Conditions: Pancreatic Cancer Metastatic
Keywords: Metastatic Pancreatic Cancer Adenocarcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 44
Healthy volunteers: no

Brief summary:
The purpose of this research study is to determine if the study drug, dasatinib, given in combination with 5-Fluorouracil, leucovorin and oxaliplatin (FOLFOX) will work against metastatic pancreatic cancer.

Dasatinib is a Food and Drug Administration (FDA) approved drug for treating chronic myelogenous leukemia and acute lymphoblastic leukemia, however it is not currently approved for use in the treatment of pancreatic cancer.

Detailed description:
Systemic control of pancreatic cancer remains a clinical unmet need. The recent superiority of 5-FU based combination therapies over the historical standard gemcitabine represents an opportunity to develop novel combinations of synergistic and effective cytotoxic and biologic targeted therapies. Src excess activity has been demonstrated in pancreatic cancer and is implicated in the invasive and metastatic phenotype clearly represented by this disease. Inhibition of Src activity is associated with numerous biologic modifications capable of positively modifying this phenotype and appears to have synergy with restoring inherent chemosensitivity. The addition of dasatinib to FOLFOX (FOLFOX-D) represents a novel therapeutic regimen in pancreatic cancer with safety and pharmacokinetic data already having been established in colorectal cancer. This protocol will test the safety and activity of this combination in pancreatic cancer where current clinical outcomes remain far from optimal.

Arms:
arm 1: Dasatinib and mFOLFOX6

Interventions: intervention 1: Dasatinib intervention 2: mFOLFOX6
Intervention descriptions: intervention 1: Dasatinib 150mg PO daily on days 1-14 of each 14 day cycle intervention 2: mFOLFOX6 (oxaliplatin 85mg/m2 IV, leucovorin 400mg/m2 IV, 5-Fluorouracil bolus 400mg/m2 IV, and 5-Fluorouracil 2400mg/m2 IV) on day 1 of each 14 day cycle

Protocol document:
Prot_SAP_000.pdf: 
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V6.0; 7/26/2018 
 
Phase II study of 5-fluorouracil, oxaliplatin plus dasatinib 
(FOLFOX-D) in first-line metastatic pancreatic 
adenocarcinoma 
Protocol ID#: 
CA180-359 
 
Coordinating Center: 
University of Florida 
 
Principal Investigator: 
Thomas J. George, Jr., MD, FACP 
 
Co-Investigators: 
Carmen Allegra, MD 
Kevin Behrns, MD  
                                                      Miles Cameron 
                                                      Karen Daily, DO 
Long Dang, MD, PhD 
Steven Hughes, MD 
                                                      Dennie Jones, MD 
Hiral Parekh, MD, MPH 
Jason Starr, DO 
Jose Trevino, MD  
Maria Zajac-Kaye, PhD 
 
Statistician: 
UFHCC Division of Quantitative Sciences & Biostatistics 
 
Supervisory Research 
Manager: 
Alison Ivey, RN, BSN, OCN, CCRP 
 
Alisha Daniels, MD, MHA, CCRC 
 
Responsible Data 
Manager: 
Margaret Veal, CCRP 
 
Experimental Agent: 
Dasatinib 
 
IND Status: 
Exempt 
 
Commercially Available 
Oxaliplatin 
Agent: 
Leucovorin 
5-Fluorouracil 
 
Participating Sites: 
University of Florida, UF Health Cancer Center 
                                                             UF Health Cancer Center – Orlando Health 
Protocol Version 6.0 
Protocol Version Date: 7/26/18 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ....................................................................................... 2 
PROTOCOL SYNOPSIS ...................................................................................... 6 
1 
INTRODUCTION ................................................................................. 8 
1.1 
Background ....................................................................................... 8 
1.2 
Pancreatic Cancer Therapy .............................................................. 8 
1.3 
FOLFOX Activity and Safety ............................................................. 9 
1.4 
Src Inhibition with Dasatinib, Activity and Safety ........................ 10 
1.5 
Combination of FOLFOX and Dasatinib ........................................ 11 
1.6 
Summary of Results of Dasatinib Investigational Program ......... 12 
1.6.1 
Human Pharmacokinetics of Dasatinib ......................................... 12 
1.6.2 
Clinical Experience with Dasatinib in Solid Tumors .................... 13 
1.7 
Safety of Dasatinib in Clinical Studies .......................................... 13 
1.7.1 
Experience in CML and Ph+ ALL Clinical Trials ........................... 13 
1.7.2 
Experience in Phase 2 Breast Cancer Studies.............................. 17 
1.7.3 
Anticipated Adverse Events with Dasatinib .................................. 17 
1.8 
Overall Risk/Benefit Assessment................................................... 19 
1.9 
Study Rationale ............................................................................... 19 
2 
STUDY OBJECTIVES ....................................................................... 19 
2.1 
Primary Objective ............................................................................ 19 
2.2 
Secondary Objectives ..................................................................... 19 
3 
ETHICAL CONSIDERATIONS ......................................................... 20 
3.1 
Good Clinical Practice .................................................................... 20 
3.2 
Institutional Review Board/Independent Ethics Committee ........ 21 
3.3 
Informed Consent ............................................................................ 21 
4 
INVESTIGATIONAL PLAN ............................................................... 21 
4.1 
Study Design and Duration ............................................................ 21 
4.1.1 
Number of Patients Planned ........................................................... 21 
4.1.2 
Duration of Treatment ..................................................................... 22 
4.1.3 
Duration of Follow Up ..................................................................... 22 
4.2 
Study Population ............................................................................. 22 


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4.2.1 
Inclusion Criteria ............................................................................. 22 
4.2.2 
Exclusion Criteria ............................................................................ 24 
4.2.3 
Discontinuation of Subjects from Treatment ................................ 25 
5 
TREATMENTS .................................................................................. 27 
5.1 
Study Treatment .............................................................................. 27 
5.1.1 
Agent Administration ...................................................................... 27 
5.1.2 
mFOLFOX-6 ..................................................................................... 27 
5.1.3 
Dasatinib .......................................................................................... 28 
5.1.4 
Supportive Care ............................................................................... 28 
5.2 
Dasatinib .......................................................................................... 29 
5.2.1 
Identification .................................................................................... 29 
5.2.2 
Packaging and Labeling ................................................................. 29 
5.2.3 
Storage, Handling, and Dispensing ............................................... 30 
5.2.3.1 
Storage ............................................................................................. 30 
5.2.3.2 
Handling and Dispensing ............................................................... 30 
5.3 
Drug Ordering and Accountability ................................................. 30 
5.3.1 
Initial Orders .................................................................................... 30 
5.3.2 
Re-Supply ......................................................................................... 31 
5.3.3 
Drug Accountability ........................................................................ 31 
5.3.4 
IND Status ........................................................................................ 31 
5.4 
Method of Assigning Subjects to a Treatment ............................. 31 
5.5 
Dose Modifications ......................................................................... 31 
5.5.1 
Dose Modification Table ................................................................. 32 
5.5.2 
Dose Modifications Due to Combined Drug Toxicity ................... 32 
5.5.3 
Dose Modifications due to Oxaliplatin Toxicity ............................ 34 
5.5.4 
Dose Modifications due to Dasatinib Toxicity .............................. 34 
5.5.5 
Myelosuppression ........................................................................... 35 
5.5.6 
Non-hematological Adverse Events .............................................. 35 
5.5.7 
Adverse Event Information ............................................................. 35 
5.6 
Blinding/Unblinding ........................................................................ 35 
5.7 
Concomitant Treatments ................................................................ 35 
5.7.1 
Prohibited and/or Restricted Treatments ...................................... 35 


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5.7.1.1 
Potent CYP3A4 Inhibitors ............................................................... 36 
5.7.1.2 
Medications that prolong QT Interval ............................................ 36 
5.7.2 
Other Restrictions and Precautions .............................................. 36 
5.7.2.1 
CYP3A4 Inducers, Inhibitors, Substrates ...................................... 36 
5.7.2.2 
Medications that may Prolong QT Interval .................................... 37 
5.7.2.3 
Antacids ........................................................................................... 37 
5.7.2.4 
St. John's Wort (Hypericum perforatum) ....................................... 37 
5.7.2.5 
Medications that Inhibit Platelet Function and 
Anticoagulants ................................................................................ 37 
5.7.2.6 
Bisphosphonates ............................................................................ 38 
5.7.3 
Additional Supportive Care Guidance for Dasatinib .................... 38 
5.8 
Treatment Compliance .................................................................... 38 
6 
STUDY ASSESSMENTS AND PROCEDURES ............................... 40 
6.1 
Time and Events Schedule ............................................................. 40 
6.2 
Study Materials ................................................................................ 41 
6.3 
Safety Assessments ........................................................................ 41 
6.4 
Efficacy Assessments ..................................................................... 41 
6.4.1 
Tumor response .............................................................................. 41 
6.4.2 
Primary Efficacy Assessment ........................................................ 45 
6.4.3 
Secondary Efficacy Assessments ................................................. 45 
6.5 
Other Assessments ......................................................................... 45 
7 
ADVERSE EVENT REPORTING ...................................................... 47 
7.1 
Adverse Events ............................................................................... 47 
7.1.1 
Serious Adverse Events ................................................................. 47 
7.1.2 
Nonserious Adverse Events ........................................................... 48 
7.2 
Assignment of Adverse Event Intensity and Relationship to 
Investigational Product ................................................................... 48 
7.3 
Collection and Reporting ................................................................ 48 
7.3.1 
Serious Adverse Events ................................................................. 48 
7.3.2 
Handling of Expedited Safety Reports .......................................... 50 
7.3.3 
Nonserious Adverse Events ........................................................... 50 
7.4 
Laboratory Test Abnormalities ....................................................... 50 
7.5 
Overdose .......................................................................................... 51 


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7.6 
Pregnancy ........................................................................................ 51 
7.6.1 
Requirements for Pregnancy Testing ............................................ 51 
7.6.2 
Reporting of Pregnancy .................................................................. 51 
7.7 
Other Safety Considerations .......................................................... 52 
7.8 
Data Safety Monitoring Plan ........................................................... 52 
7.9 
Data Management System .............................................................. 52 
8 
STATISTICAL CONSIDERATIONS .................................................. 52 
8.1 
Sample Size Determination ............................................................ 53 
8.2 
Analysis of Primary Endpoint ........................................................ 53 
8.3 
Analysis of Secondary Endpoints .................................................. 53 
8.4 
Analysis of Safety Data ................................................................... 54 
8.5 
Duration of Response and Other Endpoint Definitions ............... 54 
9 
ADMINISTRATIVE SECTION ........................................................... 55 
9.1 
Compliance with the Protocol ........................................................ 55 
9.2 
Records Retention .......................................................................... 55 
9.3 
Destruction of Investigational Product .......................................... 56 
10 
GLOSSARY OF TERMS ................................................................... 57 
11 
LIST OF ABBREVIATIONS .............................................................. 58 
12 
REFERENCES .................................................................................. 60 
APPENDIX 1: ECOG Performance Status 
APPENDIX 2: Dasatinib Pill Diary 
APPENDIX 3: Pancreatic Cancer Patient Quality of Life and Satisfaction 
Questionnaires 


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PROTOCOL SYNOPSIS 
 
Protocol Title: 
Phase II study of 5-fluorouracil, oxaliplatin plus dasatinib 
(FOLFOX-D) in first-line metastatic pancreatic adenocarcinoma 
Site Numbers & 
Names: 
University of Florida, UF Health Cancer Center 
UF Health Cancer Center – Orlando Health 
Research 
Hypothesis: 
Reduction in metastatic spread, assessment of safety and activity 
of FOLFOX-D in patients with advanced pancreatic cancer 
Study Schema: 
Drugs / Doses / 
Length of Treatment) 
Dasatinib days 1-14 and mFOLFOX-6 day 1 of each 14 day cycle 
until progression or unacceptable toxicity. 
Study Objectives: 
• Primary: 
• Secondary: 
Primary Objective: 
Determine activity of 5-fluorouracil, leucovorin, and oxaliplatin 
(FOLFOX) plus dasatinib on progression free survival (PFS) in 
patients with metastatic pancreatic adenocarcinoma 
Secondary Objectives: 
• To determine the response rate (RR) by RECIST criteria 
• To determine the rate of freedom from metastasis (FFM) 
• To determine the time to progression (TTP) 
• To determine overall survival (OS) 
• To determine the clinical benefit rate (CBR) 
• To determine the site of failure of this regimen in this 
population 
• To determine the safety profile and tolerability of this 
regimen in this population 
• To determine patient compliance with oral therapy 
• To determine the quality of life (QOL) of patients 
receiving this therapy 
• Exploratory tissue and serum correlative analyses to 
identify predictors of response. 
Study Design: 
This is a single arm, prospective open-label multicenter phase II 
clinical study. 
Accrual Goal: 
(Total number of 
subjects) 
42 patients 
Accrual Rate: 
(Number of subjects 
expected per month) 
One to two patients per month over a 42 month accrual period. 
FPFV: 
LPFV: 
Follow Up: 
January 2013 
July 2016 
July 2017 


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Correlative 
Studies: 
(PK/PD, etc.) 
Plasma, mononuclear cells, circulating tumor cells, previously 
obtained tumor biopsy material. 
Evaluation of Src inhibition, pathway suppression, molecular 
markers for prognosis, prediction of response, and post hoc 
molecular testing. 
Inclusion Criteria: 
• Metastatic, measurable, biopsy-proven pancreatic 
adenocarcinoma 
• ECOG PS 0-2 
• No prior chemotherapy or radiotherapy for metastatic 
pancreatic cancer. More than 6 months elapsed since 
prior treatment in adjuvant setting 
• Adequate organ and marrow function 
• Patent biliary system 
• Stable anticoagulation regimen 
• Ability to take oral medications 
Exclusion 
Criteria: 
• Known brain metastases or carcinomatous meningitis 
• Recent major surgery 
• Clinically significant pleural or pericardial effusion 
• Major cardiac conditions 
• Significant bleeding disorder 
• Inability to comply with contraceptive requirements 
Criteria for 
Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
RECIST Radiographic criteria and clinical evaluations 
Standard AE monitoring and reporting 
Statistics: 
Prospective non-randomized phase II study with modified 
intention-to-treat 


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1 
INTRODUCTION 
1.1 
Background 
Pancreatic cancer represents a dismal prognosis when metastatic disease is diagnosed. 
Despite significant improvements in the understanding of pancreatic adenocarcinoma 
biology and pathophysiology, median survival for most patients with advanced disease 
remains at less than 6 months. It remains a highly lethal disease. In the U.S., pancreatic 
cancer will afflict nearly 43,000 patients and will result in 39,000 deaths, representing the 
4th most common cause of cancer-related deaths in 2011. 1,2,3 Cytotoxic systemic therapy 
in advanced disease must balance risks of toxicity with benefits of disease control and 
symptom alleviation. New approaches to the management or prevention of metastatic 
disease represent a clinical unmet need for a large number of cancer patients. 
 
Gemcitabine has served as the cytotoxic therapy foundation for numerous failed attempts 
to improve survival. This has been clearly demonstrated for both cytotoxic as well as 
biologic targeted combination therapies. However, a renewed interest has emerged in 5- 
fluorouracil (5-FU) and leucovorin (LV)-based combinations in advanced pancreatic 
cancer, with some recently published impressive results. Thus, a new platform to which 
novel combinations of active cytotoxic therapies in combination with biologic targeted 
agents appears to be available. 
 
