Phase I/II Study of Dasatinib in Combination With Zoledronic Acid for the Treatment of Breast Cancer With Bone Metastasis
Phase: PHASE1
Conditions: Breast Cancer, Bone Metastases
Sponsor: M.D. Anderson Cancer Center

 
March 28, 2011
Phase I/II Study of Dasatinib in Combination with Zoledronic 
Acid for the Treatment of Breast Cancer Bone Metastasis 
BMS Protocol Number: CA180094 
Stacy Moulder, M.D., M.S.C.I. 
Breast Medical Oncology, Unit 1354 
The University of Texas M.D. Anderson Cancer Center 
P.O. Box 301438 
Houston, TX 77230-1439 
 
Physical address: 
1155 Pressler Street 
Houston, TX 77030 
 
Telephone: 
(713) 792-2817 
 
Fax: 
(713) 794-4385 
 
email: 
smoulder@mdanderson.org 
 
Protocol Version/Date: Version 8, 03/28/2011 
Protocol Revision Date:  03/28/2011 
 
Co-principal Investigator:  
 
Marjorie Green, M.D. 
 
Co-investigators:  
 
 
Gabriel Hortobagyi, M.D. 
Lajos Pusztai, M.D. 
 
Statistician:  
 
 
 
Kristine Broglio/Marcy Johnson, M.S. 
 
Imaging Collaborator: 
 
 
Juri Gelovani, M.D., PhD 
 
Laboratory Collaborator:  
 
Bryant G. Darnay, PhD 
1 

 
March 28, 2011
 
TABLE OF CONTENTS 
BMS Protocol Number: CA180094 .................................................. 1 
PROTOCOL SYNOPSIS....................................................................
 7
16
16
16
16
16
17
17
17
17
18
18
19
19
19
19
20
20
20
20
22
24
25
26
27
28
1 
INTRODUCTION ...............................................................
 
1.1 
Hypothesis .......................................................................
 
1.2 
Background......................................................................
 
1.2.1 
Bone Metastasis in Patients with Breast Cancer..........................
 
1.2.2 
The Role of Src in Breast Cancer...................................................
 
1.2.3 
The Role of Src in the Regulation of Osteoclast Function...........
 
1.2.4 
The Role of PDGF in Bone Metastasis...........................................
 
2 
OVERVIEW OF STUDY DRUGS ......................................
 
2.1 
Dasatinib ..........................................................................
 
2.1.1 
Preclinical Anti-tumor Activity........................................................
 
2.1.1.1 
In Vitro Molecular Studies...............................................................
 
2.1.1.2 
In Vivo Studies.................................................................................
 
2.1.2 
Preclinical Toxicology.....................................................................
 
2.1.3 
Clinical Pharmacokinetics ..............................................................
 
2.1.3.1 
Absorption........................................................................................
 
2.1.3.2 
Distribution.......................................................................................
 
2.1.3.3 
Metabolism.......................................................................................
 
2.1.3.4 
Elimination .......................................................................................
 
2.1.4 
Clinical Experience with Dasatinib.................................................
 
2.1.5 
Safety of Dasatinib in Clinical Studies...........................................
 
2.1.6 
Laboratory Abnormalities ...............................................................
 
2.1.7 
Anticipated Adverse Events ...........................................................
 
2.1.8 
Phase I experience in Solid Tumors ..............................................
 
2.2 
Zoledronic Acid................................................................
 
3 
STUDY RATIONALE.........................................................
 
2 

 
March 28, 2011
3.1 
Rationale for the Use of Dasatinib in Combination 
with Zoledronic Acid for the Treatment of 
Hormone Receptor Negative Metastatic Breast 
Cancer and in Combination with Antiestrogen 
Therapy in Patients with Hormone Receptor 
Positive Breast Cancer.................................................... 28 
29
32
32
33
33
34
35
35
35
35
36
36
36
36
36
38
40
40
41
41
41
42
42
3.2 
Rationale for the Use of N-telopeptide of Type I 
Collagen (Ntx) as the Primary Endpoint to Measure 
Therapeutic Response ....................................................
 
4 
OVERVIEW OF STUDY DESIGN AND EVALUATION ....
 
4.1 
Dose-finding and Cohort Definitions .............................
 
4.2 
Phase I Study Design ......................................................
 
4.2.1 
Definition of Dose Limiting Toxicity...............................................
 
4.3 
Phase II Study Design .....................................................
 
5 
STUDY OBJECTIVES.......................................................
 
5.1 
Primary Objective ............................................................
 
5.1.1 
Phase I:.............................................................................................
 
5.1.2 
Phase II:............................................................................................
 
5.2 
Secondary Objective(s)...................................................
 
5.2.1 
Phase I:.............................................................................................
 
5.2.2 
Phase II:............................................................................................
 
6 
SELECTION OF PATIENTS .............................................
 
6.1 
Inclusion Criteria .............................................................
 
6.2 
Exclusion Criteria ............................................................
 
7 
TREATMENT OF SUBJECTS ..........................................
 
7.1 
Study Registration...........................................................
 
7.2 
Study Treatment ..............................................................
 
7.2.1 
Phase I ..............................................................................................
 
7.2.2 
Phase II .............................................................................................
 
7.3 
Drug Dosing and Routes of Administration..................
 
7.3.1 
Dasatinib...........................................................................................
 
3 

 
March 28, 2011
7.3.2 
Zoledronic Acid................................................................................
 
42
43
43
44
44
45
45
45
46
47
49
49
53
53
53
54
54
54
54
55
55
55
55
55
55
55
55
56
56
7.4 
Dose Modifications..........................................................
 
7.4.1 
Dasatinib...........................................................................................
 
7.4.2 
Dose Modifications for Zoledronic Acid ........................................
 
7.5 
Discontinuation of Therapy ............................................
 
7.5.1 
Follow up After Discontinuation of Protocol Therapy:.................
 
7.6 
Prohibited and Restricted Therapies During Study......
 
7.6.1 
Prohibited Therapies .......................................................................
 
7.6.2 
Restricted Therapies .......................................................................
 
7.7 
Concomitant Therapy......................................................
 
8 
STUDY PROCEDURES ....................................................
 
8.1 
Evaluation and visit schedule ........................................
 
9 
EFFICACY AND SAFETY ASSESSMENTS.....................
 
9.1 
Efficacy Assessment.......................................................
 
9.1.1 
N-telopeptide of Type I Collagen (Ntx)...........................................
 
9.1.2 
Measurement of Tumor Response....... Error! Bookmark not defined. 
9.2 
Safety Assessment..........................................................
 
10 
STUDY DRUG(S) ..............................................................
 
10.1 
Dasatinib Product Identification.....................................
 
10.2 
Packaging and Labeling..................................................
 
10.3 
Storage, Handling and Dispensing of Dasatinib...........
 
10.3.1 
Storage .............................................................................................
 
10.3.2 
Handling and Disposal ....................................................................
 
10.3.3 
Dispensing .......................................................................................
 
10.4 
Drug Ordering and Accountability.................................
 
10.4.1 
Initial Orders.....................................................................................
 
10.4.2 
Re-supply .........................................................................................
 
10.5 
Dasatinib Accountability.................................................
 
10.6 
Destruction of Dasatinib .................................................
 
10.7 
Zoledronic Acid................................................................
 
4 

 
March 28, 2011
10.7.1 
Supply...............................................................................................
 
56
56
57
58
59
59
60
62
62
62
63
63
64
64
64
64
64
65
65
65
66
66
68
79
80
10.7.2 
Preparation.......................................................................................
 
10.7.3 
ANTICIPATED TOXICITY .................................................................
 
10.7.3.1 
Osteonecrosis of the Jaw (ONJ).....................................................
 
10.7.3.2 
Monitoring of Renal Function.........................................................
 
11 
ADVERSE EVENTS..........................................................
 
11.1 
Reporting of SAEs...........................................................
 
12 
STATISTICAL METHODOLOGY......................................
 
12.1 
PHASE I ............................................................................
 
12.2 
Phase II .............................................................................
 
12.2.1 
Cohort A: Patients with moderate or high baseline levels of 
Ntx:....................................................................................................
 
12.2.2 
Cohort B: Patients with low levels of Ntx:.....................................
 
13 
ADMINISTRATIVE SECTION ...........................................
 
13.1 
Compliance with the Protocol and Protocol 
Revisions..........................................................................
 
13.2 
Ethical Considerations and Informed Consent.............
 
13.3 
Records and Reports ......................................................
 
13.4 
Institutional Review Board (IRB)....................................
 
13.5 
Records Retention...........................................................
 
14 
CORRELATIVE STUDIES ................................................
 
14.1 
Biologic Characterization of Response Using 18F-
FDG PET:..........................................................................
 
14.2 
Determination of Molecular Correlates in Paraffin 
Embedded or Frozen Tissue: .........................................
 
14.3 
Banking of Blood Samples .............................................
 
REFERENCES.................................................................................
 
APPENDIX 1 LIST OF ABBREVIATIONS ....................................
 
APPENDIX 2 KNOWN INDUCERS & INHIBITORS OF 
ISOENZYME CYP3A4.......................................................
 
5 

 
March 28, 2011
APPENDIX 3 DASATINIB PATIENT DIARY FOR 
STUDY:CA180094 ............................................................
 
81
APPENDIX 4   STUDY MONITORING PLAN FOR 
COLLABORATING SITES….............................................................82 
 
6 

 
March 28, 2011
 
PROTOCOL SYNOPSIS 
 
Protocol 
Title: 
 
Phase I/II Study of Dasatinib in Combination with Zoledronic Acid 
for the Treatment of Breast Cancer Bone Metastasis 
# Sites and 
Names: 
Multicenter: M.D. Anderson Cancer Center, University of Chicago, and Duke University 
 
Phase I Study 
Schema:  
 
 
 
 
Phase I Dose Escalation Schema 
Dosing cohort 1:
•Three patients will be initially treated in cohort 1.
•If < 1 out of 3 patients in cohort 1 develop DLT, 3 additional patients will 
be accrued to cohort 2. 
•If If < 1 out of 3 patients in cohort 2 develop DLT, 3 additional patients will 
be accrued. 
•If > 2 out of 3 or > 2 out of 6 patients develop DLT, further accrual will 
continue until 6 patients are treated at the next lower dosing cohort.
•If < 1 out of 6 patients develop DLT, this dose level will be deemed the 
recommended phase 2 dose (RP2D) and the phase II portion of the trial 
will open to accrual.
Dosing Cohort –1 :
•Three patients will be initially treated
•If < 1 out of 3 patients develop DLT, 3 additional patients will be accrued.
•If < 1 out of 6 patients develop DLT, this dose level will be deemed RP2D 
and the phase II portion of the trial will open to accrual.
•If > 2 out of 3 or 2 out of 6 patients develop DLT, the study will be closed 
due to intolerability of the combination
Phase I Drug Adminis trati on
Stand ard  do sing 
(se e sect ion 7 .3.2 )
10 0 m g p o d aily
1
Stand ard  do sing 
(se e sect ion 7 .3.2 )
70  m g po daily
-1
Zoledronic Acid
Dasatinib
Dosing Cohort
7 

 
March 28, 2011
Phase II 
Study 
Schema 
1. Zoledronic acid to be administered at standard doses as defined in section 7.3.2. 
2. Ntx= N-telopeptide of Type I Collagen   
 
 
Study 
Design: 
 
This is an open label, Phase I/II, dose escalation study to evaluate the safety and tolerabilit
of dasatanib in combination with a standard 28-day cycle of zoledronic acid in patients wit
metastatic breast cancer to bone.  
 
Zoledronic acid will be administered as a 15-minute infusion on day 1(+/- 48 hours) of 
28-day cycle. The dose of zoledronic acid administered will be calculated using th
standard dosing guidelines outlined in section 7.3.2. 
Dasatinib will be taken by mouth using a daily dosing schedule on days 1-28 of each cycl
(i.e. continuous dosing).  
 
The primary objective of the phase I portion of this trial will be to determine the RP2D fo
dasatinib in combination with zoledronic acid.  
 
The first 3 patients will be treated with 100 mg of dasatinib daily in combination with fu
dose zoledronic acid. If < 1 patient develop(s) DLT within cycle one of therapy, then 
additional patients will be accrued.  
 
If < 1 of 6 enrolled patients experiences DLT, then this will be deemed the RP2D an
accrual will begin for the phase 2 portion of the trial.  
If > 2 patients develop DLT during initial accrual to any cohort (n=3) or during the dos
expansion (n=6), further accrual will continue at the next lower dosing cohort until a total o
six patients are treated at the lower dosing cohort.  
If > 2 patients develop DLT during accrual to cohort –1, the study will be closed due t
Phase II 
Initial Registration 
Baseline measurement of Ntx2
Patients with High 
(> 100nM/mmol) 
or Moderate (50-
99nM/mmol) 
levels of Ntx
Patients with Low 
(< 50nM/mmol) 
levels of Ntx
Stratify
Repeat measurement of Ntx2 and radiographic 
assessment of response (repeat Q 3months)
Zoledronic Acid1 IV Q 
4 weeks + Dasatinib 
PO (Dose established 
by Phase I portion of 
trial)
Repeat measurement of Ntx2
2 month
1 month
8 

 
March 28, 2011
intolerability. 
Definition of Dose Limiting Toxicity 
Toxicity will be assessed using the NCI Common Toxicity Criteria (CTC) Scale, versio
3.0.  
 
By definition a DLT must occur during cycle 1, be suspected as being drug-related, an
includes any of the following: 
 Any grade 4 non-hematological toxicity 
 Grade 4 neutropenia lasting > 7 days or any febrile neutropenia 
 Grade 3 non-hematological toxicity that persists >72 hours despite adequat
supportive care  
 Grade 2 or greater neutropenia (ANC<1.5x109/L) or thrombocytopeni
(PLT<75x109/L) which fails to revert to grade 1 (level at which treatment 
permitted) by the time of the scheduled start of cycle 2 
 50% decrease in calculated creatinine clearance 
 Diagnosis of osteonecrosis of the jaw 
Phase II Study Design 
 
The dose identified as the RP2D in the phase I portion of this study will be evaluated fo
efficacy in the phase II portion of this trial. The primary objective of this phase II study is t
assess the efficacy (as defined by disease response) of dasatinib in combination wit
zoledronic acid.  Patients will be divided into two cohorts dependant upon Ntx leve
obtained prior to the initiation of therapy. All patients will receive same therapy, lab draw
and radiographic assessment for response. 
 
Patients treated at the RP2D in the phase I portion of this study will be included in the 
efficacy analysis for the phase II portion of the trial. 
Up to 25 patients will be enrolled in this phase II study to assess the efficacy of dasatinib in
combination with zometa (zoledronic acid).  The primary endpoint is the response rate.  Th
trial will be conducted by the Simon’s two-stage design using the minimax criterion and th
response rate will be estimated accordingly [1]. 
 
It is assumed that dasatinib in combination with zometa will have a target response rate of 
25%.  A response rate of 5% or lower is considered a failure.  When the probability of 
accepting a “bad” regimen (i.e. response rate 5%) is 0.05 and the probability of rejecting 
“good” regimen (i.e. response rate  25%) is  0.10, Simon’s design to minimize the 
maximum sample size requires 15 patients in the first stage.  If no patients respond to the 
treatment, the trial will be stopped and the regimen will be declared as ineffective.  If at 
least one of the first 15 patients respond to the treatment, 10 additional patients will be 
entered in the study to reach a total of 25 patients.  By the end of the study, the new regime
will be rejected if response rate is less than or equal to 3 out of 25 patients and will be 
9 

 
March 28, 2011
accepted otherwise.  The operating characteristics of the trial are given as follows.  When 
the true response rate is 0.05, the probability of stopping the trial early is 46.3%.  On the 
other hand, if the true response rate is 0.25, the probability to stop the trial early is 1.3%.  
The expected sample sizes are 20.37 and 24.97 when the true response rates are 0.05 and 
0.25, respectively.  At the end of the study, the response rate and the 95% confidence 
interval will be reported and the toxicity profile of the regimen will be summarized.  If the 
trial continues to the second stage (i.e., accrual = 25) and the 5 of 25 patients response for a
point estimate of 20.0%, the exact binomial 95% confidence interval would be (6.8%, 
40.7%).   
 
 
Accrual Goal: 
(Total number of 
patients) 
 
 
6-28 patients 
6-18 patients may be enrolled in the phase I portion of the trial. 
In the phase II portion of the trial, 25 patients will be needed to establish efficacy. We will 
accrue an additional 10% of patients, a maximum of 28, to account for inevaluable patients
 
Accrual Rate: 
(Number of patients 
expected per month) 
2-3 patients/month 
FPFV: 
LPLV: 
Follow Up: 
(dd-mm-yy) 
11/06 
11/10 
Follow up will be completed on all patients by 11/30/11 
Trial 
Objectives: 
(Primary and 
Secondary) 
Primary Objectives: 
Phase I: 
To determine the maximum tolerated dose (MTD) and recommended phase II dose 
(RP2D) for dasatinib in combination with zoledronic acid. 
Phase II: 
Determine the efficacy of dasatinib in combination with zoledronic acid usin
disease response. 
Secondary Objectives: 
Phase I: 
To determine toxicity of combination therapy with dasatinib and zoledronic acid in 
patients with breast cancer and bone metastasis. 
Phase II: 
 Changes in Ntx levels will be correlated with traditional measurements of tumo
response in bone (using WHO criteria), progression free survival and overa
survival at 2 years  
 Biologic characterization of response using 18F-FDG PET 
 Determination of molecular correlates of response in paraffin embedded or froze
tissue 
 Determine time to tumor progression, response, time to tumor respons
10 

 
March 28, 2011
progression free survival (PFS) up to 2 years 
 Determine overall survival (OS) at 2 years 
 Banking of blood for future studies of novel markers of bone health 
 Determine changes in urinary Ntx with protocol therapy 
 Correlate response with tumor estrogen receptor (ER), progesterone receptor (PR
and HER2 status 
 
Correlative 
Studies: 
 
Biologic Characterization of Response Using 18F-FDG PET: 
Characterization of response using PET will be performed through collaboration with D
Juri Gelovani, chair of the Department of Experimental Diagnostic Imaging in the Divisio
of Diagnostic Imaging at MDACC. Patients who consent to participate will underg
optional 18F-FDG PET imaging at baseline, between days 12-16 of therapy (2 week value
and at disease progression.  The fold change from baseline will be calculated for the 2 wee
value and progression of disease value. These values will then be graphed using scatterplo
against urine Ntx to assess the relationship of response to this biologic endpoint.  I
addition, it is known that variations in 18F-FDG PET avidity can occur within different foc
of disease in individual patients. These variations may represent biologic difference
between responding and non-responding cells; therefore, core needle biopsies will b
performed on a subset of patients who consent to biopsy of >2 sites of metastatic tumor
that differ in 18F-FDG PET uptake (see Molecular Correlates below). 
Determination of Molecular Correlates in Paraffin Embedded or Frozen Tissue: 
Tumor biopsies will be obtained by imaging (CT or Ultrasound) guided core needle biops
from patients who sign informed consent for tissue biopsy. Biopsies will be obtained at pre
treatment and at day 28 of cycle 1 (+/- 48 hours). Tumor samples will be analyzed fo
biomarkers of SRC, PDGFR, c-kit, FAK, and EPHA2 total kinase and phosphorylate
activity, including Caveolin, Phospho-Caeolin, IGFBP2 and pSTAT3 using standar
immunohistochemistry techniques. Furthermore, markers of angiogenesis VEGF and IL-
will also be analyzed using the same techniques. 
 
