A Prospective Phase II Trial of Molecular Profiling to Guide Neoadjuvant Therapy for Resectable and Borderline Resectable Adenocarcinoma of the Pancreas
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma
Sponsor: Medical College of Wisconsin

Protocol Title:  A Prospective, Phase II Trial of Molecular Profiling to Guide Neoadjuvant 
Therapy for Resectable and Borderline Resectable Adenocarcinoma of the Pancreas 
 
NCT01726582 
 
Date:  June 28, 2018 

A Prospective, Phase II Trial of Molecular Profiling to Guide Neoadjuvant Therapy for 
Resectable and Borderline Resectable Adenocarcinoma of the Pancreas 
 
June 28, 2018 /Amendment 18 
INVESTIGATORS:   
Principal Investigators:  
Kathleen K. Christians, MD, FACS,  
Susan Tsai MD, MHS,  
Paul Ritch MD 
Douglas B. Evans, MD 
Medical College of Wisconsin 
9200 W Wisconsin Ave. 
Milwaukee, WI  53226 
 
CO-INVESTIGATORS: 
 
Edward Quebbeman, MD, PhD 
Bryan Hunt, MD 
James Thomas, MD, PhD 
Kulwinder Dua, MD 
Beth Erickson, MD, FACR 
Abdul Khan, MD 
Tracy Kelly, MD 
Ben George, MD 
Syed A. Ahmad, MD 
Kiran Turaga, MD, MPH 
T. Clark Gamblin, MD, MS 
W. Dennis Foley, MD 
A. Craig Mackinnon, MD, PhD 
Robert Hellman, MD 
Paul Knechtges, MD 
 
Study Coordinator: 
For Medical College of Wisconsin: 
Haley Heaviland9200 W Wisconsin Ave 
Milwaukee, WI   53226 
Phone 414-805-8696 
Fax:  414-805-8840 
hheavila@mcw.edu 
 
 
 
 
 

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For University of Cincinnati: 
Alison Kastl, BS, CCRC 
Director of Clinical Trials 
University of Cincinnati Cancer Institute 
200 Albert Sabin Way, Suite 1012 
Cincinnati, OH 45267-0502 
Phone 513-584-0436 
Fax 513-584-5680 
Email kastla@ucmail.uc.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CLINICAL STUDY PROTOCOL 
Protocol Number = MCW PRO 15565;  
A Prospective, Phase II Trial of Molecular Profiling to Guide Neoadjuvant Therapy for 
Resectable and Borderline Resectable Adenocarcinoma of the Pancreas 
 
 
 
 
 
Indication: 
Resectable and Borderline Resectable Pancreatic Cancer  
Phase: 
Phase II  
 
 
 
 
 
 
 
 
 
 
 
 
This is an investigator-initiated study.  The principal investigator Kathleen Christians, MD (who 
may also be referred to as the sponsor-investigator), is conducting the study and acting as the 
sponsor.  Therefore, the legal/ethical obligations of the principal investigator include both those 
of a sponsor and those of an investigator. 
 
 

