dasatinib has shown to inhibit proliferation of numerous solid tumor cell lines that expressed 
activated SRC or c-KIT, including breast, prostate, lung, colon carcinoma and rhabdomyosarcoma 
cell lines. In human prostate carcinoma xenografts, the combination of dasatinib and paclitaxel 
produced antitumor effects against that were significantly better than the effects of either single agent 
alone (P = 0.05). (15) 


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More specifically, recent data showed that dasatinib selectively inhibits growth of basal-type 
/ER/PR/HER2 negative breast cancer cell lines growing in vitro. (16) Bristol-Myers Squibb (BMS) 
has developed promising pharmacogenomic markers of response to dasatinib in preclinical models of 
cancer. Using in vitro assays, 7 of 23 well-characterized breast cancer cell lines were shown to be 
relatively sensitive to dasatinib (IC50 ≤ 1µM). It was noted that these were predominantly those 
known to be of ‘basal-like’ subtype. Pharmacogenomic analysis demonstrated a 161-gene subset that 
correlated with growth inhibition by dasatinib. Several genes in this subset were shown to be 
modulated in vitro by exposure to dasatinib. The existence of this expression-defined gene subset was 
demonstrated in a large number of patient samples and found to consist largely of ‘triple-negative’ 
cancers. Similar results, i.e. identification of the triple-negative subtype as that likely inhibited by 
dasatinib, were obtained independently and using somewhat different methodologies by investigators 
both at UCLA and at Duke. (16) 
 
 
We identified patterns of gene expression from these human breast cancer specimens. Total RNA was 
isolated from these biopsies using TRIzol reagent, and double-stranded cDNA was synthesized by a 
chimeric oligonucleotide with oligo-dT and a T7 RNA polymerase promoter. Reverse transcription 
was carried out followed by biotin labeling and approximately 250-fold linear amplification by in 
vitro transcription followed by pre-hybridization, hybridization, washing, and staining with 
streptavidin-phycoerthyrin. The labeled cRNA was hybridized to the Affymetrix U133A GeneChipTM 
(Santa Clara, CA), which contains an array of 45,000 probe sets with more than 39,000 human genes. 
These confirmed differences in gene expression will be validated by relative quantitative reverse 
transcription polymerase chain reaction (q-RTPCR) assays. Over 100 ER-negative primary breast 
cancers has been molecularly profiled, and their gene expression profiles and DNA snp haplotypes 
compared to normal breast epithelial (n=50) profiles to accurately refine ER- tumors into clinical 
useful subtypes. Clinical molecular and histochemical assays will be developed and validated for the 
ER negative subtypes. The growth networks exploited by ER negative tumors that reflect pathways 
critical for proliferation and survival have been examined. Interestingly, in ER negative tumors, there 
was an increased differential expression of various tyrosine kinases, including EGFR, YES-1, KIT, 
EPH receptors B4, ABL. (Jenny Chang, Personal Communication) 
 
 
Targeted agents have shown best results when combined with chemotherapy (13, 14), and therefore 
the combination of dasatinib and paclitaxel is appealing. 
 
The combination of paclitaxel  and dasatinib has never been tested in humans, although combination 
trials with other chemotherapeutic agents are ongoing. . This study will aim at defining the maximum 
tolerated dose (MTD), for the combination of weekly paclitaxel and dasatinib. 
 
Once established the MTD, the phase II portion of the study will aim at defining efficacy and safety 
of the combination in patients with HER2 negative metastatic breast carcinoma 


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3.4.1 Dosing Rationale 
 
Starting dose of dasatinib in the two ongoing phase II trials for patients with breast carcinoma (CA 
180059 and CA 180088) was 100 mg BID with continuous dosing, which was considered to be safe, 
based on data from the phase I experience. However, suboptimal tolerance was observed at this dose- 
level, in terms of gastro-intestinal toxicity including nausea and vomit, and fluid retention, including 
pleural and pericardial effusions, prompting reduction to 70 mg BID with continuous dosing as 
starting dose. (Bristol Myers Squibb, data on file). 
 
In large randomized studies in CML,  daily dosing was better tolerated in long-term use. In chronic- 
phase CML, the efficacy of daily and BID schedules is equivalent. Theoretically, higher peak levels 
attained on  daily could yield some benefit, but this rationale may be disease-specific. In the ongoing 
SWOG trial for bone-predominant disease, 100  daily vs 70 BID dosing arms are being studied. 
 
The initial component of the Phase I trial with dasatinib on BID schedule in patients with solid tumors 
was performed with intermittent dosing, 5 days on and 2 days off. DLTs were observed at dasatinib 
dose of 90 and 120 mg BID given continuously, and (in subsequent expansion phase, data not yet 
available for distribution) at 100 BID, but not until 160 BID on 5 days out of 7 schedule. Although 5 
days out of 7 seems to be better tolerated, it is not completely clear (due to limited patient numbers) 
whether this is really due to the 'rest break' or to a lower total dose (4). 
 
Given the possibility of a combined treatment toxicity of dasatinib with paclitaxel, the data from the 
Phase I and II trials, and the fact that other trials of tyrosine kinase inhibitors in combination with 
chemotherapy have found better tolerance when dosing is omitted at the time of the chemotherapy 
pulse, we will plan to start the trial at a continuous dosing schedule of dasatinib, but then switch to 
the alternate schedule of 5 days per week if the MTD is exceeded at that particular dose-level. If 
tolerated, then dose-escalation will resume on the intermittent schedule. (see Section 4.3) 
 
3.5 
Correlative Studies: 
 
3.5.1 Pharmacogenomic Identification 
Validation of putative predictive markers remains a major challenge in oncology. Bristol- 
Myers Squibb (BMS) has developed promising pharmacogenomic markers of response to 
dasatinib in preclinical models of cancer. Using in vitro assays, 7 of 23 well-characterized 
breast cancer cell lines were shown to be relatively sensitive to dasatinib (IC50 ≤ 1µM). It 
was noted that these were predominantly those known to be of ‘basal-like’ subtype. 
Pharmacogenomic analysis demonstrated a 161-gene subset that correlated with growth 
inhibition by dasatinib. Several genes in this subset, including EphA2 (see Section 3.5.4) 
were shown to be modulated in vitro by exposure to dasatinib. The existence of this 
expression-defined gene subset was demonstrated in a large number of patient samples 
and found to consist largely of ‘triple-negative’ cancers. 
Similar results, i.e. identification of the triple-negative subtype as that likely inhibited by 


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dasatinib, were obtained independently and using somewhat different methodologies by 
investigators both at UCLA and at Duke. (16) 
Furthermore, a 6-gene subset was identified which correlated with in vitro response, and 
was then validated as a predictor in a separate set of 12 breast cancer cell lines, (thus 11 of 
35 cell lines were sensitive in toto). The receiver operating characteristics of this predictor 
set were sensitivity 75%, specificity 100%, positive predictive value 100%,negative 
predictive value 89%. Similarly-small (and partly-overlapping) gene subsets were also 
identified independently by investigators at UCLA and at Duke. The ‘triple-negative’ subset 
with basal-like phenotype (cytokeratin-positive) was again identified by these expression 
subsets. 
 
3.5.2 Role of Tyrosine Kinases in Breast Cancer 
 
Dasatinib is a potent inhibitor of Src-family kinases, EphA2 and other tyrosine kinases 
strongly implicated in expression of the malignant phenotype. The IC50 of dasatinib for Src- 
family kinases is in the range of 1 nM and that for EphA2 is approximately 17 nM, depending 
on experimental conditions. 
 
3.5.3 Src-family Kinases 
Src-family kinases (SFKs) are a group of closely-related non-receptor tyrosine kinases 
which participate in numerous cellular signaling pathways. SRC is a non-receptor tyrosine 
kinase that plays a critical role in cellular proliferation, and SRC family kinases have been implicated 
in driving the development and progression of human malignancies. The role of Src-family kinases 
in tumor progression and expression of the metastatic phenotype has been extensively 
reviewed.(17, 18 ) Evidence has been developed for multiple specific activities of Src-
family kinases, including mediation of growth factor signals, cell-cell and cell-substrate 
adhesion, functional membrane activation and motility, invasion and migration, and 
angiogenesis. As this literature is extensive, only a few representative lines of 
evidence bearing specifically on breast cancer will be summarized here. 
 
It is well established that signaling via ErbB receptors (i.e., EGFR and Her2/neu) 
involves activation of c-Src.(19, 20) SFK activity was shown to synergize with 
anchorage-independent heregulin-mediated growth and mediate MAPK pathway 
activation. (21) A variety of mechanisms have been suggested, including pSrc stabilization 
as well as activation by Her2/neu (ErbB2), formation of a complex with STAT5b, or 
“reverse” activation of Her2/neu kinase by the CXCL-12 chemokine via SFK activity. 
(22, 23) Growth and survival signaling can also occur through direct Src activation by 
EstrogenReceptor (ER) or Progesterone Receptor (PgR). (24, 25) Other mitogenic 
pathways require 
activation of Src-family kinases; for example, STAT3 signaling appears to be a major 
downstream effector of Src kinase activation in breast cancers.(26) 
 
Altered structural and cell surface properties are key characteristics of the metastatic 
phenotype, and include membrane ruffling and podosome formation, loss of anoikis, 


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changes in cell-cell and cell-basement membrane adhesiveness, motility and 
invasiveness - all of which are “typical” Src-related phenomena. Although less well studied 
than mitogenic pathways, the focal adhesion proteins are essential membrane 
elements implicated in tumorigenesis. (27) 
The cadherin/catenin system mediates cell-cell adhesion, loss of which is characteristic of 
epithelial malignancy. Inhibition of Src kinase activity restores E-cadherin/catenin 
expression and cell-cell adhesion in breast cancer cells, reducing metastasis.(28) In a series 
of experiments, Src activity was shown to stimulate phosphorylation of focal adhesion 
kinase (FAK) and paxillin, suppressing adhesion-dependent apoptosis and increasing 
expression of α2-integrin. (29) A variety of mechanisms have been advocated, including 
H2O2 
stimulation of Src, increased cap-dependent translation, or direct activation of STAT5 
by Type IV collagen via Src-dependent pathways. (30) 
 
Caveolins, primary structural components of caveolae (active vesicular invaginations of 
the cell membrane), are Src kinase substrates. Moreover, Caveolin-1 and -2 are two of the 
six-gene set expression of which correlates with in vitro response to dasatinib 
(Section 26.5.1). In general, caveolin acts as a tumor suppressor, but the relationship 
between caveolin activation and malignancy is complex. On one hand, mutation or 
inactivation of caveolin-1 leads to highly metastatic o r invasive phenotype and 
non-genomic nuclear signaling via ER is markedly stimulated by direct interaction with 
caveolin-1,even in the absence of ligand. (31) Most recently, direct stimulation of 
proliferation by progestin and full transcriptional activity of PgR were reported to be 
mediated by tyrosine phosphorylation of caveolin-1.(32) Consistent with its 
tumor-suppressor role, inactivating mutations of Cav-1 gene are found in approximately 
35% of ER-positive breast cancer samples (more than half of which are the 
dominant-negative P132L mutation), but in none of the ER-negative samples.(33) On the 
other hand, an inverse relationship has been reported between caveolin-1 expression and 
ErbB-mediated signaling. (34) 
 
Finally, Src-family kinases are known to mediate VEGF-induced angiogenesis and 
vascular permeability.(35) Both VEGF production and downstream VEGF 
action appear to require Src kinase. (36, 37) Normal endothelial cell Src-family kinase 
activity (specifically Src or Yes, but not Fyn) appears to be responsible for 
VEGF-stimulated disruption of the cadherin-catenin complex leading to tumor cell invasion 
and metastasis. (38) 
 
Pharmacodynamic data with the biomarker phospho-SRC (pSRC) was recently presented, to evaluate 
the relationship between dasatinib exposure and inhibition of SRC kinase activity. (39) The level of 
pSRC in peripheral blood mononuclear cells was used in two trials (CA 180002 and CA 180003) as a 
surrogate biomarker of the level of kinase activity of the SRC family members. On the BID regimen, 
pSRC inhibition was approximately dose-dependent across the dosing range. SRC family kinase 
activity was substantially inhibited at the exposures of dasatinib achieved. 


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3.5.4 EphA2 Kinase 
EPH kinases are the largest family of receptor tyrosine kinases, best characterized for 
their role in embryogenesis, cell migration and cytoskeletal organization, and more recently 
shown to be involved in malignancy.(40) Overexpression of EphA2 has been demonstrated 
in breast cancer specimens by several independent investigators.(41) Direct inhibition of 
EphA2 using monoclonal antibody provided selective reversal of malignant behavior of 
breast carcinoma cells in vitro. (42, 43) 
 
3.5.5 Circulating Tumor Cells (CTCs) 
 
Micrometastasis was originally a theoretical concept: CTC were presumed to exist because cancers 
spread hematogenously, but by definition CTC were not detectable by standard clinical methods. 
New and emerging technologies now make it possible to sensitively detect CTC in peripheral blood 
and bone marrow of patients with cancer. Yet, the biological and clinical meanings of CTC have not 
been fully determined. 
 