1.2 
Pancreatic Cancer Therapy 
Systemic cytotoxic therapy for metastatic pancreatic cancer was historically limited to 5- 
fluorouracil (5-FU) and leucovorin (LV). In the metastatic setting, these agents produced 
response rates of <10%, clinical benefit rates of <10% and a median overall survival (OS) 
of 4.5 months. 4,5 However, with the development of gemcitabine, clinical trials 
suggested an improvement in both the quality of life and survival of patients receiving 
this drug despite a relatively low objective response rate of still < 10%. 6 There was 
also a statistically significant, but not clinically meaningful, increase in the median 
survival (5.7 vs 4.4 months, p= 0.0025) and one year survival (18% vs 2%) favoring 
those treated with gemcitabine. Confirmatory studies rapidly established gemcitabine 
as the new standard of care. 7,8 
 
For the following decade, multiple trials have compared gemcitabine to combination 
therapy with multiple active cytotoxic agents. Unfortunately, none of these trials has 
proven positive for the primary endpoint of survival, although response rates are 
generally higher with the doublets, along with toxicity. 9 Two recent meta-analyses 
have suggested a possible survival improvement with gemcitabine-based doublets 
coupled to platinums or fluoropyrimidines, but with benefit restricted only to those with 
good performance status. 10,11 The incorporation of biologic therapies to a gemcitabine 
backbone have been similarly disappointing, with only a marginal improvement in 
survival noted (median OS 6.24 months vs 5.91 months; HR 0.82 [95% CI, 0.69-0.99]; 
p= 0.038) with the addition of the anti-epidermal growth factor receptor  (EGFR) 
tyrosine kinase inhibitor (TKI) erlotinib.  12  Alternative approaches to gemcitabine- 
based combination therapy are desperately needed. 


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1.3 
FOLFOX Activity and Safety 
Systemic disease control using 5-fluorouracil (5-FU), leucovorin, and oxaliplatin as 
second-line therapy in patients with metastatic pancreatic cancer has been prospectively 
evaluated.  13, 14  In these previously treated patients,  the combination resulted in a 
partial response rate of 23% with stable disease seen in an additional 17-30%. Median 
OS was 17-25 weeks with notable improvements in some patient’s performance status. 
Toxicity was tolerable and consistent with previous experiences using this combination 
therapy in patients with colorectal cancer. Specifically, Grade 3/4 toxicity included 
leukopenia 16%, anemia 3.2%, thrombocytopenia 3.2%, diarrhea 14.2%, fatigue 
16.1% and neurotoxicity 4.2%. There were no treatment related deaths. In a phase III 
RCT, the combination of 5-FU/LV/Oxaliplatin was determined to be superior to 5- 
FU/LV alone in patients with metastatic pancreatic cancer who progressed on 
gemcitabine therapy. 15 The specific combination of these agents (FOLFOX) has also 
been prospectively evaluated in the first-line setting with a similar response rate of 
27%, stable disease in another 30% of patients, median PFS of 4 months and median 
OS of 7.4 months. 16, 17 
 
At the 2010 Annual Meeting of the American Society of Clinical Oncology, results  
were presented from the PRODIGE 4/ACCORD 11 trial. 18 This phase III controlled 
trial in patients with first line metastatic pancreatic cancer randomized gemcitabine 
against the combination of 5-FU/LV/oxaliplatin/irinotecan (FOLFIRINOX). At a 
median follow-up of 26 months, 342 randomized patients demonstrated superior OS for 
the combination therapy (11.1 months) compared to gemcitabine (6.8 months; HR 0.57; 
95% CI, 0.45-0.73; p< 0.001). Progression free survival (PFS) (6.4 months vs 3.3 
months; HR 0.47; 95% CI, 0.37-0.59; p< 0.001) and response rate (32% vs 9%; 
p< 0.001) also favored the combination treatment. However, toxicities were 
significantly increased with FOLFIRINOX including diarrhea (13% vs 2%), peripheral 
neuropathy (9% vs 0), thrombocytopenia (9% vs 3%), neutropenia (46% vs 21%), and 
febrile neutropenia (5% vs 1%). There were also trends towards worsening vomiting 
(14% vs 8%) and fatigue (23% vs 17%) with FOLFIRINOX. There was one toxicity- 
related death in each arm. 19 Despite the favorable clinical outcomes and incorporation 
of FOLFIRINOX into NCCN Guidelines,  many clinical providers reject this therapy as 
a significantly toxic treatment in a disease where palliation of symptoms remains a 
primary goal. 20, 21 
 
Thus, 5-FU-based combination therapies reflect an opportunity to improve survival in 
advanced pancreatic cancer where dozens of gemcitabine-based combinations have 
repeatedly failed.  In advanced pancreatic cancer,  FOLFOX chemotherapy is active 
with significantly less toxicity than FOLFIRINOX therapy. It can therefore serve as a 
new backbone for the addition of novel targeted therapeutics, a place where prior 
attempts with gemcitabine combinations have failed to produce meaningful 
improvements. FOLFOX remains an internationally recognized combination treatment 
in widespread use for colorectal cancer and other gastrointestinal malignancies. 22 
Academic, community, and institutional oncology providers are familiar with FOLFOX 


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dosing, administration, toxicities, and patient management with NCCN Guidelines 
supporting its use in first or second-line advanced pancreatic cancer. 21 
 
Toxicity of 5-FU, leucovorin, and oxaliplatin is well characterized and is outlined in 
more detail in Section 5. 
 
1.4 
Src Inhibition with Dasatinib, Activity and Safety 
A number of studies have shown that Src tyrosine kinase activity is commonly activated 
and elevated in many human cancers, including pancreatic cancer, with prognostic 
implications as associated with disease stage and patient survival. 23,24,25,26,27, The major 
consequence of increased Src activity is to promote an invasive and metastatic cancer 
phenotype characterized by breakdown of cell-cell adhesion, increased cell-matrix 
adhesion, mediation of lymph/angiogenesis, and formation of focal adhesions. 28,29,30,31 
Intracellular cytoplasmic Src (c-Src) activates a number of substrates critical to these 
processes including focal adhesion kinase (FAK), signal transducers and activators of 
transcription 3 (STAT-3), vascular endothelial growth factor (VEGF), hypoxia-inducible 
factor-1 alpha (HIF), and other components of the epidermal growth factor (EGF) 
pathway. 28,32,33,34 Inhibition of Src activity in preclinical models restores cell-cell 
adhesion, inhibits cell migration and invasion, and reverses the Src-mediated invasive 
and metastatic cancer phenotype. 35,36,37,38 
Dasatinib (SPRYCEL®, Bristol-Myers Squibb [BMS]-354825) is a potent, broad 
spectrum inhibitor of 5 critical oncogenic tyrosine kinases/kinase families, including the 
Src family of kinases with sub-nanomolar inhibition constant (IC50). Dasatinib is 
approved in the United States, Europe, and several other countries for chronic myeloid 
leukemia (CML) with resistance or intolerance to prior treatment including imatinib. 
Dasatinib has been studied in more than 2500 subjects with CML or Ph+ ALL and with 
solid tumors. Clinical pharmacokinetic (PK) data indicate that dasatinib has good oral 
absorption, is > 90% protein bound, and is predicted to have a large volume of 
distribution. The overall mean terminal half life is around 4 hours in subjects, and it is 
expected to be eliminated mainly through metabolism. 
 
Dasatinib has an acceptable safety profile with most subjects having some degree of 
myelosuppression. Myelosuppression is common finding in most hematologic 
malignancies and is also a common side effect of most chemotherapeutic agents. 
Thrombocytopenia, neutropenia, leukopenia, and anemia were frequently reported as 
Grade 3 to 4 laboratory abnormalities in all subject populations studied. In cases of 
severe myelosuppression, recovery generally occurred following brief (2 to 4 weeks) 
dose interruptions or reductions. Other severe hematologic toxicities were uncommon. 
Most subjects continued treatment without further evidence of myelosuppression. The 
most common nonhematologic toxicities include gastrointestinal AEs, in particular 
diarrhea, nausea, and vomiting. Most gastrointestinal events were mild to moderate in 
severity. Other dasatinib toxicities to note included fluid retention, bleeding-related 
events, and QT prolongation. The incidence of edema associated with dasatinib 
treatment was similar across all phases of CML and Ph+ ALL, and pleural effusion in 
dasatinib-treated subjects mostly occurred in advanced stage CML and Ph+ ALL. 
Overall, one third of subjects had a bleeding event and of those, half were considered 


11 
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study drug related. These events occurred mostly in subjects with thrombocytopenia. 39 
Given inherent hematologic toxicity differences between the hematologic malignancy 
and solid tumor population of patients, separate dose finding and toxicity studies have 
been undertaken. Indeed, results from the solid tumor phase I dasatinib studies 
demonstrated infrequent myelosuppression and thrombocytopenia, relative to those 
patients in the hematologic malignancy studies. This indicates that dasatinib is not likely 
to be directly or significantly toxic to the hemapoietic progenitor cells. However, those 
patients with pleural effusions in the solid tumor studies had dose-limiting toxicities of 
expansion of their effusions, and have subsequently been excluded from future 
enrollment on studies with dasatinib. 40 
 
Dasatinib toxicity is well characterized and is outlined in more detail in Section 1.7. 
 
 
1.5 
Combination of FOLFOX and Dasatinib 
The role of single agent Src antagonists appears to be of limited clinical value in the 
salvage setting of metastatic pancreatic cancer. 40 This is consistent with pre-clinical data 
suggesting that dasatinib use can significantly inhibit migration and invasion, with 
marked inhibition in the development of metastases. However, there is no survival 
advantage in dasatinib treated animals owing to continued growth of their already 
established tumors. 41 Dasatinib is currently undergoing prospective investigation in a 
phase II study as monotherapy in first-line metastatic pancreatic cancer (Protocol ID# 
NCT00474812). 42 Nevertheless, incorporating dasatinib with cytotoxic therapies may 
improve clinical outcomes. Constitutively active Src is associated with increased 
gemcitabine and 5-FU chemoresistence in pancreatic cancer cells. 43,44 Inhibition of Src 
reduces tumor expression of thymidylate synthase (TS), the target enzyme of 5-FU. 
Lowering TS levels is associated with subsequent 5-FU chemoresistance reversal 
resulting in substantially decreased in vivo tumor growth and inhibition of distant 
metastases. 45  Dasatinib can synergistically inhibit oxaliplatin-induced Src activation. 
45,46 Src inhibition also increases oxaliplatin activity both in vitro and in vivo. 47 
Safety regarding the specific combination of FOLFOX and dasatinib in patients with 
previously treated metastatic colorectal cancer was presented at the 2010 Annual Meeting 
of the American Society of Clinical Oncology. 48 In this study of thirty total patients, all 
received FOLFOX plus cetuximab plus dasatinib in one of 3 dasatinib dosing cohorts. 
This phase IB prospective protocol with escalating doses of dasatinib including an 
expansion cohort included patients who had received a median of 3 prior regimens, 
making this a heavily pretreated population of subjects. Grade 3-4 toxicities included 
neutropenia (23%), fatigue (20%), pleural effusions (3%), and thrombocytopenia (3%). 
The dose limiting toxicity was fatigue and myelosuppression with maximum tolerated 
dose of dasatinib in combination with FOLFOX being 150 mg daily. The recommended 
dose for further phase II development was 100 mg based on myelosuppression. 
However, pharmacodynamic studies confirmed subtherapeutic inhibition of Src at 100 
mg, thus 150 mg with growth factor support is recommended for this study. 
Interestingly, clinical activity was seen including in patients previously reported to be 
refractory to oxaliplatin.49 


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1.6 
Summary of Results of Dasatinib Investigational 
Program 
 
SPRYCEL®50 (dasatinib, Bristol-Myers Squibb [BMS]-354825) is a potent, broad 
spectrum inhibitor of 5 critical oncogenic tyrosine kinases/kinase families (BCR-ABL, 
Src, c-KIT, PDGF receptor β [PDGFRβ], and ephrin [EPH] receptor kinases), each of 
which is linked to multiple forms of human malignancies, and was discovered and 
developed by BMS. SPRYCEL is approved in the United States (US)50, Europe (EU)51, 
and several other countries for the treatment of adults in all phases of chronic myeloid 
leukemia (CML) with resistance or intolerance to prior therapy including imatinib, and 
Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) who are 
resistant or intolerant to prior therapy. 
 
The recommended starting dosage for subjects with chronic phase CML is 100 mg 
administered orally once daily (QD). The recommended starting dosage for accelerated 
phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg/day 
administered orally once daily. In clinical studies of adult CML and Ph+ ALL patients, 
dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily 
(advanced phase CML and Ph+ ALL) was allowed in patients who did not achieve a 
hematologic or cytogenetic response at the recommended starting dosage. 
 
1.6.1 
Human Pharmacokinetics of Dasatinib 
 
Dasatinib is rapidly absorbed following oral administration in subjects with leukemia.52 
Across all treatment regimens, disease status, and study days, mean Cmax values were 
attained at median Tmax values that ranged from 0.45 to 3.18 hours postdose. The overall 
median Tmax value was approximately 1 hour. There was no influence of treatment 
regimens, disease status, or study days on the half-life (T-HALF) of dasatinib. The 
overall mean T-HALF value was approximately 3 to 5 hours. Dasatinib has an apparent 
volume of distribution of 2505 L, suggesting that the drug is extensively distributed in the 
extravascular space. There were no clinically meaningful relationships between steady 
state CLo and body weight or body surface area. Statistical linear regression analyses 
were performed on log (AUC) versus log (DOSE) to assess dose proportionality. The 
AUC of dasatinib is approximately dose proportional in the dose range of 15 to 
240 mg/day, suggesting that the drug exhibited linear kinetics over the entire dose range. 
However, the 90% CIs are wide, indicating that the variability in AUC is high. There was 
no marked effect of disease state, age, gender, and race on the PK parameters CLo, Vz/F, 
and T-HALF, suggesting that dose adjustment in these subpopulations may not be 
necessary.53 The geometric mean accumulation index (AI) ranged from 1.01 to 1.61 
between days 5/8 and 26/29 and no consistent dose-related trends were observed in the 
accumulation of dasatinib after repeated administration. 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.54 The observed food effects were not clinically relevant. 
Dasatinib is extensively metabolized in humans. Unchanged dasatinib represented 29% 


13 
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of circulating radioactivity in plasma after a 100 mg dose of [14C]-labeled dasatinib was 
administered to 8 healthy subjects in study CA180019.55 Elimination is predominantly in 
the feces, mostly as metabolites. Following a single oral dose of [14C]-labeled dasatinib, 
approximately 85% of the dose was recovered in the feces within 10 days, and 
approximately 4% of the administered radioactivity was recovered in the urine. 
 
The cytochrome p450 enzyme CYP3A4 plays a major role in the metabolism of dasatinib 
in the humans. Dasatinib has little potential to induce CYP3A4 and, at concentrations 
≤ 25 μM (1 μM = 488 ng/mL), dasatinib did not induce CYP1A2, CYP2B6, CYP2C9, 
and CYP3A4 in primary cultures of human hepatocytes.56 Based on these data and 
plasma concentrations observed in vivo, dasatinib is unlikely to decrease the exposure of 
co-administered drugs that are metabolized by CYP1A2, CYP2B6, CYP2C9, or 
CYP3A4. In human liver microsomes, dasatinib did not inhibit CYP1A2, CYP2B6, 
CYP2C19, CYP2D6, or CYP2E1 at concentrations up to 50 μM.57 It inhibited CYP2A6 
(IC50 = 35 μM), CYP2C8 (IC50 = 12 μM), CYP2C9 (IC50 = 50 μM), and CYP3A4 
(IC50 values of 18 and 10 μM for midazolam and testosterone substrates, respectively). 
 
 
1.6.2 
Clinical Experience with Dasatinib in Solid Tumors 
 
Studies in the solid tumor program for dasatinib include four Phase 1 studies (CA180003, 
CA180021, CA180004, CA180086) and three Phase 2 studies (CA180059, CA180088, 
CA180085). CA180003 and CA180021 were exploratory studies in refractory solid 
tumors and advanced solid tumors, respectively, and have been completed. CA180004, 
CA180059, and CA180088 are ongoing in breast cancer, and CA180085 and CA180086 
are ongoing in prostate cancer (ongoing as of November 2008). 
 