Fresh tissue obtained by core needle biopsy of metastatic sites differing in PET avidity i
individual patients (see above) will be snap frozen and used for microarray analysis t
determine potential pathways of drug resistance. When possible, these results will b
confirmed using IHC, western blotting or PCR. 
 
Banking of Blood Samples: 
Patients will be asked to donate 10cc of blood pretreatment and on days 28 (+/- 48 hours) o
cycles 1 and 3. Blood will also be collected at the time of disease progression.  Serum wi
be banked for future treatment efficacy analyses including potential markers of bon
turnover.  
Inclusion 
Criteria: 
1) 
Patients must have a pathologically confirmed diagnosis of invasive carcinoma o
the breast. 
2) 
Patients must carry a diagnosis of metastatic breast cancer with predominant bon
involvement. For the purposes of this study, predominant bone involvement will b
11 

 
March 28, 2011
defined as radiographically detected bone metastasis in the presence or absence of othe
sites of metastatic breast cancer (i.e. visceral involvement). If visceral involvement 
present, patients must be asymptomatic and have no tumors in visceral organs tha
measure >3cm in size.  
3) 
Patients must agree to serial urine collections for measurement of Ntx according t
the schedule defined in sections 8 and 9. 
4) 
Age >18 years. 
5) 
Patients must be able to swallow oral medications. Dasatinib must be taken whol
and cannot be crushed.  
6) 
Patients must have evaluable disease using WHO Criteria for Assessment of Diseas
Response in Bone or the MDACC modified response criteria in bone (Post tex
supplement 4).  
7) 
Patients must not have >1 chemotherapy regimen for metastatic disease. Patien
with metastasis diagnosed <6 months after completion of adjuvant chemotherapy ar
considered to have had chemotherapy for metastatic breast cancer. 
8) 
Patients with ER positive disease must have had disease progression on at least on
prior hormonal therapy for metastatic disease. Patients must also have developed diseas
progression on their most recent hormonal therapy regimen and be agreeable to continu
this regimen in combination with protocol therapy. For the purposes of this study diseas
progression while receiving hormonal therapy will be defined as: 
 Radiographic evidence of progressive disease according to RECIST or WHO
criteria 
 Progression of disease by physical exam in patients with skin involvement. 
 25% increase in tumor marker as measured on two evaluations no less than 72 hour
apart.  
9) 
Patients must have and ECOG performance status of <2.  
10) Patients must not require concurrent radiation, or chemotherapy therapy whil
receiving protocol therapy. 
11) Patients must not have an active infection requiring the use of intravenou
antibiotics. The use of oral antibiotics as prophylaxis is allowed.  
12) Patients must have a baseline ECG with QTc within the normal range within 2
days prior to registration.  
13) Patients must be informed of the investigational nature of the study and must sig
and give written informed consent. 
14) Patients may have received previous radiation but must have completed radiation a
least 2 weeks (8 weeks for radiation to the brain) prior to registration. Patients wit
irradiated tumor as the only site of evaluable disease will not be eligible for protoco
therapy unless there is documented disease progression within the previously radiated site
15) Patients must have recovered to grade <1 from all acute toxicity of previou
radiation or hormonal therapy.  
16) Adequate hematologic and hepatic function: 
 Granulocyte count > 1,500/mcL 
 Platelet count > 100,000/mcL 
 Bilirubin < 1.5 x ULN 
12 

 
March 28, 2011
 AST and/or ALT < 2 x ULN 
 Alkaline phosphatase (liver component, if fractionated) < 2 x ULN 
 Serum Na, K+, Mg2+, Phosphate and Ca2+Lower Limit of Normal (LLN) [subjec
with low electrolyte levels must be repleted to normal for protocol entry] 
17) Patients must not receive any concurrent bisphosphonate therapy other than tha
prescribed by the study. 
18) Sexually active patients with reproductive potential must agree to use an effectiv
method of birth control during the course of the study and for no less than 4 weeks afte
discontinuing study drug. Contraceptives must be used in a manner such that risk o
failure is minimized. Oral contraceptives should be avoided in women with estrogen o
progesterone receptor positive breast cancer.  
19) Prior to study enrollment, women of childbearing potential (WOCBP) must b
advised of the importance of avoiding pregnancy during trial participation and th
potential risk factors for an unintentional pregnancy.  In addition, men enrolled on th
study should understand the risks to any sexual partner of childbearing potential an
should practice an effective method of birth control. 
20) All WOCBP MUST have a negative serum or urine pregnancy test within 72 hour
prior to the start of study drug administration. If the pregnancy test is positive, the patien
must not receive investigational product and must not be enrolled in the study. 
21) Patients with disease progression while receiving previous therapy in combinatio
with bisphosphonates (including zoledronic acid) will be considered eligible for protoco
participation.  
 
Exclusion 
Criteria: 
 
1) No malignancy (other than breast cancer) which required radiotherapy or systemi
treatment within the past 5 years.  
2) Concurrent medical condition which may increase the risk of toxicity, including: 
 Pleural or pericardial effusion of any grade 
 Clinically-significant coagulation or platelet function disorder (e.g. known vo
Willebrand’s disease) 
3) Cardiac Symptoms, including the following:  
 Uncontrolled angina, congestive heart failure or MI within (6 months) 
 Diagnosed congenital long QT syndrome 
 Any history of clinically significant ventricular arrhythmias (such as ventricula
tachycardia, ventricular fibrillation, or Torsades de pointes) 
 Prolonged QTc interval on pre-entry electrocardiogram (> normal range) 
 Subjects with hypokalemia or hypomagnesemia if it cannot be corrected 
4) History of significant bleeding disorder unrelated to cancer, including: 
 Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease) 
 Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-facto
VIII antibodies) 
13 

 
March 28, 2011
 Ongoing or recent ( 3 months) significant gastrointestinal bleeding 
5) Concomitant Medications, consider the following prohibitions (Drugs must b
discontinued for 7 days prior to starting protocol therapy):  
 Drugs that are generally accepted to have a risk of causing Torsades de Pointe
including:  
quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, dofetilide, 
erythromycins, clarithromycin, chlorpromazine, haloperidol, mesoridazine, 
thioridazine, pimozide, cisapride, bepridil, droperidol, methadone, arsenic, 
chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, 
lidoflazine. 
 The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is no
recommended. The use of antacids should be considered in place of H2 blockers o
proton pump inhibitors in patients receiving dasatinib therapy. 
 Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy  
 Patient may not be receiving any prohibited CYP3A4 inhibitors [see section 7.6] 
6) Women and men of child bearing potential: 
 Who are unwilling or unable to use an acceptable method to avoid pregnancy for th
entire study period and for at least 4 weeks after cessation of study drug, or 
 Women of childbearing potential (CBP) who have a positive pregnancy test a
baseline, or 
 Women who are pregnant or breastfeeding  
 Sexually active men and women capable of reproduction must use an effectiv
method of birth control during the course of the study, in a manner such that risk o
failure is minimized 
 Prior to study enrollment, men and women capable of reproduction must be advise
of the importance of avoiding pregnancy during trial participation and the potentia
risk factors for an unintentional pregnancy   
7) Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) fo
treatment of either a psychiatric or physical (e.g., infectious) illness 
8) Untreated or uncontrolled brain metastasis 
9) Patient inability to take or absorb oral medications 
10) Current active dental problems including: ongoing infection of the teeth or jawbon
(maxilla or mandibula); current exposed bone in the mouth; and current or prio
diagnosis of osteonecrosis of the jaw 
11) Recent (within 8 weeks) or planned dental or jaw surgery (e.g., extraction, implants
12) Diagnosis of metabolic bone disease other than osteoporosis (e.g., Paget’s disease o
bone) 
13) Known hypersensitivity to zoledronic acid or aspirin 
14) Corrected serum calcium  8.0 mg/dL (2.0 mmol/L) or  12.0 mg/dL (3.0 mmol/L
at Visit 1.  The formula to be used is:  Corrected serum calcium (mg/dL) = Patient
serum calcium (mg/dL) + [0.8 x Midrange Albumin (g/dL) – Patient’s Albumin (g/dL)
14 

 
March 28, 2011
4.0g/dL to be used for the Midrange Albumin 
15) Serum creatinine 1.5 times the institutional upper limits of normal or a creatinin
clearance of <40 ml/min when calculated by the Cockroft and Gault formula: 
Estimated creatinine clearance=  
(140-age in years) x (weight in kg)  (x 0.85, if female) 
72 x creatinine (mg/dL) 
 
Criteria for 
Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
 
For the phase 2 portion of the trial, a minimum of  15 and a maximum of 28 patients will b
accrued.  Simon’s two stage design will be used to minimize the maximum sample size 
requires 15 patients in the first stage.  If no patients respond to the treatment, the trial will 
be stopped and the regimen will be declared as ineffective.  If at least one of the first 15 
patients respond to the treatment, 10 additional patients will be entered in the study to reach
a total of 25 patients. 
15 

 
March 28, 2011
1 INTRODUCTION 
1.1 
Hypothesis 
Dasatinib in combination with zoledronic acid will disrupt both the 
autocrine and paracrine loops that sustain breast cancer metastasis within 
the bone. This therapeutic effect will result in a significant reduction of N-
telopeptide of Type I Collagen (Ntx), a marker of bone resorption, which 
will correlate with clinical outcomes of tumor response, time to 
progression and overall survival. 
1.2 
Background 
1.2.1 
1.2.2 
Bone Metastasis in Patients with Breast 
Cancer 
Up to 70% of patients with advanced breast cancer develop metastasis to 
the bone and, although bone metastasis is associated with a favorable 
prognosis, a median survival of 9 months has been published in patients 
with progressive bony metastasis or hormone refractory breast cancer (1, 
2). Many of these patients are also ineligible for most clinical trials 
because of the complexities involved in measuring the therapeutic 
response of lesions within the bone(3).  Skeletal related events (SREs) 
resulting from bone metastasis are also the source of a significant amount 
of morbidity, which may necessitate additional medical or surgical 
intervention.  
 
Metastasis to the bone initiates a vicious cycle where the metastatic cells 
stimulate osteoclast mediated bone resorption and growth factors released 
from resorbed bone promote tumor growth (1). Src has been implicated in 
the autocrine and paracrine interactions involved in promoting bone 
metastasis and is thus a potential target for the treatment of breast cancer 
that has metastasized to the bone. 
The Role of Src in Breast Cancer 
Src kinase modulates oncogenic signal transduction through multiple 
pathways such as EGFR, HER2, PDGFR, FGFR and VEGFR. 
Approximately 50-65% of human breast carcinomas overexpress c-Src 
and up to 85% of human breast carcinomas have detectable levels of 
activated Src (Src-pY416)(4-6). Src signaling is significantly activated in 
breast tumors compared with normal breast tissue and has been correlated 
with chemotherapy resistance and antiapoptotic signaling in both cell lines 
and clinical trials involving breast cancer patients (7, 8). Elevated Src 
tyrosine kinase activity has also been associated with poor metastasis-free 
survival in breast cancer patients and with tumor colonization in bone and 
lung in animal models of human breast cancer metastasis(9). In these 
16 

 
March 28, 2011
models, activation of Src was associated with increased tumor cell 
production of PTH-rP, a powerful stimulator of osteoclast bone resorption 
that has been shown to play an important role in osteolytic bone 
metastasis. 
1.2.3 
1.2.4 
The Role of Src in the Regulation of 
Osteoclast Function 
Osteoclasts are multinucleated giant cells which contain ruffled borders or 
polarized portions of cell membrane where bone resorption occurs. 
Osteoclasts express high levels of Src which is involved with 
osteoclastogenesis, cytoskeletal organization and formation of ruffled 
boarders [reviewed in (10)]. Expression of c-Src in osteoclasts is 
controlled by NF-B and AP-1 and disruption of this pathway using 
antisense src or c-src knock-out mice results in perturbations in the 
formation of multinucleated cells and morphologically abnormal cells with 
aberrant cytoskeletal organization and absence of ruffled borders 
[reviewed in (10)]. Disruption of Src with small molecular weight tyrosine 
kinase inhibitors (TKIs) has also been demonstrated to dose-dependently 
reduce interleukin- induced hypercalcemia in mice and partially 
prevented bone loss in young ovariectomized rats(11). 
The Role of PDGF in Bone Metastasis 
Breast cancer specimens evaluated by immunohistochemistry (IHC) show 
expression of PDGF in the cancer cells and associated expression of 
PDGFRs predominately within the stroma, including vascular endothelial 
cells in the periepithelial stroma [reviewed in (12)]. In addition, inhibition 
of PDGF by neutralizing antibody, transfection with antisense vector or 
treatment with tyrosine kinase inhibitors (TKIs) has been shown to block 
cancer induced osteoblastic bone formation, reduce bone metastasis and 
inhibit growth of established metastasis in breast cancer xenograft 
models(12, 13). 
 
 
2 OVERVIEW OF STUDY DRUGS 
2.1 
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(14).  
Drug discovery and nonclinical pharmacology studies showed that 
Dasatinib(15): 
 
17 

 
March 28, 2011
 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 
 
2.1.1 
Preclinical Anti-tumor Activity 
2.1.1.1 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(15).   
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(14).  
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 from patients who failed imatinib mesylate 
therapy. These cells remained highly sensitive to the cell-killing effects of 
dasatinib(15).  
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. 
18 

 
March 28, 2011
2.1.1.2 In Vivo Studies 
The activity of dasatinib against CML cells in vitro was reproduced in vivo 
against several human CML xenograft models grown subcutaneously in 
SCID mice. Against the K562/imatinib mesylate/R CML model, Dasatinib 
was curative in 100% of the treated animals. In contrast, at its optimal 
dose and schedule, imatinib mesylate was inactive. 
2.1.
2.1.
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 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(15).  
3 
Clinical Pharmacokinetics 
The pharmacokinetics of dasatinib have been evaluated in 229 healthy 
subjects and in 137 patients with leukemia.  
2.1.3.1 Absorption 
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(14).  
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.  
19 

 
March 28, 2011
2.1.3.2 Distribution 
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(14).  
2.1.3.3 Metabolism 
Dasatinib is extensively metabolized in humans, primarily by the 
cytochrome P450 enzyme 3A4 (see section 7.6).  CYP3A4 was the 
primary enzyme responsible for the formation of the active metabolite. 
Flavin-containing 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.  
2.1.3.4 Elimination 
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(14).  
2.1.4 
Clinical Experience with Dasatinib 
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. Resistance to imatinib included 
failure to achieve a complete hematologic response (within 3–6 months) or 
major cytogenetic response (by month 12) or progression of disease after a 
previous cytogenetic or hematologic response. Imatinib intolerance 
included inability to tolerate 400 mg or more of imatinib per day or 
discontinuation of imatinib because of toxicity. The studies are ongoing. 
The results are based on a minimum of 6 months follow-up after the start 
of DASATINIB therapy. Most patients had long disease histories with 
extensive prior treatment, including imatinib, cytotoxic chemotherapy, 
interferon, and stem cell transplant. The maximum imatinib dose had been 
20 

 
March 28, 2011
400–600 mg/day in about one-half of the patients and >600 mg/day in the 
other half(14).  
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(14).  
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 Table 3. 
Most cytogenetic responses occurred after 12 weeks of treatment, when 
the first cytogenetic analyses were performed. Hematologic and 
cytogenetic responses were stable during the 6-month follow-up of 
patients with chronic phase, accelerated phase, and myeloid blast phase 
CML. The median durations of major hematologic response were 3.7 
months in lymphoid blast CML and 4.8 months in Ph+ ALL.   
There were no age- or gender-related response differences(14).  
21 

 
March 28, 2011
Table 3: 
Efficacy in Dasatinib Clinical Studies (All Treated 
Populations)a 
 
Chronic 
(n=186) 
Accelerated 
(n=107) 
Myeloid 
Blast 
(n=74) 
Lymphoid 
Blast 
(n=42) 
Ph+  ALL 
(n=36) 
Hematologic Response Rateb (%) 
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 Responsec (%) 
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/mm3 and <1000/mm3, and/or platelets 20,000/mm3 and 100,000/mm3. 
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. 
 
2.1.5 
Safety of Dasatinib in Clinical Studies 
The data described below reflect exposure to dasatinib in 911 patients with 
leukemia from 1 Phase I and 5 Phase II clinical studies. The median 
duration of therapy was 6 months (range 0–19 months).  
The majority of dasatinib -treated patients experienced adverse drug 
reactions at some time. Drug was discontinued for adverse drug reactions 
in 6% of patients in chronic phase CML, 5% in accelerated phase CML, 
11% in myeloid blast phase CML, and 6% in lymphoid blast phase CML 
or Ph+ ALL.  
The most frequently reported serious adverse events (SAEs) included 
pyrexia (9%), pleural effusion (8%), febrile neutropenia (7%), 
gastrointestinal bleeding (6%), pneumonia (6%), thrombocytopenia (5%), 
dyspnea (4%), anemia (3%), cardiac failure (3%), and diarrhea (2%).   
All 
treatment-emergent 
adverse 
events 
(excluding 
laboratory 
abnormalities), regardless of relationship to study drug, that were reported 
in at least 20% of the patients in dasatinib clinical studies are shown in 
Table 4. 
22 

 
March 28, 2011
Table 4: 
Adverse Events Reported ≥20% in Clinical Studies 
All Patients 
(n=911) 
Chronic 
Phase 
(n=488) 
Accelerated 
Phase 
(n=186) 
Myeloid 
Blast 
Phase 
(n=132) 
Lymphoid 
Blast Phase 
and 
Ph+ ALL 
(n=105) 
All 
Grades 
Grades 
3/4 
Grades 3/4 
Grades 3/4
Grades 
3/4 
Grades 3/4 
Preferred Term 
Percent (%) of Patients 
Fluid Retention 
50 
9 
6 
6 
23 
9 
 
Superficial Edema 
36 
1 
0 
2 
3 
2 
 
Pleural Effusion 
22 
5 
3 
3 
14 
8 
Diarrhea 
49 
5 
3 
10 
8 
6 
Headache 
40 
2 
2 
2 
4 
6 
Hemorrhage 
40 
10 
3 
18 
23 
17 
Musculoskeletal Pain 
39 
4 
2 
3 
6 
13 
Pyrexia 
39 
5 
1 
5 
13 
9 
Fatigue 
39 
3 
2 
4 
4 
8 
Skin Rash  
a
35 
1 
1 
1 
1 
4 
Nausea 
34 
1 
<1 
0 
5 
2 
Dyspnea 
32 
6 
5 
7 
11 
9 
Cough 
28 
<1 
<1 
1 
1 
0 
Infection (including bacterial, 
viral, fungal, non-specified) 
34 
7 
4 
8 
15 
13 
 
Infection/Inflammation 
26 
1 
1 
1 
5 
1 
Abdominal Pain 
25 
2 
1 
2 
4 
6 
Pain 
26 
2 
<1 
1 
5 
4 
Vomiting 
22 
1 
1 
2 
2 
2 
Febrile Neutropenia 
9 
8 
2 
11 
17 
20 
23 

 
March 28, 2011
2.1.6 
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 CML or Ph+ ALL than in chronic phase 
CML. Myelosuppression was reported in patients with normal baseline 
laboratory values as well as in patients with pre-existing laboratory 
abnormalities.  (Table 5) 
In patients who experienced severe myelosuppression, recovery generally 
occurred following dose interruption and/or reduction; permanent 
discontinuation of treatment occurred in 1% of patients.  
Grade 3 or 4 elevations of transaminases 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 CML and Ph+ ALL. Elevations in 
transaminases 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.  (Table 5). 
 