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PROTOCOL SUMMARY  
Study Title:  A Prospective, Phase II Trial of Molecular Profiling to Guide Neoadjuvant 
Therapy for Resectable and Borderline Resectable Adenocarcinoma of the Pancreas 
Phase:  Phase II 
Number of Patients:  130 patients 
Study Objectives  
Primary Objectives: 
1. 
To compare the resectability rate (percent of all patients completing therapy to include 
surgical resection) using a neoadjuvant treatment regimen selected by molecular 
profiling to historical results with standard neoadjuvant therapy and surgical resection. 
Secondary Objectives: 
1. 
To compare overall survival (OS) rates of resectable and borderline resectable 
pancreatic cancer patients treated with molecularly targeted neoadjuvant therapy 
followed by surgical resection to historical controls treated with standard neoadjuvant 
therapy and surgical resection. 
2. 
To compare progression-free survival (PFS) rates of patients with resectable and 
borderline resectable pancreatic cancer treated with molecularly targeted neoadjuvant 
therapy followed by surgical resection to historical controls treated with standard 
neoadjuvant therapy and surgical resection. 
3. 
To determine the frequency with which molecular profiling of a patient’s tumor by IHC 
identifies a target for an approved, commercially-available chemotherapeutic regimen. 
4. 
To compare the molecular profile of pretreatment biopsies and resected tumors. We will 
compare the molecular profile obtained at time of diagnosis (FNA) with the molecular 
profile obtained from the resected specimen. 
5. 
To determine the extent of histologic treatment response to targeted chemotherapeutic 
regimens in resected tumors.* 
6. 
To determine the prognostic relevance of radiological response among patients 
undergoing neoadjuvant therapy. 
7. 
To determine the ability to generate primary xenografts of pancreatic cancer from 
resected tumors.* 
8. 
To compare quality and outcomes of both patterns of recurrence and ultimately survival 
in patients who receive radiation therapy at FH/MCW versus other institutions.   
Overview of Study Design:   
This is a phase II study for resectable and borderline resectable pancreatic cancer which  utilizes 
molecular profiling of tissue samples from the pancreatic cancer (obtained either through EUS/FNA 
biopsy at the time of diagnosis or from the surgical specimen) to guide chemotherapy selection. 

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Study Population:   
Resectable Pancreatic Cancer (defined by): 
1. No evidence of extra pancreatic disease 
2. No evidence of tumor-arterial abutment (celiac, SMA or HA) 
3. If tumor induced narrowing of the SMV, PV, or SMV-PV confluence is present, it must be 
<50% of the diameter of the vessel 
4.   Ca 19-9 <5000, when bilirubin is <2 
 
Borderline Resectable Pancreatic Cancer (to include at least one of the following): 
1. Tumor abutment <180° of the SMA or celiac axis 
2. Tumor abutment or encasement of a short segment of the HA 
3.  Tumor induced narrowing of SMV, PV or SMV-PV of >50% of the diameter of the vessel. 
4. Short segment occlusion of the SMV, PV or SMV-PV with a suitable PV above and SMV 
below, for reconstruction 
5. CT or MRI findings suspicious for, but not diagnostic of, metastatic disease (based on 
review at each site’s weekly multidisciplinary pancreatic cancer conference)  
6. Biopsy proven N1 disease (regional lymph nodes involved) from pre-referral biopsy or 
EUS-guided FNA 
7. Resectable tumor and CA 19-9 >5000 
 
Inclusion criteria: 
Eligibility for Screening consent: 
1. Have adenocarcinoma of the pancreas or highly suspicious for pancreas adenocarcinoma 
per CT or MRI 
2. 18 years of age or older 
3. Able to understand and provide written informed consent or have LAR Legally Authorized 
Representative  
Eligibility for Treatment  consent,: 
1. Histologic diagnosis of pancreatic adenocarcinoma 
2. Have an ECOG performance status < 2  
3. Resectable or borderline resectable  adenocarcinoma of the pancreas based on CT or MRI 
findings  
4.  Total leukocytes >3 x103/μL 

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5.  Absolute neutrophil count (ANC) >1.5x 103/μL 
6.  Hemoglobin >9 g/dL  
7.  Platelets >100 x 10e3/μL 
8.  Creatinine clearance >60 mL/min or creatinine <1.5 mg/dL 
9. Total bilirubin < 2 mg/dL:  At two weeks from biliary decompression, if the subject’s 
serum bilirubin remains greater than two, but has demonstrated a progressive decline, the 
subject may be enrolled into the trial and appropriate modification and dose adjustments 
will be made to the predicted regimen.  
 
Exclusion Criteria: 
1. Have received chemotherapy or chemoradiation within  5 years prior to study enrollment 
2. Have any previous history of another malignancy (other than cured basal or squamous cell 
carcinoma of the skin or cured in-situ carcinoma of the cervix) within 5 years of study 
enrollment 
3. Uncontrolled co morbidities including, but not limited to, ongoing or active serious 
infection, symptomatic congestive heart failure, unstable angina, unstable cardiac 
arrhythmias, psychiatric illness, excessive obesity, or situations that would limit 
compliance with the study requirements or the ability to willingly give written informed 
consent 
4. Known HIV, HBV, or HCV infection 
5. Pregnant or breast-feeding patients or any patient with child-bearing potential not using 
contraception 4 weeks prior to treatment 
Duration of Study:  Accrual period: Approximately 48 months. 
 