The efficacy and safety observations in the solid tumor studies are presented in the 
following sections. 
1.7 
Safety of Dasatinib in Clinical Studies 
1.7.1 
Experience in CML and Ph+ ALL Clinical Trials 
 
The data presented in Table 1.7.1 reflect exposure to dasatinib in 2182 patients with 
leukemia in clinical studies (starting dosage 100 mg once daily, 140 mg once daily, 
50 mg twice daily, or 70 mg twice daily). The median duration of therapy was 11 months 
(range 0.03-26 months). 
 
The majority of dasatinib-treated patients (1,864 [85%]) experienced at least 1 drug- 
related adverse reactions at some time. Drug was discontinued for adverse reactions in 
14% (296/2182) of subjects. Drug related AEs leading to discontinuation in any 
1 category occurred in ≤ 1% of the subjects with the exception of pleural effusion 
(85/2182; 4%). In subjects with chronic phase CML, drug-related pleural effusion 
accounted for discontinuation in 52 of the 1150 subjects. Only 1 subject in the 100 mg 
QD group had discontinuation due to drug-related pleural effusion compared with 
35 subjects in the 70 mg BID group. In subjects with advanced phase CML or Ph+ ALL, 
drug-related pleural effusion accounted for discontinuation in 33 of the 1032 subjects. Six 
subjects in the 140 mg QD group had discontinuation due to drug-related pleural effusion 


14 
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compared with 27 subjects in the 70 mg BID group. 
 
Overall, 59% (1287/2182) of subjects across all disease phases reported SAEs (any 
grade). Drug-related SAEs were reported in 53% (681/2182) of subjects. In subjects with 
chronic phase CML, notable common drug-related AEs included dyspnea, pleural 
effusion, congestive heart failure, febrile neutropenia, and thrombocytopenia. In most 
cases, a lower proportion of subjects in the 100 mg QD group reported drug-related SAEs 
than subjects in the 70 mg BID or other dose groups. In subjects with advanced phase 
CML or Ph+ ALL, notable common drug-related AEs included dyspnea, pleural effusion, 
diarrhea, and hematological toxicities. In most cases, there was little difference in these 
SAEs between the 140 mg QD and 70 mg BID groups. Rates of severe drug-related 
pleural effusion were lower in the 140 mg QD group (3%) vs the 70 mg BID (6%). 
 
 
The most frequently reported AEs are presented in Table 1.7.1 
 
Table 1.7.1: 
Very Common and Common AEs Reported in Subjects in 
Clinical Studies 
All Subjects (N= 2182) 
  
Percent (%) of Subjects 
All Grades 
Grades 3/4 
Nervous system disorders 
Very common: headache 
25 
1 
Common: neuropathy (including peripheral neuropathy) 
7 
<1 
dizziness 
5 
<1 
dysgeusia 
2 
0 
somnolence 
2 
<1 
Respiratory, thoracic and mediastinal disorders 
Very common: pleural effusion 
27 
7 
dyspnea 
24 
5 
cough 
10 
<1 
Common: pulmonary edema 
2 
<1 
lung infiltration 
2 
<1 
pneumonitis 
2 
<1 
pulmonary hypertension 
1 
<1 
Gastrointestinal disorders 
Very common: diarrhea 
33 
4 
nausea 
23 
1 
vomiting 
13 
1 
abdominal pain 
11 
<1 
Common: gastrointestinal bleeding 
8 
4 
mucosal inflammation (including mucositis/stomatitis) 
7 
<1 
dyspepsia 
6 
0 
abdominal distension 
5 
0 


15 
V6.0; 07/26/2018 
 
Table 1.7.1: 
Very Common and Common AEs Reported in Subjects in 
Clinical Studies 
All Subjects (N= 2182) 
  
Percent (%) of Subjects 
 
All Grades 
Grades 3/4 
constipation 
5 
<1 
gastritis 
2 
<1 
colitis (including neutropenic colitis), 
2 
<1 
oral soft tissue disorder 
2 
0 
Skin and subcutaneous tissue disorders 
Very common: skin ras a 
h 
23 
<1 
Common: pruritus 
7 
<1 
acne 
5 
<1 
alopecia 
5 
0 
dry skin 
3 
0 
hyperhidrosis 
2 
0 
urticaria 
1 
<1 
dermatitis (including eczema) 
1 
0 
Musculoskeletal and connective tissue disorders 
Very common: musculoskeletal pain 
15 
1 
Common: arthralgia 
9 
<1 
myalgia 
8 
<1 
muscle inflammation 
3 
<1 
muscular weakness 
1 
<1 
musculoskeletal stiffness 
1 
0 
Metabolism and nutrition disorders 
Common: anorexia 
9 
<1 
appetite disturbances 
2 
<1 
hyperuricaemia 
1 
<1 
Infections and infestations 
Very Common: infection (including bacterial, viral, fungal, 
nonspecific) 
11 
3 
Common: pneumonia (including bacterial, viral, fungal) 
5 
3 
upper respiratory tract infection/inflammation 
5 
<1 
herpes viral infection 
1 
<1 
enterocolitis infection 
1 
<1 
sepsis (including fatal outcome) 
1 
<1 
Cardiac Disorders 
Common: pericardial effusion 
5 
1 
arrhythmia (including tachycardia) 
3 
<1 
congestive heart failure/cardiac dysfunctionb 
3 
2 


16 
V6.0; 07/26/2018 
 
Table 1.7.1: 
Very Common and Common AEs Reported in Subjects in 
Clinical Studies 
All Subjects (N= 2182) 
  
Percent (%) of Subjects 
All Grades 
Grades 3/4 
palpitations 
2 
0 
Vascular disorders 
Very common: hemorrhagec 
16 
2 
Common: flushing 
4 
0 
hypertension 
2 
<1 
Blood and lymphatic system disorders 
Common: febrile neutropenia, 
5 
5 
pancytopenia 
1 
<1 
General disorders and administration site conditions 
Very common: fatigue 
23 
2 
superficial edemad 
22 
1 
pyrexia 
14 
1 
Common: asthenia 
9 
<1 
pain 
8 
<1 
chest pain 
6 
<1 
generalized edema 
4 
<1 
chills 
3 
<1 
Psychiatric disorders 
Common: insomnia 
2 
0 
depression 
2 
<1 
Eye disorders 
Common: visual disorder (including visual disturbance, vision 
blurred, and visual acuity reduced) 
2 
<1 
dry eye 
1 
<1 
Ear and labyrinth disorders 
Common: tinnitus 
1 
0 
Investigations 
Common: weight increased 
5 
<1 
weight decreased 
5 
<1 
Injury, poisoning, and procedural complications 
Common: contusion 
2 
<1 
Source: SPRYCEL (dasatinib) BMS-354825, Bristol-Myers Squibb Investigator Brochure, Version 8, 200858 
a Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, fungal rash, 
generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash 
generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, 
skin exfoliation, skin irritation, and urticaria vesiculosa. 
b Includes ventricular dysfunction, cardiac failure chronic, cardiac failure congestive, cardiomyopathy, 
congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure. 


17 
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c Excludes gastrointestinal bleeding and CNS bleeding; These adverse drug reactions are reported under the 
gastrointestinal disorders system organ class and the nervous sytem disorders system organ class, 
respectively. 
d Includes auricular swelling, conjunctival edema, eye edema, eye swelling, eyelid edema, face edema, 
gravitational edema, lip edema, localized edema, mascular edema, edema genital, edema mouth, edema 
peripheral, orbital edema, penile edema, periorbital edema, pitting edema, scrotal edema, swelling face, 
and tongue edema. 
 
1.7.2 
Experience in Phase 2 Breast Cancer Studies 
 
Drug related AEs in ≥ 25% of the subjects in the completed Phase 2 studies in breast 
cancer are given in Table 1.7.2. 53 
 
Table 1.7.2: 
Drug Related Adverse Events in ≥ 25% Subjects for Phase 2 
Breast Cancer Studies CA180059 and CA180088 
Preferred Term 
CA180059, n (%) 
CA180088, n (%) 
70 mg BID 
(N=21) 
70 mg BID 
(N=21) 
70 mg BID 
(N=44) 
100 mg BID 
(N=23) 
Nausea 
14 (67) 
10 (44) 
15 (34) 
8 (35) 
Fatigue 
14 (67) 
10 (44) 
15 (34) 
3 (13) 
Diarrhea 
7 (33) 
12 (52) 
23 (52) 
10 (44) 
Rash 
5 (24) 
11 (48) 
10 (23) 
9 (39) 
Asthenia 
0 (0) 
0 (0) 
13 (30) 
9 (39) 
Dyspnea 
6 (29) 
11 (48) 
10 (23) 
9 (39) 
Pleural effusion 
7 (33) 
9 (39) 
12 (27) 
9 (39) 
Anorexia 
3 (14) 
9 (39) 
0 (0) 
0 (0) 
Headache 
4 (19) 
8 (35) 
15 (34) 
9 (39) 
Cough 
5 (24) 
7 (30) 
0 (0) 
0 (0) 
Abdominal pain 
2 (10) 
7 (30) 
13 (30) 
5 (22) 
Vomiting 
6 (29) 
7 (30) 
8 (18) 
8 (35) 
Flushing 
6 (29) 
3 (13) 
0 (0) 
0 (0) 
 
1.7.3 
Anticipated Adverse Events with Dasatinib 
 
Myelosuppression 
Treatment with dasatinib is associated with severe (NCI CTCAE 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. Myelosuppression 
was generally reversible and usually managed by withholding dasatinib temporarily or 
dose reduction.51 In a Phase 3 dose-optimization study in patients with chronic phase 
CML, Grade 3 or 4 myelosuppression was reported less frequently in patients treated 
with 100 mg once daily than in patients treated with 70 mg twice daily. At doses of 
150 mg in combination with FOLFOX, empiric growth factor use is recommended. 
(Personal Communication, Kopetz S.) 


18 
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        Bleeding Related Events 
Severe CNS hemorrhages, including fatalities, occurred in ≤ 1% of patients receiving 
dasatinib. Severe gastrointestinal hemorrhage occurred in 4% of patients and generally 
required treatment interruptions and transfusions. Other cases of severe hemorrhage 
occurred in 2% of patients. Most bleeding events were associated with severe 
thrombocytopenia. (Incidences in this paragraph reflect drug-related adverse reactions 
based on investigator’s attribution.) 
 
Patients were excluded from participation in dasatinib clinical studies if they took 
medications that inhibit platelet function or anticoagulants. In some trials, the use of 
anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was 
allowed concurrently with dasatinib if the platelet count was 50,000 to 75,000. Caution 
should be exercised if patients are required to take medications that inhibit platelet 
function or anticoagulants.51 
 
Fluid Retention 
Dasatinib is associated with fluid retention. In all clinical studies, severe fluid retention 
was reported in 10% of patients, including pleural and pericardial effusion reported in 7% 
and 1% of patients, respectively. Severe ascites and generalized edema were each 
reported in < 1% of patients. Severe pulmonary edema was reported in 1% of patients. 
Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry 
cough should be evaluated by chest X-ray. Severe pleural effusion may require 
thoracentesis and oxygen therapy. Fluid retention events were typically managed by 
supportive care measures that include diuretics or short courses of steroids. (Incidences in 
this paragraph reflect drug-related adverse reactions based on investigator’s attribution). 
52 
 
 
In the Phase 3 dose-optimization study in patients with chronic phase CML, fluid 
retention events were reported less frequently in patients treated with 100 mg once daily 
than in patients treated with 70 mg twice daily.51 
 
QT Prolongation 
A comprehensive evaluation of data from Phase 2 studies (N = 865) examined the 
possible effect of dasatinib on ECG parameters, particularly the QTc interval. The mean 
QTc interval changes from baseline using Fridericia’s method (QTcF) were 4 to 6 msec; 
the upper 95% confidence intervals for all mean changes from baseline were < 7 msec. 
On-study, a total of 5 subjects (< 1%) reported a QTcF > 500 msec; 1 of these 5 subjects 
reported a QTcF > 500 msec on both Day 1 and Day 8. No events of torsade de pointes 
were reported.52 
 
Nine of the 1150 subjects with chronic phase CML had QTc prolongation reported as an 
adverse event. Of these 9 subjects, 7 were considered related to drug. None of the 
9 subjects who reported QTc prolongation were from the 100 mg QD group compared 
with 8 subjects from the 70 mg BID group. Ten of the 1032 subjects with advanced 
disease had QTc prolongation reported as an adverse event. Of these 10 subjects, 7 were 
considered drug-related. All 10 of the subjects who reported QTc prolongation were from 
the 70 mg BID group. Overall, of the 2182 subjects treated with dasatinib, 21 (1%) 
subjects across the studies reported a QTcF > 500 msec.68 


19 
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1.8 
Overall Risk/Benefit Assessment 
The clinical studies discussed in Section 1 indicate that the safety profile for dasatinib in 
solid tumor subjects has been similar to that in chronic phase CML subjects with the 
exception of severe myelosuppression, which has not been observed in solid tumor 
subjects and is considered related to efficacy against the leukemia as noted above, and 
severe bleeding which is secondary to thrombocytopenia in most instances. 
 
Preliminary analysis indicated modest clinical efficacy in the completed Phase 2 breast 
cancer study. Also, ongoing prostate cancer studies appear to be promising. The 
characterization of clinical efficacy of dasatinib in solid tumor cancer is pending 
completion of the ongoing studies and data analysis. 
 
Adequate safety data exists to support the use of FOLFOX plus dasatinib in patients with 
advanced pancreatic cancer. There is not expected to be more severe toxicity in this 
population that is different from that seen in previously treatment solid tumor patients 
with this combination. Given the poor outcomes based on standards of care in this 
disease, new clinical management approaches are desperately needed. 
 
1.9 
Study Rationale 
Systemic control of pancreatic cancer remains a clinical unmet need. The recent 
superiority of 5-FU based combination therapies over the historical standard gemcitabine 
represents an opportunity to develop novel combinations of synergistic and effective 
cytotoxic and biologic targeted therapies. Src excess activity has been demonstrated in 
pancreatic cancer and is implicated in the invasive and metastatic phenotype clearly 
represented by this disease. Inhibition of Src activity is associated with numerous 
biologic modifications capable of positively modifying this phenotype and appears to 
have synergy with restoring inherent chemosensitivity. The addition of dasatinib to 
FOLFOX (FOLFOX-D) represents a novel therapeutic regimen in pancreatic cancer with 
safety and pharmacokinetic data already having been established in colorectal cancer. 
This protocol will test the safety and activity of this combination in pancreatic cancer 
where current clinical outcomes remain far from optimal. 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
Determine activity of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus 
dasatinib on progression free survival (PFS) in patients with metastatic pancreatic 
adenocarcinoma. 
 
2.2 
Secondary Objectives 
Clinical Objectives 
• To determine the response rate (RR) by RECIST criteria 


20 
V6.0; 07/26/2018 
 
• To determine the rate of freedom from metastasis (FFM) 
• To determine the time to progression (TTP) 
• To determine overall survival (OS) 
• To determine the clinical benefit rate (CBR) 
• To determine the site of failure of this regimen in this population 
• To determine the safety profile and tolerability of this regimen in this population 
• To determine patient compliance with oral therapy 
• To determine the quality of life (QOL) of patients receiving this therapy 
 
Exploratory Objectives 
 
• Exploratory tissue and serum correlative analyses in this population receiving this 
regimen. 
• Plasma, mononuclear cells, circulating tumor cells, previously obtained tumor 
biopsy material. Evaluation of Src inhibition, pathway suppression, molecular 
markers for prognosis, prediction of response, and post hoc molecular testing. 
 
3 
ETHICAL CONSIDERATIONS 
3.1 
Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as 
defined by the International Conference on Harmonisation (ICH) and in accordance with 
the ethical principles underlying European Union Directive 2001/20/EC and the United 
States Code of Federal Regulations, Title 21, Part 50 (21CFR50). 
 