Table 5: 
CTC Grades 3/4 Laboratory Abnormalities in Clinical 
Studies 
 
Chronic Phase
(n=488) 
Accelerated 
Phase 
(n=186) 
Myeloid Blast 
Phase 
(n=132) 
Lymphoid Blast 
Phase and 
Ph+ ALL 
(n=105) 
 
Percent (%) of Patients 
Hematology Parameters 
 
 
 
 
 
Neutropenia 
49 
74 
83 
81 
 
Thrombocytopenia 
48 
83 
82 
83 
 
Anemia 
18 
70 
70 
51 
Biochemistry Parameters 
 
 
 
 
 
Hypophosphatemia 
11 
13 
23 
21 
 
Hypocalcemia 
2 
9 
20 
15 
 
Elevated SGPT (ALT) 
1 
4 
7 
11 
 
Elevated SGOT (AST) 
1 
2 
5 
8 
 
Elevated Bilirubin 
<1 
1 
5 
8 
 
Elevated Creatinine 
0 
2 
1 
1 
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 normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 
4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × 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).  
24 

 
March 28, 2011
 
2.1.7 
Anticipated Adverse Events 
Myelosuppression  
Treatment with dasatinib B 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(14).  
Bleeding Related Events 
In addition to causing thrombocytopenia in human subjects, dasatinib 
caused platelet dysfunction in vitro. Severe CNS hemorrhages, including 
fatalities, occurred in 1% of patients receiving dasatinib. Severe 
gastrointestinal hemorrhage occurred in 7% of patients and generally 
required treatment interruptions and transfusions. Other cases of severe 
hemorrhage occurred in 4% 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. 
Caution should be exercised if patients are required to take medications 
that inhibit platelet function or anticoagulants. 
Fluid Retention 
Dasatinib is associated with fluid retention, which was severe in 9% 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%. 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(14).  
25 

 
March 28, 2011
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(14).  
2.1.8 Phase I 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. To date, doses up to 160 mg BID on a 5-day on/2-
day off schedule have been administered. A dose of 120 mg BID 
continuous daily schedule is currently under investigation.  
No severe clinical toxicity has been encountered. Gastrointestinal 
symptoms were reported in most subjects, fatigue was reported in 17 
subjects (40%) and rash in 10 subjects (24%). Edema, lethargy and 
headache were uncommon, and appear to be dose-related. Grade 3 
asymptomatic hypocalcemia was considered dose-limiting in one subject, 
Grade 2 rash was considered dose-limiting in two other subjects, and 
Grade 2 nausea and vomiting (with dysarthria, lightheadedness and 
lethargy in a 49 kg subject taking concurrent diazepam) was considered 
dose-limiting in one subject.   
In another Phase I study (CA180021), dasatinib was administered on a QD 
schedule to 24 subjects at doses up to 180 mg. Pleural effusions were 
observed in three subjects at the 180 mg dose level (one with pneumonia 
and two with malignant effusion). A dose of 250 mg QD is currently under 
consideration. Hypocalcemia, GI symptoms and skin rash have been mild 
and infrequent.   
To date, the safety profile in solid tumor subjects has been similar to that 
in CP CML subjects with the exception of severe myelosuppression, 
26 

 
March 28, 2011
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.  
2.2 
Zoledronic Acid 
The principle pharmacologic action of zoledronic acid is inhibition of 
bone resorption.  Although the antiresorptive mechanism is not completely 
understood, several factors are thought to contribute to this action.  In 
vitro, Zoledronic acid inhibits osteoclastic activity and induces osteoclast 
apoptosis.  Zoledronic acid also blocks the osteoclastic resorption of 
mineralized bone and cartilage through its binding to bone.  Zoledronic 
acid inhibits the increased osteoclastic activity and skeletal calcium 
release induced by various stimulatory factors released by tumors.   
Zoledronic acid has demonstrated efficacy and safety in phase II and 
phase III clinical trials(16). The phase II study was a randomized, double-
blind study of 280 patients with malignant bone lesions associated with 
multiple myeloma or breast cancer(16). Patients were randomized to a 5-
minute infusion of 0.4, 2.0, or 4.0 mg of zoledronic acid, or a 2-hour 
infusion of 90 mg of pamidronate. Adverse events with zoledronic acid 
and pamidronate were similar, and the 5-minute 4.0-mg zoledronic acid 
infusion was equally efficacious when compared to a 2-hour 90-mg 
pamidronate infusion.  
Zoledronic acid has been evaluated in three prospective, randomized, 
controlled studies.  [Study 0010] was a randomized, double-blind, double-
dummy, 12-month study of 1,122 patients with at least one osteolytic bone 
lesion secondary to multiple myeloma or at least one bone metastasis 
secondary to Stage IV breast carcinoma(17). Patients were randomized to 
15-minute 4-mg infusions of zoledronic acid, or to 120-minute 90-mg 
infusions of pamidronate, while receiving standard antineoplastic therapy.  
Analysis of the primary endpoint revealed that zoledronic acid was at least 
as effective as pamidronate at reducing skeletal related events.  
Tolerability was similar for the two drugs, with bone pain, nausea, and 
fatigue the most common adverse events. There was no significant 
difference between the renal safety profiles for zoledronic acid and 
pamidronate after renal safety amendments for zoledronic acid were 
implemented.  
Two additional phase III studies demonstrated the safety and efficacy of 
zoledronic acid in patients with bone metastases associated with prostate 
cancer, and non-small cell lung cancer or other solid tumors.  Saad, et al. 
reported a phase III, double-blind, placebo-controlled study that enrolled 
422 patients with prostate cancer receiving antineoplastic therapy, and 
who had metastatic bone lesions and three consecutive rises in serum PSA 
level(18). In this study, zoledronic acid reduced the proportion of patients 
with SREs during the study by 25%, when compared with placebo.  
27 

 
March 28, 2011
Rosen, et al. published a phase III double-blind, placebo-controlled study 
in 507 patients with malignancies other than breast, prostate, or multiple 
myeloma, and documented bone metastases(19). This study demonstrated 
that treatment with zoledronic acid induced a significant delay to the first 
SRE and a significant reduction in the risk of developing SRE, compared 
to placebo. Both studies confirmed the safety profile of zoledronic acid.  
 
For details regarding drug preparation mechanism of action and 
prescribing information please see section 10.7 and Post-text supplement 2 
[Package Insert for Zometa (Zoledronic acid)]. 
 
3 STUDY RATIONALE 
3.1 
Rationale for the Use of Dasatinib in 
Combination with Zoledronic Acid for the Treatment 
of Hormone Receptor Negative Metastatic Breast 
Cancer and in Combination with Antiestrogen 
Therapy in Patients with Hormone Receptor Positive 
Breast Cancer 
Dasatinib is a novel, broad spectrum ATP competitive inhibitor of tyrosine 
kinases such as BCR-ABL, Src, c-KIT, PDGFR and ephrin (EPH). Src has 
been implicated as a target in both hormone receptor positive and triple 
negative breast cancer cell lines. In estrogen receptor (ER) positive cell 
lines, inhibition of ER/Src interaction leads to inactivation of the Src/Erk 
pathway, reduction in cyclin D1 expression and DNA synthesis induced 
by estradiol.(20) Disruption of the ER/Src association also leads to 
inhibited tumor growth in MCF-7 xenografts.(20) Additionally, PGC-1 
beta (a strong enhancer of ER activity) and SRC-1 have been 
demonstrated to functionally interact and promote the agonist activity of 
tamoxifen. Inhibition of the ER/Src association through peptide mimetics 
or Src inhibitors results in diminished growth in breast cancer xenograft 
models and restores sensitivity to anti-estrogen therapy in these same 
models.(20, 21) Preclinical data have demonstrated cytotoxic activity 
against the breast cancer cell line MDA-MB-231 and complete inhibition 
of PTH-stimulated bone resorption in thyro-parathyroidectomized 
rats(15).  
 
Zoledronic acid has been evaluated in three randomized double blind trials 
which demonstrated reductions in the risk of skeletal events of 27-36% in 
patients with prostate cancer, non-small cell lung cancer and other solid 
tumors(22-24) . In breast cancer, zoledronic acid was compared to 
pamidronate and demonstrated an additional 20% reduction in skeletal 
events (25). Zoledronic acid is a nitrogen containing bisphosphonate that 
inhibits osteoclast mediated bone resorption by blocking FFP synthase and 
28 

 
March 28, 2011
subsequent prenylation of GTPases that regulate osteoclast cytoskeletal 
organization(26). As mentioned in section 1.2.3, Src is also important in 
regulating the cytoskeletal organization necessary for formation of the 
ruffled boarder where bone resorption occurs. As such, both agents may 
offer an additive effect in combination for the prevention of bone 
resorption and improvement in skeletal related events. 
 
 In addition, preclinical data indicate that zoledronic acid sensitizes 
endothelial cells to tumor necrosis factor (TNF) programmed cell death by 
inhibiting focal adhesion kinase (FAK) and protein kinase B 
(PKB/Akt)(27). These effects were independent of c-Src activation and 
suggest that treatment with zoledronic acid may augment the anti-
angiogenic effects previously described with dasatinib.  
    
Taken together, these data support a potential therapeutic role for the 
combined use of dasatinib with zoledronic acid to inhibit osteolytic bone 
destruction and the subsequent release of growth factors that support 
cancer cell proliferation and survival. 
 
3.2 
Rationale for Evaluating Therapeutic Response 
in Bone and Correlating N-telopeptide of Type I 
Collagen (Ntx) with Therapeutic Response 
Traditional assessment of bone tumor response using imaging studies 
remains challenging and often limits patients with bone only metastasis 
from participating in clinical trials. In addition, traditional imaging studies 
such as bone scan or plain films used by the World Health Organization 
(WHO) criteria for response in bone were published in 1977 and show 
only moderate sensitivity when assessing for response, may lead to false 
diagnoses of tumor progression (flare phenomenon), or take months to 
show response because they measure skeletal architecture changes that 
occur slowly over time. These guidelines also were not adopted by 
RECIST or RECIST 1.1, creating a void regarding the evaluation of bone 
metastases. This void lead to the development of bone-specific response 
criteria at the M. D. Anderson Cancer Center in 2004.(45) The MDA 
criteria revised the evaluation of bone metastases previously adopted by 
UICC and WHO by modifying radiographic assessment and updating the 
technology to include both CT and MRI.  
 
The MDA criteria divide response into 4 standard categories (CR, PR, PD 
and SD, see post-text supplement 4) and include quantitative and 
qualitative assessments of the behavior of bone metastases. Quantitatively, 
the MDA criteria adopted the method of physical measurement put forth 
by the UICC and WHO criteria which define PR as a decrease of 50% or 
more in the sum of the perpendicular measurements of a lesion and PD as 
a reduction of 25% or more in this sum. 
29 

 
March 28, 2011
 
Using the MDA criteria, complete response is defined as complete 
sclerotic fill-in of lytic lesions on radiographs (XR) or CT; the restoration 
of normal bone density at the site of a blastic lesion on XR or CT; the 
disappearance of abnormal tracer uptake on skeletal scintigraphy (SS); and 
normalization of signal intensity on MRI. The PR category includes the 
development of a sclerotic rim or partial (rather than complete) sclerotic 
fill-in of lytic metastases on XR or CT, > 50% decrease in measurable 
lesions on XR, CT or MRI (Fig. 7), subjective unequivocal decrease in the 
size of blastic lesions on XR or CT that cannot be accounted for by 
changes in obliquity or slice placement and unequivocal decrease in tracer 
uptake on SS. A caveat to the PR designation involves osteosclerotic 
“flare.” Interval visualization of sclerotic lesions or lytic lesions with 
sclerotic rims, in the setting of other signs of PR, does not indicate disease 
progression but the healing of previously inconspicuous lesions. The 
caveat does not apply if any pre-existing lesions show signs of progression 
(e.g. enlargement of lytic lesions, development of new lytic lesions). The 
PD category includes a > 25% increase in the size of any measurable 
lesion on XR, CT or MRI; unequivocal increase in the size of 
unmeasurable (ill-defined) lytic or blastic lesions that cannot be accounted 
for by obliquity or slice placement, unequivocal increase in tracer uptake 
on SS; or the development of new metastases. Flare occurs when healing 
sclerosis results in more tracer uptake than was caused by the untreated 
lesion. Correlation of SS with another imaging modality is also suggested 
for the rapid resolution of tracer uptake in pre-existing lesions. Rarely, this 
is due to the rapid progression of lytic metastases. When lytic lesions 
progress quickly, the bone is unable to produce reparative sclerosis, 
rendering tracers such as methylene diphosphate (MDP) ineffective 
because they normally bind to the crystalline phase of hydroxyapetite laid 
down by the bone as it attempts to heal the damage caused by the lesion. 
In this unusual situation, the rapidly progressing metastases destroy pre-
existing skeletal tissue that demonstrated tracer uptake. SD is defined as < 
25% increase, < 50 % increase in measurable lesions or no change and no 
new lesions. 
 
Upon comparison of the MDA, UICC and WHO criteria in a study of 41 
breast cancer patients with bone-only metastases, MDA was shown to 
better differentiate responders from non-responders and was the only set 
of criteria to correspond to progression-free survival. Using the MDA 
criteria, time to disease progression was found to be 5.5 months for non-
responders and 23.3 months for responders (p = 0.025) while it was 10.4 
months and 12.4 months respectively, using the WHO criteria (p = 0.55). 
MDA identified non-responders earlier and was also found to better 
correlate with clinical response in the first 2-6 months of therapy in 
comparison to the WHO criteria. Early signs of disease progression are 
valuable, allowing ineffective therapy to be halted in a timely fashion and 
30 

 
March 28, 2011
the possible substitution of effective therapy. In addition to clinical utility, 
the MDA bone response criteria closely reflect the behavior of bone 
metastases on radiographs and CT and can be used as guidelines for the 
interpretation of these studies whether or not a patient is enrolled in a 
therapeutic trial. The MDA criteria can be considered for use in 
conjunction with other cancer response criteria or in patients with bone-
only metastases and no measurable disease. 
 
Though the MDACC bone response criteria have been helpful in 
determining response to therapy in bone metastasis, no imaging study 
exists to measure the benefits of bisphosphonates in preventing skeletal 
related events in patients with metastatic breast cancer. Such limitations, 
combined with the expense of traditional imaging studies, suggest a need 
for novel measures of tumor response and bone health.  Ntx, a marker of 
bone resorption, has been found to significantly correlate with risk of 
negative clinical outcomes(28), response to systemic therapy(29) and 
response to bisphosphonate therapy(25).  
 
Ntx has shown significant correlation with clinically relevant skeletal 
related events (SREs) (r=0.62, p<0.001) in patients with bone metastasis 
and in a multivariate logistic regression model was highly predictive for 
adverse event or death (30). In randomized bisphosphonate studies, 
reductions in Ntx and decreased SREs were similar in patients treated with 
zoledronic acid compared to pamidronate (23). 
 
Several studies have correlated reductions in Ntx with response to therapy. 
Costa et al. demonstrated that increases in Ntx were strongly associated 
with progression in bone and that the increase in Ntx occurred 
independent of bisphosphonate administration(31). In this study, urinary 
Ntx was associated with the highest positive predictive value for disease 
progression (71%) when compared to other markers of bone metabolism.  
A second study conducted by Lipton, et al randomized patients to receive 
either pamidronate or placebo and correlated urinary Ntx with response to 
therapy(32). Of the 25 patients who received pamidronate, 21 had elevated 
Ntx prior to therapy administration and 12 of these patients normalized 
Ntx values. When compared to the patients who did not normalize Ntx, the 
proportion of patients with progression in bone was significantly higher 
(p=0.03) in those who did not normalize. Although not directly correlated 
with tumor response, several bisphosphonate dosing studies have also 
demonstrated a dose dependant effect on Ntx levels [summarized in (33)], 
suggesting that variations in bone resorption for individual patients can be 
detected using this technique. Finally, the existing clinical data for the use 
of Ntx to monitor response to bisphosphonate therapy has led to 
development and implementation of the Bisphosphonate Therapy Directed 
by Bone Resorption Markers (BISMARK) trial. This study is a large 
31 

 
March 28, 2011
randomized phase III trial currently accruing patients to prove non-
inferiority between standard and marker-directed bisphosphonate therapy.    
  
Because this proposal hypothesizes that combined therapy with dasatinib 
and zoledronic acid will inhibit bone resorption through combined effects 
on osteoclasts and may also exert anti-tumor effects through disruption of 
the tumor cell/osteoclast paracrine loop, biomarkers of bone resorption 
would be expected to accurately predict improvement in bone health as 
well as tumor response and time to disease progression in this special 
cohort of patients.  
 
Urinary measures of Ntx will be performed using standard techniques at 
baseline, 1 month, 3 months and then every 3rd month until disease 
progression or protocol withdrawal. Patients will be divided into three 
categories: high (Ntx> 100nm/mmol creatinine), moderate (Ntx=50-
99nm/mmol creatinine) and low (Ntx <50nm/mmol creatinine) as 
previously described by Coleman et al.(25). This study demonstrated that 
treatment with various systemic therapies in combination with zoledronic 
acid resulted in a 67% decrease in the proportion of patients with moderate 
to high levels of Ntx after only one month of therapy; an effect which was 
sustained for > 6 months. Zoledronic acid was also more effective than 
pamidronate in reducing the levels of Ntx from a moderate or high state to 
a low state within the breast cancer subset, a subset in which zoledronic 
acid significantly improved clinical benefit compared to pamidronate. 
 
4 OVERVIEW OF STUDY DESIGN AND EVALUATION 
4.1 
Dose-finding and Cohort Definitions 
This is an open label, Phase I/II, dose escalation study to evaluate the 
safety and tolerability of dasatanib in combination with a standard 28-day 
cycle of zoledronic acid (Figure 4.1) in patients with metastatic breast 
cancer to bone.  
 
Zoledronic Acid IV1
Dasatinib1 PO daily x 28 days
Cycle=28 days
Figure 4.1: Dosing Schedule for Phase I and Phase II
1. Dosing as per protocol section 7.3.
32 

 
March 28, 2011
Zoledronic acid will be administered as a 15-minute infusion on day 1(+/- 
48 hours) of a 28-day cycle. The dose of zoledronic acid administered will 
be calculated using the standard dosing guidelines outlined in section 
7.3.2. 
 
Dasatinib will be taken by mouth using a daily dosing schedule on days 1-
28 of each cycle (i.e. continuous dosing). Dasatinib will be given 
continuously unless patients develop toxicity requiring dose adjustment as 
outlined in section 7.4. 
 
4.2 
 Phase I Study Design 
The primary objective of the phase I portion of this trial will be to 
determine the RP2D for dasatinib in combination with zoledronic acid.  
 
The first 3 patients (dosing cohort 1) will be treated with 100 mg of 
dasatinib daily in combination with full dose zoledronic acid using the 
dosing guidelines outlined in section 7.3.2. If < 1 of 3 patients develops 
DLT within cycle one of therapy, then 3 additional patients will be 
accrued to this dose level . 
 