 
 

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Table of Contents 
TITLE PAGE .............................................................................................................................................................. 1 
PROTOCOL SUMMARY ..................................................................................................................................... 4 
ABBREVIATIONS .............................................................................................................................................. 12 
1. INTRODUCTION ............................................................................................................................................ 14 
1.1. Background ......................................................................................................................................... 14 
1.2. Proposed Therapeutic Intervention .................................................................................................... 15 
2. OBJECTIVES AND STUDY DESIGN ....................................................................................................... 15 
2.1. Objectives ............................................................................................................................................ 15 
2.1.1. Primary Objective .............................................................................................................................. 15 
2.1.2. Secondary Objectives ........................................................................................................................ 15 
2.2. Study Design ........................................................................................................................................ 16 
2.2.1. Treatment Strategy ............................................................................................................................ 18 
TABLE 1: .............................................................................................................................................. 20 
2.2.2. [Neoadjuvant] Pre-operative Pathway for Resectable Patients .......................................................... 21 
2.2.3. [Neoadjuvant] Pre-operative Pathway for Borderline Resectable Patients ........................................ 22 
2.2.4. [Neoadjuvant] Preoperative Treatment .............................................................................................. 23 
2.2.4.1 [Neoadjuvant] Preoperative FNA Profiling Schema ................................................................ 23 
2.2.4.2. [Neoadjuvant] Preoperative Treatment Regimens ................................................................. 23 
a. Gemcitabine-based XRT Treatment Regimen: .................................................................. 23 
b. Capecitabine-based XRT Treatment Regimen: .................................................................. 23 
c. FOLFIRINOX Treatment Regimen: .................................................................................. 23 
d. FOLFIRI Treatment Regimen: ........................................................................................... 23 
e. Gemcitabine w/irinotecan Treatment Regimen: ................................................................. 23 
f. Gemcitabine w/ oxaliplatin Treatment Regimen: ............................................................... 24 

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g. Gemcitabine w/ cisplatin Treatment Regimen: .................................................................. 24 
h. Gemcitabine/capecitabine Treatment Regimen: ................................................................. 24 
i. Gemcitabine/nab-paclitaxel Treatment Regimen: ............................................................... 24 
j. Capecitabine/nab-paclitaxel Treatment Regimen: .............................................................. 24 
2.2.4.3. Disease Progression on Therapy ............................................................................................ 24 
2.2.5. [Adjuvant] Pathways for all patients after Postoperative Restaging .................................................. 25 
2.2.6. [Adjuvant] Postoperative Treatment .................................................................................................. 25 
2.2.6.1  [Adjuvant] Postoperative Profiling Schema no prior XRT .................................................... 25 
2.2.6.2  [Adjuvant] Postoperative Profiling Schema when patient DID receive pre-operative XRT . 25 
2.2.6.3.  [Adjuvant] Postoperative Treatment Regimens .................................................................... 25 
a. Gemcitabine-based XRT Treatment Regimen: .................................................................. 25 
b. Capecitabine-based XRT Treatment Regimen: .................................................................. 26 
c. FOLFIRINOX Treatment Regimen: .................................................................................. 26 
d. FOLFIRI Treatment Regimen: ........................................................................................... 26 
e. Gemcitabine w/ irinotecan Treatment Regimen: ................................................................ 26 
f.. Gemcitabine w/ oxaliplatin Treatment Regimen: .............................................................. 26 
g. Gemcitabine w/ cisplatin Treatment Regimen: .................................................................. 26 
h. Gemcitabine/capecitabine Treatment Regimen: ................................................................. 26 
i. Gemcitabine/nab-paclitaxel Treatment Regimen: ............................................................... 27 
j.  Capecitabine/nab-paclitaxel Treatment Regimen: ............................................................. 27 
k. Gemcitabine alone Treatment Regimen: ............................................................................ 27 
l. Capecitabine alone Treatment Regimen: ............................................................................ 27 
m. 5FU alone Regimen: ......................................................................................................... 27 
n. No further treatment recommended: .................................................................................. 27 
2.2.7. Outcome Measures ............................................................................................................................ 27 
3. PATIENT SELECTION ................................................................................................................................. 28 
3.1. Screening and Eligibility Criteria ....................................................................................................... 28 