The study will be conducted in compliance with the protocol. The protocol, any 
amendments, and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion before 
initiation of the study. 
 
All potential serious breaches must be reported to Bristol-Myers Squibb (BMS) 
immediately. A serious breach is a breach of the conditions and principles of GCP in 
connection with the study or the protocol, which is likely to affect, to a significant degree, 
the safety or physical or mental integrity of the subjects of the study or the scientific 
value of the study. 
 
Study personnel involved in conducting this study will be qualified by education, 
training, and experience to perform their respective tasks. This study will not use the 
services of study personnel where sanctions have been invoked or where there has been 
scientific misconduct or fraud (eg, loss of medical licensure; debarment). Systems with 
procedures that ensure the quality of every aspect of the study will be implemented. 


21 
V6.0; 07/26/2018 
 
3.2 
Institutional Review Board/Independent Ethics 
Committee 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment 
materials/process (eg, advertisements), and any other written information to be provided 
to subjects. The investigator should also provide the IRB/IEC with a copy of the 
Investigator Brochure or product labeling, information to be provided to subjects, and any 
updates. The investigator should provide the IRB/IEC with reports, updates, and other 
information (eg, expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures. 
 
3.3 
Informed Consent 
Investigators must ensure that subjects (or, in those situations where consent cannot be 
given by subjects, the legally acceptable representative) are clearly and fully informed 
about the purpose, potential risks, and other critical issues regarding clinical studies in 
which they volunteer to participate. Freely given written informed consent must be 
obtained from every subject (or, in those situations where consent cannot be given by 
subjects, the legally acceptable representative) before clinical study participation, 
including informed consent for any screening procedures conducted to establish subject 
eligibility for the study. 
 
The rights, safety, and well-being of the study subjects are the most important 
considerations and should prevail over interests of science and society. 
 
Subjects unable to give their written consent (eg, stroke patients, or those with severe 
dementia) may be enrolled in the study only with the consent of a legally acceptable 
representative. The subject must also be informed about the nature of the study to the 
extent compatible with the subjects’ understanding, and should they become capable, 
they must personally sign and date the consent form as soon as possible. The explicit 
wish of a subject unable to give his or her written consent, who is capable of forming an 
opinion and assessing this information to refuse participation in, or to be withdrawn from, 
the clinical study at any time, should be considered by the investigator. 
 
4 
INVESTIGATIONAL PLAN 
4.1 
Study Design and Duration 
This is a single arm, prospective open-label multicenter phase II clinical study in the first- 
line setting of patients with metastatic pancreatic adenocarcinoma treated with FOLFOX 
plus dasatinib (FOLFOX-D) with primary and secondary endpoints as noted in Section 2. 
4.1.1 
Number of Patients Planned 
 
A total of 42 patients is planned to be included in this study, from three 
investigational sites, over a 30 month accrual period. 


22 
V6.0; 07/26/2018 
 
4.1.2 
Duration of Treatment 
 
Patients will continue with protocol therapy until one of the criteria for study 
treatment discontinuation is met as described in Section 4.2.3. 
 
4.1.3 
Duration of Follow Up 
 
Patients will be contacted for survival status every 8 weeks until death or patient 
withdrawal. Subsequent therapies will also be collected and recorded. 
 
4.2 
Study Population 
For entry into the study, the following criteria MUST be met. 
4.2.1 
Inclusion Criteria 
 
Signed Written Informed Consent 
a) Before any study specific procedures are performed, subjects will have the details 
of the study described to them, and they will be given a written informed consent 
document to read. Then, if subjects consent to participate in the study, they will 
indicate that consent by signing and dating the informed consent document in the 
presence of study personnel. 
b) Written consent should include HIPAA language according to institutional 
guidelines. 
Target Population 
a) Histologically or cytologically proven pancreatic adenocarcinoma with evidence 
of metastatic disease on diagnostic imaging studies. 
b) Measurable disease (per RECIST 1.1 criteria) 
c) ECOG Performance Status 0-2 (See Appendix I) 
d) No prior chemotherapy or radiotherapy for metastatic pancreatic cancer. Patients 
may have received prior chemotherapy or radiotherapy for non-metastatic disease; 
however the diagnosis of metastatic disease must have been made more than 6 
months after completion of prior treatment. Prior radiation therapy for palliation of 
symptomatic primary tumors (ie. for pain control) is allowable at the discretion of 
the Principal Investigator. Radiated lesions may not be used as target (measurable) 
lesions for RECIST purposes. 
e) Patients may have had a history of other malignancies if there is no current evidence 
of persistent or recurrent disease and they are not undergoing any active therapy 
(including hormonal). 
f) Patent biliary system. Surgical bypass or internal stent is preferred if clinical 
concern for obstructive potential during duration of study participation. 
g) Patients receiving anti-coagulation treatment with an agent such as Coumadin or 
heparin may be allowed to participate, provided the following criteria are met; 
i) 
Receiving low- molecular weight heparin, or a stable dose of Coumadin for at 
least 3 weeks. If on coumadin, an INR between 2 and 3 must be documented on 
two sequential occasions prior to enrollment. 


23 
V6.0; 07/26/2018 
 
ii) No active bleeding or pathological condition that carries a high risk of bleeding 
(e.g. active GI mucosal ulceration or history of known variceal bleeding). 
iii) Patients temporarily (<3 weeks) placed on prophylactic doses of heparin or low-
molecular weight heparin related routine inpatient hospital stays or post- 
hospital rehabilitation are eligible. 
h) Adequate organ and marrow function 
i) 
Total bilirubin < 1.5 times the institutional Upper Limit of Normal (ULN) 
ii) AST, ALT and Alk Phos ≤ 2.5 times the institutional ULN (< 5 x ULN for 
patients with known liver metastases) 
iii) Serum Creatinine < 1.5 time the institutional ULN 
iv) Hemoglobin ≥ 9.0 g/dL (patient may be transfused to maintain or exceed this 
level) 
v) Absolute neutrophil count (ANC) ≥ 1,500/mm3 
vi) Platelet count ≥ 100,000/mm3 
vii) No other clinically significant lab abnormalities 
i) Ability to take oral medication (dasatinib must be swallowed whole) 
j) Concomitant Medications 
i) 
Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy 
(discontinue St. Johns Wort at least 5 days before starting dasatinib) 
ii) Patient agrees that IV bisphophonates will be withheld for the first 8 weeks of 
dasatinib therapy due to risk of hypocalcemia. 
iii) Patient agrees to discontinue use of potent CYP3A4 inhibitors or Category 1 
anti-arrhythmic agents (see exclusion criteria section or Section 5.7 for 
detailed lists) at least 7 days prior to starting dasatinib. 
Age and Sex 
k) Subject, age ≥ 18 years. 
l) Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception to avoid pregnancy throughout the study and for at least 4 weeks after 
the last dose of study drug to minimize the risk of pregnancy. Prior to study 
enrollment, women of childbearing potential must be advised of the importance of 
avoiding pregnancy during trial participation and the potential risk factors for an 
unintentional pregnancy. 
WOCBP include any woman who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, 
or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is 
defined as: 
• 
Amenorrhea that has lasted for ≥ 12 consecutive months without another 
cause, or 
• 
For women with irregular menstrual periods who are taking hormone 
replacement therapy (HRT), a documented serum follicle-stimulating 
hormone (FSH) level of greater than 35 mIU/mL. 
Women who are using oral contraceptives, other hormonal contraceptives 
(vaginal products, skin patches, or implanted or injectable products), or 


24 
V6.0; 07/26/2018 
 
mechanical products such as an intrauterine device or barrier methods (diaphragm, 
condoms, spermicides) to prevent pregnancy, or who are practicing abstinence or 
where their partner is sterile (eg, vasectomy) should be considered to be of 
childbearing potential. 
WOCBP must have a negative serum pregnancy test within 7 days prior to the 
start of protocol therapy. 
A male subject of fathering potential must use an adequate method of contraception 
to avoid conception throughout the study [and for at least 4 weeks after the last dose 
of study drug] to minimize the risk of pregnancy. 
4.2.2 
Exclusion Criteria 
 
Sex and Reproductive Status 
a) WOCBP 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 the last dose of 
study drug. 
b) Women who are pregnant or breastfeeding. 
c) Women with a positive pregnancy test. 
d) Sexually active fertile men not using effective birth control if their partners are 
WOCBP. 
Target Disease Exceptions 
e) History of known brain metastases or carcinomatous meningitis 
Medical History and Concurrent Diseases 
a) Recent major surgery (within 4 weeks) or minor surgery (within 2 weeks), 
excluding placement of a vascular access device or biliary stent 
b) Uncontrolled diabetes in the opinion of the treating physician 
c) Any sensory neuropathy > grade 1 at baseline 
d) Serious active or uncontrolled infection 
e) Concurrent medical condition which may increase the risk of toxicity, including: 
i) 
Clinically significant pleural or pericardial effusion requiring therapeutic 
thoracentesis or chest tube placement, pericaridocentesis, or causing ≥ grade 2 
dyspnea 
ii) Patients with known dihydropyrimidine dehydrogenase deficiency 
iii) Patients with a history of allergic reactions attributed to oxaliplatin, 5-FU or 
leucovorin 
f) Cardiac Symptoms; any of the following should be considered for exclusion: 
i) 
Unstable angina or stable angina markedly limiting ordinary physical activity 
(angina occurs on walking one to two blocks and/or climbing one flight of stars 
in normal conditions and at a normal pace) 
ii) New York Heart Association class III or IV congestive heart failure 
iii) Myocardial infarction or stroke within 6 months of study enrollment 
iv) Diagnosed congenital long QT syndrome 
v) Any history of clinically significant ventricular arrhythmias (such as 
ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) 
vi) Prolonged QTc interval on pre-entry electrocardiogram (> 475 msec) 


25 
V6.0; 07/26/2018 
 
vii) Clinically significant peripheral vascular disease 
g) Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to 
dasatinib administration 
h) History of significant bleeding disorder unrelated to cancer, including: 
i) 
Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease) 
ii) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti- 
factor VIII antibodies) 
iii) Ongoing or recent (≤ 3 months) significant gastrointestinal bleeding 
i) History of any other disease, metabolic dysfunction, physical examination finding, 
or clinical laboratory finding giving reasonable suspicion of a disease or condition 
that contraindicates the use of protocol therapy or that might affect the 
interpretation of the results of the study or that puts the subject at high risk for 
treatment complications, in the opinion of the treating physician. 
Prohibited Treatments and/or Therapies 
j) Category I drugs that are generally accepted to have a risk of causing Torsades de 
Pointes including: (Patients must discontinue drug 7 days prior to starting dasatinib; 
see Section 5.7 for details) 
i) 
quinidine, procainamide, disopyramide 
ii) amiodarone, sotalol, ibutilide, dofetilide 
iii) erythromycin, clarithromycin 
iv) chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide 
v) cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, 
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine. 
k) Potent CYP3A4 inhibitors that significantly increase dasatinib exposure. Patients 
must discontinue drug 7 days prior to starting dasatinib; see Section 5.7.1.1 for 
details). 
Other Exclusion Criteria 
l) Prisoners or subjects who are involuntarily incarcerated. 
m) Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness. 
n) Inability to comply with study and/or follow-up procedures 
Eligibility criteria for this study have been carefully considered to ensure the safety of the 
study subjects and to ensure that the results of the study can be used. It is imperative that 
subjects fully meet all eligibility criteria. 
 
4.2.3 
Discontinuation of Subjects from Treatment 
 
Patients who discontinue participation in the clinical study on their own or patients who 
are withdrawn by the investigator, for reasons other than disease progression or toxicity, 
will be defined as premature withdrawals. 
 
Patients who are not initiated on study drug, but sign informed consent and undergo at 
least some of the screening procedures will be considered screening failures. A record of 
these patients will be maintained by the study site. 


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Subjects MUST discontinue study treatment for any of the following reasons: 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• Progressive disease at any time 
• Patient meets criteria for stopping study medication due to toxicity as outlined in 
Section 5.5 
• Any clinical adverse event (AE), laboratory abnormality, or intercurrent illness 
which, in the opinion of the investigator, indicates that continued participation in 
the study is not in the best interest of the subject 
• The patient uses illicit drugs or other substances that may, in the opinion of the 
Investigator, have a reasonable chance of contributing to toxicity or otherwise 
interfering with results 
• Pregnancy 
− Instruct WOCBP to contact the investigator or study staff immediately if they 
suspect they might be pregnant (eg, 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 if a study subject becomes 
pregnant. The mechanism for reporting pregnancy is described in Section 7.6. 
• Termination of the study by BMS. 
• Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) 
illness 
• Substantial non-compliance with the requirements of the study 
• The patient is lost to follow up 
 
The Investigator will make every reasonable effort to keep each patient in the study 
unless it is in the patient’s best interests to discontinue participation. If a patient is 
removed from the study or declines further participation, all End of Treatment 
evaluations should be performed if the patient is willing and able to be assessed. A 
description of the reason(s) for withdrawal from the study must be recorded on the case 
report form (CRF). The Investigator should also ensure that all patients are followed up 
for survival status after the Final Visit. Patients who elect to withdraw from treatment 
prematurely may still be followed per the study calendar with their permission. 
 
Relevant visit data should be entered on the CRF and any unused study medication will 
be accounted for and returned for all patients participating in the study, even for a brief 
period of time. Patients who discontinue following entry will have relevant information 
completed and recorded on the CRF. All patients who discontinue because of adverse 
events or clinically significant laboratory abnormalities should be followed up until they 
recover or stabilize, and the subsequent outcome will be recorded. If any patient should 
die during the trial or within 30 days of stopping study treatment, the Investigator will 
inform the BMS representative. The cause of death should be recorded in detail, within 
24 hours, on a serious adverse event (SAE) form and reported to the sponsor Drug Safety 
Unit (refer to Section for SAE reporting). 


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5 
TREATMENTS 
5.1 
Study Treatment 
An investigational product, also known as investigational medicinal product in some 
regions, is defined as follows: A pharmaceutical form of an active substance or placebo 
being tested or used as a reference in a clinical study, including products already with a 
marketing authorization but used or assembled (formulated or packaged) in a way 
different from the authorized form, or used for an unauthorized indication, or when used 
to gain further information about the authorized form. In this protocol, the investigational 
product is dasatinib. 
 
Other medications used in the study for therapeutic reasons as components of a given 
standard of care are considered non-investigational products. In this protocol, non- 
investigational products include oxaliplatin, 5-fluorouracil, and leucovorin. 
 
5.1.1 
Agent Administration 
 
One treatment cycle is equal to 14 days. 
 
Agent 
Dose 
Route/Duration 
Schedule 
Dasatinib* 
150 mg 
Oral 
Daily on days 1-14 
Oxaliplatin+ 
85 mg/m2 
IV over 120 minutes 
1 every 14 days 
Leucovorin+ 
400 mg/m2 
IV over 120 minutes 
1 every 14 days 
5-fluorouracil 
bolus+ 
400mg/m2 
IV push over less than 5 
minutes 
1 every 14 days 
5-fluorouracil 
infusion+ 
2400mg/m2 
IV continuous infusion for 
46 hours 
1 every 14 days 
* If the start of a cycle is delayed due to scheduling, logistical issues or non-dasatinib 
related toxicities, dasatinib may be continued in the interim. 
+Administer sequentially as written, except oxaliplatin and leucovorin, which may be 
administered concurrently in separate bags using a Y-line. In the event that oxaliplatin is 
discontinued, leucovorin can be administered alone and the administration duration may 
be shortened to 15 min. See section 5.5 for levoleucovorin substitution. 
 