In principle, CTC technologies can be applied to many aspects of cancer management, including 
detection, staging/prognosis, assessment of treatment response, surveillance during remission, 
validation of novel therapies, and isolation of tumor cells for molecular analysis. For example, CTC 
detection may be of particular value in the initial management of breast cancer by better identifying 
those patients at risk of metastasis, thus allowing more judicious use of chemotherapy. Indeed, 
multiple studies have now shown that detection of CTC in marrow by immunocytochemistry (ICC) is 
strongly prognostic of recurrence and death. (44-46) 
 
A number of studies have suggested that the presence of CTCs in patients with metastatic disease is 
associated with poorer survival and disease burden.  (47, 48) Recent studies have quantified CTCs in 
late stage breast cancer to evaluate prognosis and monitor response to therapy. (49) These studies 
have found high sensitivity in detecting CTC using immunomagnetic bead enrichment of peripheral 
blood samples.  The threshold for detection is often only a few cells/ml of peripheral blood, however 
many metastatic patients have > 100 CTC/ml. (50)  Using a newly developed technology for 
automated ICC (CellSearch System), the presence of at least 5 or more CTCs per 7.5 ml of blood at 
start of treatment and first follow-up in a study of 177 patients with metastatic disease, correlated 
with a shorter median progression free survival, and overall survival. In a multivariate analysis, CTCs 
were the most significant independent predictor of progression free and overall survival. 
 
Studies of targeted agents in the treatment of breast cancer have been complicated by the lack of 
target identification to individualize therapy.  The success of specific targeting has been demonstrated 
in the treatment of HER2 positive cancers with trastuzumab. (51) Evaluating potential targets is 
particularly difficult in metastatic disease, where novel therapeutics undergo initial testing and 
generally meet with success or failure - due in part to the difficulty in obtaining initial and serial 
tissue for study.  CTCs provide a readily accessible source of tumor cells for comparison of markers 
pre- and post-therapy. 


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4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This is an open-label, single arm, dose-escalation phase I-II study to determine the MTD of dasatinib 
in combination with weekly paclitaxel, and to determine the safety and efficacy of this combination 
when given to patients with advanced and metastatic breast carcinoma. 
 
4.2 
Intervention 
 
A treatment cycle will consist of 28 days, according to the following schedule: 
 
 
Dasatinib PO once daily 
 
Weekly paclitaxel 80 mg/m2 given intravenously over 1 hour on day 1, 8, and 15 of a 28 
day cycle 
 
The trial will initially test the combination of weekly paclitaxel and dasatinib given PO, once daily, 
continuously. In case of 2 dose-limiting toxicities (DLT) in the first cohort (0), the next cohort will 
test dasatinib given with a different schedule, 5 days on and 2 days off, omitting dasatinib the day 
prior and the day of administration of paclitaxel. 
 
4.3 
Phase I Design 
 
A standard, three-patient per cohort, dose escalation schedule will be used. Between 6 and 54 patients 
will likely be necessary to determine the MTD of dasatinib in combination with weekly paclitaxel. 
There will be no intrapatient dose escalation. The starting dose of dasatinib is 70 mg once daily, 
continuously (Dose level 0). One dose reduction level have been included, if necessary. 
 
 
The dose for each cohort in this phase I is presented below: 
 
Cohort 
Paclitaxel dose 
Dasatinib dose 
+ 3 
80 mg/m2 weekly 3/4 
150 mg daily continuously 
+2 
80 mg/m2 weekly 3/4 
120 mg daily continuously 
+1 
80 mg/m2 weekly 3/4 
100 mg daily continuously 
0 
80 mg/m2 weekly 3/4 
70 mg daily continuously 
-1 
80 mg/m2 weekly 3/4 
70 mg daily 5 days out of 7 


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In the event that the MTD is with dasatinib  < 100 mg daily given continuously, then the dasatinib 
dosing of 5 days out of 7 will be explored ; if tolerated, escalation may resume on the intermittent 
schedule. If dasatinib > 120 mg  daily continuous is tolerated, there will be no need to investigate the 
intermittent dose-schedule. 
 
 
 
Cohort 
Paclitaxel dose 
Dasatinib dose 
+ 3b 
80 mg/m2 weekly 3/4 
150 mg daily 5 days out of 7 
+2b 
80 mg/m2 weekly 3/4 
120 mg daily 5 days out of 7 
+1b 
80 mg/m2 weekly 3/4 
100 mg daily 5 days out of 7 
-1 
80 mg/m2 weekly 3/4 
70 mg daily 5 days out of 7 
-2 
80 mg/m2 weekly 3/4 
50 mg daily 5 days out of 7 
 
 
 
Dose limiting toxicity is defined as: 
 
 
Clinically significant grade 3 or 4 non-hematologic toxicity according to the NCI CTC version 3. 
(for example, not alopecia or nausea and vomit controlled by anti-emetics) 
 
Grade 3 or 4 hematologic toxicity including neutropenia and thrombocytopenia lasting greater 
than 2 weeks. Grade 3 or 4 anemia lasting two weeks despite the use of red blood cell growth 
factor support. Usage of growth factor support will be noted for data analysis. 
 
Grade 2 non-hematologic toxicity that persists despite adequate medical management and requires 
withholding dasatinib for more than 4 days in cycle #1. 
 
The following dose escalation scheme will be utilized: 
 
 
 
If none of the initial three patients in a cohort experience dose-limiting toxicity (DLT), then a 
new cohort of three patients will be treated at the next higher dose level. 
 
 
 If one of the three patients in a cohort experiences DLT, then up to three additional patients 
will be treated at the same dose level.  Escalation will continue if only one of the six patients 
experiences DLT. 
 
 
If two or more patients in a cohort experience DLT, then the maximum tolerated dose (MTD) 
will have been exceeded, and no further dose escalation will occur.  The previous dose level 
will be considered as the MTD. 


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 
If the MTD is exceeded at any given dose level < 120 mg  daily, on the continuous schedule, 
then  that  dose  will  be assessed  on  5  days  per  week  schedule,  corresponding  to  a  28% 
reduction  in  total  weekly  dose.  If  tolerated,  escalation  may  resume  on  the  intermittent 
schedule. (if > 120 mg  daily continuous is tolerated, there will be no need to investigate the 
intermittent dose-schedule). 
 
Therefore: 
 
o If two or more patients in cohort 0 (paclitaxel 80 mg/m2  and dasatinib 70 mg  daily 
continuously), experience DLT, then patients will be enrolled at dose level -1, with 
paclitaxel 80 mg/m2 weekly and dasatinib 70 mg  daily 5 days out of 7, omitting 
dasatinib the day prior and the day of administration of paclitaxel. If this dosing is 
tolerated, escalation may resume on the intermittent schedule. 
 
o Similarly, if two or more patients in cohort 1 (paclitaxel 80 mg/m2  and dasatinib 100 
mg  daily continuously), experience DLT, then patients will be enrolled at dose level 
+1b, with  paclitaxel 80 mg/m2 weekly and dasatinib 100 mg  daily 5 days out of 7, 
omitting dasatinib the day prior and the day of administration of paclitaxel. If 
this dosing is tolerated, escalation may resume on the intermittent schedule. 
 
o Similarly, if two or more patients in cohort 2 (paclitaxel 80 mg/m2  and dasatinib 120 
mg  daily continuously), experience DLT, then patients will be enrolled at dose level 
+2b, with  paclitaxel 80 mg/m2 weekly and dasatinib 120 mg  daily 5 days out of 7, 
omitting dasatinib the day prior and the day of administration of paclitaxel. If 
this dosing is tolerated, escalation may resume on the intermittent schedule. 
 
 
 If only three patients were treated at a dose level under consideration as the MTD, then up to 
three additional patients will be accrued.  If no more than one of the six patients at that dose 
level experiences a DLT, then that dose level will be confirmed as the MTD.  If two or more 
patients in that cohort experience DLT, then the previous dose level will be studied in the 
same fashion. 
 
 
If the MTD is exceeded at any given dose level on the continuous schedule, and the previous 
dose-level had only 3 patients in the cohort, than that cohort will be expanded to 6 patients, to 
establish MTD on the continuous schedule. 
 
 
If greater than or equal to 2 DLTs are experienced by cohort -1 (with dasatinib 70 mg  daily 5 
days out of 7), then cohort –2 (with dasatinib 50 mg   daily 5 days out of 7) will be under 
consideration for the MTD. Six patients will be accrued at this level to establish the MTD. If 
one or less DLTs are experienced by cohort –2, then this will be considered the MTD. If 2 or 
more DLTs occur within cohort –2, then the study will be terminated and the IRB will be 
notified. 


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 
If the MTD were not to be exceeded, additional dose-escalation steps in the 30% range will be 
explored. 
 
All patients within a cohort will be observed for toxicity for one cycle (28 days) prior to entering 
patients at the next dose level. 
 
We do not expect peripheral neuropathy to be a side effect of dasatinib, but rather of paclitaxel. For 
patients experiencing peripheral neuropathy, the following dose-modification schema can be utilized: 
 
Dose-modification schema for peripheral neuropathy caused by paclitaxel: 
 
Level 
0 
-1 
-2 
Dose (mg/m2) 
80 
70 
60 
 
Neuropathy: 
 
Grade 
Dose reduction 
 
0-1 
No change 
2 
One level 
3 
Two levels 
4 
Two levels or stop therapy 
 
4.4 
Phase II design 
 
 
The phase II portion of this trial has a Simon two-stage design to determine the efficacy of dasatinib 
when administered in combination with paclitaxel. The eligibility criteria for the phase II study are 
more restrictive than for the phase I study because patients must have had 0 to 2 prior regimens; these 
additional eligibility criteria may be found in Section 6.0. Patients treated at the MTD in the Phase I 
portion of the study will not be included in the Phase II portion, as eligibility criteria are different for 
the two portions. 
 
Twenty-three patients will initially enter the study.  As described further in Section 14 Biostatistics, if 
there are 3 or fewer responses observed, the study will be terminated early and declared to have a 
negative result.  If 4 or more responses are observed, enrollment will be extended to 55 patients.  If > 
12 responses are observed among the 55 patients, the study will be considered to have a positive 
result and this regimen would be considered worthy of further testing.  patients will be entered into 
Stage 1 of the phase II trial. Overall, a minimum of 23 patients and a maximum of 55 patients will be 
entered on the phase II portion of this study. 


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The phase II study will be conducted at the maximum tolerated dose of dasatinib in combination with 
paclitaxel, determined upon completion of the phase I portion of the protocol. The treatment schedule 
will be the same as for the phase I portion of this trial. A treatment cycle will consist of 28 days, 
according to the following schedule: 
 
 
Agent 
Dose 
Route 
Treatment 
days 
Interval 
Notes 
Dasatinib 
120 mg 
PO 
Recommended 
phase II schedule 
28 days 
Daily dose 
once 
Paclitaxel 
80 mg/m2 
IV 
Day 1, 8 and 15 
28 days 
Weekly 3/4 
 
 
 
5.0 THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1  Dasatinib 
 
Dasatinib tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the 
following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of 
hypromellose, titanium dioxide, and polyethylene glycol. 
 
5.1.1 
Dasatinib Product Identification 
 
Dasatinib will be supplied in two different strengths by BMS. 
 
20 mg film-coated tablets, biconvex, round, white to off-white in appearance with“BMS” or “20” 
debossed on one side and "527" on the other side 
 
50 mg film-coated tablets, biconvex, oval, white to off-white in appearance with“BMS” or “50” 
debossed on one side and "528" on the other side 
 
 
5.1.2 Packaging and Labeling 
 
Dasatinib will be packaged in bottles as follows: 
 
dasatinib 20 mg film-coated tablets, 30 tabs/bottle 
 
dasatinib 50 mg film-coated tablets, 30 tabs/bottle 
 
 
Each bottle will be labeled in an open label.  Labels will contain, at a minimum, the following 
information: product name, tablet strength, batch number, directions for use, storage conditions, and 
appropriate caution statements. 


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5.2  Storage, Handling and Dispensing of Dasatinib 
 
5.2.1 Storage 
 
Dasatinib tablets should be stored in a secure area at 25C (77F); excursions permitted between 15°– 
30C (59–86F). 
 
5.2.2 Handling and Disposal 
 
Procedures for proper handling and disposal of anticancer drugs should be considered. 
 
Dasatinib tablets consist of a core tablet (containing the active drug substance), surrounded by a film 
coating to prevent exposure of pharmacy and clinical personnel to the active drug substance. If tablets 
are crushed or broken, pharmacy and clinical personnel should wear disposable chemotherapy gloves. 
Personnel who are pregnant should avoid exposure to crushed and/or broken tablets. 
 