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3.1.1. Treatment Eligibility Criteria: ........................................................................................................... 28 
3.1.2.Definition of Resectable Pancreatic Cancer includes all of the following:......................................... 29 
3.1.3. Definition of Borderline Resectable Pancreatic Cancer .................................................................... 29 
3.1.4. Definition of Locally Advanced ........................................................................................................ 29 
3.1.5. Definition of Metastatic Disease ....................................................................................................... 30 
3.2. Exclusion Criteria ............................................................................................................................... 30 
4. INFORMED CONSENT ................................................................................................................................ 30 
5. SCREENING AND ENROLLMENT ......................................................................................................... 30 
6. CLINICAL MEASUREMENTS AND PROCEDURES ......................................................................... 31 
6.1. Methodology for Obtaining FNA Specimen ....................................................................................... 31 
6.2. Methodology for Processing FNA Specimen and Shipping to Coordinating Site .............................. 31 
6.3. Characterization of Specimen ............................................................................................................. 31 
6.3.1. Overview ........................................................................................................................................... 31 
6.3.2. Immunohistochemistry ...................................................................................................................... 32 
6.3.3. Molecular Analysis ............................................................................................................................ 32 
6.3.4 Communication with treating physicians regarding STREET profiled therapy ................................. 32 
6.3.5 Radiation Therapy Data Review………………………………………………………….32  
6.4. Study Assessments ............................................................................................................................... 32 
6.5. Follow-up ............................................................................................................................................. 33 
7. ASSESSMENT OF ACTIVITY .................................................................................................................... 36 
7.1. Definition of Treatment Response ...................................................................................................... 36 
7.2. Evaluation of Treatment Response ..................................................................................................... 36 
7.2.1. CT Imaging ........................................................................................................................................ 36 
7.2.2. PET-Scan Imaging ............................................................................................................................. 36 
7.2.3. Diffusion Weighted MRI Imaging ..................................................................................................... 36 

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7.2.4. Biochemical Testing .......................................................................................................................... 37 
7.3. Survival ............................................................................................................................................... 37 
8. ASSESSMENT OF SAFETY, RISKS, AND BENEFITS ....................................................................... 37 
8.1. Adverse Events .................................................................................................................................... 37 
8.1.1 Recording Adverse Events ................................................................................................................. 37 
8.1.2 Reporting Adverse Events (AE) ......................................................................................................... 38 
8.2. Serious Adverse Events (SAEs) ........................................................................................................... 38 
8.3. Study Risks .......................................................................................................................................... 38 
8.3.1. Known Risks ..................................................................................................................................... 38 
8.3.2. Risk Discussion ................................................................................................................................. 39 
8.4. Study Benefits ...................................................................................................................................... 39 
9. PATIENT DISCONTINUATION ................................................................................................................ 39 
10. DISCONTINUATION OF THE STUDY ................................................................................................. 40 
11. STATISTICAL METHODS ........................................................................................................................ 40 
12. ADJUNCT TRANSLATIONAL STUDIES AT COORDINATING SITE ONLY ........................ 41 
12.1. Generation of Direct Xenograft Tumors ........................................................................................... 41 
12.1.1. Rationale .......................................................................................................................................... 41 
12.1.2. Murine Model .................................................................................................................................. 42 
12.2. Characterization of Resected Primary & Metastatic Tumors .......................................................... 42 
12.2.1. Rationale .......................................................................................................................................... 42 
12.2.2. Molecular Characterization of Primary Resected and Metastatic Tumors ...................................... 42 
12.2.3. Biomarkers in peripheral blood ....................................................................................................... 43 
13. ADMINISTRATION ..................................................................................................................................... 43 
13.1. Training ............................................................................................................................................. 43 