 
5.1.2 
mFOLFOX-6 
 
Doses should be based on actual body weight. Body surface area (BSA) will be 
calculated prior to each treatment cycle from body weight in kg, recorded up to 72 hrs 
prior to day 1 of each cycle, and height in cm, recorded at baseline. The formula for BSA 
calculation should remain consistent throughout treatment. Pre-medications should be 
administered per institutional practice. 


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5.1.3 
Dasatinib 
 
Dasatinib should be taken in the morning at approximately the same time every day. The 
medication may be taken with or without food. Patients should not consume greater than 
one 8 oz glass per day of grapefruit or pomegranate juice per day while taking dasatinib. 
Crushing or cutting dasatinib is prohibited. If vomiting occurs, the dose should not be 
replaced. Short-acting antacid agents may be taken, but it is recommended that these not 
be taken from 2 hours before to 2 hours after dosing of dasatinib. 
 
On days of chemotherapy administration, dasitinib should be taken at least 3 hours prior 
to chemotherapy, even if this represents a time different from the patient’s usual 
administration time. Please note, there is no dose adjustment for BSA. 
 
5.1.4 
Supportive Care 
 
All supportive measures consistent with optimal patient care will be given throughout the 
study. 
 
Nausea: Antiemetics should be administered per institutional guidelines. 
 
Diarrhea: Patients should be provided with instructions on use of loperamide 
(Imodium) in the event of diarrhea, as well as instructions to contact the treating 
physician. Other anti-diarrheals are also allowed. Patients should be given mouth 
care instructions per institutional guidelines. 
 
Neutropenia: Prophylactic use of G-CSF or Peg-G-CSF is not permitted. Please 
refer to table 5.5.2 for neutropenia adverse event guidelines. When needed, either 
G-CSF 5mcg/kg/dose (total dose rounded per institutional guidelines) SQ on days 
4-10 of each cycle or Peg-G-CSF 6mg SQ on day 4 of each cycle are acceptable 
options. 
 
Peripheral Nerve Cold Hypersensitivity: When appropriate, intravenous calcium 
gluconate plus magnesium sulfate, may be administered immediately before and 
after each dose of oxaliplatin per institutional protocol (see table 5.5.3 for details). 
 
Infusional Hypersensitivity: Platinum hypersensitivity can cause dyspnea, 
bronchospasm, itching and hypoxia. Appropriate treatment includes supplemental 
oxygen, steroids, antihistamines and epinephrine; bronchodilators and 
vasopressors may be required. Platinum hypersensitivity is an extremely rare 
event (approximately 0.5% of patients) and should be treated promptly. 
 
Pharyngo-laryngeal Dysesthesias: Oxaliplatin may cause discomfort in the larynx 
or pharnyx associated with dyspnea, anxiety and/or swallowing difficulty and is 
exacerbated by cold. Appropriate therapy includes use of anxiolytics and cold 
avoidance. If grade 1 (mild) pharyngo-laryngeal dysesthesias occurs while 
treatment is being administered, increase the duration of infusion to 6 hours. If 
grade 2 (moderate) or grade 3 (severe) pharyngo-laryngeal dysesthesias occurs 
during treatment administration, stop oxaliplatin infusion, administer 
benzodiazepine, reassure the patient and monitor. At the discretion of the 


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investigator, the infusion may be re-started at 1/3 original infusion rate. Increased 
duration of infusions is not required for subsequent treatment administration. 
 
Inflammation: Signs of inflammation, including pneumonitis, colitis, or skin rash, 
have been observed during dasatinib therapy. During interruption and short-term 
steroid treatment (i.e. 5-7 days methylprednisolone with rapid taper) may be 
appropriate. Concurrent antibiotics are appropriate if there is a clinical suspicion 
for infection. 
 
Fluid Retention: Fluid retention, commonly including pleural effusion, has been 
noted during treatment with dasatinib. Early institution of diuresis is appropriate 
(i.e. furosemide 20-40 mg, PO, daily, and/or spirinolactone 25-50 mg, PO, daily 
with titration to symptoms). Pleural effusions that remain or become 
symptomatic despite dieresis should be managed with thoracentesis. Steroid may 
also be effective for pleural effusion. Chest discomfort may be related to a 
pericardial effusion; an echocardiogram should be performed to investigate this 
side effect, at the discretion of the treating physician. 
 
See also additional details in Section 5.7.3. 
 
5.2 
Dasatinib 
5.2.1 
Identification 
 
Dasatinib will be provided in 2 different strengths for this trial: 
 
Table 5.1.1: 
Description of Dasatinib Dosage Forms 
Strength 
Description 
20 mg 
white to off-white, biconvex, round, film coated tablet with either “20” 
or “BMS” debossed on one side and “527” on the other side 
50 mg 
white to off-white, biconvex, oval, film coated tablet with either “50” or 
“BMS” debossed on one side and “528” on the other side 
 
 
5.2.2 
Packaging and Labeling 
 
Dasatinib is supplied as 5 mg, 20 mg, and 50 mg film-coated tablets containing dasatinib 
with lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, 
hydroxypropyl cellulose, and magnesium stearate. The tablet coating contains 
hydroxypropyl methylcellulose, titanium dioxide, and polyethylene glycol (triacetin in 
the 5 mg film-coated tablet). Tablets for clinical studies are supplied in high-density 
polyethylene bottles containing a desiccant and cotton. The bottles are heat-induction 
sealed with child resistant caps. 
 
Each bottle is labeled in an open label manner. Labels contain, at a minimum, the 


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following information: product name, tablet strength, batch number, directions for use, 
storage conditions, and appropriate caution statements. 
 
5.2.3 
Storage, Handling, and Dispensing 
 
5.2.3.1 
Storage 
 
Bottles containing dasatinib tablets should be stored at 15° - 25°C. 
 
All investigational product should be stored in a secure area according to local 
regulations. The investigator is responsible for ensuring that it is dispensed only to study 
subjects and only from official study sites by authorized personnel, as dictated by local 
regulations. 
 
The investigator is responsible for ensuring that the investigational product is stored 
under the appropriate environmental conditions (temperature, light, and humidity. 
 
If concerns regarding the quality or appearance of the investigational product arise, do 
not dispense the investigational product, and contact BMS immediately. 
 
5.2.3.2 
Handling and Dispensing 
 
Procedures for proper handling and disposal of anticancer drugs should be considered. 
 
Dasatinib tablets consist of a core tablet (containing the active drug substance), 
surrounded by a film coating to prevent exposure of pharmacy and clinical personnel to 
the active drug substance. If tablets are crushed or broken, pharmacy and clinical 
personnel should wear disposable chemotherapy gloves. Personnel who are pregnant 
should avoid exposure to crushed and/or broken tablets. 
 
The Investigator (or assigned designee, i.e., study pharmacist) will dispense the proper 
number of each strength tablet to the subject to satisfy dosing requirements for the study. 
The containers provided to the subject should be labeled with proper instructions for use. 
The lot numbers, dosing start dates and the number of tablets for each dosage strength 
must be recorded on the drug accountability pages of record for the site. The subject must 
be instructed to return all unused dasatinib in the provided packaging at each subsequent 
visit. 
 
5.3 
Drug Ordering and Accountability 
5.3.1 
Initial Orders 
 
Initial Orders of dasatinib should be requested by completing the Dasatinib (Sprycel®) 
Drug Supply Form for Investigator Sponsored Studies and submitting the request form 
electronically via e-mail at least 5-7 business days before the expected delivery date. 
Deliveries will be made Tuesday through Friday. 
 
Initial drug supply will be provided for a 12-week treatment period per subject. 


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5.3.2 
Re-Supply 
 
Re-supply requests should be sent to srcsupply@bms.com. 
 
Please check “Re-supply” on the drug supply form. Re-supply requests should be 
submitted at least 5-7 business days before the expected delivery date. Deliveries will be 
made Tuesday through Friday. 
 
5.3.3 
Drug Accountability 
 
Please refer to Section 9.2 for drug accountability requirements. 
 
5.3.4 
IND Status 
 
The use of Dasatinib in this trial is classified as “off-label” or approved use of FDA- 
approved drugs. When a drug or combination of drugs used in an off-label manner as part 
of a clinical trial, it is, by rule, considered as an investigational treatment regimen. 
However, while these treatment regimens are not approved by the FDA, their use is 
exempt from the requirements for an IND to conduct this study as defined under Title 21 
CFR 312.2(b) of the codified FDA regulations. 
 
5.4 
Method of Assigning Subjects to a Treatment 
This is a single arm phase II study where all subjects receive the same treatment. 
 
5.5 
Dose Modifications 
All toxicities should be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0. 
 
Dose modifications are based on dose level administered on the last treatment day. Dose 
adjustments of each agent may be made independently based on the specific types of 
toxicities observed. If oxaliplatin is discontinued due to toxicity dasatinib, 5-FU and LV 
may be continued. If dasatinib is discontinued due to toxicity oxaliplatin, 5-FU and LV 
may be continued. If more than two dose reductions are required for 5-FU/LV, the 
patient must discontinue protocol therapy. In general, a dose reduction of 5-FU is always 
associated with an equal dose reduction of LV, except in the setting of a LV-specific AE. 
Levoleucovorin can be substituted for LV, with the appropriate pharmacologic equivalent 
dose (ie, 50%), at the discretion of the treating physician. If treatment is held for greater 
than 2 cycles (28 days) the patient must discontinue protocol therapy, unless otherwise 
approved by the Principal Investigator. 
 
If criteria for treatment discontinuation is met, but the treating oncologist feels that it is in 
the best interest of the patient to receive additional therapy (for example, if the patient has 


32 
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demonstrated a response to therapy), additional therapy may only be given after 
discussion with the Principal Investigator following a resolution of the toxicity to Grade 1 
or to baseline level. 
 
If a dasatinib dose is not taken due to an error, it may be taken up to 12 hours later. If 
vomiting occurs, the dose should not be replaced. 
 
If a dose level had been reduced due to toxicity, re-escalation is not permitted. 
5.5.1 
Dose Modification Table 
 
Agent 
Starting Dose 
Dose Level -1 
Dose Level -2 
Dasatinib 
150 mg 
120 mg 
100 mg* 
Oxaliplatin 
85 mg/m2 
65 mg/m2 
50 mg/m2 
Leucovorin 
400 mg/m2 
300 mg/m2 
200 mg/m2 
5-fluorouracil bolus 
400mg/m2 
300 mg/m2 
200 mg/m2 
5-fluorouracil 
infusion 
2400mg/m2 
1800 mg/m2 
1200 mg/m2 
* Additional dose reductions may be instituted at the Principal Investigator’s discretion for 
exceptional responders (subjects demonstrating stable disease at or beyond 32 weeks of 
treatment). Dose Level -3: 80mg. Dose Level -4: 60mg. 
5.5.2 
Dose Modifications Due to Combined Drug Toxicity 
 
Table 5.5.2: Dose Modifications for Associated Combined Toxicities 
Toxicity – NCI Grade 
(v.4) 
Suggested Dose Modification 
Hematologic 
Hold treatment and check weekly until ANC ≥ 1500/mm3. 
 
Upon recovery, initiate standard empiric therapy with colony stimulating 
factors to prevent recurrence on subsequent cycles. Resume treatment at 
same dose level. 
 
2nd occurrence - ↓ 5-FU/LV bolus one dose level 
 
3rd occurrence - ↓ 5-FU infusion one dose level 
 
4th occurrence - ↓ 5-FU/LV bolus and infusion a second dose level and 
oxaliplatin one dose level 
 
5th occurrence - discontinue protocol therapy 
Either GCSF or Peg-GCSF is permitted when appropriate (see Section 5.1.4). 
Neutrophils/ 
granulocytes 
Grade 3,4 
Thrombocytopenia 
Grade 2 (1st Event) 
Hold treatment and check weekly until platelets are ≥ 75,000/mm3. Resume 
treatment at same dose level. 
Grade 2 (2nd Event) 
Grade 3, 4 
Hold treatment and check weekly until platelets are ≥ 75,000/mm3. 
 
Upon recovery - ↓ oxaliplatin one dose level 
 
2nd occurrence - ↓ 5-FU/LV bolus one dose level 
 
3rd occurrence - ↓ oxaliplatin and 5-FU/LV bolus second dose level 


33 
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 
4th occurrence – discontinue 5-FU/LV bolus 
 
5th occurrence - ↓ dasatinib one dose level 
 
6th occurrence - discontinue protocol therapy 
Other hematologic toxicities do not require dose modification. However, red blood cell transfusion should be 
considered for hemoglobin < 8 g/dL or significant symptoms of anemia. 
Gastrointestinal 
Diarrhea or mucositis 
Grade 1 
For any GI toxicity, verify and provide supportive care as described in section 5.1.4 
Grade 2, 3 
Hold treatment until ≤ grade 1 
 
1st occurrence - ↓ 5-FU/LV bolus one dose level 
 
2nd occurrence - ↓ 5-FU/LV bolus second dose level and 5-FU infusion 
one dose level 
 
3rd occurrence - ↓ dasatinib one dose level 
 
4th occurrence - ↓ dasatinib second dose level 
 
5th occurrence - discontinue protocol therapy 
Hepatic 
Total bilirubin, AST, 
or Alk Phos 
Grade 3 
Hold treatment until ≤ grade 2 – provide/replace biliary stent if needed 
 
1st occurrence – resume at previous dose 
 
2nd occurrence - ↓ 5-FU/LV bolus and oxaliplatin one dose level 
 
3rd occurrence - ↓ 5-FU/LV bolus and oxaliplatin second dose level 
 
4th occurrence – discontinue protocol therapy 
Grade 4 
Discontinue protocol therapy. 
Fatigue 
Grade 3,4 
Hold treatment until ≤ grade 2 
 
1st occurrence - ↓ 5-FU/LV bolus one dose level 
 
2nd occurrence - ↓ 5-FU/LV bolus second dose level and 5-FU infusion one 
dose level 
 
3rd occurrence - ↓ dasatinib one dose level 
 
4th occurrence - ↓ dasatinib second dose level 
 
5th occurrence - discontinue protocol therapy 
Other Clinically 
Significant 
Toxicities* 
Grade 3 
Hold treatment until AE resolves to ≤ grade 1. Reduce suspected offending drug 
one dose level. 
 
2nd occurrence – suspected offending drug second dose level 
 
3rd occurrence – discontinue protocol therapy 
Grade 4 
Hold treatment until AE resolves to ≤ grade 1. Reduce suspected offending drug 
one dose level. 
 
2nd occurrence – discontinue protocol therapy 
* Determination of “clinically significant” AEs and “offending drug” is at the discretion of the treating 
physician. 


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5.5.3 
Dose Modifications due to Oxaliplatin Toxicity 
 
Dose modifications and delays due to single drug toxicities should follow the defined 
dose modifications as described in Table 5.5.1 as well as below. Descriptions of 
individual drug AEs are provided in more detail in the oxaliplatin package insert. 
 