If < 1 of  3 patients treated in dosing cohort 1 develops DLT within cycle 
one of therapy, then 3 additional patients will be accrued to this cohort 
(n=6 total). If < 1 of 6 enrolled patients experiences DLT, then this will be 
deemed the RP2D and accrual will begin for the phase 2 portion of the 
trial.  
If > 2 patients develop DLT during initial accrual (n=3) or during the dose 
expansion (n=6 total) of any cohort, further accrual will begin at the lower 
dosing cohort until a total of six patients are treated at the lower dosing 
cohort or accrual is halted due to DLT. The RP2D will be defined as the 
dose at which < 1 out of 6 patients develops DLT. 
If > 2 patients develop DLT during accrual to cohort – 1 (100 mg of 
dasatinib daily), the study will be closed due to intolerability. 
4.2.1 
Definition of Dose Limiting Toxicity 
Toxicity will be assessed using the NCI Common Toxicity Criteria (CTC) 
Scale, version 3.0.  
 
By definition a DLT must occur during cycle 1, be suspected as being 
drug-related, and includes any of the following: 
 Any grade 4 non-hematological toxicity 
 Grade 4 neutropenia lasting > 7 days or any febrile neutropenia 
33 

 
March 28, 2011
 Grade 3 non-hematological toxicity that persists >72 hours despite 
adequate supportive care  
 Grade 2 or greater neutropenia (ANC<1.5x109/L) or thrombocytopenia 
(PLT<75x109/L) which fails to revert to grade 1 (level at which 
treatment is permitted) by the time of the scheduled start of cycle 2 
 50% decrease in calculated creatinine clearance 
 Diagnosis of osteonecrosis of the jaw 
 
4.3 
Phase II Study Design 
The dose identified as the RP2D in the phase I portion of this study will be 
evaluated for efficacy in the phase II portion of this trial. The primary 
objective of this phase II study is to assess the efficacy of dasatinib in 
combination with zoledronic acid as measured by disease response. .  
Patients will be stratified into two cohorts dependent upon Ntx levels 
obtained prior to the initiation of therapy (Figure 4.2). All patients will 
receive same therapy, lab draws and radiographic assessment for response. 
 
Figure 4.2: Phase II Trial Design
Initial Registration 
Baseline measurement of Ntx
Patients with High 
(> 100nM/mmol) 
or Moderate (50-
99nM/mmol) 
levels of Ntx
Patients with Low 
(< 50nM/mmol) 
levels of Ntx
Stratify
Zoledronic Acid IV Q 4 
weeks + Dasatinib PO 
(Dose established by 
Phase I portion of trial)
Repeat measurement of Ntx
1 month
Repeat measurement of Ntx and radiographic 
assessment of response (repeat Q 3months)
2 month
Figure 4.2: Phase II Trial Design
Initial Registration 
Baseline measurement of Ntx
Patients with High 
(> 100nM/mmol) 
or Moderate (50-
99nM/mmol) 
levels of Ntx
Patients with Low 
(< 50nM/mmol) 
levels of Ntx
Stratify
Zoledronic Acid IV Q 4 
weeks + Dasatinib PO 
(Dose established by 
Phase I portion of trial)
Repeat measurement of Ntx
1 month
Repeat measurement of Ntx and radiographic 
assessment of response (repeat Q 3months)
2 month
 
The primary efficacy analysis will not be dependant upon urinary Ntx 
levels, but this the effects of therapy on urinary Ntx will be evaluated as a 
secondary endpoint. 
Patients treated at the RP2D (n=6) in the phase I portion of this study will 
be included in the efficacy analysis for the phase II portion of the trial. 
34 

 
March 28, 2011
Up to 25 patients will be enrolled in the phase II study to assess the 
efficacy of dasatinib in combination with zometa (zoledronic acid).  The 
primary endpoint is the response rate.  The trial will be conducted by the 
Simon’s two-stage design using the minimax criterion and the response 
rate will be estimated accordingly. 
 
It is assumed that dasatinib in combination with zometa will have a target 
response rate of 25%.  A response rate of  5% or lower is considered a 
failure.  When the probability of accepting a “bad” regimen (i.e. response 
rate  5%) is 0.05 and the probability of rejecting a “good” regimen (i.e. 
response rate  25%) is  0.10, Simon’s design to minimize the maximum 
sample size requires 15 patients in the first stage.  If no patients respond to 
the treatment, the trial will be stopped and the regimen will be declared as 
ineffective.  If at least one of the first 15 patients respond to the treatment, 
10 additional patients will be entered in the study to reach a total of 25 
patients.  By the end of the study, the new regimen will be rejected if 
response rate is less than or equal to 3 out of 25 patients and will be 
accepted otherwise.  The operating characteristics of the trial are given as 
follows.  When the true response rate is 0.05, the probability of stopping 
the trial early is 46.3%.  On the other hand, if the true response rate is 
0.25, the probability to stop the trial early is 1.3%.  The expected sample 
sizes are 20.37 and 24.97 when the true response rates are 0.05 and 0.25, 
respectively.  At the end of the study, the response rate and the 95% 
confidence interval will be reported and the toxicity profile of the regimen 
will be summarized.  If the trial continues to the second stage (i.e., accrual 
= 25) and the 5 of 25 patients response for a point estimate of 20.0%, the 
exact binomial 95% confidence interval would be (6.8%, 40.7%). 
Assuming that 10% of patients may not be evaluable for response, a total 
of 28 patients will be accrued to the study.    
5 STUDY OBJECTIVES 
5.1 
Primary Objective  
5.1.1 
Phase 
5.1.2 
Phase 
I: 
To determine the maximum tolerated dose (MTD) and recommended 
phase II dose (RP2D) for dasatinib in combination with zoledronic acid. 
II: 
Determine the efficacy of dasatinib in combination with zoledronic acid as 
measured by disease response. 
35 

 
March 28, 2011
5.2 
Secondary Objective(s) 
5.2.1 
Phase 
5.2.2 
Phase 
I: 
To determine toxicity of combination therapy with dasatinib and 
zoledronic acid in patients with breast cancer and bone metastasis. 
II: 
 Determine the effects of therapy on urinary Ntx levels. 
 Changes in Ntx levels will be correlated with traditional measurements 
of tumor response in bone (using WHO criteria), progression free 
survival and overall survival at 2years 
 Biologic characterization of response using 18F-FDG PET 
 Determination of molecular correlates of response in paraffin 
embedded or frozen tissue 
 Determine time to tumor progression, response (as defined in section 
9.1.2), time to tumor response, progression free survival (PFS) up to 2 
years 
 Determine overall survival (OS) at 2 years 
 Banking of blood for future studies of novel markers of bone health 
 Correlate response with tumor estrogen receptor (ER), progesterone 
receptor (PR) and HER2 status  
 
 
6 SELECTION OF PATIENTS 
6.1 
Inclusion Criteria  
For entry into the study, the following criteria MUST be met: 
1) 
Patients must have a pathologically confirmed diagnosis of 
invasive carcinoma of the breast. 
2) 
Patients must carry a diagnosis of metastatic breast cancer with 
predominant bone involvement. For the purposes of this study, 
predominant bone involvement will be defined as radiographically 
detected bone metastasis in the presence or absence of other sites of 
metastatic breast cancer (i.e. visceral involvement). If visceral 
involvement is present, patients must be asymptomatic and have no 
tumors in visceral organs that measure >3cm in size.  
3) 
Patients must agree to serial urine collections for measurement of 
Ntx according to the schedule defined in sections 8 and 9. 
4) 
Age >18 years. 
5) 
Patients must be able to swallow oral medications. Dasatinib must 
be taken whole and cannot be crushed.  
36 

 
March 28, 2011
6) 
Patients must have evaluable disease using WHO Criteria for 
Assessment of Disease Response in Bone or MDACC Modified Response 
Criteria for Assessment of Disease Response in Bone (Post text 
supplement 4).  
7) 
Patients must not have had >1 chemotherapy regimens for 
metastatic disease. Patients with metastasis diagnosed <6 months after 
completion of adjuvant chemotherapy are considered to have had 
chemotherapy for metastatic breast cancer.  
8) 
Patients with ER positive disease must have had disease 
progression on at least one prior hormonal therapy for metastatic disease. 
Patients must also have developed disease progression on their most recent 
hormonal therapy regimen and be agreeable to continue this regimen in 
combination with protocol therapy. For the purposes of this study disease 
progression while receiving hormonal therapy will be defined as: 
 Radiographic evidence of progressive disease according to RECIST 
or WHO criteria for measurement of response in bone 
 Progression of disease by physical exam in patients with skin 
involvement 
 25% increase in tumor marker as measured on two evaluations no 
less than 72 hours apart 
9) 
Patients must have and ECOG performance status of <2.  
10) 
Patients must not require concurrent radiation or chemotherapy 
while receiving protocol therapy. 
11) 
Patients must not have an active infection requiring the use of 
intravenous antibiotics. The use of oral antibiotics as prophylaxis is 
allowed.  
12) 
Patients must have a baseline ECG with QTc within the normal 
range within 28 days prior to registration.  
13) 
Patients must be informed of the investigational nature of the study 
and must sign and give written informed consent. 
14) 
Patients may have received previous radiation but must have 
completed radiation at least 2 weeks (8 weeks for radiation to the brain) 
prior to registration. Patients with irradiated tumor as the only site of 
evaluable disease will not be eligible for protocol therapy unless there is 
documented disease progression within the previously radiated site.  
15) 
Patients must have recovered to grade <1 from all acute toxicity of 
previous radiation or hormonal therapy.  
 Adequate hematologic and hepatic function: 
 Granulocyte count > 1,500/mcL 
 Platelet count > 100,000/mcL 
 Bilirubin < 1.5 x ULN 
 AST and/or ALT < 2 x ULN 
 Alkaline phosphatase (liver component, if fractionated) < 2 x ULN 
 Serum Na, K+, Mg2+, Phosphate and Ca2+ Lower Limit of 
Normal (LLN) [subjects with low electrolyte levels must be repleted 
to normal for protocol entry] 
37 

 
March 28, 2011
16) 
Patients must not receive any concurrent bisphosphonate therapy 
other than that prescribed by the study. 
17) 
Sexually active patients with reproductive potential must agree to 
use an effective method of birth control during the course of the study and 
for no less than 4 weeks after discontinuing study drug. Contraceptives 
must be used in a manner such that risk of failure is minimized. Oral 
contraceptives should be avoided in women with estrogen or progesterone 
receptor positive breast cancer.  
18) 
Prior to study enrollment, women of childbearing potential 
(WOCBP) must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional 
pregnancy.  In addition, men enrolled on this study should understand the 
risks to any sexual partner of childbearing potential and should practice an 
effective method of birth control. 
19) 
All WOCBP MUST have a negative serum or urine pregnancy test 
within 72 hours prior to the start of study drug administration. If the 
pregnancy test is positive, the patient must not receive investigational 
product and must not be enrolled in the study. 
20) 
Patients with disease progression while receiving previous therapy 
in combination with bisphosphonates (including zoledronic acid) will be 
considered eligible for protocol participation.  
 
6.2 
Exclusion Criteria 
Subjects may NOT have any of the following:  
 
1) Any malignancy (other than breast cancer) that required radiotherapy 
or systemic treatment within the past 5 years.  
2) Concurrent medical condition which may increase the risk of toxicity, 
including: 
 Pleural or pericardial effusion of any grade 
 Clinically-significant coagulation or platelet function disorder (e.g. 
known von Willebrand’s disease) 
3) Cardiac Symptoms, including the following:  
 Uncontrolled angina, congestive heart failure or MI within (6 months) 
 Diagnosed congenital long QT syndrome 
 Any history of clinically significant ventricular arrhythmias (such as 
ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) 
 Prolonged QTc interval on pre-entry electrocardiogram (> normal 
range) 
 Subjects with hypokalemia or hypomagnesemia if it cannot be 
corrected 
38 

 
March 28, 2011
4) History of significant bleeding disorder unrelated to cancer, including: 
 Diagnosed congenital bleeding disorders (e.g., von Willebrand’s 
disease) 
 Diagnosed acquired bleeding disorder within one year (e.g., acquired 
anti-factor VIII antibodies) 
 Ongoing or recent ( 3 months) significant gastrointestinal bleeding 
5) Concomitant Medications, consider the following prohibitions (Drugs 
must be discontinued for 7 days prior to starting protocol therapy):  
 Drugs that are generally accepted to have a risk of causing Torsades de 
Pointes including:  
quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, 
dofetilide 
erythromycins, 
clarithromycin, 
chlorpromazine, 
haloperidol, 
mesoridazine, thioridazine, pimozide, cisapride, bepridil, droperidol, 
methadone, 
arsenic, 
chloroquine, 
domperidone, 
halofantrine, 
levomethadyl, pentamidine, sparfloxacin, lidoflazine. 
 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. 
 Patient agrees to discontinue St. Johns Wort while receiving dasatinib 
therapy  
 Patient may not be receiving any prohibited CYP3A4 inhibitors [see 
section 7.6] 
6) Women and men of child bearing potential: 
 Who are unwilling or unable to use an acceptable method to avoid 
pregnancy for the entire study period and for at least 4 weeks after 
cessation of study drug, or 
 Women of childbearing potential (CBP) who have a positive 
pregnancy test at baseline, or 
 Women who are pregnant or breastfeeding  
 Sexually active men and women capable of reproduction must use an 
effective method of birth control during the course of the study, in a 
manner such that risk of failure is minimized 
 Prior to study enrollment, men and women capable of reproduction 
must be advised of the importance of avoiding pregnancy during trial 
participation and the potential risk factors for an unintentional pregnancy   
7) Prisoners or subjects who are compulsorily detained (involuntarily 
incarcerated) for treatment of either a psychiatric or physical (e.g., 
infectious) illness 
8) Untreated or uncontrolled brain metastasis 
9) Patient inability to take or absorb oral medications 
39 

 
March 28, 2011
10) Current active dental problems including: ongoing infection of the 
teeth or jawbone (maxilla or mandibula); current exposed bone in the 
mouth; and current or prior diagnosis of osteonecrosis of the jaw 
11) Recent (within 8 weeks) or planned dental or jaw surgery (e.g., 
extraction, implants) 
12) Diagnosis of metabolic bone disease other than osteoporosis (e.g., 
Paget’s disease of bone) 
13) Known hypersensitivity to zoledronic acid or aspirin 
14) Corrected serum calcium  8.0 mg/dL (2.0 mmol/L) or  12.0 mg/dL 
(3.0 mmol/L) at Visit 1.  The formula to be used is:  Corrected serum 
calcium (mg/dL) = Patient’s serum calcium (mg/dL) + [0.8 x Midrange 
Albumin (g/dL) – Patient’s Albumin (g/dL)].  4.0g/dL to be used for the 
Midrange Albumin 
15) Serum creatinine  1.5 times the institutional upper limits of normal or 
a creatinine clearance of <40 ml/min when calculated by the Cockroft and 
Gault formula: 
Estimated creatinine clearance=  
(140-age in years) x (weight in kg)  (x 0.85, if female) 
                             72 x creatinine (mg/dL) 
 
7 TREATMENT OF SUBJECTS 
This is an open label, Phase I/II, dose escalation study to evaluate the 
safety and tolerability of dasatanib in combination with a standard 28-day 
cycle of zoledronic acid in patients with metastatic breast cancer to bone. 
Zoledronic acid will be administered as a 15-minute infusion on day 1(+/- 
48 hours) of a 28-day cycle (see section 7.3.2). Dasatinib will be taken by 
mouth using a daily dosing schedule on days 1-28 of each cycle (i.e. 
continuous administration). Dasatinib will be given continuously unless 
patients develop toxicity requiring dose adjustment as outlined in section 
7.4. 
 
Patients with ER positive disease who have progressed on their most 
recent hormonal therapy will continue this therapy (at the previously 
prescribed dose) in combination with protocol treatment. 
 
7.1 
Study Registration 
Patients will be registered after the Principal Investigator or her designee 
has verified that they are eligible per criteria in Section 6.1 and Section 
6.2. Patients withdrawn from the study prior to completing the first course 
of therapy due to non drug-related reasons will be replaced.  
 
40 

 
March 28, 2011
The Principal Investigator or her designee will provide the dosing 
assignment form. No subject may start therapy prior to dosing assignment. 
 
7.2 
Study Treatment 
7.2.1 
Phase I 
On cycle 1, day 1, patients will receive a single IV infusion of zoledronic 
acid using dosing guidelines outlined in section 6.4.2. Dasatinib will be 
taken daily by mouth beginning on cycle 1 day 1 and continued daily for 
the duration of the cycle (Table 7.1 and section 4.2).   
 
Table 7.1.  Dosing of Dasatinib for Phase I Dosing 
Cohorts  
Dose Level 
Dose of Dasatinib (+ Full Dose Zoledronic Acid) 
-1 
70 mg po daily 
1 
100 mg po daily 
 
Patients will be monitored for toxicity every week during the first cycle of 
therapy and on day 1 (+/- 48 hours) prior to therapy for subsequent cycles. 
ECG and laboratory assessments will be performed weekly (see section 
7.0) during the first cycle. ECG will be performed on day 1 (+/- 48 hours) 
of cycle 2 only.  Laboratory assessment will be performed on day 1 (+/- 48 
hours) prior to therapy during cycle 2 and all subsequent cycles.   
 
7.2.2 
Phase II 
Zoledronic acid will be administered as a single 15-minute infusion on day 
1(+/- 48 hours) of a 28-day cycle. The dose of zoledronic acid 
administered will be calculated using the standard dosing guidelines 
outlined in section 7.3.2. 
 
Dasatinib will be taken by mouth using a daily dosing schedule on days 1-
28 of each cycle (i.e. continuous dosing). Dasatinib will be given 
continuously unless patients develop toxicity requiring dose adjustment as 
outlined in section 7.4. 
 
Both drugs will be given at the RP2D as determined by the phase I portion 
of the trial.  
 
Patients will be monitored for toxicity on day 1 (+/- 48 hours) prior to 
therapy during subsequent cycles. Physical exams and laboratory 
41 

 
March 28, 2011
assessments will be performed monthly (see section 8.0) on day 1 (+/- 48 
hours) prior to therapy.  Measurement of Ntx will occur at baseline (up to 
7 days prior to therapy), at day 28 (+/- 48 hours) of cycle 1 and at day 28 
(+/- 48 hours) of every 3rd cycle of therapy, (see figure 4.2 and section 
8.0). Patients will undergo radiographic evaluation of response every 3 
cycles.  
7.3 
Drug Dosing and Routes of Administration 
NOTE: Although the dose of dasatinib may differ between the phase I 
and phase II portions of the trial, the schedule and route of 
administration of both dasatinib and zoledronic acid will be the same 
for the phase I and phase II portions of the trial. 
7.3.1 
Dasatinib 
7.3
Dasatinib will be supplied as 20 and 50 mg tablets for oral administration. 
Patients treated at the 70 mg dose level will receive a 50 mg tablet and a 
20 mg tablet daily. Patients treated at the 100 mg dose level will receive 
two 50 mg tablets daily.  
 
If a dose is missed by more than 12 hours, the dose should be omitted. 
Missed doses should not be made up.  
 