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13.2. Multi-site Approval and Activation .................................................................................................. 43 
13.2.1 Site Initiation .................................................................................................................................... 44 
13.2.2 Monitoring ........................................................................................................................................ 44 
13.3 Modification of the Protocol ............................................................................................................... 44 
13.4. Completion of Case Report Forms .................................................................................................... 44 
13.5 Access to Source Data and Study Documents .................................................................................... 44 
13.6. Data Safety Monitoring ..................................................................................................................... 45 
13.7. Retention of Study Documentation ................................................................................................... 46 
13.8. Ethics Consideration ......................................................................................................................... 46 
13.9. Publication Policy .............................................................................................................................. 47 
FIGURE A ................................................................................................................................................................ 48 
FIGURE B ................................................................................................................................................................ 49 
FIGURE C ................................................................................................................................................................ 50 
FIGURE E ................................................................................................................................................................ 52 
APPENDICES A – M (SEE SEPARATE APPENDICES DOCUMENT) .............................................. 53 
14. REFERENCES ............................................................................................................................................... 54 
  
 
 
 
 

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ABBREVIATIONS 
 
ADC  
apparent diffusion coefficient 
ALKP  
alkaline phosphatase 
ALT/SGPT 
alanine transaminases 
ANC  
absolute neutrophil count 
APTT  
activated partial thromboplastin time 
AST/SGOT 
aspartate transaminases 
CR 
 
complete response 
CRF 
 
case report form 
CT 
 
computed tomography 
CTCAE 
common toxicity criteria for adverse events 
ECOG  
Eastern Cooperative Oncology Group 
ERCC1 
Excision Repair Cross-Complementation 1 
EUS   
endoscopic ultrasound 
FNA   
fine needle aspiration 
FOLFOXIRI irinotecan, oxaliplatin, leucovorin, 5-fluorouracil 
Gem-XRT 
gemcitabine and radiation  
GGT  
gamma glutamyl transferase 
IRB 
 
institutional review board 
HA  
 
hepatic artery 
hENT1 
human equilibrative nucleoside transporter 1 
HIV 
 
human immunodeficiency virus 
HBV  
hepatitis B virus 
HCV  
hepatitis C virus 
HPB  
hepato-pancreatico-biliary 
IHC/FISH 
immunohistochemistry/fluorescence in situ hybridization (IHC/FISH) 
LDH  
lactate dehydrogenase 
MPI 
 
molecular profiling institute 
N1 
 
regional lymph nodes positive for tumor 
NCI 
 
national cancer institute 

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OS 
 
overall survival 
PBD  
pancreatico-biliary disposition conference 
PD 
 
pancreaticoduodenectomy 
PET 
 
positron emission tomography 
PFS 
 
progression free survival 
PR 
 
partial response 
PGD  
progressive disease 
PT 
 
prothrombin time 
PV  
 
portal vein 
PV-SMV 
portal vein-superior mesenteric vein 
RECIST 
response evaluation criteria in solid tumors 
RPMI  
Roswell Park Memorial Institute (media) 
RRM1  
ribonucleotide reductase M1 
SD 
 
stable disease 
SMA    
superior mesenteric artery 
SMV   
superior mesenteric vein 
SPARC 
Secreted Protein And Rich in Cysteine 
SUV  
Standardized Uptake Value  
TOP1  
Topoisomerase 1 inhibitor 
TYMS  
Thymidylate synthase 
ULN  
upper limits of normal 
XRT  
radiation 

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1. INTRODUCTION 
   1.1. Background 
 
Pancreatic cancer is the fourth leading cause of cancer death in the United States. There were 43,140 
estimated new cases of pancreatic cancer in 2010 and 36,800 will succumb to this disease. Despite two 
decades of advances in imaging, diagnostics, and perioperative and intraoperative care, the actual 5-year 
survival rate of patients with small tumors, no lymphadenopathy and who are completely resected 
remains <30%.1 These sobering statistics have led clinicians to search for new modalities and/or 
sequencing of therapy as part of a multidisciplinary approach to pancreatic cancer treatment.  
 