Table 5.5.3: Dose Modifications for Oxaliplatin-specific Toxicities 
Suggested Dose Modifications for Oxaliplatin Toxicity 
Toxicity – NCI Grade (v.4) 
Duration of Event 
Persistent between 
cycles 
< 7 days 
> 7 days 
Neuropathies 
Grade 1: Paresthesias/ 
dysesthesias of short duration 
that resolve and do not 
interfere with function 
No change 
No change 
No change 
Grade 2: Paresthesias/ 
dysesthesias interfering with 
function, but not activities of 
daily living (ADL) 
No change 
1st time: ↓oxaliplatin one 
dose level 
2nd time: ↓oxaliplatin 
second dose level 
↓ oxaliplatin one 
dose level 
Grade 3: Paresthesias/ 
dysesthesias with pain or with 
functional impairment that 
also interfere with ADL 
1st time: ↓oxaliplatin one 
dose level 
2nd time: ↓oxaliplatin 
second dose level 
Discontinue oxaliplatin 
Discontinue 
oxaliplatin 
Grade 4: Persistent 
paresthesias/dysesthesias that 
are disabling or life- 
threatening 
Discontinue oxaliplatin 
Discontinue oxaliplatin 
Discontinue 
oxaliplatin 
Pharyngo-laryngeal 
dysesthesias 
Please refer to section 5.1.4 
Hypersensitivity reaction 
In the event of an acute oxaliplatin hypersensitivity reaction, the treating 
physician may attempt to administer subsequent oxaliplatin doses with steroid 
and antihistamine pre-medication, and lengthening of the oxaliplatin infusion 
time to 4-6 hours. Partial dose reduction in oxaliplatin is not undertaken for 
hypersensitivity reaction. In the event of a hypersensitivity reaction that the 
treating physician believes warrants discontinuation of oxaliplatin, the other 
agents should be continued without dose modification 
Pulmonary fibrosis 
Signs and symptoms associated with PF (cough, dyspnea, rales, hypoxia, 
tachypnea) should be investigated to rule out PF as their cause. If suspected, 
hold oxaliplatin until PF is ruled out or an alternate diagnosis is confirmed. 
Oxaliplatin may then be resumed at previous dose. If PF is confirmed, 
discontinue oxaliplatin. 
 
 
5.5.4 
Dose Modifications due to Dasatinib Toxicity 
 
Table 5.5.4: Dose Modifications for Dasatinib Toxicity 
Single Drug Clinically 
Significant Toxicities* 
Grade 3 
Hold treatment until AE resolves to ≤ grade 1. Reduce dasatinib one dose 
level. 


35 
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 
2nd occurrence – decrease dasatinib to the second dose level 
 
3rd occurrence – discontinue protocol therapy# 
Grade 4 
Hold treatment until AE resolves to ≤ grade 1. Reduce dasatinib one dose 
level. 
2nd occurrence – discontinue protocol therapy 
* Determination of “clinically significant” is at the discretion of the treating physician. 
# Exceptional responders (see section 5.5.1) may continue protocol therapy at the discretion of the Principal 
Investigator 
 
If clinically relevant pleural effusion is noted, confirm with imaging and consider 
thoracentesis. Initiation of methylprednisolone (Medrol Dose Pack™ or equivalent; 24mg 
PO daily x 1 followed by 20mg followed by 16mg followed by 12mg followed by 8mg 
followed by 4mg then done) with or without lasix is recommended. For symptomatic 
effusion, dasatinib requires treatment hold for a minimum of 2 days during initiation of 
steroid use, prior to dose reduction. 
 
Chest discomfort or dyspnea may also be related to pericardial effusion; an 
echocardiogram may be indicated. Dose reduction of dasatinib is required if fluid 
retention is severe or recurrent. 
 
5.5.5 
Myelosuppression 
 
See Table 5.5.2. 
 
5.5.6 
Non-hematological Adverse Events 
 
See above Tables 5.5.2, 5.5.3, and 5.5.4. 
 
See also supportive care guidelines for symptom management in Section 5.1.4. 
 
5.5.7 
Adverse Event Information 
 
For the most current safety updates, please refer to the current Prescribing Information 
for oxaliplatin, 5-fluorouracil and leucovorin. Please refer to section 1.7.3 and the most 
recent Investigator’s Brochure for more information on dasatinib. 
 
5.6 
Blinding/Unblinding 
Not applicable to this protocol. 
 
5.7 
Concomitant Treatments 
5.7.1 
Prohibited and/or Restricted Treatments 
 
No other systemic therapy for treatment of pancreatic cancer is permitted while subject is 
on study. Concomitant palliative radiotherapy is not permitted for disease progression on 
treatment, but may be allowed for pre-existing non-target lesions with approval of BMS 


36 
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Medical Monitor. Bisphosphonate treatment may not be initiated during study; if already 
begun, it may be continued at Investigator discretion (see Sections 4.2.1). 
 
Subjects requiring any prohibited therapy should not be enrolled. If enrolled, the 
prohibited agent(s) will be withdrawn prior to first dose of study drug. 
 
5.7.1.1 
Potent CYP3A4 Inhibitors 
 
Dasatinib is primarily metabolized by the CYP3A4 enzyme. In drug-drug interaction 
studies, concomitant use of ketoconazole (a potent CYP3A4 inhibitor) produced an 
increase of > 5-fold in dasatinib exposure. Therefore, potent inhibitors of CYP3A4 are 
prohibited during study; for such medications, a wash-out period of ≥ 7 days is required 
prior to starting dasatinib. Subjects should be advised not to consume substantial 
quantities of grapefruit or pomegranate juice. (Less-potent inhibitors, inducers and 
substrates of CYP3A4 are restricted, see Section 5.7.2.1.) Most commonly-used potent 
CYP3A4 inhibitors are: 
• itraconazole, ketoconazole, miconazole, voriconazole; 
• amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir; 
• ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, imatinib, 
isoniazid, ketamine, nefazodone, nicardipine, propofol, quinidine, telithromycin. 
 
5.7.1.2 
Medications that prolong QT Interval 
 
Subjects enrolled in this study may not take concomitant medications known to prolong 
the QT interval (Class I; see http://www.qtdrugs.org/medical-pros/drug-lists/drug- 
lists.htm). For such medications, a wash-out period of ≥ 7 days is required prior to 
starting dasatinib. Agents which possibly prolong the QT interval are restricted; see 
Section 5.7.2.2. Medications known to prolong the QT interval are: 
• 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. 
5.7.2 
Other Restrictions and Precautions 
 
The following restricted therapies are not recommended, but are permitted with caution 
when clearly medically indicated. 
 
5.7.2.1 
CYP3A4 Inducers, Inhibitors, Substrates 
 
Drugs that induce CYP3A4 activity may decrease dasatinib plasma concentrations. In 
subjects in whom enzyme-inducing anticonvulsants (eg, phenytoin, carbamazepine, 
phenobarbital) are used, alternative agents with lesser enzyme-induction potential should 
be considered. 
 
Dasatinib is predominantly metabolized by the CYP3A4 isoenzyme. Potent inhibitors are 
prohibited, but less-potent inhibitors may also increase exposure to dasatinib. If 


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administration of a CYP3A4 inhibitor cannot be avoided in subjects receiving dasatinib, 
close monitoring for toxicity and dasatinib dose reduction should be considered. Subjects 
should be advised not to consume substantial quantities of grapefruit or pomegranate 
juice. 
 
Other 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 subjects receiving dasatinib. Note: subjects treated with a fentanyl patch 
are eligible for this trial. 
 
As warfarin is metabolized through the CYP450 system, therapeutic anticoagulation with 
warfarin (eg, Coumadin or Cournadine) is not recommended. As an alternative, 
therapeutic anticoagulation may be accomplished using low-molecular weight heparin 
(eg, Lovenox) or heparin. Mini Dose Coumadin (eg, 1 mg QD) is permitted for 
prophylaxis of central venous catheter thrombosis. 
 
5.7.2.2 
Medications that may Prolong QT Interval 
 
Concomitant medications known to prolong the QT interval are prohibited 
(Section 5.7.1); medications which may possibly prolong the QT interval (non-Class I; 
see http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm) are restricted. Should 
the Investigator believe that beginning therapy with a potentially QT-prolonging 
medication (other than those prohibited) is vital to an individual subject’s care, the 
Investigator must check that the prior on-therapy ECG does not show QTc ≥ 475 msec or 
an increase in QTc ≥ 60 msec over the baseline value. 
 
5.7.2.3 
Antacids 
 
Nonclinical data demonstrate that the solubility of dasatinib is pH dependent and a 
clinical study has shown that dasatinib exposure is substantially and durably reduced after 
treatment with famotidine. Administration of dasatinib with H2 inhibitors or proton pump 
inhibitors should therefore be avoided. If antacid therapy is needed, a locally-acting 
antacid may be used, and should be administered at least 2 hours before or after the dose 
of dasatinib. 
 
5.7.2.4 
St. John's Wort (Hypericum perforatum) 
 
Data suggests that St. John’s Wort may decrease dasatinib plasma concentrations 
unpredictably. Subjects receiving dasatinib should not take St. John's Wort. Subjects 
should discontinue St. John’s Wort at least 5 days before starting dasatinib. 
 
5.7.2.5 
Medications that Inhibit Platelet Function and Anticoagulants 
 
Src-family kinase inhibition potentially reduces platelet aggregation. Caution should thus 
be exercised if subjects are required to take medications that inhibit platelet function or 
anticoagulants. Such medications include: 


38 
V6.0; 07/26/2018 
 
• aspirin or aspirin-containing combinations, clopidogrel, dipyridamole 
• tirofiban, dipyridamole, epoprostenol, eptifibatide, cilostazol, abciximab, 
ticlopidine, cilostazol 
• warfarin, heparin/low molecular weight heparin [eg, danaparoid, dalteparin, 
tinzaparin, enoxaparin] 
• exceptions are low-dose warfarin for prophylaxis to prevent catheter thrombosis 
and heparin for flushes of intravenous lines. 
 
5.7.2.6 
Bisphosphonates 
 
Subjects who had been receiving bisphosphonates prior to study entry may continue on 
therapy with caution. Bisphosphonates should be temporarily discontinued during the 
first 8 weeks of protocol therapy however they may be resumed after that time at the 
discretion of the treating physician. Please refer to section 4.2.1 for protocol required 
treatment modifications. Although concomitant use of bisphosphonates is not 
recommended, clinically-significant hypocalcemia has been uncommon. Oral serum 
calcium (Ca+2) supplementation, including Vitamin D if appropriate, is warranted. 
 
5.7.3 
Additional Supportive Care Guidance for Dasatinib 
 
Supportive care, especially pain control, will be optimized in all subjects. Guidance is 
provided for management of common side effects of dasatinib in order to maximize 
opportunity for benefit. Investigators are strongly urged to discuss with Medical Monitor 
and/or the Principal Investigator prior to discontinuing study treatment for reasons other 
than radiographic PD. 
 
Non-hematologic side effects are typically CTCAE v4.0 Grade 1 - 2. Interruption and/or 
dose reduction may be necessary, especially if Grade ≥ 2. Usual supportive care measures 
should be used for nausea/emesis, diarrhea, pain, fever or headache. Neither clinically 
significant myelosuppression nor use of hematopoietic growth factors is expected. 
 
Osteoclast inhibition is expected; therefore, calcium supplementation (eg, calcium 
carbonate 500 mg PO TID) may be warranted to maintain serum Ca+2 above LLN during 
dasatinib treatment. Vitamin D supplementation (eg, ergocalciferol 400 IU PO QD) may 
be appropriate for persistent hypocalcemia. Bisphosphonate therapy should be deferred in 
the presence of hypocalcemia. 
 
Fluid retention, including clinically-significant pleural effusion, has been observed during 
dasatinib treatment. Refer to Section 5.1.4 for treatment recommendations. 
 
5.8 
Treatment Compliance 
Patients will be required to return all bottles of study medication at the beginning of each 
cycle. The number of tablets remaining should be documented and recorded on the Case 
Report Form. In addition, each patient will complete a dasatinib pill diary to document 
compliance with each cycle of therapy (see Appendix II). When possible, drug 
reconciliation will take place in the presence of the patient in order to account for 


39 
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possible discrepancies. Deviations from prescribed therapy will be recorded. Deviations 
greater than 10% from the expected dose (accounting for delays and dose modifications 
per protocol) will be considered deviations for IRB reporting purposes. 


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6 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Time and Events Schedule 
Table 6.1: Study Schedule and Procedures 
 
Evaluation 
Screeninga 
Treatment Phase (1 cycle = 14 days) 
Follow Up 
Before each cycle 
Every fourth cycle 
End of treatment 
History & Physical 
X 
X 
X 
Xk 
Performance Status 
X 
X 
X 
Vital Signsb 
X 
X 
X 
AE Assessment 
X 
X 
X 
Xl 
ECG 
Xc 
Xc 
Drug Dispensation 
Xd 
Pregnancy testa 
X 
CMPe,f 
X 
X 
X 
CBC w/Diffe 
X 
X 
X 
PT/INRg 
X 
CA19-9e 
X 
X 
CT or MRIh 
X 
X 
X 
QOL questionnaires 
Xi 
Xi 
Xi 
Research Blood 
Collection 
Xj 
Xj 
X 
FFPE Tumor Block 
Retrieval 
X 
Survival Status 
Xm 
a. 
All screening procedures should be completed within 28 days of treatment except for serum pregnancy testing 
which should be completed within 7 days of treatment. History & Physical, Vital Signs, ECOG PS, CMP, CBC w 
Diff and CA19-9 are not required to be repeated at treatment initiation if they were completed within 7 days prior 
to Cycle 1 Day 1. 
b. 
Vital signs include height, weight, blood pressure, pulse, temperature and pain level (subjective 1-10 self-reported 
scale). Height should be obtained at screening only. 
c. 
ECGs will be obtained at screening as well as prior to cycle #3 (day 28; +/- 7 days). Patients who are placed on QT 
prolonging medications while on study should have ECGs performed at regular intervals (interval timing is at the 
discretion of the treating investigator). 
d. 
Only enough dasatinib for 2 cycles of therapy (28 days) may be given to a patient prior to reassessment. 
e. 
Laboratory testing may be performed up to 72 hours prior to day 1 of the next cycle of therapy. 
f. 
CMP: Na, K, Cl, CO2, Glucose, BUN, Creatinine, Ca, Albumin, Total Bilirubin, Alk Phos, Total Protein, AST, 
ALT. 
g. 
PT/INR should be followed closely for patients on warfarin. 
h. 
CT of the chest, abdomen and pelvis or CT of the chest and MRI of the abdomen and pelvis are allowed. 
Consistent imaging modality should be used throughout the study. Imaging should be performed every 8 weeks 
(+/- 7 days) until disease progression. 
i. 
FACT-Hep should be completed at screening, every fourth cycle starting at cycle 5, and at EOT. CTSQ should be 
completed at C2, every fourth cycle starting at cycle 5, and at EOT. 
j. 
Baseline blood sample will be collected prior to first dose of therapy administered. Additional blood samples will 
be collected at completion of cycle 1 infusional 5-FU (day 3; cycle 1 only), day 1 of every cycle starting with cycle 
2, and at EOT. Reasonable efforts to obtain the C1D3 sample will be made however collection is optional. Red, 
green top and cell prep tubes will be collected at all time points. EDTA tubes will be collected once, preferably at 
screening. 
k. 
H&P is required at 30 days (+ 7 days) following the last dose of study drug. Additional H&Ps are required as 
needed to follow ongoing AEs. 
l. 
Adverse events should be followed for 30 days after the last dose of protocol therapy or until the initiation of 
subsequent treatment. AEs continuing > 30 days should be monitored until resolution. 
m. Patients or providers should be contacted every 8 weeks to assess survival status and subsequent therapies. 


41 
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6.2 
Study Materials 
Bristol-Myers Squibb (BMS) will provide dasatinib at no cost for this study. Oxaliplatin, 
5-fluorouracil and leucovorin will be obtained from commercial supply and will be billed 
to the patient or patient’s insurance. 
 
6.3 
Safety Assessments 
Subjects must undergo a history and physical examination by a licensed provider at the 
beginning of each treatment cycle. Vital signs and AE assessments should be done 
concurrently with the H&P. 
 
Laboratory testing should be completed as outlined in the study schedule and procedures 
table as outlined above. Additional laboratory testing may be done at the Investigator’s 
discretion. 
 
An ECG is required pre-treatment (baseline) and prior to cycle 3 (day 28). Additional 
ECGs may be done at the Investigator’s discretion to ensure the subject’s safety. 
Concomitant medications should be monitored by the Investigator. In the event the 
subject undergoes an on-study drug treatment modification with a potentially QT 
prolonging medication, ECGs should occur at regular intervals throughout treatment. 
 