5.2.3 Dispensing 
 
It is the responsibility of the Investigator to ensure that dasatinib is only dispensed to study subjects. 
Dasatinib must be dispensed only from official study sites by authorized personnel according to local 
regulations. 
 
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.  The lot numbers, dosing 
start dates and the number of tablets for each dosage strength must be recorded on the drug 
accountability pages of record for the site.  The subject must be instructed to return all unused 
dasatinib in the provided packaging at each subsequent visit. 
 
5.3  Drug Ordering and Accountability 
 
Drug Supply – Initial Order and Re-supply 
 
Initial Orders of dasatinib are requested by completing the Dasatinib (Sprycel®) Drug Supply Form 
for Investigator Sponsored Studies and submitting the request form electronically via e-mail at least 
5-7 business days before the expected delivery date. Deliveries will be made Tuesday through Friday. 
Initial drug supply is provided for a 12-week treatment period per subject. 
Send the drug supply form with the subject heading: "BMS CA180-xxx [insert assigned number] 
Dasatinib Supply Request" to bms.ist@acculogix-usa.com. 
 
Please note: The BMS study ID (CA180-XXX) and “dasatinib” must be recorde d in the  
subject line of the email. 


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Send re-supply requests to the appropriate email address.   Check “Re-supply” on the drug supply 
form.  Re-supply requests should be submitted at least 5-7 business days before the expected delivery 
date.  Deliveries will be made Tuesday through Friday. 
 
5.4  Dasatinib Accountability 
 
It is the responsibility of the Investigator to ensure that a current record of dasatinib disposition is 
maintained at each study site where dasatinib 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. 
     Label ID number or batch number and use date or expiry date. 
     Dates and initials of person responsible for each dasatinib inventory entry/movement. 
     Amount dispensed to and returned by each subject, including unique subject identifiers. 
     Amount transferred to another area/site for dispensing or storage. 
     Non-study disposition (e.g., lost, wasted, broken). 
     Amount returned to BMS, if applicable. 
     Amount destroyed at study site, if applicable. 
     Retain samples sent to third party for bioavailability/bioequivalence, if applicable. 
 
Dasatinib 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. 
 
5.5  Destruction of Dasatinib 
 
It is the Investigator’s responsibility to ensure that arrangements have been made for disposal and that 
procedures for proper disposal have been established according to applicable regulations, guidelines, 
and institutional procedures. Appropriate records of the disposal must be maintained. 
 
Consult with the PI for instructions on disposal of unused dasatinib tablets. 
 
 
 
5.6  Paclitaxel 
 
Paclitaxel is a taxane originally derived from the bark of the Pacific yew tree (Taxus Brevifolia) one 
of the most active and commonly used agents for the treatment of breast carcinoma. Paclitaxel binds 
to the dimeric tubulin preventing microtubule disassembly by stabilizing microtubules so that the 
spindle cannot be dismantled. This microtubule disruption halts mitosis, interferes with other critical 
interphase functions and subsequently leads to cell death. 
 
Paclitaxel (as Taxol) is generically available and will not be supplied by Bristol-Myers Squibb 
Company . 


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Paclitaxel is a clear colorless to slightly yellow viscous solution. Paclitaxel is supplied as a 
non-aqueous solution intended for dilution with a suitable parenteral fluid prior to 
intravenous 
infusion. Paclitaxel is available as 30 mg (5 ml) 100 mg (16.7 ml) and 300 mg (50 ml) 
multiuse vials. 
 
Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of purified 
Cremophor® EL and 49.7% of v/v dehydrated alcohol. 
 
5.6.1 Packaging and Labeling - Paclitaxel 
 
Paclitaxel will be supplied as 100 mg (16.7 ml) multi-use vials. Vials will be labeled 
according to the respective country regulations and may contain information regarding 
the product strength, quantity, storage conditions and direction of use. Sites will be 
responsible for recording the label batch number/lot number of the supplies dispensed on 
drug accountability forms. Commercial supply for paclitaxel will be utilized for the study. 
 
5.6.2 Storage Requirements/Stability - Paclitaxel (Taxol) 
 
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 SmPC/reference label. 
 
Unopened vials of Taxol (paclitaxel) injection are stable until the date indicated on the 
package when stored between 20 - 25°C (68 - 77°F), in the original package. Neither 
freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration 
components in the paclitaxel vial may precipitate, but will re-dissolve upon reaching 
room temperature with little or no agitation. 
 
5.6.3 Preparation and Administration - Paclitaxel 
 
Prior to infusion paclitaxel should be diluted in 0.9% Sodium Chloride injection or 
5% Dextrose injection or 5% Dextrose and 0.9% Sodium Chloride or 5% Dextrose in 
ringers lactate to a final concentration of 0.3 to 1.2 mg/mL. Paclitaxel must be prepared 
in glass, polypropylene or polyolefin containers and non-PVC containing (nitroglycerin) 
infusion sets. Prepared solutions are stable at room temperature (20 - 25°C (68 - 77°F)) 
and protected from light, up to 72 hours. In-line filtration with micropore no greater than 
0.22 micron filter is required. Chemo dispensing pin devices or similar devices with 
spikes should not be used with paclitaxel vials since they can cause the stopper to 
collapse resulting in loss of sterile integrity. 


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5.6.4 Incompatibilities - Paclitaxel 
 
Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl) 
phthalate] show that levels increase with time and concentration when dilutions are 
prepared in PVC containers. Consequently, the use of plasticized PVC containers and 
administration sets is not recommended. Therefore, paclitaxel solutions should be 
prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC 
containing administration sets, such as polyethylene-lined, should be used. 
 
5.6.5 Safety Precautions - Paclitaxel 
 
Paclitaxel does not contain any antimicrobials therefore extreme care must be taken to 
ensure sterility of the prepared solution. 
Subjects should be premedicated to reduce risk of severe hypersensitivity reaction. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
1.   Female or male patients with diagnosis of invasive adenocarcinoma of the breast confirmed at 
MSKCC. 
 
 
For the phase I portion, patients with any ER/PR/HER2 disease status, no longer 
eligible for hormonal therapy or HER2-targeted therapy, will be eligible. 
 
 
For the phase II portion, there needs to be documentation of negative HER2 (IHC 0- 
1+  or  FISH/CISH  negative)  status.  Patients  with  any  ER/PR  disease  status  are 
eligible. 
 
2.   A paraffin-embedded tissue block or unstained slides from prior surgery must be available. 
 
 
3.   Evidence of recurrent or progressive locally advanced or metastatic breast cancer 
 
 
4.   Presence of 
 
 
For the phase I portion: at least one evaluable or measurable metastatic lesion , 
 
 
For the phase II portion:  at least one measurable metastatic lesion according to the 
RECIST criteria which has not been irradiated (i.e. newly arising lesions in previously 
irradiated areas are accepted).Ascites, pleural effusion, and bone metastases are not 
considered measurable.  Minimum indicator lesion size: > 10 mm measured by spiral 
CT or > 20 mm measured by conventional techniques. 


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5.   Prior therapies: 
 
 
For the phase I portion: Any number of prior endocrine or biologic therapies is 
permitted. In addition, patients may be untreated in the metastatic setting or have 
received any number of prior cytotoxic regimens. 
 
 
For  the  phase  II  portion:  0-2  prior  chemotherapies  for  metastatic  disease  are 
allowed. Prior taxane therapy, either in the adjuvant or in the metastatic setting, either 
deliver weekly, q 2 weeks or q 3 weeks, will be permitted. Prior therapy with 
bevacizumab will be allowed. All previous chemotherapy, radiotherapy and 
intravenous bisphosphonates must have been discontinued at least 3 weeks prior to 
study entry, 3 weeks also for trastuzumab and bevacizumab. All acute toxic effects 
(excluding alopecia) of any prior therapy must have resolved to NCI CTC (Version 3) 
Grade ≤1. 
 
6.   Endocrine  therapy  with  an  aromatase-inhibitor,  SERM  (i.e.,  tamoxifen)  or  fulvestrant  is 
permitted, however it must be discontinued before enrolling in the study. 
 
7.   ECOG performance status of 0 or 1. 
 
 
8.   Age > 18 years old. 
 
9.   Adequate Organ Function 
 
Total bilirubin < 1.5  times the institutional Upper Limit of Normal (ULN) 
 
Hepatic enzymes (AST, ALT ) ≤ 2.5 times the institutional ULN 
 
Serum Na, K+, Mg2+, Phosphate and Ca2+ Lower Limit of Normal (LLN) 
 
Serum Creatinine < 1.5 time the institutional ULN 
 
Neutrophil count, Platelets, both Grade 0-1 
 
PT (INR) and PTT Grade 0-1, except for patients on Coumadin or low molecular weight 
heparin 
 
 
10. Ability to take oral medication (dasatinib must be swallowed whole) 
11. Concomitant Medications: 
 
Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy 
 
Patient agrees that IV bisphophonates will be withheld for the first 8 weeks of dasatinib 
therapy due to risk of hypocalcemia. Concomitant Medications, any of the following 
should be considered for exclusion: 
 
Patient agrees to discontinue QT-prolonging agents strongly associated with Torsades de 
Pointes  (patients must discontinue drug ≥7 days prior to starting dasatinib) such as [see 
also section 6.2.1]: 


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o quinidine, procainamide, disopyramide 
o amiodarone, sotalol, ibutilide, dofetilide 
o erythromycin, clarithromycin 
o chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide 
o cisapride,  bepridil,  droperidol,  methadone,  arsenic,  chloroquine,  domperidone, 
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine. 
 
The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is not 
recommended. The use of antacids should be considered in place of H2 blockers or proton 
pump inhibitors in patients receiving dasatinib therapy.    If antacid therapy is needed, the 
antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of 
dasatinib. 
 
Patient may not be receiving any potent CYP3A4 inhibitors. These are prohibited (patients 
must discontinue drug ≥7 days prior to starting dasatinib) and include:  [see also section 
6.2.1] 
o itraconazole, ketoconazole, miconazole, coriconazole 
o amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir 
o ciprofloxacin, 
clarithromycin, 
diclofenac, 
doxycycline, 
enoxacin, 
imatinib, 
isoniazid 
o ketamine, nefazodone, nicardipine, propofol, quinidine, telithromycin 
 
 
12. Women of childbearing potential (WOCBP) must have: 
 
A negative serum or urine pregnancy test within 72 hours prior to the start of study drug 
administration 
 
Persons of reproductive potential must agree to use an adequate method of contraception 
throughout treatment and for at least 4 weeks after study drug is stopped 
 
Pregnant or nursing women may not participate. Patients of reproductive potential may not 
participate unless they have agreed to use an effective method of contraception and to 
continue contraception for 30 days from the date of the last study drug administration. 
Postmenopausal woman must be amenorrheic for at least 12 months to be considered of 
non-childbearing potential. 
 
13. Signed written informed consent including a HIPAA form according to institutional guidelines. 
 
 
6.2 
Subject Exclusion Criteria 
 
1.   Life expectancy < 3 months. 
 
 
2.   Prior severe allergic reaction to paclitaxel therapy. 


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3.  Presence of new or recurrent pleural effusion which is symptomatic and/or requiring medical 
intervention (NCI CTC Grade 2, 3, or 4) 
 
4.   Completion of previous chemotherapy regimen < 3 weeks prior to the start of study treatment. 
 
 
5.  Prior hormonal therapy must be discontinued prior to treatment start. Biologic therapy (eg, 
bevacizumab, trastuzumab) for the treatment of metastatic disease must be discontinued >3 weeks 
from the start of protocol treatment. 
 
6.   Concurrent medical condition which may increase the risk of toxicity. 
Patients may not have any clinically significant cardiovascular disease including the 
following: 
 
 
myocardial infarction or ventricular tachyarrhythmia within 6 months 
 
prolonged QTc >480 msec (Fridericia correction) 
 
ejection fraction less than institutional normal 
 
major conduction abnormality (unless a cardiac pacemaker is present) 
 
Patients with any cardiopulmonary symptoms of unknown cause (e.g. shortness of breath, chest 
pain, etc.) should be evaluated by a baseline echocardiogram with or without stress test as needed 
in addition to electrocardiogram (EKG) to rule out QTc prolongation.  The patient may be referred 
to a cardiologist at the discretion of the principal investigator.  Patients with underlying 
cardiopulmonary dysfunction should be excluded from the study. 
 
 
 
Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib 
administration 
 
History of significant bleeding disorder unrelated to cancer, including: 
o Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease) 
o Diagnosed acquired bleeding disorder within one year (e.g., acquired  anti- 
factor VIII antibodies) 
o Ongoing or recent ( 3 months) significant gastrointestinal bleeding 
 
Other  medical  condition  which  in  the  opinion  of  the  Investigator  might  confer  an 
unacceptable increase in risk. 
 
 
7.   Patients  with  symptomatic  CNS  metastases  that  remain  untreated  by  radiation  therapy  are 
excluded from this trial. The presence of asymptomatic brain metastases or brain metastases that 
have been previously irradiated are not grounds for trial exclusion. 
 