Neoadjuvant, as opposed to adjuvant, therapy allows delivery of therapy to a well-vascularized tumor, 
ensuring that the drug can reach the tumor. It allows for the completion of therapy prior to surgery to 
prevent patient drop-out due to perioperative complication. Neoadjuvant therapy also acts as a selection 
tool for optimal surgical candidates by identifying aggressive tumor biology prior to surgery and therefore 
selecting out those who will not benefit from resection. Indeed, the recent report of gemcitabine-based 
preoperative (neoadjuvant) therapy has demonstrated the most favorable patient survival reported in a 
prospective trial.2 More recently, there has been an increase in interest in developing anti-cancer agents 
which are targeted, such as Herceptin against HER2/neu in breast cancer, and bevacizumab against VEGF 
and tyrosine kinase inhibitors against GIST tumors. In contrast to indiscriminate applications of 
chemotherapy, targeted therapies developed based on tumor molecular profiles have been effective in 
several solid organ tumors. Similarly, in pancreatic cancer, the identification of key molecular targets may 
increase the efficacy of existing systemic agents by delivering the appropriate chemotherapy to the most 
vulnerable tumors.  
 
The most common chemotherapeutic agents used in pancreatic cancer include gemcitabine, platinum 
agents, irinotecan, and 5-fluorouracil (5-FU) derivatives. In review of the literature, six specific molecular 
targets have been identified which are predictive of chemo sensitivity to these agents in in vitro and in 
vivo models. Specifically, low thymidylate synthase (TYMS) levels predict efficacy of 5-FU-based 
therapies and Capecitabine.  Excision repair cross-complementing (ERCC1) protein repairs DNA damage 
caused by platinum agents. As a result, low ERCC1 protein levels have been demonstrated to predict 
efficacy of platinum agents. Similarly, low ribonucleotide reductase M1 (RRM1) predicts efficacy of 
gemcitabine, and elevated SPARC predicts sensitivity to nab-paclitaxel. Polymorphisms of topoisomerase 
I (TOP1) have been implicated in irinotecan resistance in lung and colorectal cancer.3,4,5,6 hENT1 is a 
major transporter of gemcitabine and low levels are associated with gemcitabine resistance. In addition 
SMAD4 expression has been identified as a predictor of local versus distant disease progression in 
pancreatic cancers.7,8 

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1.2. Proposed Therapeutic Intervention 
 
This protocol uses state-of-the-art immunohistochemistry (IHC) to determine if molecular targets are 
present in a patient’s tumor. Then, chemotherapeutic regimens will be individualized and optimized for 
each patient’s tumor, based on the molecular characterization of these targets. Success of the approach 
will be measured by comparing resectability rates, overall survival and progression-free survival for the 
study patients to historical data (i.e. gemcitabine or capecitabine-based chemo radiation for resectable 
patients and combined modality therapy for borderline resectable patients).2,9 Prior to chemotherapy, 
radiation or surgery, the patient will consent to providing a specimen by (Endoscopic Ultrasound Fine 
Needle Aspiration) EUS/FNA or traditional biopsy for molecular profiling to determine the neoadjuvant 
therapy agent(s) of choice. Postoperatively the surgical specimen will also be profiled to guide any 
potential adjuvant regimen. We have previously shown proof of concept in our feasibility study entitled 
Molecular Profiling of Endoscopic Ultrasound Fine Need Aspiration Specimens in Pancreas Cancer: A 
Feasibility Study.10 
2. OBJECTIVES AND STUDY DESIGN 
2.1. Objectives 
2.1.1. Primary Objective 
 
The primary objective is to compare the resectability rate (percent of all patients completing therapy 
to include surgical resection) using a neoadjuvant treatment regimen selected by molecular profiling to 
historical results with standard neoadjuvant therapy and surgical resection. 
2.1.2. Secondary Objectives (objectives noted by an asterisk (*) will be pursued only at the coordinating 
site) 
1. To compare overall survival (OS) rates of resectable and borderline resectable pancreatic cancer 
patients treated with molecularly targeted neoadjuvant therapy followed by surgical resection to 
historical controls treated with standard neoadjuvant therapy and surgical resection. 
2. To compare progression-free survival (PFS) rates of patients with resectable and borderline resectable 
pancreatic cancer treated with molecularly targeted neoadjuvant therapy followed by surgical 
resection to historical controls treated with standard neoadjuvant therapy and surgical resection. 
3. To determine the frequency with which molecular profiling of a patient’s tumor by IHC identifies a 
target for an approved, commercially-available chemotherapeutic regimen. 