Tablets should not be crushed or cut; they should be swallowed whole. 
Dasatinib can be taken with or without a meal. 
 
Patients will be provided with a diary to record drug dosing (see Appendix 
3).  
.2 
Zoledronic Acid 
Zoledronic acid will be administered as a 15-minute IV infusion on day 
1(+/- 48 hours) of each 28-day cycle. The dose of zoledronic acid 
administered will be calculated using the schema in Figure 7.1. 
 
Figure 7.1: Dosing of zoledronic acid 
Dosing will be based upon serum creatinine obtained within 2 weeks prior to 
zoledronate dose.  
 
Creatinine Clearance =(140 – age in years) x (weight in kg)     (x 0.85, if female)  
                                                           72 x serum Creatinine 
Creatinine Clearance (mL/min) 
Zoledronic acid Dose 
>60 
4 mg 
50-60 
3.5 mg 
40-49 
3.3 mg 
30-39 
3 mg 
42 

 
March 28, 2011
<30 
Hold 
  
Doses of zoledronic acid may not be given earlier than 48 hours prior to 
day 1 of each cycle of therapy; however doses of zoledronic acid may be 
delayed for up to 4 weeks if the delay in therapy is felt to be in the best 
interest of the patient. The duration and reason for the delay should be 
documented on the appropriate treatment forms. Patients should continue 
with laboratory and toxicity assessments as outlined in section 8.0.  
Patients requiring a delay in therapy administration for > 4 weeks will 
discontinue protocol therapy. Dasatinib may be administered as a single 
agent while zoledronic acid is held.  
 
Patients should receive supplemental oral calcium (1000-2000 mg daily) 
and vitamin D (400-800 IU daily) unless felt to be medically 
contraindicated by the treating physician. 
 
7.4 
Dose Modifications  
7.4.1 
Dasatinib 
NOTE: Toxicity will be assessed using the NCI Common Toxicity 
Criteria (CTC) Scale, version 3.0. Dasatinib should be held for 
treatment related toxicities > grade 2.  
 
Treatment modifications will proceed as outlined in Table 7.2.   
 
Table 7.2: Dose Modifications for Dasatinib. 
Dose Level 
Dose (if RP2D=100 mg 
daily) 
Dose (if RP2D=70 mg 
daily) 
 
A 
70 mg daily 
50 mg daily 
 
B 
50 mg daily 
Discontinue protocol 
therapy 
 
C 
Discontinue protocol 
therapy 
 
 
Toxicity 
Treatment Modification 
Grade 1 
Proceed without dose modification. Consider appropriate supportive 
measures. 
Grade 2 
If 1st episode, hold therapy until recovery to Grade <1, then continue 
treatment at dose level A. 
If 2nd episode, hold therapy until recovery to Grade <1, then continue 
treatment at dose level B. 
43 

 
March 28, 2011
If 3rd episode, discontinue protocol therapy 
 
Grade 3 
If 1st episode, hold therapy until recovery to Grade <1, then continue 
treatment at dose level B. 
If 2nd episode, discontinue protocol therapy 
Grade 4 
May discontinue treatment permanently or, at the discretion of the treating 
physician, hold therapy until recovery to Grade <1, then continue treatment at 
dose level B. If any grade > 1 toxicity recurs, patient must discontinue 
protocol therapy.  
 
Decisions for dose reductions will be made according to grade of toxicity 
and will be independent of the type of toxicity. For example, if a patient 
develops grade 2 hypokalemia that resolves and, upon re-treatment, 
develops grade 2 elevation of AST; the second event (i.e. elevated AST) 
will require a dose reduction because it is the second episode of grade 2 
toxicity.  
 
Zoledronic acid may be continued if dasatinib is held or discontinued. 
The dosing time may be adjusted as 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. 
7.4.2 
 Dose Modifications for Zoledronic Acid 
Dosing of zoledronic acid will be performed as outlined in section 7.3.2. 
Zoledronic acid will be permanently held in patients who develop 
evidence of osteonecrosis, acute renal failure attributed to therapy with 
zoledronic acid, or hypersensitivity to zoledronic acid that recurs despite 
appropriate prophylaxis. Patients may continue single agent dasatinib if 
zoledronic acid is discontinued. 
7.5 
Discontinuation of Therapy  
Study therapy must be immediately discontinued for the following 
reasons: 
 Progressive disease at any time 
 Any clinical adverse event, laboratory abnormality or intercurrent 
illness which, in the opinion of the Investigator, indicates that 
continued treatment with study therapy is not in the best interest of the 
subject 
 Excessive toxicity despite dose reduction 
 Withdrawal of informed consent (subject’s decision to withdraw for 
any reason) 
44 

 
March 28, 2011
 Pregnancy  
 All WOCBP should be instructed to contact the Investigator 
immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
Institutional policy and local regulations should determine the 
frequency of on study pregnancy tests for WOCBP enrolled in the 
study. 
 The Investigator must immediately notify BMS in the event of a 
confirmed pregnancy in a patient participating in the study. 
7.5.1 
7.6
 Follow up After Discontinuation of Protocol 
Therapy: 
All patients will be followed for 2 years after discontinuation of protocol 
therapy or until death, whichever occurs first. Patients will follow up 1 
month after completing therapy for toxicity assessment. After this, patients 
will be followed every 3-6 months for survival outcome. This follow up 
can include contacting an outside treating physician if the patient does not 
wish to return to the treating institution.  
7.6 
Prohibited and Restricted Therapies During 
Study 
.1 
Prohibited Therapies 
Subjects requiring any of the following prohibited therapies should not be 
enrolled.  
CYP3A4 
Dasatinib is primarily metabolized by the CYP3A4 enzyme. 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. Subjects should be advised not to consume substantial 
quantities of grapefruit juice.  
Drugs that may increase dasatinib plasma concentrations 
CYP3A4 Inhibitors:  Dasatinib is a CYP3A4 substrate. Concomitant use 
of Dasatinib and drugs that inhibit CYP3A4 (See Appendix 2) may 
increase exposure to dasatinib and should be avoided. 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.  
Medications that prolong QT Interval 
Subjects enrolled in this study should not take or begin to take 
concomitant medications known to prolong the QT interval. For such 
medications, a wash-out period of 7days is required prior to starting 
45 

 
March 28, 2011
dasatinib. (Agents which may possibly prolong the QT interval are 
restricted). Medications known to prolong the QT interval (Class I; see 
http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm) are: Drugs 
that are generally accepted to have a risk of causing Torsades de Pointes 
include: 
 quinidine, procainamide, disopyramide 
 amiodarone, sotalol, ibutilide, dofetilide 
 erythromycins, clarithromycin 
 chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide 
 cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, 
domperidone, 
halofantrine, 
levomethadyl, 
pentamidine, 
sparfloxacin, lidoflazine 
 Should the Investigator believe that beginning therapy with a potentially 
QT prolonging medication (other than the ones explicitly prohibited) is 
vital to an individual subject’s care, the Investigator must check that the 
subject’s prior on-therapy ECG has not shown a QTcF  450 msec or an 
increase in QTc  60 msec over the baseline value.  
7.6.2 
Restricted Therapies 
Drugs that may decrease dasatinib plasma concentrations 
CYP3A4 Inducers:  Drugs that induce CYP3A4 activity may decrease 
dasatinib plasma concentrations. In patients in whom CYP3A4 inducers 
(See Appendix 2) are indicated, alternative agents with less enzyme 
induction potential should be used.  If dasatinib must be administered with 
a CYP3A4 inducer, a dose increase in dasatinib should be considered. 
Drugs that may have their plasma concentration altered by dasatinib 
CYP3A4 Substrates:  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.    
Less-potent inhibitors, inducers, and substrates of CYP3A4 are restricted.  
(Appendix 2) 
St. John's wort (Hypericum perforatum) may decrease dasatinib plasma 
concentrations unpredictably.  Patients receiving dasatinib should not take 
St. John's wort.  
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.  
46 

 
March 28, 2011
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.  
Medications that inhibit Platelet Function and Anticoagulants 
Caution should be exercised if patients are required to take medications 
that inhibit platelet function or anticoagulants. 
Subjects enrolled in this study should not take concomitant medications 
which durably inhibit platelet function. For such medications, a wash-out 
period of 7days is required prior to starting dasatinib. (Agents which 
inhibit platelet function transiently or inhibit coagulation by other 
mechanisms are restricted.)  
Medications which directly and durably inhibit platelet function include: 
 aspirin or aspirin-containing combinations, clopidogrel, dipyridamole 
 tirofiban, 
dipyridamole, 
epoprostenol, 
eptifibatide, 
cilostazol, 
abciximab, ticlopidine, cilostazol 
Medications which directly and durably inhibit anticoagulation 
include: 
 warfarin, heparin/low molecular weight heparin [e.g., danaparoid, 
dalteparin, tinzaparin, enoxaparin] 
 Exceptions: low-dose warfarin for prophylaxis to prevent catheter 
thrombosis, and heparin for flushes of IV lines.  
 
7.7 
Concomitant Therapy 
NOTE: For the phase I portion of the trial, concomitant medications 
may be used to treat symptoms that develop during therapy; however, 
the routine use of concomitant medications (except antibiotics) as 
prophylaxis for toxicity is not allowed during cycle 1 of therapy. 
Concomitant medications can be used as prophylaxis for toxicity 
during cycles > 1.  
 
In general, the use of any concurrent medications deemed necessary for 
the care of the patient are allowed. For patients receiving cycles > 1 in the 
phase I portion of the trial and for all patients enrolled in the phase II 
portion of the trial, drugs may be given prophylactically to reduce the side 
effects of therapy. The following exceptions apply: 
 No other investigational therapy will be given to patients. 
47 

 
March 28, 2011
48 
 The use of anticancer agents (other than hormonal therapy) or 
radiation therapy is not allowed (an exception would be the use of 
megestrol acetate for the treatment of anorexia). 
 Patients enrolled in the Phase I portion of the trial may not receive 
GCSF or GMCSF during cycle 1 of therapy.  The use of 
hematologic growth factors for the treatment of anemia is allowed 
at any time during protocol therapy. Patients enrolled in the Phase 
II portion of the trial or those who have completed >1 cycle of 
therapy in the phase I portion of the trial may receive growth factor 
support as per ASCO guidelines.  
 Where possible, drugs known to inhibit CYP3A4 should be 
avoided as systemic therapy as a pharmacokinetic interaction may 
occur during the concomitant use of dasatinib (see section 7.5).  
 
 
 

 
March 28, 2011 
ja 
a 
49 
8 STUDY PROCEDURES  
8.1 
Evaluation and visit schedule 
Table 8.1 Evaluation and visit schedule in Phase I  
Dasatinib + Zoledronic Acid 
Final 
visit 
Screening 
Cycle 1 
Continuing Cycles 
 
 
 
 
 
Evaluations: 
D-14 to D- 0 
Day 1 
Day 8 
Day 15  Day 21 
Day 28 
Day 1  Day 8 Day 15
Day 21 
Every 3rd 
Cycle 
 
Selection (inclusion/exclusion criteria), medical 
history, demography, signed informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam3, ECOG performance status 
X 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Blood pressure, pulse, temperature, weight 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
Laboratory1: hematology, serum biochemistry, 
urinalysis 
X 
X1 
X 
X 
X 
 
X 
 
 
 
 
X 
Pregnancy Test 
X8 
 
 
 
 
 
 
 
 
 
 
 
Calculate Creatinine Clearance 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
X 
Concomitant medications 
X 
Continuous  ------------------------------------------------------------------------------------------------------------------------- 
Adverse events, toxicity 
 
Continuous  ------------------------------------------------------------------------------------------------------------------------- 
ECG5 
X 
X 
X 
X 
X 
 
X5 
 
 
 
 
 
Tumor evaluation/staging2 (Radiographic 
imaging and/or turmor markers) 
X 
 
 
 
 
 
 
 
 
 
X 
 
Treatment: 
Dasatinib3 
 
Continuous  --------------------------------------------------------------------------------------------------------------- 
 
 
 
Zoledronic Acid3 
 
X 
 
 
 
 
X 
 
 
 
 
 
Response Assessment:   Ntx4 
X 
 
 
 
 
X 
 
 
 
 
X 
 
                                         Imaging Studies2 
X 
 
 
 
 
 
 
 
 
 
X 
 
Correlative Studies (optional):  
 
 
 
 
 
 
 
 
 
 
 
 
                         PET scan 
X 
 
 
X 
 
 
 
 
 
 
 
X6 
                         Biopsy 
X 
 
 
 
 
X 
 
 
 
 
 
 
                         Blood Samples7 
X 
 
 
 
 
X7 
 
 
 
 
X 
X6 

 
a 
50 
March 28, 2011 
ja 
1. 
May be drawn on day 1 (+/- 48 hours) however, results must be reviewed prior to patient receiving day 1 of therapy.  Hematology: hemoglobin, hematocrit, platelets, 
total white blood cell count (WBC) and differential. Serum biochemistry: sodium, potassium, chloride, bicarbonate, creatinine, blood urea nitrogen, albumin, total protein, 
SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase, uric acid, calcium, Glucose, magnesium. Urinalysis will only be performed during cycle 1 of therapy. 
Screening lab may be used for day 1 cycle 1 of therapy. 
2. 
Baseline scans may be performed 1 month prior to initiating protocol therapy. All known sites of metastasis must be imaged prior to initiating protocol therapy. For 
response assessment, only imaging studies with detectable tumor-related abnormalities will be required to follow response. Bone scan will be performed pretreatment 
and used as a baseline for comparison, if needed, to verify disease progression or response as assessed using plain films.  
3. 
Physical exam must be performed on day 1 (+/- 48 hours) of cycles 1 and 2 and occur prior to administration of protocol therapy. After cycle 2, physical exams can be 
performed every 2 cycles of therapy. 
4. 
Urine for N-telopeptide. Must be collected as scheduled on day 28 (+/- 48 hours) of cycle 1 and every 3
rd cycle of therapy(after 8 weks of treatment are completed and 
restagning takes place). Must be collected before receiving subsequent cycles of therapy.  
5. 
ECG will only be performed during cycles 1 and 2 of therapy. Screening ECG may be performed up to 28 days prior to protocol therapy. 
6. 
PET scan will be done at time of disease progression to restage patients. Blood samples will be drawn at the time of documented disease progression (+/- 14 days). 
7. 
Blood will be collected for MUC-1 (CA27-29) levels and serum will be banked. Blood will be drawn during weeks 4, 8, 16 and 24. May be drawn +/- 72 hours of time 
points indicated but must be drawn prior to administration of therapy. 
8. 
Must be performed in women of childbearing potential within 72 hours of dasatinib administration. 
 

 
March 28, 2011 
ja 
a 
51 
Table 8.2 Evaluation and visit schedule in Phase II 
Dasatinib + Zoledronic Acid 
Final 
visit 
Screening 
Cycle 1 
Continuing Cycles 
 
 
 
 
Evaluations: 
D-14 to D- 0 
Day 1 
Day 8 
Day 15  Day 21 Day 28 
Day 1 
 Day 8
Day 15
Day 21 
Every 3rd 
Cycle 
 
Selection (inclusion/exclusion criteria), medical 
history, demography, signed informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam3, ECOG performance status 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Blood pressure, pulse, temperature, weight 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Laboratory1: hematology, serum biochemistry,
X 
X1 
 
 
 
 
X 
 
 
 
 
X 
Pregnancy test 
X8 
 
 
 
 
 
 
 
 
 
 
 
Calculate Creatinine Clearance 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Concomitant medications 
X 
Continuous  ---------------------------------------------------------------------------------------------------------------------------------- 
Adverse events, toxicity 
 
Continuous  ---------------------------------------------------------------------------------------------------------------------------------- 
ECG6 
X 
 
 
 
 
X 
 
 
 
 
 
 
Tumor evaluation/staging2 (Radiographic 
imaging and/or tumor markers) 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Treatment: 
Dasatinib3 
 
Continuous  ------------------------------------------------------------------------------------------------------------ 
 
 
 
Zoledronic Acid3 
 
X 
 
 
 
 
X 
 
 
 
 
 
Response Assessment:   Ntx4 
X4 
 
 
 
 
X 
 
 
 
 
X 
 
                                         Imaging Studies2 
X 
 
 
 
 
 
 
 
 
 
X 
 
Correlative Studies (optional): 
 
 
 
 
 
 
 
 
 
 
 
 
                         PET scan 
X 
 
 
X 
 
 
 
 
 
 
 
X6 
                         Biopsy 
X 
 
 
 
 
X 
 
 
 
 
 
 
                         Blood Samples7 
X 
 
 
 
 
 
X7 
 
 
 
 
X6 
1. 
May be drawn on day 1 (+/- 48 hours) however, results must be reviewed prior to patient receiving day 1 of therapy.  Hematology: hemoglobin, hematocrit, platelets, total 
white blood cell count (WBC) and differential. Serum biochemistry: sodium, potassium, chloride, bicarbonate, creatinine, blood urea nitrogen, albumin, total protein, SGOT 
(AST), SGPT (ALT), total bilirubin, alkaline phosphatase, uric acid, calcium, Glucose, magnesium. Screening lab may be used for day 1 cycle 1 of therapy. 

 
a 
a 
52 
March 28, 2011 
j
2. 
Baseline scans may be performed 1 month prior to initiating treatment. All known sites of metastasis must be imaged prior to initiating protocol therapy. For response 
assessment, only imaging studies with detectable tumor-related abnormalities will be required to follow response. Bone scan will be performed pretreatment and used as a 
baseline for comparison if needed to verify disease progression or response as assessed using plain films. 
3. 
Physical exam must be performed on day 1 (+/- 48 hours) of cycles one and two and occur prior to administration of protocol therapy.  After cycle 2 of therapy, physical 
exam may be performed every 2 cycles. 
4. 
Urine for N-telopeptide. Must be collected as scheduled  on day 28 (+/- 48 hours) of cycle 1 and every 3
rd cycle of therapy(after 8 weeks of treatment are completed and 
restaging takes place). Must be collected before receiving subsequent cycles of therapy. Accrual to the low Ntx cohort will be capped after 10 patients. If > 10 patients with 
low levels of Ntx are accrued prior to study completion, patients will undergo screening Ntx prior to study entry.   
5. 
Screening ECG may be performed up to 28 days prior to protocol therapy. 
6. 
PET scan will be done at time of disease progression to restage patients. Blood samples will be drawn at the time of documented disease progression (+/- 14 days). 
7. 
 Blood will be collected for MUC-1 (CA27-29) levels and research serum will be banked. Research blood will be drawn during weeks 4, 8, 16 and 24. May be drawn +/- 48 
hours of time points indicated but must be drawn prior to administration of therapy. (Cycle =28 days/4 weeks) 
8. 
Must be performed in women of childbearing potential within 72 hours of dasatinib administration. 
 
 

 
March 28, 2011
9 EFFICACY AND SAFETY ASSESSMENTS 
9.1 
Efficacy Assessment 
9.1.1 
9.1.2 
Measurement of Tumor Response 
Tumor response will be assessed for individual patients and will be used to determine 
which patients should continue protocol therapy in the absence of toxicity.  Patients 
with bone only involvement or disease considered non-measurable by RECIST will be 
followed for response using the WHO Criteria for Assessment of Disease Response in 
Bone or the MDACC Modified Response Criteria for Assessment of Disease Response 
in Bone  (Post-text supplement 4). Patients with measurable disease outside of the bone 
will have response measured using a combination of RECIST criteria (Post-text 
supplement 3) and the WHO Criteria for Assessment of Disease Response in Bone 
(Post-text supplement 4).  
 