 
6.4 
Efficacy Assessments 
6.4.1 
Tumor response 
 
Tumor response will be assessed using RECIST 1.159 criteria. 
Tumor measurement 
• Measurable disease: the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
• Measurable lesions: lesions that can be accurately measured in at least one 
dimension (the longest diameter), and with a minimum size of 10 mm by CT scan, 
or 10 mm by caliper measurement during clinical exam, or 20 mm by chest X-ray. 
− A malignant lymph node may be considered pathologically enlarged and 
measurable if it is ≥ 15 mm in short axis by CT scan. 
− A lytic or mixed blastic-lytic bone lesion, with identifiable soft tissue 
component which is evaluable by CT or MRI, may be considered as measurable 
lesion if the soft tissue component meets the criteria for measurable lesions. 
− Cystic metastases may be considered as measurable lesions if they meet the 
criteria for measurable lesions, however, non-cystic lesions, if present, are 
preferred as target lesions. 


42 
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− Tumor lesions in an area previously subjected to loco-regional treatment, may 
be considered measurable if there has been demonstrated progression. 
• Non-measurable lesions: all other lesions, including simple cysts, small lesions 
(longest diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short 
axis) and other truly non-measurable lesions. These include: leptomeningeal 
disease; ascites; pleural/pericardial effusion; inflammatory breast disease; 
lymphangitis cutis/pulmonis; abdominal masses that are not measurable by 
reproducible imaging techniques; blastic bone lesions. 
 
All measurements should be recorded in metric notation, using a ruler or calipers. All 
baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. 
 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes), and ≥ 10 mm diameter using calipers. For the case of 
skin lesions, documentation by color photography including a ruler to estimate the size of 
the lesions is recommended. Whenever possible, imaging evaluation should be preferred 
over clinical exam. 
 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint. The measurability of lesion by CT scan is based on the assumption that CT 
slice thickness is ≤ 5 mm. 
 
Baseline documentation of target and non-target lesions 
• When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions and 
recorded and measured at baseline. 
• Target lesions should be selected on the basis of their size (lesions with the longer 
diameter) and their suitability for accurate repetitive measurements (either by 
imaging techniques or clinically). 
• A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters. 
The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
• All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as ‘present’ 
‘absent’, or in rare cases ‘unequivocal progression’. Multiple non-target lesions 
involving the same organ may be recorded as a single item. 
 
Response criteria 


43 
V6.0; 07/26/2018 
 
Evaluation of target lesions 
• Complete Response (CR): disappearance of all target lesions. Any pathological 
lymph nodes must have reduction in short axis to < 10 mm. 
• Partial Response (PR): at least a 30% decrease in the sum of diameters of the target 
lesions taking as reference the baseline sum diameters. 
• Progression (PD): at least a 20% increase in the sum of diameters of the target 
lesions taking as reference the smallest sum on study, and an absolute increase of at 
least 5 mm. The appearance of one or more new lesions is also considered 
progression. 
• Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum diameters while on 
the study. 
Evaluation of non-target lesions 
• Complete Response (CR): disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological (< 10 mm short 
axis). 
• Non-complete response (non-CR)/non-progression (non-PD): persistence of one or 
more non-target lesion(s) or/and maintenance of tumor marker level above the 
normal limits. 
• Progressive disease (PD): unequivocal appearance of one or more new malignant 
lesions. Unequivocal progression of existing non-target lesions. Although a clear 
progression of non-target lesions only is exceptional, in such circumstances, the 
opinion of the treating physician should prevail and the progression status should be 
confirmed later on by a review panel (or study chair/primary investigator). 
Evaluation of best overall response 
• The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). In general, 
the patient’s best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
• Table 6.4.1 provides a summary of the overall response status calculation at each 
time point for patients who have measurable disease at baseline. When patients have 
non-measurable (therefore non-target) disease only, Table 6.4.2 should be used. 
 
Table 6.4.1: 
Evaluation of Best Overall Response: Patients with Target 
Disease, with or without Non-target Disease 
Target Lesion 
Non-target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
PR 
Non-PD or not at all evaluate 
No 
PR 
SD 
Non-PD or not at all evaluated 
No 
SD 


44 
V6.0; 07/26/2018 
 
Table 6.4.1: 
Evaluation of Best Overall Response: Patients with Target 
Disease, with or without Non-target Disease 
 
Target Lesion 
Non-target Lesions 
New Lesions 
Overall 
Response 
Not at all evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
 
Table 6.4.2: 
Evaluation of Best Overall Response: Patients with Non-target 
Disease Only 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/ non-PD 
No 
a 
Non-CR/ non-PD 
Not all evaluated 
No 
Inevaluable 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised. 
 
 
• When nodal disease is included in the sum of target lesions and the nodes decrease 
to ‘normal’ size (<10 mm), they may still have a measurement reported on scans. 
This measurement should be recorded even though the nodes are normal in order 
not to overstate progression should it be based on increase in size of the nodes. 
• Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to  document 
the objective progression even after discontinuation of treatment. 
• In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends upon this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) before confirming the complete response status. FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in  cases 
where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. 
• For equivocal findings of progression (e.g. very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment. If at the next scheduled assessment, progression is 


45 
V6.0; 07/26/2018 
 
confirmed, the date of progression should be the earlier date when progression was 
suspected. 
Confirmation 
• In non-randomized trials where response is the primary endpoint, confirmation of 
PR or CR must be confirmed by repeat measurements that should be performed no 
less than 4 weeks after the criteria for response are first met. 
• In randomized trials or studies where the primary endpoints are stable disease or 
progression, confirmation of response is not required. Elimination of the 
requirement for response confirmation may increase the importance of central 
review to protect against bias, particularly in studies which are not blinded. 
• In the case of SD, follow-up measurements must have met the SD criteria at least 
once after study entry at a minimum interval of 6-8 weeks. 
 
6.4.2 
Primary Efficacy Assessment 
 
Determine activity of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus 
dasatinib on progression free survival (PFS) in patients with metastatic pancreatic 
adenocarcinoma. 
 
6.4.3 
Secondary Efficacy Assessments 
 
Determine the radiographic response rate by RECIST 1.1 criteria, the rate of freedom 
from metastasis (FFM), the time to progression (TTP), the overall survival (OS), the 
clinical benefit rate (CBR), the site of failure of this regimen in this population, the safety 
profile and tolerability of this regimen in this population, the patient compliance with oral 
therapy, and the quality of life (QOL) of patients receiving this therapy. All radiographic 
images and responses will be reviewed and confirmed by a 3rd party investigator- 
independent radiographic review. 
 
Quality of life and Satisfaction measurements will be collected and recorded by patients 
(see Appendix III) with subsequent analysis performed on all patients. Specifically, the 
Cancer Quality Satisfaction Survey (CTSQ, 2007)60 and the FACT-Hep (Functional 
Assessment of Chronic Illness Therapy; Hepatobiliary Cancer - Version 4.0) 61 will be 
employed as previously validated patient self-reporting tools in this population of 
patients. Analysis will be undertaken in consultation with cancer behavioral scientists. 
 
Additional exploratory tissue and serum correlative analyses in this population receiving 
this regimen are further detailed in Section 6.5 
. 
6.5 
Other Assessments 
The correlative science goal is to identify biomarkers predictive of response, ideally from 
analysis of the serum or more likely via molecular analysis of the neoplasm. We plan to 
collect blood products for the following purposes: 1) serially collected blood specimens 
to measure alterations in circulating factors during therapy, identify potential non- 
invasive biomarkers of Src inhibition, and to assess correlations with outcome; and 2) 


46 
V6.0; 07/26/2018 
 
DNA to identify relevant pharmacogenetic markers. Biospecimens will be banked and 
stored until funding can be secured from the industry sponsor of the trial and/or other 
sources. Approximately 40mL of whole blood will be collected and processed for future 
use at study enrollment as well as periodically throughout the period of active study 
participation. An additional 20mL of whole blood will be collected at one time point 
during the study, preferably screening, for genomic analysis (see Table 6.1). 
 
Extracted mononuclear cells will be analyzed with regard to thymidylate synthase (TS) 
expression and correlated with tissue/tumor expression. Src levels and downstream 
targets in mononuclear cells will also be analyzed to document inhibition during 
treatment. Blood will be analyzed for specific pathway molecules see below, evidence of 
tumor injury, and predictive factors which may correlate to therapeutic outcomes or 
target selection, including plasma deoxyuridine levels as an indirect measure of TS 
inhibition. Additional molecular or chemical analyses may also be undertaken either 
during the study progress or in a post-hoc fashion, including assessment of circulating 
tumor cells. 
 
Previously obtained and stored individual patient tumor samples will be requested and 
retrieved. Specifically, formalin fixed paraffin-embedded (FFPE) tissue will be sought. 
No additional biopsies are required as part of this protocol, however, if biopsies are 
obtained for clinical reasons, submission of this tissue block for analysis is included in 
the standard protocol consent document and is required. Subsequent molecular or 
genomic analyses may also be undertaken either during the study progress or in a post- 
hoc fashion (see below). 
 
All collected tissue will undergo immunohistochemical (IHC) analysis of expression and 
when relevant, phosphorylation status for  c-Src , thymidylate synthase (TS), 
ribonuclease reductase (RNR), dihidrofolate reductase (DHFR), integrins, EGFR, AKT, 
STAT, MET, FAK, HIF, and TRAIL pathway molecules. Additional molecules may also 
be examined either during the study progress or in a post-hoc fashion pending novel 
discoveries. When adequate sample is available, mutational analysis of k-ras and b-raf 
will be performed. While beyond feasible scope at this time, high quality microRNA 
should be extractable from these specimens, and microarray expression patterns with 
confirmatory PCR of relevant MiRNAs of interest may be analyzed in the future. 
 
Collection, handling and storage of whole blood specimens: 
1. Fill serum separator tubes (red top, approximately 20mL total), 
plasma separator tubes (sodium heparin green top, 10mL total), 
cell prep tubes (sodium heparin green/red top, 16mL total), and 
EDTA tubes (purple top, 20mL total) completely 
2. Do not spin or manipulate the green top or cell prep tubes other 
than ensuring good distribution in the tube 
3. Transfer green top and cell prep tubes to lab immediately for 
further processing 
4. Red top and EDTA tubes will be processed and stored per CTSI 
guidelines 


47 
V6.0; 07/26/2018 
 
7 
ADVERSE EVENT REPORTING 
7.1 
Adverse Events 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a pre-existing medical condition in a patient or clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product. 
 
7.1.1 
Serious Adverse Events 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see note below for exceptions) 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is an important medical event, defined as a medical event that may not be 
immediately life-threatening or result in death or hospitalization but, based on 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention (eg, medical, surgical) to prevent one of the other serious 
outcomes listed above. Examples of such events include but are not limited to 
intensive treatment in an emergency department or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization. 
 
All pregnancies, regardless of outcome, must be reported to BMS, including 
pregnancies that occur in the female partner of a male study subject. All 
pregnancies must be followed to outcome. See Section 7.6 for instructions on reporting 
pregnancies. 
 
Although overdose and cancer are not always serious by regulatory definition, these 
events should also be reported to BMS in an expedited manner, as described in 
Section 7.2. 
 
NOTE: The following hospitalizations are not considered SAEs in BMS clinical studies: 
• a visit to the emergency room or other hospital department lasting less than 
24 hours that does not result in admission (unless considered an “important 
medical event” or a life-threatening event) 
• elective surgery planned before signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health 


48 
V6.0; 07/26/2018 
 
status (eg, routine colonoscopy) 
• medical/surgical admission for purpose other than remedying ill health state that 
was planned before study entry. Appropriate documentation is required in these 
cases. 
• admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative). 
 
7.1.2 
Nonserious Adverse Events 
 
Nonserious adverse events are all adverse events that are not classified as SAEs. 
 
7.2 
Assignment of Adverse Event Intensity and 
Relationship to Investigational Product 
All adverse events, including those that are serious, will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE), Version 4.0. 
 
The following categories and definitions of causal relationship to investigational product 
as determined by a physician should be used: 
• Related: There is a reasonable causal relationship to investigational product 
administration and the adverse event. 
• Not Related: There is not a reasonable causal relationship to investigational 
product administration and the adverse event. 
 
The expression “reasonable causal relationship” is meant to convey in general that there 
are facts (eg, evidence such as de-challenge/re-challenge) or other arguments to suggest a 
positive causal relationship. 
 
7.3 
Collection and Reporting 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. To prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more adverse events. 
 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather 
than its individual symptoms. The following information should be captured for all AEs: 
onset, duration, intensity, seriousness, relationship to investigational product, action 
taken, and treatment required. If treatment for the event was administered, it should be 
recorded in the medical record. The investigator must supply BMS and the IRB/IEC with 
any additional information requested, notably for reported deaths of subjects. 
 
7.3.1 
Serious Adverse Events 
 
Following the subject’s written consent to participate in the study, all SAEs must be 
collected, including those thought to be associated with protocol-specified procedures. 


49 
V6.0; 07/26/2018 
 
Collection of all SAEs must continue for 30 days after the last administration of the 
investigational product. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy). The investigator should notify 
BMS of any SAE occurring after this time period that is believed to be related to the 
investigational product or protocol-specified procedure. 
 
All SAEs, whether considered related or unrelated to dasatinib, must be reported to BMS 
(by the investigator or designee) within 24 hours of study personnel becoming aware of 
the event. If only limited information is initially available, follow-up reports are required. 
The original SAE form must be kept on file at the study site. 
 
All SAEs should be faxed or emailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the Food and Drug Administration (FDA) as soon as 
possible and no later than 7 days (for a death or life-threatening event) or 15 days (for 
all other SAEs) after the investigator’s or institution’s initial receipt of the 
information. BMS will be provided with a simultaneous copy of all adverse events filed 
with the FDA. SAEs should be reported on 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 BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
If the investigator believes that an SAE is not related to the investigational product but is 
potentially related to the conditions of the study (such as withdrawal of previous therapy, 
or a complication of a study procedure), the potential relationship should be specified in 
the narrative section of the SAE report. 
 
If an ongoing SAE changes in its intensity or relationship to the investigational product, a 
follow-up SAE report should be sent within 24 hours to BMS. As follow-up information 
becomes available it should be sent within 24 hours using the same procedure used for 
transmitting the initial SAE report. All SAEs should be followed to resolution or 
stabilization. 


50 
V6.0; 07/26/2018 
 
7.3.2 
Handling of Expedited Safety Reports 
 
In accordance with local regulations, BMS will notify investigators of all SAEs that are 
suspected (related to the investigational product) and unexpected (ie, not previously 
described in the Investigator Brochure). In the European Union, an event meeting these 
criteria is termed a Suspected Unexpected Serious Adverse Reaction (SUSAR). BMS will 
send investigators an expedited safety report (ESR) to notify them of such an event. 
 
Other important findings that BMS may report as ESRs include increased frequency of a 
clinically significant expected SAE, an SAE considered associated with study procedures 
that could modify the conduct of the study, lack of efficacy that poses significant hazard 
to study subjects, clinically significant safety findings from a nonclinical (eg, animal) 
study, important safety recommendations from a study data monitoring committee, or the 
decision by BMS to end or temporarily halt a clinical study for safety reasons. 
 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with 
the Investigator Brochure. Where required by local regulations or when there is a central 
IRB/IEC for the study, BMS will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. When 
BMS has a written agreement with a local IRB/IEC, BMS will directly submit ESR(s). 
The investigator should also comply with the IRB/IEC procedures for reporting any other 
safety information. 
 
In addition, BMS will report suspected serious adverse reactions (whether expected or 
unexpected) to the relevant health authorities in all concerned countries according to local 
regulations (either as expedited and/or in aggregate reports). 
7.3.3 
Nonserious Adverse Events 
 
The investigator will begin collecting nonserious adverse event (NSAE) information once 
administration of the investigational product is initiated. This NSAE information should 
also be collected from the start of a placebo lead-in period or other observational period 
intended to establish a baseline status for the subjects. 
 