8.   History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged 
by the investigator to be clinically significant, precluding informed consent, or interfering with 
compliance of oral drug intake. 


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9. Presence of uncontrolled gastrointestinal malabsorption syndrome. 
  
10. Unwillingness to give written informed consent or unwillingness to participate or inability to 
comply with the protocol for the duration of the study. Willingness and ability to comply with 
scheduled visits, treatment plan, laboratory tests and other study procedures are necessary for 
participation in this clinical trial. 
 
11. Concurrent radiotherapy is not permitted for disease progression on treatment on protocol, but 
might allowed for pre-existing non-target lesions with approval from the principal investigator of 
the trial. 
 
12. Patients with > Grade 1 neuropathy will be excluded form this trial. 
 
 
6.2.1 Prohibited and Restricted Therapies During Study 
 
6.2.1.1 Prohibited Therapies 
 
No other systemic therapy for treatment of breast cancer is permitted while subject is on 
study. 
 
Subjects requiring any of the following prohibited therapies should not be enrolled. If 
enrolled, the prohibited agent(s) must be withdrawn prior to first dose of study drug: 
 
Bisphosphonates 
 
Intravenous bisphosphonates will be withheld for the first 8 weeks of treatment due to the 
risk of hypocalcemia. After the need for Ca2+ supplementation has been assessed and 
levels documented to be > LLN, subjects on prior bisphosphonate may be restarted with 
caution at investigator discretion. 
 
QT-prolonging agents strongly associated with Torsades de Pointes 
 
Patients must discontinue drug ≥7 days prior to starting dasatinib such as: 
o quinidine, procainamide, disopyramide 
o amiodarone, sotalol, ibutilide, dofetilide 
o erythromycin, clarithromycin 
o chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide 
o cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, 
levomethadyl, pentamidine, sparfloxacin, lidoflazine 
 
Potent CYP3A4 inhibitors 
 
Dasatinib is primarily metabolized by the CYP3A4 enzyme. In drug-drug interaction studies, 
concomitant use of ketoconazole (a potent CYP3A4 inhibitor) produced an increase of >5-fold in 


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dasatinib exposure. Therefore, potent inhibitors of CYP3A4 are prohibited during study; for such 
medications, a wash-out period of ≥7 days is required prior to starting dasatinib (less potent 
inhibitors, inducers and substrates of CYP3A4 are restricted, see section 6.2.1.2). Subjects should be 
advised not to consume substantial quantities of grapefruit or pomegranate juice. 
 
Most commonly-used potent CYP3A4 inhibitors are: 
o itraconazole, ketoconazole, miconazole, voriconazole 
o amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir 
o ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, imatinib, isoniazid 
o ketamine, nefazodone, nicardipine, propofol, quinidine, telithromycin 
 
St. John’s wort (Hypericum perforatum) may decrease dasatinib plasma concentrations unpredictably. 
Patients receiving dasatinib should not take St. John’s wort. 
 
6.2.1.2 Restricted Therapies 
 
 
Restricted treatments are allowed to be used during the study. However, they should be used with 
caution when medically indicated. 
 
 
Medications that inhibit platelet function or anticoagulants: 
 
Caution should be exercised if subjects are required to take medications that inhibit platelet 
function or anticoagulants. Antiplatelet agents or anticoagulants should be avoided in the 
setting of Grade 3 or 4 thrombocytopenia. 
 
 
Medications that prolong QT Interval: 
 
Ideally, subjects enrolled in this study should not begin taking other medications known to 
prolong the QT interval. Information on where to find a partial list of medications known to 
prolong the QT interval is found at http://www.azcert.org/medical-pros/drug- 
lists/bycategory.cfm. 
 
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, then additional ECG(s) will be done at the investigator’s discretion to ensure 
the subject’s safety. 
 
As  stated  above,  subjects  enrolled  in  this  study  should  not  take  or  begin  to  take  concomitant 
medications strongly associated with  Torsades de Pointes such as: 
 
 
quinidine, procainamide, disopyramide 
 
 
amiodarone, sotalol, ibutilide, dofetilide 


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 
erythromycin, clarithromycin 
 
chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide 
 
cisapride, 
bepridil, 
droperidol, 
methadone, 
arsenic, 
chloroquine, 
domperidone, 
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine 
 
 
 
CYP3A4 Inducers, Inhibitors and Substrates 
 
Caution is warranted when administering dasatinib to subjects taking drugs that are highly 
dependent on CYP3A4 for metabolism and have a narrow therapeutic index. (See Appendix 
C). 
 
 
Dasatinib is a CYP3A4 substrate. Drugs that induce CYP3A4 activity may decrease dasatinib plasma 
concentrations.  In  patients  in  whom  CYP3A4  inducers  (eg,  dexamethasone,  phenytoin, 
carbamazepine,  rifampicin,  phenobarbital)  are  indicated,  alternative  agents  with  less  enzyme 
induction potential should be preferred. 
 
Concomitant use of dasatinib and drugs that inhibit CYP3A4 (e.g., ketoconazole, itraconazole, 
erythromycin, clarithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, 
telithromycin) may increase exposure to dasatinib. 
 
CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, 
terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot 
alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving 
dasatinib. 
 
Potent CYP3A4 inhibitors are prohibited (See Section 6.2.1.1). Less-potent inhibitors, inducers, and 
substrates of CYP3A4 are restricted (see also Appendix C). 
 
In patients receiving treatment with dasatinib, close monitoring for toxicity and a dasatinib dose 
reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be 
avoided. 
 
Subjects should be advised not to consume substantial quantities of grapefruit juice. 
 
 
 
Antacids 
 
Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. Simultaneous 
administration of dasatinib with antacids should be avoided.  If antacid therapy is needed, the antacid 
dose should be administered at least 2 hours prior to or 2 hours after the dose of dasatinib. Medicines 
that neutralize stomach acid, such as MAALOX® (aluminum hydroxide/magnesium hydroxide), 


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TUMS® (calcium carbonate), or ROLAIDS® (calcium carbonate and magnesia) may be taken up to 
2 hours before or 2 hours after dasatinib. (1) 
  
 
H2 Blockers/Proton Pump Inhibitors 
 
Long-term suppression of gastric acid secretion by H2 blockers or proton pump inhibitors (eg, 
famotidine and  omeprazole) is  likely to  reduce  dasatinib  exposure.  The concomitant  use of H2 
blockers or proton pump inhibitors with dasatinib is not recommended. The use of antacids should be 
considered in place of H2 blockers or proton pump inhibitors in patients receiving dasatinib therapy. 
 
 
6.2.1.3 Other Restrictions and Precautions 
 
Based on pre-clinical data, dasatinib might increase the likelihood of bleeding. Hence, subjects 
undergoing surgical procedures, including dental procedures, should be instructed to inform their 
doctors of this potential increased risk. 
 
 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be recruited through the outpatient clinics of the Breast Cancer Medicine Service of 
Memorial Sloan-Kettering Cancer Center. All patients will be under the care of attending medical 
oncologists of MSKCC.  Both men and women and members of all ethnic groups are eligible for this 
trial. 
 
Patients will be required to sign a statement of informed consent that meets the requirements of the 
code of Federal Regulations (Federal Register Vol. 46, No. 17, Jan. 27, 1981, part 50) and the IRB of 
this center.  A consent form is appended.  The medical record will include a statement that written 
informed consent was obtained (and documented in the record the date written consent was obtained 
before) and the patient is enrolled in the study. 
 
The estimated number of study participants is between 29 and 109 patients. The target population 
estimates have been based upon 109 patients participating. As the incidence of breast cancer in men is 
rare, exact numbers for enrollment have not been provided, although men are not excluded from this 
trial. Efforts to maintain similar proportions to that of the female study participants will be made. 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
 
Diagnosis of invasive adenocarcinoma of the breast confirmed at MSKCC by histology. 
 
 
 
Baseline extent of disease evaluation up to 4 weeks prior to treatment on Cycle #1 including 


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o CT scans of the chest, abdomen and pelvis with oral and intravenous contrast (if not 
contraindicated) 
o  Bone scan. Target lesions according to RECIST criteria should be identified at this 
time. 
 
Baseline demographics and medical history will be collected within 4 weeks of initiating 
study treatment. These data will include but is not limited to confirmation of breast pathology 
review at MSKCC, menopausal status, estrogen receptor status, progesterone receptor status, 
Her2 status (by immunohistochemistry or FISH), prior treatment history (including: 
chemotherapy, hormone therapy, trastuzumab, bevacizumab and radiation). 
 
Baseline history and physical examination within 14 days of treatment initiation including 
ECOG performance status assessment, blood pressure, pulse, temperature, weight and height. 
 
Baseline laboratory/cardiac assessment may be performed up to 14 days prior to treatment 
including: 
 
CBC 
 
Comprehensive metabolic panel 
 
Serum or urine pregnancy test, if applicable 
 
EKG 
 
PT/PTT 
 
Magnesium 
 
Phosphorous 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 
Phase I Study 
 
A treatment cycle consists of 28 days, according to the following schedule: 
 
Agent 
Route 
Treatment days 
Interval 
Notes 
Dasatinib 
PO 
Per cohort schedule 
(either continuously 
or 5 days out of 7) 
28 days 
Daily dose 
once 
Paclitaxel 80 mg/m2 
IV 
1, 8, 15 
28 days 
Weekly 3/4 
 
9.1.1 Dasatinib 
 
Dasatinib will be administered orally and is expected to be taken as an outpatient. No premedications 
are required for the oral administration of dasatinib as hypersensitivity reactions are not anticipated. 
 
Dasatinib will be administered in the Phase I dose escalation study at a starting total daily dose of 70 
mg DAILY, on a continuous schedule. The dose of dasatinib will be fixed, not calculated on the basis 
of body surface area. 


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As explained in Section 4.3, if the MTD is  with dasatinib < 100 mg daily given continuously, then 
that dose will be assessed on 5 days per week schedule, corresponding to a 28% reduction in total 
weekly dose. In that case dasatinib tablets will be administered 5 days a week, starting the day after 
the administration of paclitaxel, and stopping two days before the following administration of 
paclitaxel. (i.e. Day 1 paclitaxel, Day 2-6 dasatinib, Day 7 off). During the week off (4th week of 
every treatment cycle), patients will continue with dasatinib daily, stopping two days prior the 
administration of the next dose of paclitaxel (Day 1 of following cycle). 
 
The total daily dose of dasatinib should be taken once daily and may be taken with meals. Patients 
will be provided with a diary in which to record study drug intake. Dosing times may be adjusted if 
required. If doses are missed for toxicity, they should not be replaced. If a dose is not taken due to an 
error, it may be taken up to 12 hours later. If vomiting occurs within 30 minutes of intake, that dose 
may be repeated. 
 
Both gastrointestinal tolerance and drug absorption may be improved if dasatinib is taken 
with a light meal; there is no requirement, however, to administer with food. 
Based on pre-clinical data, dasatinib may inhibit platelet aggregation and uncommon 
instances of increased bleeding risk have been observed. Dasatinib should be interrupted 
for 1 day before and 1 - 2 days after any surgical (including dental) procedure or until 
adequate hemostasis is achieved. 
 
Patients will keep a drug diary (Appendix D) to document degree of compliance with dasatinib 
therapy. For phase I patients within the first two cycles of treatment, the exact number of pills 
necessary for 2 weeks of treatment will be dispensed to patients at one time. For phase II patients, the 
exact number of pills necessary for one cycle (four weeks) of treatment will be dispensed to patients 
at one time. 
 
Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to 
initiating dasatinib and during treatment.  Symptoms of pulmonary arterial hypertension (PAH) 
include dyspnea, fatigue, hypoxia, and edema.  Since other medical conditions may also cause these 
symptoms, non-invasive procedures (including echocardiogram) should be done first to rule out more 
the common etiologies of these symptoms, such as pleural effusion, pulmonary edema, anemia, and 
lung infiltration.  Right heart catherization can confirm the diagnosis of PAH.  Hypertension is “pre- 
capillary” and not a consequence of left heart failure or chronic lung disease if there is normal 
pulmonary capillary wedge pressure (<15 mm Hg) but elevated pulmonary artery pressure (mean 
pulmonary artery pressure >25 mm Hg).  Since PAH may be reversible upon discontinuation of 
dasatinib, a diagnostic approach of interruption of dasatinib treatment may be considered at the 
discreation of the treating physician; however, if PAH is confirmed, dasatinib should be permanently 
discontinued. 
 
9.1.2 Paclitaxel 


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Body surface area (BSA) should be calculated at the start of therapy (Day 1 of Cycle 1). In 
calculating surface areas actual heights and weights should be used; that is, there should 
be no adjustment to “ideal” weight. 
 
Paclitaxel will be administered as a 1 hour IV infusion on Days 1, 8 and 15 in 
a 28 day cycle, provided the subject meets the re-treatment criteria. The initial dose will 
be 80 mg/m2. 
 