Patients who meet criteria for disease progression within the bone (as measured by 
WHO criteria) or in non-bone disease (as measured by RECIST criteria) or both will be 
considered to have progression of disease and will be withdrawn from protocol therapy.  
 
It is feasible that patients may have response in bone metastasis and disease progression 
in non-bone metastasis. Because these patients have met criteria for disease progression, 
they will discontinue protocol therapy; however, (for statistical purposes only) patients 
with disease progression by RECIST in areas outside of the bone but disease response   
in the bone will be counted as responders for the purpose of correlation of bone 
response with changes in Ntx. Such patients will be counted as non-responders for all 
other endpoint analyses.  
 
Radiologic assessments must account for all lesions that were present at screening and 
must use the same imaging techniques that were used at screening. Any bone lesions 
that have been previously treated with radiation therapy or surgical resection should not 
be used for tumor assessment unless the lesions have shown definite progression since 
treatment.  
N-telopeptide of Type I Collagen (Ntx) 
Ntx, a marker of bone resorption, has been found to significantly correlate with risk of 
negative clinical outcomes(28), response to systemic therapy(29) and response to 
bisphosphonate therapy(25). Because this proposal hypothesizes that combined therapy 
with dasatinib and zoledronic acid will exert anti-tumor effects through disruption of the 
tumor cell/osteoclast paracrine loop, biomarkers of bone resorption would be expected 
to accurately predict tumor response and time to disease progression in this special 
cohort of patients. Urinary measures of Ntx will be performed using standard 
techniques at baseline, 1 month, 3 months and then every 3rd months until disease 
progression or protocol withdrawal.  
 
53 

 
March 28, 2011
Urine for Ntx analysis will be obtained on day 28 (+/- 48 hours) of cycle 1, cycle 3 and 
every subsequent 3rd cycle while the patient is receiving protocol therapy.  Urine will be 
obtained during the second morning void prior to day 1 of specified cycles.  Assessment 
of Ntx will be performed through an outside lab using a commercially available assay. 
 
Although Ntx will be used as an endpoint for efficacy analysis and statistical design, 
changes in Ntx will not be used for decisions regarding continuation of therapy on an 
individual patient basis.  
 
9.2 
Safety Assessment 
Safety assessments will consist of monitoring and recording all adverse events (AEs) 
and serious adverse events (SAEs), the regular monitoring of hematology, blood 
chemistry and urine values, regular measurement of vital signs, and performance of 
physical examinations. The AE and SAE reporting period will begin with the signing of 
informed consent and end 30 days after discontinuation of protocol therapy. Reporting 
of AEs and SAEs will be as designated in section 11.   
 
10 
STUDY DRUG(S) 
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.  
10.1 Dasatinib Product Identification 
Dasatinib will be supplied in two different strengths by Bristol-Myers Squibb. 
 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 
 
10.2 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. 
54 

 
March 28, 2011
10.3 Storage, Handling and Dispensing of Dasatinib  
10.3.1 
Storage 
10.3.2 
10
10
10
Dasatinib tablets should be stored in a secure area at 25C (77F); excursions permitted 
between 15°–30C (59–86F). 
Handling and Disposal 
Procedures for proper handling and disposal of anticancer drugs should be considered. 
There is no general agreement that all of the procedures recommended in the guidelines 
are necessary or appropriate. 
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. However, 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.  
.3.3 
Dispensing 
It is the responsibility of the Investigator to ensure that dasatinib is only dispensed to 
study subjects.  The 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. 
10.4 Drug Ordering and Accountability 
.4.1 
Initial Orders 
Initial Orders of dasatinib will be requested by the assigned BMS protocol manager.  
Initial drug supply is provided for a 12-week treatment period per subject. 
.4.2 
Re-supply 
Re-supply requests can be obtained by completing the SRC re-supply request form and 
submitting the request form electronically via e-mail to srcsupply@bms.com.  
Re-supply requests should be submitted at least 5-7 business days before the expected 
delivery date.  Deliveries will be made Tuesday through Friday. 
10.5 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.  
55 

 
March 28, 2011
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. 
10.6 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.   
10.7 Zoledronic Acid 
10
10.7.2 
Preparation 
.7.1 
Supply 
Zoledronic acid will be purchased from Novartis in plastic vials containing 4mg 
zoledronic acid in a 5 mL concentrate as a solution for infusion.  
The zoledronic acid 4 mg/5 mL concentrate solution is not for direct infusion and has to 
be further diluted prior to the use.  Prior to administration, the 5 mL of the concentrate 
solution must be diluted with 100 mL calcium-free infusion solution (0.9% sodium 
chloride solution or 5% glucose solution).  The appropriate volume of the reconstituted 
zoledronic acid solution is 105 mL.  The necessary infusion bags/bottles, containing 
either 100ml calcium free 0.9% sodium chloride or 5 % dextrose solution, that have to 
be used for the set up of the infusion will be provided by the study center.  Glass bottles 
and infusion bags or tubing made from  polyvinylchloride (PVC), polypropylene (PP) 
and polyethylene (PE) are appropriate for use with Zoledronic acid.  
56 

 
March 28, 2011
If not used immediately after dilution with infusion media, for microbiological integrity, 
the final solution must be placed in a refrigerator with a temperature between 2-8°C. 
The refrigerated solution should then be equilibrated to room temperature prior to 
administration.   The total time between dilution, storage in a refrigerator, and end of 
administration of the infusion must not exceed 24 hours.  Reconstituted zoledronic acid 
solutions must be administered in no less than a 15-minute intravenous infusion in a line 
separate from all other drugs.  
A peripheral or central intravenous site is to be used for the study drug infusion.  Study 
drug should  be administered as a single intravenous solution in a line separate from all 
other drugs. The bore of the needle or angiocatheter used to insert the intravenous line 
will be 20 to 22 gauge.  The i.v. infusion will be preceded by and followed by a 10 ml 
normal saline flush of the intravenous line.  In order to allow constant flow a vented 
infusion line should be used.  Prior to application of the drug, the infusion line via a y-
connector or other similar set-up will be flushed with approximately 10 ml of normal 
saline.  Thereafter, the solution will be infused over a period of no less than 15 minutes. 
After emptying, approximately 3 mL of drug product solution may stay in the infusion 
bottle.  Use at least 10 ml of normal saline to flush the infusion line. 
A pharmacist or other qualified person will be responsible for the preparation of the i.v.  
The qualified person who prepares the drug to be infused must enter the appropriate 
drug preparation information requested on the sign off log for drug preparation.  
Documentation of trial-drug administration and amount infused will be maintained for 
every patient 
Preparation of reduced dose solution for patients with mild to moderate renal 
impairment (CrCl <60 mL/min) at baseline (baseline defined as the serum creatinine, 
just prior to their first ever Zoledronic acid dose, approximately one year prior to 
study entry):  
Withdraw an appropriate volume of the 5 mL – study drug concentrate: 
 
4.4 mL  
for 3.5 mg dose 
 
4.1 mL  
for 3.3 mg dose 
3.8 mL  
for 3.0 mg dose 
The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% sodium chloride, 
USP, or 5% dextrose injection, USP. The dose must be given as a single intravenous 
infusion over no less than 15 minutes. 
Medication vial labels will comply with the legal requirements of the United States. 
They will supply no information about the patient, only the medication number. The 
storage conditions for study drug will be described on the medication label. 
10.7.3 
ANTICIPATED TOXICITY 
Anticipated toxicities are as described in the package insert for zoledronic acid (see 
Post-text supplement 2). 
57 

 
March 28, 2011
10.7.3.1 
Osteonecrosis of the Jaw (ONJ) 
After study entry, any patient report of the following symptoms at interim visits will 
require an examination by a dental professional (dental hygienist or dentist) to rule out 
ONJ prior to further study drug dosing: 
 exposed bone in the oral cavity 
 rough area on the jawbone 
 “heavy jaw”, a dull aching sensation 
 numbness/tingling of the jaw 
 loosening of teeth 
 tooth pain 
 sudden change in the health of periodontal or mucosal tissue 
 failure of oral mucosa to heal 
 undiagnosed oral pain,  
 soft tissue swelling, drainage or infection 
If exposed bone is observed on dental examination, the patient will be referred to an 
oral surgeon for a panoramic x-ray, diagnosis, and treatment.  While a precise definition 
of “ONJ” does not exist, Novartis has developed a working definition of ONJ based on 
input from a panel of experts.  Thus, an AE is designated as a possible case of ONJ if 
all the following criteria are met: 
1. There is exposed bone in the maxillofacial area that occurred either  
 spontaneously; or  
 was induced by dental surgery that has no evidence of healing for more than 
3 to 6 weeks after appropriate care 
2. May or may not be associated with infection 
3. May or may not be associated with pain 
4. Appeared in the absence of prior radiation to the head or neck 
If a diagnosis of ONJ is made, study medication will be stopped permanently, the 
patient will be discontinued from the study, and further treatment will be at the 
discretion of the patient’s physician.  The patient will be followed for outcome of ONJ. 
All such diagnosed cases of ONJ should be considered as “medically significant,” 
irrespective of whether the event meets the definition of “serious adverse event (SAE)” 
under current health authority guidelines.  These cases are therefore to be reported to 
Bristol-Myers Squibb as well as local health authorities under the guideline of SAE 
reporting (see section 11).     
Osteonecrosis at any skeletal site, and osteomyelitis at any skeletal site, should also be 
considered as medically significant and reported to Bristol-Myers Squibb as well as 
local health authorities under the guidance of SAE reporting (see Section 11) 
If diagnosis of ONJ is not made, then the patient will be allowed to continue on the 
study at the discretion of the investigator. 
58 

 
March 28, 2011
10.7.3.2 
Monitoring of Renal Function 
Serum creatinine should be monitored in all patients treated with zoledronic acid 
infusion prior to each dose. A 48-hour window for checking creatinine is allowed prior 
to the each study infusion. Elevations in serum creatinine above baseline values may 
require a delay in treatment.   
Each pre-infusion serum creatinine during the study must be compared with the baseline 
serum creatinine and should be managed as follows:   
 If the patient’s baseline serum creatinine (before the first ever zoledronic acid 
dose) was < 1.4 mg/dL, an increase of 0.5 mg/dL or more will require that the 
study drug be delayed until the patient’s serum creatinine returns to no higher 
than 10% above the baseline value. 
 If the patient’s baseline (before the first ever zoledronic acid dose) serum 
creatinine was ≥ 1.4 mg/dL, then an increase in the serum creatinine of 1.0 
mg/dL or more will require that the study drug be delayed until the patients 
serum creatinine returns to no higher than 10% above the baseline value. 
 Any doubling of the baseline (before the first ever zoledronic acid dose) serum 
creatinine will require that the study drug be delayed until the patient’s serum 
creatinine returns to no higher than 10% above the baseline value. 
Zoledronic acid should be re-initiated at the same dose as that prior to treatment 
interruption. 
11 
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,  
59 

 
March 28, 2011
 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. 
11.1 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 NCI Common Toxicity 
Criteria (CTC) Scale, version 3.0.  
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) 
 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. 
60 

 
March 28, 2011
 
All SAEs should be faxed or emailed to Bristol-Myers Squibb at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number:  609-818-3804 
Email: Worldwide.safety@bms.com 
 
 For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the FDA as soon as possible and, in no event, later 
than 7 days (death or life-threatening event) or 15 days (all other SAEs) after the 
investigator’s or institution’s initial receipt of the information.  Bristol-Myers 
Squibb will be provided with a simultaneous copy of all adverse events filed with 
the FDA.  SAEs should be reported on the MedWatch Form 3500A, which can be 
accessed at: http://www.accessdata.fda.gov/scripts/medwatch/  
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD  20852-9787 
Fax:  1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/  
 
All SAEs should simultaneously be faxed or e-mailed to Bristol-Myers Squibb 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 
61 

 
March 28, 2011
of any SAE that may occur after this time period which they believe to be certainly, 
probably, or possibly related to dasatinib. 
 
12 
STATISTICAL METHODOLOGY 
12.1 PHASE I 
The primary objective of the phase I portion of this trial will be to determine the RP2D 
for dasatinib in combination with zoledronic acid.  
 
The phase I portion of the trial will use a 3+3 dose escalation design. If at least 2 of 3 
patients treated within a given dosing cohort develop DLT, it can be concluded with 
90% confidence that the true probability of DLT at that dose is greater than 20%. If 
none of the 3 patients demonstrates DLT, it can be concluded with 90% confidence that 
the true probability of DLT is less than 55%. These criteria are considered a standard 
for dose selection using the proposed phase I clinical trial design.  
 
When 1 of 3 patients develops DLT and the cohort is expanded to 6 patients, the 
proposed plan for dose escalation provides 91% probability that dose escalation will not 
be stopped at doses associated with DLT probability of < 10% and gives a 92% 
probability that escalation will not proceed beyond doses associated with DLT 
probability in excess of 60%. The stepwise dose escalation also protects against 
defining an RP2D associated with excessive toxicity. For a wide variety of dose-toxicity 
curves, the probability is approximately 85-90% that the defined RP2D will be 
associated with DLT probability of approximately 10-45%. 
 
12.2  
Phase II 
The primary objective of this phase II study is to assess the efficacy of dasatinib in 
combination with zoledronic acid.  Up to 25 patients will be enrolled in the phase II 
study to assess the efficacy of dasatinib in combination with zometa (zoledronic acid).  
The primary endpoint is the response rate.  The trial will be conducted by the Simon’s 
two-stage design using the minimax criterion and the response rate will be estimated 
accordingly. 
 
It is assumed that dasatinib in combination with zometa will have a target response rate 
of 25%.  A response rate of  5% or lower is considered a failure.  When the probability 
of accepting a “bad” regimen (i.e. response rate  5%) is 0.05 and the probability of 
rejecting a “good” regimen (i.e. response rate  25%) is  0.10, Simon’s design to 
minimize the maximum sample size requires 15 patients in the first stage.  If no patients 
respond to the treatment, the trial will be stopped and the regimen will be declared as 
ineffective.  If at least one of the first 15 patients respond to the treatment, 10 additional 
patients will be entered in the study to reach a total of 25 patients.  By the end of the 
study, the new regimen will be rejected if response rate is less than or equal to 3 out of 
25 patients and will be accepted otherwise.  The operating characteristics of the trial are 
62 

 
March 28, 2011
given as follows.  When the true response rate is 0.05, the probability of stopping the 
trial early is 46.3%.  On the other hand, if the true response rate is 0.25, the probability 
to stop the trial early is 1.3%.  The expected sample sizes are 20.37 and 24.97 when the 
true response rates are 0.05 and 0.25, respectively.  At the end of the study, the response 
rate and the 95% confidence interval will be reported and the toxicity profile of the 
regimen will be summarized.  If the trial continues to the second stage (i.e., accrual = 
25) and the 5 of 25 patients response for a point estimate of 20.0%, the exact binomial 
95% confidence interval would be (6.8%, 40.7%).   
 
Patients will be divided into two cohorts dependent upon Ntx levels obtained prior to 
the initiation of therapy. All patients will receive same therapy, lab draws and 
radiographic assessment for response. 
12.2.1 
12.2.2 
Cohort A: Patients with moderate or high baseline 
levels of Ntx: 
We will determine the association between changes in Ntx levels and tumor response, 
progression-free survival (PFS), and overall survival (OS).  
 
Changes in Ntx levels will be considered as both a continuous and a dichotomous measure.  
We will describe the percent change and the absolute change in Ntx levels from baseline to 
one month and from baseline to 3 months following the start of treatment with descriptive 
statistics such as the mean, median, range, and standard deviation.  We will use the t-test or 
Wilcoxon’s rank sum test to determine the association between changes in Ntx levels and 
tumor response.  Considering the change in Ntx levels as dichotomous (maintained moderate 
or high level versus achieved low level) we will determine the association between achieving 
a low Ntx level and tumor response with a chi-square or Fisher’s exact test as appropriate.   
PFS will be measured from the date of first treatment to the date of disease 
progression or death from any cause.  OS will be measured from the date of first 
treatment to the date of death from any cause.  The percent change and the absolute 
change in Ntx levels will be included in Cox proportional hazards models to estimate 
the change in the hazard of death and the change in the hazard of progression 
associated with a change in Ntx levels.  Considering the change in Ntx levels as 
dichotomous, the Kaplan-Meier product limit method will be used to estimate PFS 
and OS and the log-rank statistic will be used to test for differences between patients 
who do and do not achieve a low level Ntx level.  Finally, we will consider the serial 
measurements of Ntx by including them as a time-dependent covariate in Cox 
proportional hazards models.   
 
 
Cohort B: Patients with low levels of Ntx: 
 
These patients have been reported to have a more favorable outcome compared to patients 
with moderate to high levels. However, it remains uncertain if further reduction of Ntx levels 
in this subset of patients would be predictive of response to therapy.   
63 

 
March 28, 2011
We will first describe the percent change and absolute change in Ntx levels from baseline to 
one month and from baseline to three months following the start of treatment with 
descriptive statistics such as the mean, median, range, and standard deviation.  Percent 
change in Ntx will also be considered as a dichotomous measure using 30% as the threshold 
value.  We will describe both the change in Ntx levels and the proportion of patients with at 
least a 30% decrease in Ntx levels separately by tumor response groups.  We will plot the 
Kaplan-Meier curves of PFS and OS overall survival and visually assess the differences 
between patients who achieved at least a 30% decrease in Ntx and those who did not.   
 
13 
ADMINISTRATIVE SECTION 
13.1 Compliance with the Protocol and Protocol Revisions 
The study must be conducted as described in the final approved protocol.  All revisions 
to the protocol must be provided to BMS along with IRB approval verification.  The 
Investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion from the IRB of an Amendment, 
except where necessary to eliminate an immediate hazard(s) to study patients. 
 
Documentation of approval signed by the chairperson or designee of the IRB(s) must be 
sent to BMS. 
13.2 Ethical Considerations and Informed Consent 
The following must be observed in order to comply with Food and Drug Administration 
regulations for the conduct and monitoring of clinical investigations: 
 
The principles of informed consent are described by Federal Regulatory Guidelines. 
13.3 Records and Reports 
An Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated with the investigational product.  
13.4 Institutional Review Board (IRB) 
Before study initiation, the Investigator must have written and dated approval/favorable 
opinion from the IRB for the protocol, consent form, patient recruitment 
materials/process (e.g., advertisements), and any other written information to be 
provided to patients.  The Investigator should also provide the IRB with a copy of the 
product labeling, information to be provided to patients, and any updates. 
 
The Investigator will provide the IRB with reports, updates, and other information (e.g., 
Safety Updates, Amendments, Administrative Letters) according to regulatory 
requirements and Institution procedures. 
 
64 

 
March 28, 2011
A detailed list of required regulatory documents also to be submitted to BMS will be 
sent upon final approval of the protocol.  
13.5 Records Retention 
The Investigator must retain investigational product disposition records, case report 
forms and source documents for the maximum period required by applicable regulations 
and guidelines, or Institution procedures. 
 