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4. To compare the molecular profile of pretreatment biopsies and resected tumors. We will compare the 
molecular profile obtained at time of diagnosis (FNA) with the molecular profile obtained from the 
resected specimen. 
5. To determine the extent of histologic treatment response to targeted chemotherapeutic regimens in 
resected tumors.* 
6. To determine the prognostic relevance of radiological response among patients undergoing 
neoadjuvant therapy. 
7. To determine the ability to generate primary xenografts of pancreatic cancer from resected tumors.* 
8. To compare quality and outcomes of both patterns of recurrence and ultimately survival in patients 
who receive radiation therapy at FH/MCW versus other institutions.   
 
2.2. Study Design 
 
This is an open-label, multi-institution, phase II study in patients with resectable and borderline 
resectable pancreas cancer. MCW will be the coordinating site and University of Cincinnati will be a 
participating site. Patients will be staged with laboratory tests, contrast-enhanced computed tomography 
(CT) and magnetic resonance imaging (MRI) of the abdomen, a chest radiograph or contrast enhanced 
chest CT, and PET scan. MRI’s and PET scans are at the physician’s discretion.  At initial staging, each 
patient will be classified resectable or borderline resectable based on review of all CT or MRI images (see 
sections 3.1.1 and 3.1.2 for definitions).  
 
A patient is eligible for screening for this study when his/her disease is designated highly suspicious 
for cancer of the pancreas.  After signing the screening consent form, patients will undergo EUS/FNA or 
have a tumor biopsy from a prior FNA or laparotomy/laparoscopy available for molecular profiling. 
When FNA (or previous biopsy) histology confirms pancreatic adenocarcinoma, the patient is eligible to 
participate in the study and will sign the enrollment consent form. Molecular profiling will be performed 
on tumor biopsies from approximately 288 eligible patients. Of these 288, 168 patients will sign 
enrollment consent but for clinical reasons only 130will begin treatment.  Most patients will be enrolled at 
the coordinating site.  IHC will be performed to assess specific molecular targets on tumor biopsies. It is 
expected that molecular targets will be identified in approximately 70% of tumor biopsies (i.e. 120 
patients). Study patients will be treated neoadjuvantly with commercially available systemic therapy 
assigned on the basis of disease stage (resectable or borderline resectable) and identified molecular 
targets. No investigational treatments will be administered.  Study patients who have no molecular targets 
identified on pre-treatment FNA/biopsy will be treated with neoadjuvant therapy according to current best 
standard of care.2,9 

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Patients whose disease is stable or responding by biochemical, clinical, and radiographic measures 
will be offered resection.  Patients whose disease demonstrates progression but are still considered 
technically operable may receive additional therapy prior to resection (see figures A page 48  and B page 
49). Patients whose disease demonstrates progression beyond operability will be taken off study. 
Treatment response will be evaluated in a multi-disciplinary setting and assessment of operability will be 
made at the discretion of the treating surgeon and include the following components: (1) feasibility of 
surgical resection, (2) decline in Ca19-9 levels (in patients for whom Ca19-9 is evaluable), and (3) 
acceptable performance status.  
 
All study patients who proceed to surgery will undergo laparoscopy at the time of surgery to assess 
for occult metastases. Surgical resection will be performed using a standard technique11 and patients will 
be followed for major surgical complications. Resectability rate, which measures the study’s primary 
objective, is the proportion of patients who undergo a successful PD as compared to all patients who 
initiate neoadjuvant therapy.  
 
Standardized histologic evaluation of the resected specimen will be performed. Histologic response to 
preoperative therapy will be graded (see Appendix B).12Molecular profiling will also be performed on the 
surgical specimen. Study patients will be restaged and will be given up to 4 months adjuvant therapy on 
study with restaging after each 2 months of therapy. If, at any point during restaging, the patient’s disease 
has recurred, he/she will come off treatment and remain in follow-up for survival. 
 