Due to the potential for allergic reactions to paclitaxel and/or the Cremophor vehicle, all 
subjects should be premedicated prior to each paclitaxel administration to prevent or 
reduce the risk of severe hypersensitivity reactions. 
 
• Pre-medicate subject 30 - 60 minutes prior to paclitaxel administration with 
Dexamethasone 10 mg IV, Diphenhydramine 50 mg IV and Cimetidine (300 mg IV) or 
other H2 receptor antagonist (e.g. Ranitidine 50 mg IV). It is also acceptable to utilize 
the investigative sites standard pre-medication regimen for paclitaxel dosing. If no allergic 
reaction occurs after the first 3 doses of paclitaxel, it is acceptable to modify the pre- 
medication regimen at the discretion of the investigator. 
 
 
9.2 Phase II Study 
 
A treatment cycle consists of 28 days, according to the following schedule: 
 
 
 
Agent 
Route 
Treatment days 
Interval 
Notes 
Dasatinib 
PO 
120 mg 
28 days 
Daily dose 
once 
Paclitaxel 80 mg/m2 
IV 
1, 8, 15 
28 days 
Weekly 3/4 
 
 
The Phase II dasatinib dose will be the maximum tolerated dose and schedule determined in the 
Phase I study. Paclitaxel will be administered at 80 mg/m2  weekly on day 1, 8 and 15 of a 28 day 
cycle. 
 
Dasatinib and paclitaxel will be administered with the modalities described above. 
 
Patients enrolled on this trial may be asked to undergo additional radiographic studies performed 
solely for the purpose of this research. In the event that a patient has a complete response (CR), 
confirmatory imaging (4 weeks after imaging which documented CR) is requested per RECIST 
criteria. 
 
The duration of patient treatment will depend on individual response and tolerance.  Patients with 
clearly documented progressive disease by RECIST criteria will be taken off treatment at time of 
progression.  Patients who are responding (complete or partial), or whose disease is stable, will be 


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treated until progression of disease, intolerable toxicity, patient refusal to continue with study, or 
investigator decision to remove patient from study. (Definitions of response, progressive disease and 
stable disease are found in Section 12.0 Criteria for Therapeutic Response/Outcome Assessment). 
 
All patients who receive at least one full cycle (4 weeks) of dasatinib and paclitaxel will be evaluable 
for response. 
 
9.3 
Correlative Studies 
 
Correlative studies will be performed in II portion of the study and will include: 
 
1.   Analysis of mRNA expression on the tumor specimens, for a gene expression profiling of the 
responders versus non-responders, in order to identify potential predictors of response to 
dasatinib. If differentially interesting candidates emerge, immunohistochemistry assays 
including EphA2, IGFBP2, caveolin and phospho-caveolin and other potential predictive 
markers and SFK substrates as available will also be performed. 
 
2.  Exploratory tumor biomarker data: assays of p-SRC, VEGFR2, and Collagen Type IV 
(or N-Telopeptide NTX)  in plasma, obtained at baseline and after 2 cycles of 
treatment (8 weeks), will be performed by enzyme-linked immunosorbent assay. 
 
3.  Circulating tumor cells (CTC) at baseline and after 2 cycles of treatment (8 weeks). 
 
4.   Exploratory somatic gene mutations detection in archived tumor samples. 
 
9.3.1 Analysis of mRNA expression 
Total RNA will be isolated using TRIzol (Invitrogen, Carlsbad, CA), passed over a Qiagen RNeasy 
column  (Qiagen,  Valencia,  CA),  and  double-stranded  cDNA  will  be synthesized  by a  chimeric 
oligonucleotide with an oligo-dT and a T7 RNA polymerase promoter. Reverse transcription will be 
then carried out, followed by biotin labeling and approximately 250-fold linear amplification by in 
vitro transcription (Enzo Biochem, New York, NY). From each sample, ~5 micrograms of labeled 
cRNA will be hybridized onto an Affymetrix U133 GeneChip. 
 
Tissue will be analyzed for expression of mRNA. If differentially interesting candidates emerge, we 
will also perform  immunohistochemistry assays including EphA2, IGFBP2, caveolin and phospho- 
caveolin and other potential predictive markers and SFK substrates as available. These data will be 
integrated with those from other studies to explore the relationship between tumor phenotype and 
response to dasatinib. 
 
9.3.1.1 Methods 
 
Analysis of mRNA expression will be performed at Memorial Sloan Kettering Cancer Center. A 
paraffin block of either a metastatic lesion or the primary breast lesion biopsy specimen will be 


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forwarded  to Dr. Jorge Reis-Filho at the address below. If a paraffin block is unavailable, 10 or more 
unstained slides may be sent for analysis. 
 
Jorge Reis-Filho, MD, PhD 
Memorial Sloan Kettering Cancer Center 
C/O Research Team 
300 E 66th Street, 9th Floor 
New York, NY 10065 
 
9.3.2  Assays of p-SRC, VEGFR2, and Collagen Type IV 
 
The level of p-SRC in peripheral blood mononuclear cells (PBMCs) will be determined by 
enzyme-linked immunosorbent assay, and will be used a surrogate biomarker of the level of 
kinase activity of the SRC family members. 
 
Assays of VEGFR2 and Collagen Type IV in plasma, obtained at baseline and after 2 cycles 
of treatment, will be performed by enzyme-linked immunosorbent assay. 
 
9.3.2.1 p-SRC 
 
Specimens for determination of the level of p-SRC in peripheral blood mononuclear cells 
(PBMCs) will be shipped to Targeted Molecular Diagnostics lab. 
 
9.3.2.1.1 Methods, p-SRC 
 
Two 8-mL CPT blood collection tubes manufactured by BD (blue/black top) will be collected 
from patients. These tubes are provided by Targeted Molecular Diagnostics. MSKCC will 
 
▪ 
Isolate the PBMCs 
▪ 
Spin down to a pellet 
▪ 
Snap freeze and ship on dry ice to: 
 
Quintiles - Westmont 
Attention: Janice Spohn 
777 Oakmont Lane, Suite 100 
Westmont, IL 60559 
www.quintiles.com 
Phone: 630-203-6224 
 
9.3.2.2 VEGFR2 
 
MSKCC will each perform VEGFR2 and collagen Type IV on the specimens of their respective 
patients. 


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9.3.2.2.1 Methods, VEGFR2 
 
VEGFR2 is assayed in heparin plasma (EDTA tube); collagen Type IV (or N-telopeptide- NTX) is 
measured in serum (red and black top tube). Approximately 15 cc of whole blood will be drawn. 
Samples at MSKCC will be sent to Quest Labs for analysis at baseline and after 2 cycles of treatment. 
 
 
 
9.3.3  Circulating tumor cells (CTC) 
 
The measurement of CTC enumeration will be performed with a semiautomated system, CellSearch, 
which uses an EpCAM antibody-based immunomagnetic antibody-capture technology developed by 
Immunicon Corporation.  Blood collected in CellSave tubes will be processed on the CellTracks 
AutoPrep System with the CellSearch Circulating Tumor Cell Kit which is intended for the 
enumeration of CTC of epithelial origin (CD45-, EpCAM+, and cytokeratins 8, 18+, and/or 19+) in 
whole blood.  A magnetic field is used to collect cells of interest without centrifugation. After 
unbound supernatant is removed, the enriched samples are processed for nucleic acid staining with 
DAPI and for markers for epithelial cells with anti-cytokeratin CK-PE. Leukocytes are excluded with 
an anti-CD45 immunofluorescent antibody. Stained cells are analyzed on a fluorescence microscope 
using the Cell Track Analyzer II and CTC are defined as cytokeratin positive, DAPI nucleated cells 
lacking CD45 markers. Automatically selected images are reviewed by the operator for identification 
as tumor cells and quality control is maintained via standard procedures. 
 
9.3.3.1 Methods, CTCs 
 
MSKCC and will each perform these assays on the specimens of their respective patients. For the 
measurement of the circulating epithelial cells, 10 cc of whole blood will be drawn into Cell Save 
Tubes (purple and yellow tiger top tubes).  The tubes are to be kept at room temperature and shipped 
to the MSKCC Clinical Chemistry Research Laboratory. 
 
 
 
9.3.4 Somatic Gene Mutations Detection 
 
Next generation sequencing analyses will be coordinated in Jorge Reis-Filho’s laboratory (MSKCC, 
Pathology), involving Francois-Clement Bidard (Visiting investigator, SKI/Pathology), Kiu Yan 
Charlotte Ng (Post doctoral research fellow, SKI/Pathology) and Britta Weigelt (Assistant Member, 
Pathology). 
 
9.3.4.1 Methods, Next Generation Sequencing 
 
DNA will be extracted from the following materials, whenever available: 
 
archived tumor tissue (primary breast cancer and/or metastasis), after microdissection 
 
previously collected plasma samples 


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 
previously collected peripheral blood mononuclear cells (PBMC) 
 
No supplementary biopsy or blood sampling will be required for this correlative study, which will use 
previously collected samples from the above mentioned correlative studies. Next generation 
sequencing analyses will be performed in the Genomics Core Laboratory. Tumor specific point 
mutations, small insertions and deletions, and somatic rearrangements will be detected by comparing 
tumor DNA (from tumor tissue and/plasma) to its paired normal DNA (from PBMC) and using a 
series of algorithms to identify somatic events, as previously described (Shah et al, Nature 2012; 
Stephens et al, Nature 2012; Banerji et al, Nature 2012). Germline information obtained by means of 
massively parallel sequencing will only be employed in this study for the purpose of comparison to 
the tumor genome. Using computational algorithms, those variant calls in the tumor that are also 
present in the germline will be removed, or “masked” from output reports to investigators. VCF or 
other files of germline data will not be separately analyzed in the future without additional informed 
consent, anonymization, and/or human subjects review by the IRB. 
 
Once the repertoire of somatic mutations and the mutation allelic frequency of each mutation in 
tumor tissue and/or plasma are defined, we will seek any somatic mutation that may be associated 
with a specific pattern of sensitivity to the treatments tested in this clinical trial. 
 
10.0     EVALUATION DURING TREATMENT/INTERVENTION 
 
A number of measures will be taken to ensure the safety of patients participating in this trial.  These 
measures will be addressed through exclusion criteria and routine monitoring. 
 
Patients enrolled in this study will be evaluated clinically and with standard laboratory tests before 
and at regular intervals during their participation in this study, as detailed in the table below. 
 
For the phase I portion of the study, safety evaluations will be performed every 2 weeks and will 
consist of: 
 
 
medical interviews (+/- 1 day) 
 
 
recording of adverse events (+/- 1 day) 
 
 
review of diary of study drug (+/- 1 day) 
 
 
physical examinations with vital signs (blood pressure, pulse, temperature), height and 
body weight and ECOG performance status. (+/- 1 day) 
 
 
laboratory measurements.  (CBC will be performed weekly) (+/- 1 day) 
 
 
 
For the phase II portion of the trial, patients will be evaluated every four weeks. Safety evaluations 
will consist of: 
 
 
medical interviews (+/- 1 day) 


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 
recording of adverse events (+/- 1 day) 
 
 
review of diary of study drug (+/- 1 day) 
 
 
physical examinations with vital signs (blood pressure, pulse, temperature), height and 
body weight, and ECOG performance status. (+/- 1 day) 
 
 
laboratory measurements.  (CBC will be performed  weekly only on weeks that paclitaxel 
is administered +/- 1 day) 
 
 
Patients will be evaluated for adverse events (all grades), serious adverse events, and adverse events 
requiring study drug interruption or discontinuation at each study visit for the duration of their 
participation in the study. 
Patients will be provided with a diary in which to record their intake of study drug. 
 
Patients will be assessed radiographically for tumor response after the first two cycles of treatment 
(Cycle #2, Week #4), and every three cycles thereafter (eg, Cycle #5, Week 4; Cycle #8, Week 4; 
etc.). Follow-up imaging should be performed according to the same protocol as the baseline 
assessment of the target lesions. However, after the pre-study evaluation, the bone scan is only 
required at the treating physician’s discretion. 
 
 
In responding patients, the response should be confirmed a minimum of 4 weeks after the first 
response has been recorded, if possible. 
 
 
 
Tumor assessments should be made on each patient within 2 weeks of study completion, 
withdrawal or discontinuation, as appropriate, even if the patient demonstrates physical 
evidence of progressive disease and withdraws from the study before the first scheduled 
tumor assessment. 
 
End-of-Study Evaluation: At the time patients are removed from study, laboratory (eg, CBC, 
CMP) and clinical evaluations to assess adverse events (AEs) will be performed.  Radiologic 
studies for antitumor response will be repeated if they have not been done within the previous 
28 days. 
 
 
10.1 
Patients discontinued from the treatment phase of the study for any reason will be 
evaluated with a clinical visit ~30days (28–42 days) after the decision to discontinue 
treatment. 