If the Investigator withdraws from the study (e.g., relocation, retirement), the records 
shall be transferred to a mutually agreed upon designee (e.g., another Investigator, 
IRB). Notice of such transfer will be given in writing to BMS. 
14 
CORRELATIVE STUDIES 
14.1 Biologic Characterization of Response Using 18F-FDG 
PET: 
Characterization of response using PET will be performed through collaboration with 
Dr. Juri Gelovani, chair of the Department of Experimental Diagnostic Imaging in the 
Division of Diagnostic Imaging at MDACC. 18F-FDG PET imaging has demonstrated 
increased glucose consumption in breast cancer with substantial variation in uptake 
influenced by the number of viable tumor cells per volume, histological subtype (ductal 
> lobular), tumor grade, microvessel density and proliferative activity(35). In addition, 
changes in 18F-FDG PET avidity have been correlated with breast cancer response to 
both hormonal therapy and chemotherapy and in patients with predominate bone 
metastasis in small non-randomized studies(36-38). Although FDG uptake has been 
studied in patients with solid tumors treated with the angiogenesis inhibitors(39), to date 
no published phase II data exists concerning changes in 18F-FDG uptake in breast 
cancer patients treated with dasatinib. It is hypothesized that dasatinib’s inhibition of 
the paracrine loop supporting bone metastasis will result in decreased cancer cell 
proliferation, decreased microvessel density and a decrease in the number of viable 
tumor cells, which will decrease tumor avidity for18F-FDG.  MDACC has had extensive 
experience with the use of PET to image intracellular receptors, such as ER, in breast 
cancer patients(40) and in the development of biologic markers of response in patients 
undergoing therapy with angiogenesis inhibitors(39).  
Patients who consent to participate will undergo optional 18F-FDG PET imaging at 
baseline, between days 12-16 of therapy (2 week value), and at disease progression.  
The fold change from baseline will be calculated for the 2 week value and progression 
of disease value. These values will then be graphed using scatterplots against urine Ntx 
to assess the relationship of response to this biologic endpoint.  In addition, it is known 
that variations in 18F-FDG PET avidity can occur within different foci of disease in 
individual patients. These variations may represent biologic differences between 
responding and non-responding cells; therefore, core needle biopsies will be performed 
on a subset of patients who consent to biopsy of >2 sites of metastatic tumors that differ 
in 18F-FDG PET uptake (see Molecular Correlates below). 
65 

 
March 28, 2011
14.2  Determination of Molecular Correlates in Paraffin 
Embedded or Frozen Tissue: 
Tumor biopsies will be obtained by imaging (CT or Ultrasound) guided core needle 
biopsy from patients who sign informed consent for tissue biopsy. Biopsies will be 
obtained at pre-treatment and at day 28 of cycle 1 (+/- 48 hours). Dasatinib inhibits a 
number of targets including SRC, PDGFR, c-kit, FAK and EPHA2. Expression of these 
markers may be correlated with tumor response and their expression in bone metastasis 
remains ill defined. Tumor samples will be analyzed for these targets using 
immunohitochemistry.  In addition, Src regulates proteins such as cavelolin and STAT3, 
which are responsible for osteoblastic activity, tumor cell metastasis and migration, and 
response to chemotherapy (41) (42),(7). We will also use immunohistochemistry to 
measure phosphorylated activity of these proteins in pre- and post-treatment biopsies to 
determine the biologic effects of therapy. In addition, as stipulated in the biologic 
rationale for this study, Src has been linked to angiogenesis through downstream effects 
on STAT3(43, 44). We will therefore measure the effects of dasatinib on  VEGF and 
IL-8 using immunohistochemistry in pre- and post-treatment samples. 
 
Fresh tissue obtained by core needle biopsy of metastatic sites differing in PET avidity 
in individual patients (see above) will be snap frozen and used for microarray analysis 
to determine potential pathways of drug resistance. When possible, these results will be 
confirmed using IHC, western blotting or PCR. 
 
14.3 Banking of Blood Samples 
Patients will be asked to donate 10cc of research blood pretreatment and on day 28 (+/- 
48 hours) of weeks 4, 8, 16, and 24. Research blood will also be collected at the time of 
disease progression.  Serum will be banked for future treatment efficacy analyses 
including potential markers of bone turnover. (cycle = 28 days/4 weeks) 
 
The following protocol will be followed:  
 
1) 
Subject should be seated for at least five minutes prior to blood collection.  The 
draw should be from the median cubital, cephalic, or basilic veins.  If possible, the 
draws should be dedicated draws to collect these samples.   
 
2) 
Using approved, standardized methods and supplies, trained phlebotomists will 
collect one 3cc priming discard blood sample. Then collect one 10 cc test sample from 
each donor into labeled blood collection tubes without anticoagulant (red top). Tubes 
must be completely filled.  
 
3) 
Allow the blood to clot for 30 minutes to 1 hour at room temperature.  
 
4) 
Pipette the serum off of the clot and place into a clean test tube. Clarify by 
centrifugation at 3000 rpm for 15 minutes. Carefully remove the stopper tops and 
66 

 
March 28, 2011
67 
using a transfer pipette transfer the serum from the red top tube into 500 uL aliquot 
vials.   
 
5) 
Enter the number of vials and the sample information into the Freezerworks 
database.  
 
6) 
Store serum samples in -80 C freezer. 
Patients confidentiality will be guaranteed. The information gathered from each 
individual patient will be used as part of a larger statistical analysis. Patients will not be 
harmed because data from individual patients will be coded. The samples will be coded 
using consecutive numbers (1, 2, 3, etc).  A code breaker exists in the possession of the 
principal investigator. The code breaker can be used to match the coded specimens to 
the specimen source (i.e., pretreatment, post treatment). To minimize any potential 
breaches of confidentiality, specimens are stored in a secure freezer in the laboratory of 
Dr. Francisco Esteva at MDACC. Participants’ data will be stored in the principal 
investigator’s computer, which is password protected. 
Banked samples will be available to future investigators at the discretion of the 
Principal Investigator and only for use through MDACC IRB approved protocols. 
  
Samples will be shipped to: 
 
Stacy Moulder, M.D., M.S.C.I. 
 
The University of Texas M.D. Anderson Cancer Center 
 
Department of Breast Medical Oncology, Unit 1354 
                          1155 Herman P. Pressler, CPB5.3450 
                          Houston, TX  77030-3721 

 
March 28, 2011
68 
REFERENCES 
1. 
Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350: 1655-64. 
2. 
Coleman RE, Rubens RD. Bone metastases and breast cancer. Cancer Treat Rev 1985;12: 251-
70. 
3. 
Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN, Ueno NT. Bone imaging in 
metastatic breast cancer. J Clin Oncol 2004;22: 2942-53. 
4. 
Verbeek BS, Vroom TM, Adriaansen-Slot SS, et al. c-Src protein expression is increased in 
human breast cancer. An immunohistochemical and biochemical analysis. J Pathol 1996;180: 383-8. 
5. 
Belsches-Jablonski AP, Biscardi JS, Peavy DR, Tice DA, Romney DA, Parsons SJ. Src family 
kinases and HER2 interactions in human breast cancer cell growth and survival. Oncogene 2001;20: 
1465-75. 
6. 
Madan R, Smolkin MB, Cocker R, Fayyad R, Oktay MH. Focal adhesion proteins as markers 
of malignant transformation and prognostic indicators in breast carcinoma. Hum Pathol 2006;37: 9-15. 
7. 
Diaz N, Minton S, Cox C, et al. Activation of stat3 in primary tumors from high-risk breast 
cancer patients is associated with elevated levels of activated SRC and survivin expression. Clin 
Cancer Res 2006;12: 20-8. 
8. 
Gritsko T, Williams A, Turkson J, et al. Persistent activation of stat3 signaling induces survivin 
gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 
2006;12: 11-9. 
9. 
Myoui A, Nishimura R, Williams PJ, et al. C-SRC tyrosine kinase activity is associated with 
tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Cancer 
Res 2003;63: 5028-33. 
10. 
Horne WC, Neff L, Chatterjee D, Lomri A, Levy JB, Baron R. Osteoclasts express high levels 
of pp60c-src in association with intracellular membranes. J Cell Biol 1992;119: 1003-13. 
11. 
Missbach M, Jeschke M, Feyen J, et al. A novel inhibitor of the tyrosine kinase Src suppresses 
phosphorylation of its major cellular substrates and reduces bone resorption in vitro and in rodent 
models in vivo. Bone 1999;24: 437-49. 
12. 
Lev DC, Kim SJ, Onn A, et al. Inhibition of platelet-derived growth factor receptor signaling 
restricts the growth of human breast cancer in the bone of nude mice. Clin Cancer Res 2005;11: 306-
14. 
13. 
Yi B, Williams PJ, Niewolna M, Wang Y, Yoneda T. Tumor-derived platelet-derived growth 
factor-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast 
cancer. Cancer Res 2002;62: 917-23. 
14. 
SPRYCEL® (dasatinib) Tablets Prescribing Information.  Bristol-Myers Squibb Company P, 
NJ. June 2006. 
15. 
SPRYCELÒ (dasatinib) BMS-354825 B-MSIB, Version #5, 2006. 

 
March 28, 2011
69 
16. 
Berenson JR, Rosen LS, Howell A, et al. Zoledronic acid reduces skeletal-related events in 
patients with osteolytic metastases. Cancer 2001;91: 1191-200. 
17. 
Rosen LS, Gordon DH, Dugan W, Jr., et al. Zoledronic acid is superior to pamidronate for the 
treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 
2004;100: 36-43. 
18. 
Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic 
acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94: 
1458-68. 
19. 
Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the treatment 
of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, 
randomized trial--the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin 
Oncol 2003;21: 3150-7. 
20. 
Varricchio L, Migliaccio A, Castoria G, et al. Inhibition of estradiol receptor/Src association 
and cell growth by an estradiol receptor alpha tyrosine-phosphorylated peptide. Mol Cancer Res 
2007;5: 1213-21. 
21. 
Fox EM, Bernaciak TM, Wen J, Weaver AM, Shupnik MA, Silva CM. STAT5b, c-Src, and 
EGFR Signaling Play Integral Roles in Estrogen-Stimulated Proliferation of ER-Positive Breast 
Cancer Cells. Molecular endocrinology (Baltimore, Md 2008. 
22. 
Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention 
of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer 
Inst 2004;96: 879-82. 
23. 
Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic 
acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other 
solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer 2004;100: 2613-
21. 
24. 
Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid 
compared with pamidronate disodium in the treatment of skeletal complications in patients with 
advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, 
comparative trial. Cancer 2003;98: 1735-44. 
25. 
Coleman RE, Major P, Lipton A, et al. Predictive value of bone resorption and formation 
markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin 
Oncol 2005;23: 4925-35. 
26. 
Reszka AA, Halasy-Nagy JM, Masarachia PJ, Rodan GA. Bisphosphonates act directly on the 
osteoclast to induce caspase cleavage of mst1 kinase during apoptosis. A link between inhibition of the 
mevalonate pathway and regulation of an apoptosis-promoting kinase. The Journal of biological 
chemistry 1999;274: 34967-73. 
27. 
Bezzi M, Hasmim M, Bieler G, Dormond O, Ruegg C. Zoledronate sensitizes endothelial cells 
to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained 
activation of focal adhesion kinase and protein kinase B/Akt. The Journal of biological chemistry 
2003;278: 43603-14. 

 
March 28, 2011
70 
28. 
Brown JE, Cook RJ, Major P, et al. Bone turnover markers as predictors of skeletal 
complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 2005;97: 59-
69. 
29. 
Vinholes J, Coleman R, Lacombe D, et al. Assessment of bone response to systemic therapy in 
an EORTC trial: preliminary experience with the use of collagen cross-link excretion. European 
Organization for Research and Treatment of Cancer. Br J Cancer 1999;80: 221-8. 
30. 
Brown JE, Thomson CS, Ellis SP, Gutcher SA, Purohit OP, Coleman RE. Bone resorption 
predicts for skeletal complications in metastatic bone disease. British journal of cancer 2003;89: 2031-
7. 
31. 
Costa L, Demers LM, Gouveia-Oliveira A, et al. Prospective evaluation of the peptide-bound 
collagen type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status. J Clin 
Oncol 2002;20: 850-6. 
32. 
Lipton A, Demers L, Curley E, et al. Markers of bone resorption in patients treated with 
pamidronate. Eur J Cancer 1998;34: 2021-6. 
33. 
Clemons M, Cole DE, Gainford MC. Can bone markers guide more effective treatment of bone 
metastases from breast cancer? Breast cancer research and treatment 2006;97: 81-90. 
34. 
Thall PF, Simon R. A Bayesian approach to establishing sample size and monitoring criteria for 
phase II clinical trials. Control Clin Trials 1994;15: 463-81. 
35. 
Avril N, Menzel M, Dose J, et al. Glucose metabolism of breast cancer assessed by 18F-FDG 
PET: histologic and immunohistochemical tissue analysis. J Nucl Med 2001;42: 9-16. 
36. 
Mankoff DA, Dunnwald LK, Gralow JR, et al. Blood flow and metabolism in locally advanced 
breast cancer: relationship to response to therapy. J Nucl Med 2002;43: 500-9. 
37. 
Mortimer JE, Dehdashti F, Siegel BA, Katzenellenbogen JA, Fracasso P, Welch MJ. Positron 
emission tomography with 2-[18F]Fluoro-2-deoxy-D-glucose and 16alpha-[18F]fluoro-17beta-
estradiol in breast cancer: correlation with estrogen receptor status and response to systemic therapy. 
Clin Cancer Res 1996;2: 933-9. 
38. 
Stafford SE, Gralow JR, Schubert EK, et al. Use of serial FDG PET to measure the response of 
bone-dominant breast cancer to therapy. Acad Radiol 2002;9: 913-21. 
39. 
Herbst RS, Mullani NA, Davis DW, et al. Development of biologic markers of response and 
assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin. J Clin Oncol 
2002;20: 3804-14. 
40. 
Inoue T, Kim EE, Wallace S, et al. Positron emission tomography using [18F]fluorotamoxifen 
to evaluate therapeutic responses in patients with breast cancer: preliminary study. Cancer Biother 
Radiopharm 1996;11: 235-45. 
41. 
Sloan EK, Stanley KL, Anderson RL. Caveolin-1 inhibits breast cancer growth and metastasis. 
Oncogene 2004;23: 7893-7. 
42. 
Cantiani L, Manara MC, Zucchini C, et al. Caveolin-1 reduces osteosarcoma metastases by 
inhibiting c-Src activity and met signaling. Cancer research 2007;67: 7675-85. 

 
March 28, 2011
71 
43. 
Trevino JG, Gray MJ, Nawrocki ST, et al. Src activation of Stat3 is an independent 
requirement from NF-kappaB activation for constitutive IL-8 expression in human pancreatic 
adenocarcinoma cells. Angiogenesis 2006;9: 101-10. 
44. 
Gray MJ, Zhang J, Ellis LM, et al. HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are 
components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of 
VEGF in pancreatic and prostate carcinomas. Oncogene 2005;24: 3110-20. 
45. Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN, Ueno NT. Bone imaging in metastatic 
breast cancer. J Clin Oncol 2004;22: 2942-53. 
  
 
 

 
March 28, 2011
72 
Post-Text Supplement 1 (See attached Dasatinib Investigator’s Brochure) 
Post-Text Supplement 2 (See attached Zometa (Zoledronic Acid) Package 
Insert) 
Post-Text Supplement 3: RECIST Criteria 
 Solid Tumor Response Criteria (RECIST)  
Malignant Disease Evaluation  
To assess objective response, it is necessary to estimate the overall 
tumor burden at baseline to which subsequent measurements will be 
compared. Measurable disease is defined by the presence of at least 
one measurable lesion. 
All measurements should be recorded in metric notation by use of a 
ruler or calipers. The same method of assessment and the same 
technique should be used to characterize each identified lesion at 
baseline and during follow-up. All baseline evaluations should be 
performed as closely as possible to the beginning of treatment and 
never more than four weeks before registration. 
The term evaluable in reference to measurability will not be used 
because it does not provide additional meaning or accuracy. 
At baseline, tumor lesions will be characterized as either measurable or 
non-measurable. 
Measurable  
Lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as > 20 mm 
(2.0 cm) with conventional techniques or as > 10 mm (1.0 
cm) with spiral CT scan. 
If the measurable disease is restricted to a solitary lesion, its 
neoplastic nature should be confirmed by cytology/histology. 
Non-Measurable  
All other lesions, including small lesions [longest diameter < 
20 mm (2.0 cm) with conventional techniques or < 10 mm 
(1.0 cm) with spiral CT scan] and truly non-measurable 
lesions. 
Lesions considered to be truly non-measurable include the 
following: bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses that are not 

 
March 28, 2011
73 
confirmed and followed by imaging techniques, and cystic 
lesions. 
Definitions of Response  
Target Lesions  
All measurable lesions up to a maximum of five lesions per 
organ and 10 lesions in total, representative of all involved 
organs. Target lesions should be selected on the basis of 
their size (those with the longest diameters) and their 
suitability for accurate repeated measurements. 
The sum of the longest diameters of all target lesions will be 
calculated at baseline and reported as the baseline sum 
longest diameter. The sum longest diameter will be used to 
characterize the objective tumor response. For lesions 
measurable in 2 or 3 dimensions, always report the longest 
diameter at the time of each assessment. 
Complete Response (CR)  
The disappearance of all target lesions. To be assigned a 
status 
of 
complete 
response, 
changes 
in 
tumor 
measurements must be confirmed by repeat assessments 
performed no less than four weeks after the criteria for 
response are first met. 
Partial Response (PR)  
At least a 30% decrease in the sum of the longest diameters 
of target lesions, taking as reference the baseline sum 
longest diameter. To be assigned a status of partial 
response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than 
four weeks after the criteria for response are first met. 
Progressive Disease (PD)   
At least a 20% increase in the sum of the longest diameters 
of target lesions, taking as reference the smallest sum 
longest diameter recorded since the baseline measurements, 
or the appearance of one or more new lesion(s). 
Stable Disease (SD)  
Neither sufficient shrinkage to qualify for partial response nor 
sufficient increase to qualify for progressive disease. To be 
assigned a status of stable disease, measurements must 
have met the stable disease criteria at least once after study 
entry at a minimum interval of eight weeks. 