All identified NSAEs must be recorded and described in the medical record. If an 
ongoing NSAE worsens in its intensity, or if its relationship to the investigational product 
changes, a new NSAE entry for the event should be completed. NSAEs should be 
followed to resolution or stabilization, or reported as SAEs if they become serious. 
Follow-up is also required for NSAEs that cause interruption or discontinuation of 
investigational product, or those that are present at the end of study participation. 
Subjects with NSAEs at study completion should receive post-treatment follow-up as 
appropriate. 
 
7.4 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. In general, non-clinically significant laboratory deviations are 
not considered adverse events. Laboratory deviations which require treatment delay, 
modification or discontinuation or are otherwise clinically significant should be reported 
as adverse events. When reporting a test result that constitutes an adverse event, the 


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clinical term should be used; for example, the event should be reported as “anemia” not 
“low hemoglobin.” Test results that constitute SAEs should be documented and reported 
as such. 
 
7.5 
Overdose 
An overdose is defined as the accidental or intentional ingestion or infusion of any dose 
of a product that is considered both excessive and medically important. All occurrences 
of overdose must be reported as an SAE. 
 
7.6 
Pregnancy 
Sexually active WOCBP must use an effective method of birth control during the course 
of the study, in such a manner that the risk of failure is minimized. (See Section 4.2.1 for 
the definition of WOCBP.) Before enrolling WOCBP in this study, investigators must 
review the BMS-provided information about study participation for WOCBP. The topics 
include the following: 
• General Information 
• Informed Consent Form 
• Pregnancy Prevention Information Sheet 
• Drug Interactions with Hormonal Contraceptives 
• Contraceptives in Current Use 
• Guidelines for the Follow-up of a Reported Pregnancy. 
 
Before study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during study participation and of the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form documenting this discussion. 
 
7.6.1 
Requirements for Pregnancy Testing 
 
All WOCBP MUST have a negative pregnancy test within 7 days before receiving 
dasatinib. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent 
units of HCG. If the pregnancy test is positive, the subject must not receive dasatinib and 
must not continue in the study. 
 
In addition, all WOCBP must be instructed to contact the investigator and/or other 
study personnel immediately if they suspect they might be pregnant (eg, missed or 
late menstrual period) at any time during study participation. 
 
7.6.2 
Reporting of Pregnancy 
 
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 6 half-lives after administration, the investigational 
product will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for subject safety). The investigator must immediately notify BMS of this 
event and record the pregnancy on the Pregnancy Surveillance Form (not on an SAE 


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form). Initial information on a pregnancy must be reported immediately to BMS, and 
information on the outcome provided once it is available. Completed Pregnancy 
Surveillance Forms must be forwarded to BMS according to SAE reporting procedures. 
 
Note: Any pregnancy that occurs in a female partner of a male study subject must be 
reported to BMS using the Pregnancy Surveillance Form. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed 
for the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. Information regarding 
the course of the pregnancy, including perinatal and neonatal outcome, must be reported 
to BMS on the Pregnancy Surveillance Form. 
 
7.7 
Other Safety Considerations 
Any significant worsening of the subject’s condition noted during interim or final 
physical examinations, electrocardiograms, x-rays, and any other potential safety 
assessments, whether or not these procedures are required by the protocol, should also be 
recorded in the medical record. 
 
7.8 
Data Safety Monitoring Plan 
This protocol will adhere to the policies of the University of Florida Shands Cancer 
Center Data and Safety Monitoring Plan, in accordance with NCI regulations. The Data 
and Safety Monitoring Committee will review all serious adverse events and toxicity 
reports as well as annual reviews. The investigator will continuously monitor the 
progress of the study and the safety of the participants. All adverse events will be 
evaluated for causality and reported to the appropriate oversight committees as required. 
 
7.9 
Data Management System 
To provide data collection we will utilize the ONCORE database for both accrual entry 
and trial data management. ONCORE is a Clinical Trials Management System designed 
with the capability for: study setup, activation, tracking, reporting, data monitoring and 
review and eligibility verification. It is housed on secured servers maintained at the 
University of Florida Health Science Center on the University of Florida campus. The e- 
CRFs on ONCORE are 21 CFR part 11 compliant, and all users are assigned password 
protected user accounts. 
 
8 
STATISTICAL CONSIDERATIONS 
The primary statistical analysis will use the modified Intention-to-Treat (mITT) 
population consisting of patients who are enrolled and received any dose of study 
medication. The mITT population will be included in summary tables of patient 
demographics and disease characteristics, and in analysis of efficacy. 
 
Statistical analyses will be conducted by the study biostatistician using SAS v9.1 (SAS 


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institute, Cary, NC). 
 
Routine data listing or tabulation review during the study conduct will be performed to 
identify missing data, anomalies, outliers, etc. Missing data will generally not be 
imputed. Baseline is defined as the last non-missing measurement for a variable prior to 
the initial dose of any investigational product. 
 
Descriptive statistics will be provided to summarize demographic and baseline 
characteristic parameters. Categorical data will be summarized as frequency and its 
corresponding percentage. For continuous data, frequency (n), mean, standard deviation, 
median (as appropriate), minimum, and maximum will be provided for each parameter. 
 
8.1 
Sample Size Determination 
The sample size of 42 patients for this prospective non-randomized phase 2 study is 
based on the assumptions of a 30-month accrual period and a follow-up of 6 months after 
the last patient is enrolled. This sample size will allow detection of median PFS of 6 
months or greater with a 50% increase in comparison to historical controls (4 months), 
with a one-sided log-rank test at the 0.05 significance level and a power of 80%. At an 
attrition rate of 5%, 48 patients will be recruited. 
 
8.2 
Analysis of Primary Endpoint 
PFS is defined as the time from treatment start to the first of either (1) documented 
disease progression or (2) death as a result of any cause. Patients who did not progress 
nor die or are lost to follow-up will be censored at the day of their last objective tumor 
assessment. The Kaplan-Meier method will be used to estimate the median PFS time, 
together with a 95% confidence interval (CI). PFS will be determined by RECIST 
criteria. 
 
8.3 
Analysis of Secondary Endpoints 
 
The objective RR is equal to the proportion of patients achieving a best overall response 
of partial or complete response (CR + PR), according to RECIST from the start of the 
treatment until disease progression/recurrence. Clinical benefit rate is equal to the 
objective RR plus the proportion of patients attaining stable disease (CR + PR + SD). 
Patients who do not have a tumor response assessment for any reason will be considered 
nonresponders and will be included in the denominator when calculating the response 
rate. The number of patients achieving a response will be divided by the total of patients 
treated to yield the proportion responding. Exact confidence bounds (95% CI) will be 
calculated. 
 
Overall survival is defined as the time from the date of treatment start to the date of death 
from any cause. If the patient is alive at the end of the follow-up period or is lost to 
follow-up, OS will be censored on the last date the patient is known to be alive. OS will 
be evaluated by the Kaplan-Meier method and a 2-sided 95% CI will be provided for the 
median OS. 


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The time to progression (TTP) for responders only is measured from the time 
measurement criteria are first met for CR/PR (whichever is first recorded) until the first 
date that the criteria for PD are met, or death. TTP will be estimated with the Kaplan- 
Meier method; a 90% CI will be provided for the median TTP. Patients who do not 
relapse are censored at the day of their last objective tumor assessment. The freedom 
from metastasis rate is defined below and will be calculated based on an intention to treat 
principle. Determination of the anatomic site of first failure for patients with PD will be 
recorded and analyzed. Duration of response is also defined below. 
 
Proportion and exact confidence boundaries (95% CI) will be estimated for toxicity and 
compliance with oral therapy. Mean and 95% confidence interval will be estimated for 
quality of life (QOL). QOL measurements will be analyzed with regards to changes from 
baseline including total scores as well as subscores consistent with the previously 
validated instruments in use. 
 
8.4 
Analysis of Safety Data 
Safety analyses will be performed on all patients who receive any dose of study 
medication. Adverse events that occur more than 30 days after the administration of the 
last dose of treatment will not be included. 
 
The safety and tolerability of study drug is determined by reported AEs, physical 
examinations, laboratory tests, and ECGs. All patients will be assessed regularly for 
potential occurrence of AEs from the time that treatment starts until 30 days after the last 
dose of study therapy. AEs will be summarized with the incidence and percentage of 
patients with at least one occurrence of a preferred term (according to the most severe 
NCI-CTCAE Version 4.0 grade) will be included. The number of AEs reported will also 
be summarized. Causality (relationship to study drug) will be summarized separately. 
Duration of AE will be determined and included in listings along with action taken and 
outcome. Laboratory AEs will be monitored from the time that treatment starts until 30 
days after the last dose of study therapy. Laboratory results will be classified according 
to NCI-CTCAE, Version 4.0. Incidence of laboratory abnormalities will be summarized; 
laboratory results not corresponding to an NCI-CTCAE Version 4.0 term will not be 
graded. Laboratory toxicity shifts from baseline to worst grade will also be provided. 
The results from physical examination and vital sign measurement will be tabulated. 
Descriptive statistics will be provided as appropriate. 
 
8.5 
Duration of Response and Other Endpoint Definitions 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started), or death. 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented, or death. 


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Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started. 
 
Rate of freedom from metastasis (FFM) is defined as the proportion of patients with 
documentation of progression of disease, during study participation, in whom no new 
lesions appeared. 
 
In rare situations where PD or other endpoints could not be clearly assessed, the PI will 
review the records with the treating physician and provide a clinical judgment for 
purposes of endpoint documentation. 
 
9 
ADMINISTRATIVE SECTION 
9.1 
Compliance with the Protocol 
The study must be conducted as described in the final IRB/IEC-approved protocol. 
Documentation of approval, signed by the IRB/IEC chairperson or designee, will be sent 
to the BMS protocol manager. 
 
All protocol amendments and revisions to the informed consent will be submitted to the 
BMS protocol manager and to the IRB/IEC. No protocol amendments will be 
implemented until written approval has been given by the IRB/IEC, except when 
necessary to eliminate an immediate hazard to study subjects. Administrative letters 
should also be sent to the BMS protocol manager and IRB/IEC; however, they do not 
require approval. 
 
If a protocol amendment mandates a revision to the informed consent, the revised consent 
must be used to obtain consent from subjects currently enrolled in the study if it affects 
them (eg, if it contains new information regarding safety), and the revised consent must 
be used to obtain consent from new subjects before enrollment. 
 
9.2 
Records Retention 
The investigator will retain, in a confidential manner, all data pertinent to the study for all 
treated subjects as well as those entered as control subjects. The investigator will retain 
source documents and accurate case histories that record all observations and other data 
pertinent to the investigation (eg, the medical record) for the maximum period required 
by applicable regulations and guidelines or following institutional procedures. If the 
investigator withdraws from the study (eg, relocation or retirement), the records will be 
transferred to a mutually agreed upon designee, such as another investigator or an IRB. 
Written documentation of such transfer will be provided to BMS. 
 
The investigator will ensure that a current record of disposition of investigational product 
is maintained at each study site where the investigational product is inventoried and 
disposed. Records or logs must comply with applicable regulations and guidelines and 
should include: 
• amount received and placed in storage area 


56 
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• amount currently in storage area 
• label identification number or batch number and use date or expiry date 
• dates and initials of person responsible for each 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 (eg, lost, wasted, broken) 
• amount destroyed at study site, if applicable, and 
• 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. 
 
9.3 
Destruction of Investigational Product 
If the investigational product is to be destroyed on site, it is the investigator’s 
responsibility to ensure that arrangements have been made for disposal, and that 
procedures for proper disposal have been established according to applicable regulations, 
guidelines, and institutional procedures. Appropriate records of the disposal must be 
maintained. 
 
Consult with the PI for instructions on disposal of unused dasatinib tablets. 


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10 
GLOSSARY OF TERMS 
 
Term 
Definition 
Adverse Reaction 
An adverse event that is considered by either the 
investigator or the sponsor to be related to the 
investigational product 
Expedited Safety Report 
Rapid notification to investigators of all SAEs that are 
suspected (related to the investigational product) and 
unexpected (ie, not previously described in the 
Investigator Brochure), or that could be associated with 
the study procedures. 
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction as 
termed by the European Clinical Trial Directive 
(2001/20/EC). 
Unexpected Adverse 
Reaction 
An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved 
investigational product) 


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11 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ANC 
Absolute Neutrophil Count 
BID 
Twice a Day 
BMS 
Bristol-Myers Squibb Company 
CAT ( or CT scan) 
Computed Axial Tomography 
CBC 
Complete Blood Count 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EKG 
Electrocardiogram 
ESR 
Expedited Safety Report 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
HCG 
Human Chorionic Gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
Hormone Replacement Therapy 
IB 
Investigators’ Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IST 
Investigator-Sponsored Trial 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NSAE 
Non-Serious Adverse Event 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PO 
By Mouth 
PR 
Partial Response 
QD 
Once Daily 
QoL 
Quality Of Life 
RECIST 
Response Evaluation Criteria In Solid Tumors 


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SAE 
Serious Adverse Event 
SD 
Stable Disease 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TNM Staging 
Tumor, Node and Metastasis Staging 
ULN 
Upper Limit of Normal 
WBC 
White Blood Count 
WOCBP 
Women of Child-Bearing Potential 


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53 BMS-354825: Dasatinib Population Pharmacokinetic Analysis in Subjects with 
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55 Mass Balance, Pharmacokinetics and Metabolism of [14C]BMS-354825 in Healthy 
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57 In vitro evaluation of BMS-354825 as an inhibitor of human cytochrome P450 
enzymes. Bristol-Myers Squibb Pharmaceutical Research Institute, 2005. BMS 
Document Control No. 930011322. 
 
58 SPRYCEL (dasatinib) BMS-354825, Bristol-Myers Squibb Investigator Brochure, 
Version 8, 2008. 
59 Eisenhauer A, Therasse P., Bogaerts J., et al. New response evaluation criteria in solid 


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tumors: Revised RECIST guideline (version 1.1). Eur J of Cancer 2009;45:228-247. 
 
60 Abetz L, Coombs JH, Keininger DL, et al. Development of the cancer therapy 
satisfaction questionnaire: item generation and content validity testing. Value Health 
2005;8 Suppl 1:S41-53.- CTSQ © 2007 Pfizer Inc. All rights reserved. 
 
61 Heffernan, N., Cella, D., Webster, K., et al. Measuring health-related quality of life in 
patients with hepatobiliary cancers: The Functional Assessment of Cancer Therapy - 
Hepatobiliary (FACT-Hep) questionnaire. J Clin Oncol 2002; 20(9), 2229-2239. 


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APPENDIX I. Performance Status 
 
 
ECOG PERFORMANCE SCALE 
 
0 - Fully active, able to carry on all predisease activities without restriction (Karnofsky 90-100). 
1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature. For example, light housework, office work (Karnofsky 70-80). 
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 (Karnofsky 50-60). 
3 - Capable of only limited self-care, confined to bed or chair 50% or more of waking hours (Karnofsky 30- 
40). 
4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair (Karnofsky 10-20). 
5 – Deceased. 


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APPENDIX II. Dasatinib patient pill diary 
 
Patient Pill Diary 
Dasatinib 
Day of 
Treatment 
Time 
# 50mg pills 
taken 
# 20mg pills 
taken 
Comments 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
Patient’s name 
Cycle #   
 
 
Patient’s signature  
Date  
 
 
Physician’s Office will complete this section: 
1. Complete dates: Start date  
End date   
 
2. Total number of Dasatinib pills to be taken (per protocol) (50mg)  
(20mg)  
 
3. Total number of Dasatinib pills taken (per protocol) (50mg)  
(20mg)  
 
4. Compliance rate  
% 
Physician/Nurse/Research Staff’s Signature: 
 


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APPENDIX III. Pancreatic Cancer Patient Quality of Life and Satisfaction 
Questionnaires 
 
 
 
 


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