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Time and Events Schedule: Phase II 
Study Parameter 
Prestudy 
(Day –28 to 
1) 
Prestudy 
(Day -14 to 1) 
CYCLE 1-CYCLE 2 
≥ CYCLE 3 g 
Study 
Termination 
Day 1 
(+/- 1 
day) 
Day 8 
(+/- 1 day) 
Day 15 
(+/- 1 
day) 
Day 22 
(+/- 1 
day) 
Day 1 
(+/- 1 
day) 
Day 8 (+/- 
1 day) 
Day 15 
(+/- 1 
day) 
Day 22-28 
(+/- 1 day) 
Informed consent 
X 
Pathology review 
X 
History 
X 
X 
X 
X 
Pill count and diary 
review 
X 
Physical examination 
X 
X 
X 
Vital signsb 
X 
X 
X 
Height and body weight 
X 
X 
X 
ECOG performance 
status 
X 
X 
X 
Tumor assessment 
(clinical) 
X 
X 
X 
Tumor assessment 
(radiological) 
a 
X 
d,e 
X 
X 
Toxicity assessment by 
NCI CTC v.3 
X 
X 
X 
CBC with differential, 
platelet count 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistryh 
X 
Xi 
X 
X 
PT/PTT 
X 
EKG 
X 
Xi 
X 
Pregnancy testc 
X 
Correlative blood 
samples 
X 
Xf 
Analysis of mRNA 
expression on the tumor 
specimens 
X 
Protocol Therapy 
T +D* 
T+D 
T+D 
D 
T+D 
T+D 
T+D 
D 
* T= paclitaxel 
 
D= dasatinib 


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a 
Radiographic tumor assessment should include CT scan chest, abdomen and pelvis and bone scan to determine extent of disease and identify 
target lesions to be used for judging response per RECIST criteria. After pre-study evaluation, a bone scan is only needed per the physician’s 
discretion. If target lesion best visualized using MRI, then subsequent tumor assessment must utilize this same imaging modality (see d). A 
chest x-ray can be performed as the discretion of the investigator. 
b 
Vital signs include blood pressure, pulse and temperature. 
c 
Pregnancy test may be from serum or urine. 
d 
Tumor assessments performed after the first 2  cycles, and then every 3 cycles: Cycle 2, Cycle 5 , etc. All assessments obtained during the 
study should be made using the same types of study, e.g., CT scan, as was used at baseline. If possible, the same equipment should be used. 
e 
Only the indicator lesions need to be assessed every 3 cycles, unless a complete response is claimed, in which case the patient must undergo a 
complete assessment of all sites of disease. 
f 
Blood samples for correlative studies will be drawn at baseline and after 2 cycles of therapy (day 1 of cycle 3) on the phase II portion of the 
study only . 
g 
During the phase I trial, patients will be evaluated every two weeks; during the phase II trial, patients will be evaluated every 4 weeks. 
h 
Serum Chemistry includes Na, K, Cl, CO2, BUN, Creat, Ca, Glu, T. Protein, Alb, Alk Phos, T. Bili, AST, ALT, Magnesium, and 
Phosphorous. 
i 
The serum chemistry and EKG are not required for cycle 1, Day 1 as they were assessed in pre-study workup. 


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11.0     TOXICITIES/SIDE EFFECTS 
 
This study will use the NCI Common Toxicity Criteria (CTC) version 3.0 for toxicity. 
 
 
11.1 Dasatinib Toxicity 
 
Myelosuppression 
 
Treatment with dasatinib is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, 
neutropenia, and anemia. Their occurrence is more frequent in patients with advanced CML or 
Ph+ ALL than in chronic phase CML. Complete blood counts should be performed weekly for 
the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was 
generally  reversible  and  usually  managed  by  withholding  dasatinib  temporarily  or  dose 
reduction. In a Phase 3 dose-optimization study in patients with chronic phase CML, Grade 3 or 
4 myelosuppression was reported less frequently in patients treated with 100 mg once daily than 
in patients treated with 70 mg twice daily. (1) 
 
Bleeding Related Events 
 
In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction 
in vitro. In all clinical studies, severe central nervous system (CNS) hemorrhages, including 
fatalities, occurred in <1% of patients receiving dasatinib. Severe gastrointestinal hemorrhage 
occurred in 4% of patients and generally required treatment interruptions and transfusions. Other 
cases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated 
with severe thrombocytopenia. 
 
Patients were excluded from participation in dasatinib clinical studies if they took medications 
that inhibit platelet function or anticoagulants. In some trials, the use of anticoagulants, aspirin, 
and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with dasatinib if 
the platelet count was >50,000. Caution should be exercised if patients are required to take 
medications that inhibit platelet function or anticoagulants. (1) 
 
Fluid Retention 
 
Dasatinib is associated with fluid retention. In all clinical studies, severe fluid retention was 
reported in 8% of patients, including pleural and pericardial effusion reported in 5% and 1% of 
patients, respectively. Severe ascites and generalized edema were each reported in <1% of 
patients. Severe pulmonary edema was reported in 1% of patients. Patients who develop 
symptoms suggestive of pleural effusion such as dyspnea or dry cough should be evaluated by 
chest X-ray. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid 
retention events were typically managed by supportive care measures that include diuretics or 
short courses of steroids. 
 
In the Phase 3 dose-optimization study in patients with chronic phase CML, fluid retention 
events were reported less frequently in patients treated with 100 mg once daily than in patients 
treated with 70 mg twice daily. (1) 


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The following guidelines may be helpful: 
 
 
Chest x-rays are recommended if the subject presents with symptoms suggestive of pleural 
effusion 
     Early institution of diuresis – eg, furosemide 20-40 mg po daily  and/or spironolactione 25- 
50 mg po  daily, titrate to symptoms 
     Management of symptomatic pleural effusion with thoracentesis 
 
For   symptomatic   pleural   effusion,   study   drug   interruption   and   administration   of 
corticosteroids (e.g. prednisone, 40 mg/day for 3- 5 days, with taper) has been effective in 
some patients. 
     Dose reduction may be necessary if fluid retention or pleural effusion is severe or recurrent 
 
Complaints  of  chest  discomfort  -  echocardiogram  should  be  performed  to  investigate 
possible pericardial effusion 
 
Severe or recurrent pleural effusions – interrupt dosing, permit recovery to Grade 0-1, and 
restart dosing at appropriate dose level 
 
QT Prolongation 
 
In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization 
(QT interval). In single-arm clinical studies in patients with leukemia treated with dasatinib, the 
mean QTc interval changes from baseline using Fridericia’s method (QTcF) were 3–6 msec; the 
upper 95% confidence intervals for all mean changes from baseline were <8 msec. Nine patients 
had QTc prolongation reported as an adverse event.  Three patients (<1%) experienced a QTcF 
>500 msec. 
 
Dasatinib should be administered with caution to patients who have or may develop prolongation 
of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital 
long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that 
lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalemia or 
hypomagnesemia should be corrected prior to dasatinib administration. (1) 
 
Other side effects might include: 
 
 
Fatigue 
 
 
Gastrointestinal side effects, including nausea, vomiting or diarrhea, loss of appetite, 
abdominal pain, constipation, or bloating 
 
 
Muscle and joint aches 
 
 
Headaches 
 
 
Skin rashes 
 
 
Fever 
 
 
Dizziness, confusion, depression, tiredness, sleepiness, trouble sleeping, tingling or 
numbness in the arms or legs, changes in taste, and ringing in ears have been seen in 
patients taking dasatinib. 


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11.2 Paclitaxel Toxicity 
 
Side-effects include alopecia, myelosuppression, fatigue, neuropathy, arthralgia, 
myalgia, 
onycholysis, taste changes, amenorrhea, teratogenesis, hypersensitivity (hypotension, 
flushing, chest pain, abdominal or extremity pain, skin reactions, pruritus, dyspnea, 
bronchospasm, and tachycardia), sinus bradycardia, complete heart block, sinus 
tachycardia, 
premature ventricular beats, ventricular tachycardia, bigeminy, syncope, myocardial 
infarction, hypotension, hypertension, dizziness, visual changes, radiation recall, 
abdominal 
pain, diarrhea, typhlitis, ischemic colitis, abnormal liver function, pancreatitis, abnormal 
triglyceride, and seizures. 
 
11.3 Chemotherapy Delay 
 
Treatment may be delayed no more than 3 weeks to allow recovery from acute toxicity. If 
toxicity requires a dosing delay/interruption of more than three weeks, the patient will be 
withdrawn from the study for toxicity reasons. If treatment is delayed for 2 consecutive weeks 
and is ready to resume treatment on day 22 of a cycle, the patient should advance to the next 
cycle and start a new cycle.  Patients that require discontinuation of dasatinib, but who have not 
progressed, should continue paclitaxel until unacceptable toxicity/progression. These patients 
should be counted (intent to treat) towards endpoints such as progression-free survival. 
 
11.4 Dose modification for paclitaxel 
 
This study will use the NCI Common Toxicity Criteria (CTC) version 3.0 for toxicity. If a 
patient develops multiple toxicities, delay treatment or modify dose based on the greatest 
indicated dose reduction or delay. Dose re-escalations are not allowed. 
 
o 
If on the day that paclitaxel is due, platelet counts are <100, 000/µL and/or ANC 
<1,000/µL and/or non-hematologic toxicities (excluding alopecia, fatigue, peripheral 
neuropathy, nausea and arthralgias, and hepatic toxicities, described below) have not 
recovered to Grade 1, treatment should be delayed by up to 1 week and CBC and toxicity 
grading repeated weekly.  For hepatic toxicities (including ALT, AST, and total bilirubin), 
if the patient develops any hepatic grade 3 or 4 toxicity thought to be related to study 
therapy, paclitaxel may be held until the toxicity resolves, at the physician’s discretion.  If 
hematologic and non-hematologic toxicity have not recovered, a further delay of up to one 
week is allowed. If a chemotherapy treatment delay of >3 consecutive weeks is required, 
the patient will be removed from the study. 
 
Other non-hematologic toxicities: For patients who experience peripheral neuropathy, 
paclitaxel may be dose-reduced following the schema presented in Section 4.3. 
 
o 
Hypersensitivity Reactions: If a hypersensitivity reaction occurs symptoms such as 
flushing, skin reactions, dyspnea, hypotension, or tachycardia may require temporary 


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interruption of the infusion.  However, severe reactions, such as hypotension requiring 
treatment, dyspnea requiring bronchodilators, angioedema or generalized urticaria require 
immediate discontinuation of paclitaxel and aggressive symptomatic therapy.  Patients who 
develop severe hypersensitivity reactions may be re-challenged following premedication 
that the institution would typically use. (Appendix B) There are no dose reductions for 
hypersensitivity reactions. Consider discontinuation of therapy if patient experiences 2 
episodes of Grade 3 hypersensitivity reaction to paclitaxel. 
 
11.5 Dose modification for dasatinib 
 
11.5.1 Dose modification for dasatinib in the phase I trial: 
 
See also Section 4.3. Dasatinib dose may be withheld for any adverse event if the 
investigator feels it is due to dasatinib, and/or not well-controlled by medications, and/or still 
present at the time of visit. 
 
If the dasatinib was held for a DLT at Cycle#1, the patient will be removed from study. If, in 
subsequent cycles, a patient develops a Grade 2 or 3 adverse event felt to be related to 
dasatinib, and the investigator deems the patient is benefiting from study therapy, dasatinib 
might be held and then resumed either at full dose, or at the reduced dosing of the previous 
cohort. 
 
11.5.2 Dose modification for dasatinib in the phase II trial: 
 
Dasatinib dosage may be adjusted so that any drug-related toxicity is adequately 
managed with outpatient therapy or deemed by the physician as clinically acceptable. 
 
The dose adjustment of dasatinib in case of toxicity will follow the dosing schedule 
schema presented for the phase I portion of the study. For example, if the phase II 
dosing of dasatinib is 120 mg daily continuously, and a patient develops a toxicity related to 
dasatinib, the dosing may be modified as follows: 
 
Grade 
 
0-1 
No change 
2 
Not adequately managed with outpatient therapy and/or deemed to be 
clinically-unacceptable: decrease one dosing level (to 100 mg daily 
continuously) at the physician’s discretion 
3 
Not adequately managed with outpatient therapy and/or deemed to be 
clinically unacceptable: decrease one dosing level (to 100 mg daily 
continuously) or two dosing levels (to 70 mg daily continuously) at 
physician’s discretion 
4 
Decrease two levels or stop therapy at the physician’s discretion 


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12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
All patients who receive at least one dose of dasatinib or paclitaxel will be evaluable for toxicity. 
All patients who receive at least one full cycle of dasatinib and paclitaxel (4 weeks) will be 
evaluable for MTD assessment and response. 
 