 
March 28, 2011
74 
Nontarget Lesions  
All other lesions or sites of disease. Measurements of these lesions are 
not required, but the presence or absence of each should be noted 
throughout follow-up. 
Complete Response (CR)  
The disappearance of all nontarget lesions and normalization 
of tumor marker levels, if applicable. To be assigned a status 
of complete response, changes in tumor measurements must 
be confirmed by repeat assessments performed no less 
than four weeks after the criteria for response are first met. 
Incomplete Response/Stable Disease (SD)  
The persistence of one or more nontarget lesion(s) and/or 
the maintenance of tumor marker levels above the normal 
limits. To be assigned a status of stable disease, 
measurements must have met the stable disease criteria at 
least once after study entry at a minimum interval of eight 
weeks.  
Progressive Disease (PD)  
The appearance of one or more new lesion(s) and/or 
unequivocal progression of existing nontarget lesions. 
Symptomatic Deterioration  
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be classified as having symptomatic 
deterioration. 
Evaluation of Patient's Best Overall Response  
The best overall response is the best response recorded from registration until 
disease progression/recurrence, taking as reference for progressive disease the 
smallest measurements recorded since registration. The table below provides 
overall responses for all possible combinations of tumor responses in target and 
nontarget lesions, with or without new lesions. 
To be assigned a status of complete or partial response, changes in tumor 
measurements must be confirmed by repeat assessments performed no less 
than four weeks after the criteria for response are first met. 
To be assigned a status of stable disease, measurements must have met the 
stable disease criteria at least once after study entry at a minimum interval of 
eight weeks. 
Overall Response for all Possible Combinations of Tumor Response 

 
March 28, 2011
75 
Target 
Lesions 
Nontarget 
Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
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 
CR = complete response; PR = partial response; SD = stable disease; PD = 
progressive disease 
First Documentation of Response  
The time between initiation of therapy and first documentation of PR or 
CR. 
Confirmation of Response  
To be assigned a status of complete or partial response, changes in 
tumor measurements must be confirmed by repeat assessments 
performed no less than four weeks after the criteria for response are 
first met. 
Duration of Response  
Duration of overall response – the period measured from the time that 
measurement criteria are met for complete or partial response 
(whichever status is recorded first) until the first date that recurrent or 
progressive disease is objectively documented, taking as reference the 
smallest measurements recorded since treatment started. 
Duration of Overall Complete Response  
The period measured from the time measurement criteria are 
met for complete response until the first date that recurrent 
disease is objectively documented. 
Duration of Stable Disease  
A measurement from registration until the criteria for disease 
progression is met, taking as reference the smallest 
measurements recorded since registration. To be assigned a 
status of stable disease, measurements must have met the 
stable disease criteria at least once after study entry at a 
minimum interval of eight weeks. 

 
March 28, 2011
76 
Post-text Supplement 4: WHO and MDACC Criteria for Response in 
Bone 
 
Response Type 
World Health Organization Definition1,2 
Complete Response 
(CR) 
Complete disappearance of all lesions on Xray or 
scan for at least 4 weeks 
Partial Response 
(PR) 
Partial decrease in size of lytic lesions, recalcification 
of lytic lesions or decreased density of blastic lesions 
for at least 4 weeks 
No Change (NC) or 
Stable Disease (SD) 
 
Because of the slow response of bone lesions, the 
classification of “no change” should not be applied 
until at least 8 weeks have passed since the start of 
therapy 
Progressive Disease 
(PD) 
Increase in size or extent of lesions or appearance of 
new lesions 
Response Type 
MDACC Definition3 
Complete Response 
(CR) 
Complete sclerotic fill-in of lytic lesions on XR or CT 
Normalization of blastic lesions on XR or CT 
Normalization of tracer uptake on SS 
Normalization of signal intensity on MRI 
 
Partial Response 
(PR) 
Development of a sclerotic rim or partial sclerotic fill-
in of lytic lesions on XR or CT 
Osteosclerotic “flare” - Interval visualization of lesions 
with sclerotic rims or “new” sclerotic lesions in the 
setting of other signs of PR and absence of 
progressive bony disease  
> 50% decrease in measurable lesions on XR, CT or 
MRI 
Unequivocal decrease in the size of blastic lesions 
on XR or CT 
Unequivocal decrease in tracer uptake on SS (verify 

 
March 28, 2011
77 
rapid response) 
No Change (NC) or 
Stable Disease (SD) 
 
No change 
< 25% increase or < 50% decrease in measurable 
lesions 
No new lesions 
Progressive Disease 
(PD) 
> 25% increase in size of measurable lesions on XR, 
CT or MRI 
Unequivocal increase in the size of unmeasurable 
lytic or blastic lesions on XR, CT or MRI 
Unequivocal increase in tracer uptake on SS (verify 
flare) 
New bone metastases on CT or MRI or new 
symptomatic bone metastasis on bone scan 
 
1. 
Occurrence of bone compression or fracture and its healing should not be used 
as the sole indicator for evaluation of therapy. 
2. 
Tumor Measurements: 
 Lesions will be selected by size from the longest diameter and will be measured in 
centimeters. 
 The longest diameter will be used for measured lesions. 
 Size will be reported as the product of the diameters. 
3. Measurements are based on the sum of a perpendicular, bidimensional measurement 
of the greatest diameters of each individual lesion 

 
March 28, 2011
78 
 
Post-Text Supplement 5: Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours.  
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair. 
5 
Dead 
 
 

 
March 28, 2011
79 
APPENDIX 1 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
 
 
ANC 
Absolute Neutrophil Count 
BID 
Twice a Day 
CAT ( or CT scan) 
Computed Axial Tomography 
CBC 
Complete Blood Count 
 
 
CR 
Complete Response 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
 
 
 
 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IRB 
Institutional Review Board 
 
 
MRI 
Magnetic Resonance Imaging 
PD 
Progressive Disease 
 
 
PFS 
Progression Free Survival 
PO 
By Mouth 
PR 
Partial Response 
QD 
Once Twice daily 
QoL 
Quality Of Life 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
 
 
SD 
Stable Disease 
TNM Staging 
Tumor, Node and Metastasis Staging 
 
 
ULN 
Upper Limit of Normal 
WBC 
White Blood Count 
WOCPB 
Women of Child-Bearing Potential 
 

 
March 28, 2011
80 
APPENDIX 2 
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 wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
Inhibitors 
Amiodarone 
Anastrozole 
Azithromycin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
lndinavir 
lsoniazid 
ltraconazole  
 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Zafirlukast 
Zileuton 
 

 
March 28, 2011
81 
APPENDIX 3 
DASATINIB PATIENT DIARY FOR STUDY:CA180094 
Your Study ID:  
Your Doctor: 
Your Nurse: 
 
Phone: 
Phone: 
Doctor’s instructions for dasatinib: 
Name of drug 
Dosing 
How Often 
When 
Dasatinib 
___# of 20 mg 
tablets 
___# of 50 
mg tablets
   ____  day 
___After Breakfast 
___After supper 
 
 Cycle ____ 
Week of ________ to ________ 
Dasatinib dose (Check () when you take it) 
Insert Date 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
A.M. 
 
 20 mg 
 
 50 mg 
 
 20 mg 
 
 50 mg 
 
 20 mg 
 
 50 mg 
 
 20 mg 
 
 50 mg 
 
 20 mg 
 
 50 mg 
 
 20 mg 
 
 50 mg 
 
 20 mg 
 
 50 mg 
 
P.M. 
 20 mg 
 
 50 mg 
 
 20 mg 
 
 50 mg 
 
 20 mg 
 
 50 mg 
 
 20 mg 
 
 50 mg 
 
 20 mg 
 
 50 mg 
 
 20 mg 
 
 50 mg 
 
 20 mg 
 
 50 mg 
 
 
Notes (Anything you wish to tell your doctor/nurse?): 
 
 
 
 
 
 
 
 

 
March 28, 2011
82 
APPENDIX 4;  Study Management Plan 
 
1. Introduction 
The Study Management Plan outlines the procedures and requirements for institutions collaborating 
with UTMDACC in the conduct of an Investigator initiated trial sponsored by Bristol Meyer Squib. This 
plan is written in adherence to the overall BMO Medical Oncology Monitoring Plan.  
2. Purpose of a Protocol Specific Study Management Plan (SMP)  
To  establish  standards  that  will  ensure  compliance  with  Federal  Regulations,  Good  Clinical  Practice 
Guidelines; and Health Insurance Portability and Accountability Act and the Institutions for both the 
lead and sub‐investigator sites for MDACC Protocol 2006‐0900. 
 
3. General Roles and Responsibilities of the Lead Site 
 
Lead Principal Investigator’s Role  
Stacy Moulder MD and/or designated research staff is responsible for: 
 
Protocol  Development:  The  coordination,  development,  submission,  and  approval  of  the 
protocol as well as subsequent amendments by the IRB and study sponsor.  
 
 
Study Oversight: PI and designee(s) will monitor the progress and overall conduct of the study 
at all participating institutions through the regular review of data. Data items to review are as 
follows:    doctors  examination  for  status  of  patients  enrolled,  eligibility,  status  of  treatment 
(on/off  treatment,  any  dose  modifications,  and  dose  delays),  AE’s  and  SAE’s,  and  response 
evaluation. Also, included will be a review of regulatory and data management documents, 
including any amendments, memos regarding status of approvals, maintenance of regulatory 
documents, and queries.  
 
Regulatory  Management:  The  lead  site  is  responsible  for  timely  distribution  of  approved 
protocols, amendments, revisions, or status changes to participating institutions. Collaborating 
sites will be corresponded with electronically, unless traditional mail methods are required. 
Main methods of correspondence will be email or fax.  Outlook calendars will be created for 
each  collaborating  site.    Required  correspondence,  expiration  dates,  or  any  dated  or  timed 
events  will  be  noted  on  the  calendars  with  a  reminder  to  send  necessary  communication 
regarding  those  events  to  collaborating  sites.    Maintenance  of  regulatory  binders  with 
information from each site will be managed by a BMO designee with the help of the calendars. 
All regulatory documentation will be received by the Department of Breast Medical Oncology 
prior  to  initiation  of  any  protocol  related  procedures.  It  is  the  participating  institution‘s 
responsibility to notify its IRB of the above mentioned events. 
 
Registration/Enrollment of Participants: the lead site will review the signed informed consent, 
the registration form, completed eligibility CRF, Pathology Report, Relevant Scans and Labs. 
The registration form will include the sub‐investigator’s signature.  The participant, if eligible, 

 
March 28, 2011
83 
will  be  registered  in  MDACC  Clinical  Research  Oncology  system  (CORe).    BMO  will  provide 
University of Chicago/Duke with confirmation of eligibility, registration and our assigned Core 
Number within 48 hours.  If, however there is questionable data submitted to the department, 
source documents will be requested by Breast Medical Oncology (BMO) to verify and confirm 
participant’s  eligibility  prior  to  enrollment.  If  the  participant  is  deemed  ineligible  at  the 
collaborating site, they will be notified via written correspondence (i.e. email, fax) as soon as 
possible, allowing for weekend/holidays by noon of the next business day. 
 
 
Data Collection and Management: the lead site will design and distribute case report forms 
(CRF’s), 
monitor 
data 
quality, 
and 
issue 
queries 
via 
email 
if 
necessary. 
If 
questionable/conflicting data has been submitted to the department by a collaborating site, 
source documentation will be requested by BMO to verify the protocol specific data. Source 
documents (i.e. such as an on‐study note will reflect the registration/consent/and eligibility 
process).  Baseline  and  eligibility  data  should  be  received  by  the  lead  site  within  7  days  of 
registration. Protocol deviations will be reported to the lead site according to the collaborating 
site’s IRB guidelines. Violations and serious adverse events will be reported within 24 hours of 
the  research  team  being  notified.    SAE’s  should  meet  the  guidelines  of  prompt  reporting 
(causality; possible, probably, definitely related to study drug; serious and unexpected adverse 
events.  The PI will notify the collaborating sites of these SAEs within 24 hours. Violations also 
need to be reported within 24 hours of the research team becoming aware. External Adverse 
Event will be emailed to collaborating sites received from the supporter. Response evaluations 
will be made available to the lead site every eight to 10 weeks.  Serious Adverse Events will be 
reviewed by the Principal Investigator at the lead site (BMO), and shared with all collaborating 
sites through written correspondence (email). 
 
CRF’s will be made available electronically to collaborating sites. The lead site will enter data 
into the Protocol Data Management System (PDMS) within a timely manner, 21 days from the 
date of submission). 
 
BMO will assure that all collaborating sites will provide MDACC with a copy of their IRB/IEC 
initial approval and continuing review approvals. 
Miscellaneous Research Nurse Responsibilities 
Coordinates and participates in the initiation meetings. Provides reports to the lead PI regarding the 
accrual, toxicities, and responses through the review of data.  . 
The lead site will request source documents or review documents already sent to BMO to monitor and 
audit participating institutions by the inspection of selected patient records. Audits will be conducted at 
the lead site. Documents and procedures that will be examined will be the registration process, 
informed consent process, eligibility, treatment, protocol compliance, outcome and response, toxicity, 
data quality and the documentation of each. Appropriate regulatory documents and the reporting of 
deviations, violations, and required adverse events will be included in the review. 
Provide and maintain study contact list for all key personnel at each participating institution.  
Ensure that a completed registration form and a copy of the signed Informed Consent are received at 
the lead site. 

 
March 28, 2011
84 
Ensure that eligible participants are registered on study at UTMDACC prior to the initiation of any 
study- related procedures, assessments or treatments.  
Collect relevant de-identified radiology/nuclear medicine scans, lab, and pathology reports faxed or 
emailed to MDACC. These include CT Chest/Abdomen/Pelvis, Bone Scan and Survey, and MRI’s 
performed, and ECG. 
4. General Roles and Responsibilities of the Collaborating Site 
 
Participating Institution ollaborating Investigator Role:  
The investigator and/or designated research staff is responsible for compliance in the following areas: 
Protocol Management, Regulatory Management, Data Collection and Management.  
Protocol Management: 
 
All regulatory documentation will be received by the Department of Breast Medical Oncology 
prior to initiation of any protocol related procedures.  
 
Source documentation will made available to the lead site to confirm protocol compliance (i.e. 
protocol  eligibility,  the  informed  consent  process,  protocol  directed  therapy  compliance, 
adverse  events,  response  evaluation,  and  other  items  as  requested  per  the  CRF)  and  in 
accordance  with  the  Institution,  the  code  of  Federal  Regulations,  ICH,  and  Good  clinical 
Practice. In addition the necessary regulatory items from each collaborating site will be shared 
in a timely manner with the lead site. 
 
Appropriate  documentation  regarding  the  investigational  nature  of  the  protocol  and  the 
alternative diagnostic or treatment approaches will be included. 
               Regulatory Management:   
 
A list of key study personnel and updates as needed on the delegation authority log. 
 
Submission of protocol and subsequent amendments to the local IRB prior to initiating any 
protocol changes or activity is the collaborating sites responsibility. 
 
Provide all required regulatory documents to the lead site: such as  
 
Lab CLIA’s and CAP 
 
1572  
 
Training Log  
 
Delegation of Authority Log  
 
Screening Log  
 
Subject Enrollment Log 
 
IRB Acknowledgement of Investigational Drug Brochure/Package Insert 
 
Lab Normal Ranges 
 
IRB/Institutional Ethics Committee approval of the Informed Consent 
 
Medical License 
 
Curriculum vitae 
 
Financial Disclosures 
 
Initial IRB Approval 

 
March 28, 2011
85 
 
Submission of all external and internal SAE’s to local IRB with copies sent to the lead site. 
 
Participating sites will send the following required regulatory documents post‐activation: 
 
Annual Approval Documents (Continuing Reviews) 
 
Informed Consent Revisions,  
 
Serious Adverse Events  
 
Evidence of the Participating Institution’s IRB review of External Safety Reports  
 
Protocol Violations and Deviations Submitted to the Participating Institution’s IRB.   
 
Any document that the study supporter may require. 
 
Data Collection and Management  
 
The  Research  Nurse  and/or  Clinical  Coordinator  and  Data  Manager  will  assure  adherence  to  the 
protocol as noted in the source documentation and submitted as required:  
 
 
Ensure  that  all  data  is  submitted  into  the  database  within  7  to  10  business  days  and  in 
compliance with data entry schedule as outlined below:  
 
Registration Form and required documents for enrollment at the time of registration. 
 
All pre‐study data should be submitted within  7 days of registration 
 
Respond and resolve all data queries generated by the lead site within 3 weeks. 
 
Submit all subsequent protocol activity i.e. (doctor visits, treatments or exams, adverse events, 
protocol data/off treatment data) should be entered within 3 21 days of the event. 
 
Lead Site will notify participating sites of delinquent/incomplete data.  
 
Monitor / (QA) the completeness of data entered  
 
Obtain Required Regulatory Documents from Each Site Post‐Activation.  
 
annual approval documents (continuing reviews),  
 
informed consent revisions 
 
 Serious Adverse Events 
 
Evidence of Participating Institution’s IRB review of External Safety Reports 
 
Protocol  Violations  and  Deviations  submitted  according  to  the  participating 
institution’s IRB policy.  
 
Any document that the study supporter may require. 
 
5. Patient Confidentiality and Authorization Statement: 
All institutions involved in the trial will attempt to limit the use of PHI in its trials. However, because of 
the nature of these trials, certain PHI must be collected as per the sponsor requirements. 
 
6. Sub contract must be negotiated, signed and executed independently between BMS and University 
of Chicago and Duke University.               

 
March 28, 2011
86 
 
7. Correlative Studies: 
Supplies will be provided and paid for by the collaborating sites 
       Urine NTX levels will be performed according to collaborating sites policy. 
               All research lab samples (serum and tissue) will be processed by the participating institution.                     
 Samples will be shipped according to the participating sites shipping and handling policy to MDACC 
and will be stored in Dr. Francisco Esteva’s lab at the expense of the collaborating sites contract when 
accrual is complete.    
 
              Sharell Cornet-Risher or Patricia Hutchinson CIT’s will accept shipment of samples.  
              Address to be used is:  
 
              The University of Texas M.D. Anderson Cancer Center 
              Department of Breast Medical Oncology, Unit 1354 
              1155 Herman P. Pressler, CPB5.3450 
              Houston, Texas 77030‐3721 
 
 
 
1. 
Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN, Ueno NT. Bone imaging in 
metastatic breast cancer. J Clin Oncol 2004;22: 2942-53. 
2. 
Amoroso V, Pittiani F, Grisanti S, et al. Osteoblastic flare in a patient with advanced gastric 
cancer after treatment with pemetrexed and oxaliplatin: implications for response assessment with 
RECIST criteria. BMC Cancer 2007;7: 94. 
3. 
Coleman RE, Mashiter G, Whitaker KB, Moss DW, Rubens RD, Fogelman I. Bone scan flare 
predicts successful systemic therapy for bone metastases. J Nucl Med 1988;29: 1354-9. 
4. 
Schneider JA, Divgi CR, Scott AM, et al. Flare on bone scintigraphy following Taxol 
chemotherapy for metastatic breast cancer. J Nucl Med 1994;35: 1748-52. 
5. 
Janicek MJ, Hayes DF, Kaplan WD. Healing flare in skeletal metastases from breast cancer. 
Radiology 1994;192: 201-4. 
6. 
Vogel CL, Schoenfelder J, Shemano I, Hayes DF, Gams RA. Worsening bone scan in the 
evaluation of antitumor response during hormonal therapy of breast cancer. J Clin Oncol 1995;13: 
1123-8. 
7. 
Levenson RM, Sauerbrunn BJ, Bates HR, Newman RD, Eddy JL, Ihde DC. Comparative value 
of bone scintigraphy and radiography in monitoring tumor response in systemically treated prostatic 
carcinoma. Radiology 1983;146: 513-8. 
8. 
Chao HS, Chang CP, Chiu CH, Chu LS, Chen YM, Tsai CM. Bone scan flare phenomenon in 
non-small-cell lung cancer patients treated with gefitinib. Clin Nucl Med 2009;34: 346-9. 
9. 
Condon BR, Buchanan R, Garvie NW, et al. Assessment of progression of secondary bone 
lesions following cancer of the breast or prostate using serial radionuclide imaging. Br J Radiol 
1981;54: 18-23. 
10. 
Arano Y. Recent advances in 99mTc radiopharmaceuticals. Ann Nucl Med 2002;16: 79-93. 
 

 
March 28, 2011
87