12.1 
Primary Endpoint 
 
 
Phase I Portion 
 
The primary endpoint of the phase I portion of the trial is the maximum tolerated dose (MTD) of 
dasatinib when given in conjunction with paclitaxel. The MTD is defined as the highest dose 
studied for which the incidence of DLT is less than 33%. The MTD will be determined as 
described in Section 4.3 Phase I Design. 
 
 
Phase II Portion 
 
The primary endpoint of the phase II trial is the overall response rate of dasatinib plus paclitaxel, 
for patients with HER2 negative metastatic breast carcinoma. This is defined as the percentage of 
patients who achieve either an objective complete or partial target lesion response that is 
confirmed based on the RECIST criteria as described in Appendix E (Response Evaluation 
Criteria in Solid Tumors (RECIST). Only measurable lesions which have not been irradiated will 
be used as indicator lesions. These must have a minimum size of at least one diameter of 10 mm 
for liver, soft tissue lesions, lung, skin and lymph node lesions. 
 
12.2 
Secondary Endpoints 
 
Phase I Portion 
 
 
To obtain preliminary data on the therapeutic activity of dasatinib when administered 
in combination with weekly paclitaxel. 
 
Phase II Portion: 
 
 
To obtain safety and tolerability of dasatinib when administered in combination 
with weekly paclitaxel. 
 
To estimate secondary efficacy endpoints of this combination including clinical 
benefit (CR+PR+SD > 6 months), time to tumor progression (TTP), and 
progression free survival (TTP) and duration of response. 
 
To obtain exploratory tumor biomarker data: assays of p-SRC, VEGFR2 
and Collagen Type IV (NTX) in plasma, obtained at baseline and after 2 
cycles of treatment (8 weeks), will be performed by enzyme-linked 
immunosorbent assay. 
 
To perform analysis of mRNA expression on the tumor specimens, for a gene 
expression profiling of the responders versus non-responders, in order to identify 
potential predictors of response to dasatinib. If differentially interesting 


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candidates emerge, immunohistochemistry assays including EphA2, IGFBP2, 
caveolin and phospho-caveolin and other potential predictive markers and SFK 
substrates as available will also be performed. 
 
To collect circulating tumor cells (CTC) at baseline and after 2 cycles of 
treatment (8 weeks). 
 
To correlate somatic genetic alterations with tumor response. 
 
Definitions: 
 
     Clinical benefit 
Clinical benefit is defined as the sum of the percentage of patients achieving complete 
response, partial response and stable disease for greater than 6 months (as defined by 
RECIST criteria) 
     Time to tumor progression 
Time to disease progression (TTP) will be measured from the start of treatment to the time 
the patient is first recorded as having disease progression. If a patient never progresses while 
being followed, the patient will be censored at the time he or she terminates the study or by 
the date of death. Patients who die without progression of disease will be censored at time of 
death. 
     Duration of response 
Duration of response is measured from the time measurement criteria are met for CR/PR 
(whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
A secondary endpoint of the phase II trial is to assess the overall safety profile of this regimen. 
The toxicity rate will be reported. The type, frequency, severity, timing and relationship of each 
toxicity will be determined as per the NCI Common Toxicity Criteria, version 3. 
 
Safety & tolerability measures include but are not limited to: 
 
     the incidence of treatment-emergent adverse events (AEs) and serious adverse events 
(SAEs) 
     hematologic toxicity including neutropenia, anemia and thrombocytopenia 
 
non-hematological toxicity changes from baseline in hematology and clinical chemistry 
values 
     physical examination 
 
the incidence of patients experiencing dose modifications, dose interruptions, and/or 
premature discontinuation of study drug. 
 
13.0     CRITERIA FOR REMOVAL FROM STUDY 
 
Patients have a right to withdraw from the study at any time for any reason. The investigator also 
has the right to withdraw patients from the study in the event of intercurrent illness, adverse 
events, and treatment failure or protocol violations. As an excessive rate of withdrawals can 


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render the study un-interpretable, unnecessary withdrawals should be avoided. When a patient 
discontinues treatment early, the investigator will make every effort to contact the patient and to 
perform a final evaluation. The reason for withdrawal will be recorded. Criteria for terminating 
participation in the study are as follows: 
1.   Intercurrent illness which would in the judgment of the investigator effect assessments of 
clinical status to a significant degree or require discontinuation of drug. 
 
2.   Severe or unacceptable toxicity. 
 
3.   Progressive disease 
 
4.   Request by the patient to withdraw. 
 
5.   General or specific changes in the patient’s condition that would render the patient 
ineligible for further treatment according to the inclusion/exclusion criteria. 
 
6.   Administrative reasons (including but not limited to): non-compliance with medication, 
failure to return for follow up visits, termination of the clinical trial by the investigator. 
 
7.   Chemotherapy treatment delay of >3 consecutive weeks. 
 
8.   If at any time the patient is found to be ineligible for the protocol as designated in the 
section on Criteria for Patient/Subject Eligibility (i.e., a change in diagnosis), the patient 
will be removed from the study. 
  
Patients who receive additional therapy or deviate from the treatment program by adding another 
breast cancer directed agent, undergoing surgery or receiving radiation for an identifiable lesion 
or substantially modify the dosage or schedule as prescribed will be considered a major protocol 
violation. 
 
 
14.0     BIOSTATISTICS 
 
This is a multi-center (two centers), open-label phase I/II trial with MSKCC serving as the lead 
center. The objective of the phase I portion of the trial is to determine the MTD of dasatinib 
when given in combination with a fixed dose of weekly paclitaxel.  Dasatinib will be dose 
escalated to determine the MTD using a standard, three-patient per cohort dose escalation 
schedule. The starting dose of dasatinib is 70 mg daily, given continuously (Dose level 0).  Three 
dose escalations with 2 schedules (continuous and intermittent) from dose level 0 are possible.  If 
the MTD is with dasatinib < 100 mg daily given continuously, then that dose will be assessed on 
5 days per week schedule, corresponding to a 28% reduction in total weekly dose. If tolerated, 
escalation may resume on the intermittent schedule. One dose reduction level has been included, 
if necessary.   Between 6 and 54 patients will be required to determine the MTD of dasatinib. 
There will be no intrapatient dose escalation.  Details of the dose escalation strategy are provided 
in section 4.3. 


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It is expected that the maximum of 54 patients for the Phase I portion of the study will be 
enrolled in less than one year, between the two centers.  This portion of the study will be open to 
all patients with metastatic breast carcinoma, regardless of ER/PR/HER2 status and number of 
prior regimens.  Summary statistics such as mean, median, counts and proportions will be 
calculated for all secondary analyses. 
 
Once the MTD for dasatinib has been identified, additional patients will be enrolled into the 
Phase II portion of the study to determine the efficacy and of dasatinib at the MTD when 
administered in combination with weekly paclitaxel.  Efficacy will be measured in terms of 
response rate as assessed after two cycles of therapy. The target population for the Phase II 
portion of the study will be metastatic breast cancer patients who have had 0 to 2 prior regimens 
and have HER2 negative disease.  Early studies on breast cancer therapy have shown that 
paclitaxel as monotherapy induces response rates ranging from 20 - 50 %. (16, 17) 
However, more recent randomized trials have reported more modest response rates, in 
the range of 14-16%, likely due to the fact that more patients are receiving overall more 
chemotherapy in the adjuvant setting. (18, 19)  Based on these data, we have chosen a 15% 
as the response rate under which the therapy of dasatinib with paclitaxel will not be considered 
for further investigation.  We have chosen a response rate of 30% where the dasatinib with 
paclitaxel regimen will be considered for further study. 
 
 
Simon’s two-stage optimal design will be used to test the null hypothesis of a 15% response rate 
against the alternative of a 30% response rate.  Setting both the Type I and Type II errors at 10%, 
23 patients will initially enter the study.  If there are 3 or fewer responses observed, the study 
will be terminated early and declared to have a negative result.  If 4 or more responses are 
observed, enrollment will be extended to 55 patients.   If 12 or more responses are observed 
among the 55 patients, the study will be considered to have a positive result and this regimen will 
be considered worthy of further testing.  For this design, the probability of early termination is 
54% if the true response probability is < 15%.  Upon completion of the study, the true response 
rate will be estimated via the observed response rate and an exact confidence interval will be 
constructed. 
 
There are several secondary analyses planned for the Phase II portion of this study.   Selected 
non-hematologic and hematologic toxicities, as measured by the NCI CTCAE Version 3.0, will 
be described by frequency and grade, by cycle and over all cycles, with the maximum grade over 
all cycles used as the summary measure per patient.  Clinical benefit will be estimated via the 
observed  rate  and  exact  95%  confidence  interval  while  time  to  tumor  progression  and 
progression free survival will be estimated using Kaplan-Meier methodology. 
 
For all other secondary endpoints, such as of p-SRC, VEGFR2, Collagen Type IV, CTC and 
mRNA expression analysis on tumor specimens, summary statistics such as mean, median, 
counts and proportions will be calculated.  If required, summary statistics will be calculated and 
graphed by cycle to uncover any temporal trends.  No formal statistical analysis on the secondary 
endpoints will be done. 


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For the Phase II portion of the study, accrual of a maximum of 55 patients will take close to one 
year with anticipated enrollment of 4 patients per month over the two centers.  In total, both 
Phase I and Phase II portions of this study will take a maximum of 3 years to complete. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am 
– 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic Registration 
System (http://ppr/).  The completed signature page of the written consent/RA or verbal 
script/RA, a completed Eligibility Checklist and other relevant documents must be uploaded via 
the PPR Electronic Registration System. 
 
16.0 
DATA  MANAGEMENT 
 
16.1  Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001.   The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute for 
Data 
and 
Safety 
Monitoring 
of 
Clinical 
Trials” 
which 
can 
be 
found 
at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html.    The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research.  The MSKCC Data and Safety 
Monitoring 
Plans 
can 
be 
found 
on 
the 
MSKCC 
Intranet 
at: 
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety and 
quality.     There  are  institutional  processes  in  place  for  quality  assurance  (e.g.,  protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education on 
clinical research QA) and departmental procedures for quality control,   Plus, there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs.  The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center’s Research Council and Institutional Review Board. 


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During the protocol development and review process, each protocol will be assessed for its level 
of risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and the 
monitoring procedures will be established at the time of protocol activation. 
 
16.2 Regulatory Documentation 
 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSKCC Institutional Review Board/Privacy Board (IRB/PB). 
 
17.0     PROTECTION OF HUMAN SUBJECTS 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
Guidelines of the International Conference on Harmonization (ICH) of Technical Requirements 
for Registration of Pharmaceuticals for Human Use, and in full compliance with the World 
Medical Association Declaration of Helsinki and its most recent amendments. 
 
Participation in this study is entirely voluntary on the part of the patient. During the process of 
informed consent, the potential risks and benefits of trial participation will be discussed with the 
patient. Alternative treatment options will be reviewed as well. Patients who have enrolled on 
study have a right to withdraw from the protocol at any time for any reason as described in 
Section 13.0 Criteria for Removal from Study. 
 
Regarding the inclusion of children in research, this protocol/project does not include children 
because the occurrance of metastatic breast cancer in children is rare and because the majority of 
these affected children are already accessed by a nationwide pediatric cancer research network. 
This statement is based on exclusion 4b of the NIH Policy and Guidelines on the Inclusion of 
Children as Participants in Research Involving Human Subjects. 
 
17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form.  The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form.  A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board. 
 
 
 
17.2 
Serious Adverse Event (SAE) Reporting 
Any SAE must be reported to the IRB as soon as possible but no later than 5 calendar days. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org. The report should contain the following 
information: 


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Fields populated from the CRDB: 
 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
 
Medical record number 
 
Disease/histology (if applicable) 
 
Protocol number and title 
 
Data needing to be entered: 
 
The date the adverse event occurred 
 
The adverse event 
 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
 
If the AE was expected 
 
The severity of the AE 
 
The intervention 
 
Detailed text that includes the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
 
 
17.2.1 Adverse Events 
 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not necessarily have to 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of dasatinib whether or not considered related to dasatinib. 
 
During clinical trials, adverse events can be spontaneously reported or elicited during open- 
ended questioning, examination, or evaluation of a subject. (In order to prevent reporting bias, 
subjects should not be questioned regarding the specific occurrence of one or more adverse 
events.) 
 
A serious AE is any untoward medical occurrence that at any dose: 
 
     results in death, 
 
is life-threatening (defined as an event in which the patient was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe), 
     requires inpatient hospitalization or causes prolongation of existing hospitalization, 
     results in persistent or significant disability/incapacity, 
     is a congenital anomaly/birth defect, 


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     results in the development of drug dependency or drug abuse, 
 
 is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the patient or may require intervention (e.g., medical, 
surgical)  to  prevent  one  of  the  other  serious  outcomes  listed  in  the  definition  above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) For reporting purposes, also consider the occurrences of pregnancy 
or overdose (regardless of adverse outcome) as events which must be reported as important 
medical events. 
 
 
 
NOTE: 
•  Hospitalizations (exceptions): Criteria for hospitalizations not reported as SAEs 
include admissions for: 
 
− Planned as per protocol medical/surgical procedure 
− Routine health assessment requiring admission for baseline/trending of health 
status documentation (e.g., routine colonoscopy) 
− Medical/surgical admission for purpose other than remedying ill health state 
(planned prior to entry into study trial; appropriate documentation required) 
− Admission encountered for other life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g. lack of housing, 
economic inadequacy, care-giver respite, family circumstances, administrative) 
 
17.2.3 Reporting of SAEs 
 
Following the subject’s written consent to participate in the study, all SAEs should be collected 
and reported, including those thought to be associated with clinical trial procedures. Following 
study completion, any SAE thought to be related to study drug or clinical trial procedures should 
also be reported to BMS. 
 
SAE terminology and severity grading will be based on (i.e. CTCAEv3). 
 
The  following  categories  and  definitions  of  causal  relationship  to  study  drug  should  be 
considered for use for all clinical studies supported by BMS: 
 
 
Certain: There is a known causal relationship between the study drug and the SAE. The 
event responds to withdrawal of study drug (dechallenge), and recurs with rechallenge when 
clinically feasible. (>95% certainty) 
 
Probable: There is reasonable causal relationship between the study drug and the SAE. The 
event responds to dechallenge. Rechallenge is not required. (65%-95% probability) 
     Possible: There is reasonable causal relationship between the study drug and the  SAE. 
Dechallenge information is lacking or unclear. (35%-65% probability of relatedness) 


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 
Not likely: There is temporal relationship to study drug administration, but there is not a 
reasonable causal relationship between the study drug and the SAE. (5-35% probability of 
relatedness) 
 
Not related: There is not a temporal relationship to study drug administration (too early, or 
late, or study drug not taken), or there is known causal relationship between the SAE and 
another drug, concurrent disease, or other circumstance. (<5% chance of relatedness) 
 
 
 
Adverse events classified as “serious” require expeditious handling and reporting to BMS to 
comply with regulatory requirements. 
 
All SAEs whether related or unrelated to dasatinib, must be immediately reported to BMS 
(by the investigator or designee) within 24 hours of becoming aware of the event.  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 be faxed or emailed to BMS at: 
 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
 
Collection  of  complete  information  concerning  SAEs  is  extremely  important.     Full 
descriptions of each event will be followed by BMS. 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. 
 
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. 
 
AEs should be followed to resolution or stabilization, and reported as SAEs if they become 
serious. This also applies to subjects experiencing AEs that cause interruption or 
discontinuation of dasatinib, or those experiencing AEs that are present at the end of their 
participation in the study; such subjects should receive post-treatment follow-up as 
appropriate. 
 
In  BMS  supported  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 dasatinib. 


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17.3 Safety Reports 
 
 
 
MSKCC must submit safety reports to the MSKCC IRB/PB according to institutional 
guidelines. 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating 
their consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following: 
1.   The nature and objectives, potential risks and benefits of the intended study. 
2.   The length of study and the likely follow-up required. 
3.   Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4.   The name of the investigator(s) responsible for the protocol. 
5.   The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
REFERENCE(S) 
 
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13. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal 
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22. Kloth MT, Laughlin KK, Biscardi JS, et al. STAT5b, a Mediator of Synergism 
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23. Cabioglu N, Summy J, Miller C, et al. CXCL-12/Stromal Cell-Derived Factor 1α 
Transactivates HER2-neu in Breast Cancer Cells by a Novel Pathway Involving Src 
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24. Song RX-D, Zhang Z, Santen RJ. Estrogen rapid activation via protein complex 
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26. Diaz N, Minton S, Cox C, et al. Activation of STAT3 in primary tumors from 
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27. Madan R, Smolkin MB, Cocker R, et al. Focal adhesion proteins as markers of 
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28. Nam J-S, Ino Y, Sakamoto M, Hirohashi S. Src Kinase Inhibitor PP2 Restores the 
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29. Park HB, Golubovskaya V, Xu L, et al. Acrivated Src increases adhesion, 
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and α2-integrin expression in human breast cancer cells. Biochem J [2004] 378:559- 
567. 
30. Robledo T, Arriaga-Pizano L, Lopez-Perez M, Salazar EP. Type IV collagen 
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31. Schlegel A, Wang C, Pestell RG, Lisanti MP. Ligand-independent activation of 
oestrogen receptor alpha by caveolin-1. Biochem J. [2001] 359:203-210. 
32. Salatino M, Beguelin W, Proietti C, et al. Progestin-induced caveolin-1 
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mediates breast cancer cells proliferation. AACR 2005 Abstr#2937. 
33. Li T, Sotgia F, Vuolo MA, et al. Caveolin-1 Mutations in Human Breast Cancer: 
Functional Association with Estrogen Receptor (ERα) Positive Status. Am J Pathol 
[2006] in press. 
34. Zhang W, Razani B, Altschuler Y, et al. Caveolin-1 Inhibits Epidermal Growth 
Factor-stimulated Lamellipod Extension and Cell Migration in Metastatic Mammary 
Adenocarcinoma Cells (MTLn3). J Biol Chem [2000] 275:20717-20725 
35. Elicieri BP, Paul R, Schwartzberg PL, et al. Selective requirement for Src 
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during VEGF-induced angiogenesis and vascular permeability. Mol Cell [1999] 
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36. Summy JM, Trevino JG, Baker CH, Gallick GE. c-Src regulates constitutive and 
EGF-mediated VEGF expression in pancreatic tumor cells through activation of 
phosphatidyl inositol-3 kinase and p38 MAPK. Pancreas [2005] 31:263-274. 
37. Laird AD, Li G, Moss KG, et al. Src family kinase activity is required for signal 
tranducer and activator of transcription 3 and focal adhesion kinase phosphorylation 
and vascular endothelial growth factor signaling in vivo and for anchorage- 
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and -independent growth of human tumor cells. Mol Cancer Ther. [2003] 2:461-469 
38.  Weis S, Cui J, Barnes L, Cheresh D. Endothelial barrier disruption by VEGF-mediated 
Src activity potentiates tumor cell extravasation and metastasis. J Cell Biol. 2004 Oct 
25;167(2):223-9. 
39.  Luo FR, Luo FR, Barrett Y et al. Dasatinib (BMS-354825) pharmacokinetics correlate 
with pSRC pharmacodynamics in phase I studies of patients with cancer (CA180002, 
CA180003). Proc Am Soc Clin Oncol 2006, abstract 3046. 
40. Surawska H, Ma PC, Salgia R. The role of ephrins and Eph receptors in cancer. 
Growth Factor Reviews [2004] 15:419–433 
41. Fox BP, Kandpal RP. Invasiveness of breast carcinoma cells and transcript 
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Eph receptors and ephrin ligands as molecular markers of potential diagnostic and 
prognostic application. Biochem Biophys Res Comm [2004] 318:882-892. 
42. Carles-Kinch K, Kilpatrick KE, Stewart JE, Kinch MS. Antibody targeting of the 
EphA2 Tyrosine Kinase Inhibits Malignant Cell Behavior. Cancer Res [2002] 
62:2840-2847. 
43. Coffman KT, Hu M, Carles-Kinch K, et al. Differential EphA2 Epitope Display on 
Normal versus Malignant Cells. Cancer Res [2003] 63:7907-7912. 
44.  Braun S, Cevatli BS, Assemi C, et al. Comparative analysis of micrometastasis to the 
bone marrow and lymph nodes of node-negative breast cancer patients receiving no adjuvant 
therapy. J Clin Oncol 2001;19(5):1468-75. 
45.  Braun S, Pantel K, Muller P, et al. Cytokeratin-positive cells in the bone marrow and 
survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000;342(8):525-33. 
46.  Braun S, Vogl F, Schlimok G, al. E. Pooled analysis of prognostic impact of occult 
metastatic cells in bone marrow-10-year survivial of 4,268 breast cancer patients. Breast 
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47.  Weigelt B, Bosma AJ, Hart AA, Rodenhuis S, van 't Veer LJ. Marker genes for 
circulating tumour cells predict survival in metastasized breast cancer patients. Br J Cancer 
2003;88(7):1091-4. 
48.  Terstappen LW, Rao C, Gross S, Weiss AJ. Peripheral blood tumor cell load reflects the 
clinical activity of the disease in patients with carcinoma of the breast. Int J Oncol 
2000;17(3):573-8. 
49.  Hayes D, Cristofanilli M, Budd GT, al. E. Monitoring circulating tumor cell (CTC) 
levels to predict rapid progression in metastatic breast cancer (MBC): A prospective, multi- 
institutional trial. Proc Am Soc Clin  Oncol 2004. 
50.  Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, 
and survival in metastatic breast cancer. N Engl J Med 2004;351(8):781-91. 
51.  Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal 
antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 
2001;344(11):783-92. 
 
20.0 
APPENDICES 
 
Appendix A ECOG Performance Status 
Appendix B Management of Acute Hypersensitivity For Paclitaxel 
Appendix C Prohibited and Restricted Concomitant Medications with Dasatinib 
Appendix D RECIST Criteria 


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APPENDIX A 
 


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APPENDIX B 
 
 


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APPENDIX C 
  
 
KNOWN INDUCERS & INHIBITORS OF ISOENZYME CYP3A4 
Inducers 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampin 
Rofecoxib (mild) 
St John’s w ort 
Sulfadimidine 
Sulfinpyrazone 
Inhibitors 


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Amiodarone 
Anastrozole 
Azithromycin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (w eak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
lndinavir 
lsoniazid 
ltraconazole 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (w eak) 
Oxiconazole 
Paroxetine (w eak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (w eak) 
Verapamil 
Zafirlukast 
Zileuton 
 
 
Concomitant use of H2 blockers or Proton Pump inhibitors: 
The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is not recommended. The use of antacids should be considered in place 
of H2 blockers or proton pump inhibitors in patients receiving dasatinib therapy. If antacid therapy is needed, the antacid dose should be administered 
at least 2 hours prior to or 2 hours after the dose of dasatinib. 
 
 
 
 
 
 
 
 
 
 
APPENDIX D 
RECIST CRITERIA 
Tumor measurement 
 
 
Measurable disease: the presence of at least one measurable lesion.  If the measurable disease 
is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
 
Measurable lesions:  lesions that can be accurately measured in at least one dimension with 
the longest diameter 2.0 cm.  With a spiral CT scan, the lesion must be 1.0 cm in at least 
one dimension. 
 
Non-measurable lesions:  all other lesions, including small lesions (longest diameter <2.0 cm 
with conventional techniques or <1.0 cm with spiral CT scans) and other non-measurable 


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lesions.  These include:  bone lesions; leptomeningeal disease; ascites; pleural/pericardial 
effusion; inflammatory breast disease; lymphangitis cutis/pulmonis; abdominal masses that 
are not confirmed and followed by imaging techniques; and cystic lesions. 
 
All measurements should be recorded in metric notation, using a ruler or calipers.  All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 4 
weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules, 
palpable lymph nodes).   For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesions is recommended. 
 
Baseline documentation of target and non-target lesions 
 
 
All measurable lesions up to a maximum of 10 lesions representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 
 
Target lesions should be selected on the basis of their size (lesions with the longer diameter) 
and their suitability for accurate repetitive measurements (either by imaging techniques or 
clinically). 
 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD.  The baseline sum LD will be used as reference to further characterize 
the objective tumor response of the measurable dimension of the disease. 
 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements are not required and these lesions should be 
followed as “present” or “absent.” 
 
Response criteria 
 
Evaluation of target lesions 
 
     Complete response (CR)disappearance of all target lesions. 
 
Partial response (PR)at least a 30% decrease in the sum of the LD of the target  lesions 
taking as reference the baseline sum LD. 
 
Progression (PD)at least a 20% increase in the sum of the LD of the target lesions taking as 
reference the smallest sum LD recorded since the treatment started or the appearance of one 
or more new lesions. 
 
Stable disease (SD)neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as references the smallest sum LD since the treatment started. 
 
Evaluation of non-target lesions 
 
 
Complete response (CR)disappearance of all non-target lesions and normalization of tumor 
marker level. 
 
Non-complete  response  (non-CR)/non-progression  (non-PD)persistence  of  one  or  more 
non-target lesion(s) or/and maintenance of tumor marker level above the normal limits. 


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 
Progressive disease (PD)appearance of one or more new lesions.  Unequivocal progression 
of existing non-target lesions.   Although a clear progression of non-target  lesions only is 
exceptional, in such circumstances, the opinion of the treating physician should prevail and 
the progression status should be confirmed later on by a review panel (or study chair/primary 
investigator). 
 
Evaluation of best overall response 
 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  In general, the patient’s best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
 
 
 
 
 
 
 
Table 6: 
Evaluation of best overall response 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
 
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”   Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 


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Confirmation 
 
 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat studies that should be performed no less than 4 weeks after the criteria for response are 
first met. 
 
In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval of 6-8 weeks.