Study patients whose cancer does not recur after adjuvant therapy will be followed with serial CT 
scan and laboratory tests at 3 month intervals (plus or minus a 1 month window) to assess for disease 
recurrence and survival for the first 18 months following end of treatment and then at 6 month intervals 
thereafter until 5 years from date on study. Patients whose disease recurs during follow-up will remain in 
follow-up for survival only.  If patients develop metastatic disease that is amenable to minimally invasive 
biopsy or resection, surgery may be considered to obtain tissue for further molecular characterization.
 
Sample size for screening is estimated at 288.  Sample size for treatment will be 168 patients accrued 
over 4 years of which only 130patients will actually begin treatment. Details on sample size and power 
are included in Statistical Methods, Section 11. 
      Essential data will be collected while the patient is on study in order to evaluate the study objectives. 
This data will be collected directly from the patient’s medical record and/or from the HPB Clinical 
Database.  Relevant safety data concerning adverse events will also be collected. Whenever possible, 
initial staging and all restaging will be completed at the study site. Surgery must be performed by the 

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site’s pancreatic cancer team. All nonsurgical therapies may be performed under the direction of the 
individual patient’s local oncologists.   
 
Several translational correlates are incorporated into the study design to further characterize the 
primary tumor genotype as well as to evaluate the accumulation of genetic alterations associated with the 
development of metastatic disease. After pathologic evaluation is complete, resected specimens of both 
primary and metastatic lesions will undergo repeat molecular profiling to evaluate for changes in 
molecular phenotype. To prepare the resected tumor for further molecular characterization, resected 
tumors will be expanded using a direct xenograft model.  
 
2.2.1. Treatment Strategy 
 
The treatment delivered to each patient will be first determined by clinical stage of disease (resectable 
vs. borderline resectable - see 3.1.1 and 3.1.2 for definitions) as summarized by Figure A:  page 48 
(resectable) and Figure B:   page 49 (borderline resectable).  All patients will undergo EUS/FNA biopsy 
and, based on the outcome of the molecular profiling analysis of the biopsy, treatment will be assigned as 
summarized in Figure C. In particular, tumor specimens will be evaluated for expression of RRM1, 
ENT1, TYMS, TOP1, ERCC1, SPARC and SMAD4. The staining pattern of the STREET panel will be 
reviewed in a multi-disciplinary conference at the coordinating site and a final treatment plan determined.  
The treatment plan will be communicated to the Principal Investigator or his/her designee at the 
participating site and to treating physicians. (see Letter Formats, Appendix M) 
Research may take place in an inpatient or outpatient setting. The research-only procedures 
include the extra FNA passes, molecular profiling, and collection of blood at several time points 
throughout the study. Molecular profiling will be conducted only at the coordinating site, 
FH/MCW.  Extra FNA passes and collection of blood at several time points throughout the study will be 
conducted at the enrolling site (FH/MCW or University of Cincinnati). Specimen collection will be 
conducted by the Surgical Oncology Tissue Bank staff or the Clinical Cancer Center Clinical Trials 
Office lab.  
Procedures that this research encompasses but are standard of care (imaging including MRI, PET 
scan, Chest X-ray and CT Scans;  Endosopic Ultrasound-guided Fine Needle Aspiration (EUS FNA; 
blood tests, medical team consultations, pregnancy test prior to chemotherapy and prior to surgery, 
chemotherapy, chemo-radiation therapy) may take place at FH/MCW or at another cancer treatment 
location. Surgery (pancreatico-duodenectomy) will be standard cancer care treatment and take place at the 
patient’s enrolling site (FH/MCW or University of Cincinnati).   

June 28 2018, Amendment 18 
19 
Those administering treatment will be deemed qualified to administer per Froedtert policy and/or 
MCW policy. 
 
 
 
 
 
 
 
 
 
[REMAINDER OF PAGE INTENTIONALLY BLANK] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

June 28 2018, Amendment 18 
20 
TABLE 1: 
THRESHOLD VALUES USED FOR IMMUNOCHEMISTRY INTERPRETATION        
Biomarker 
Intensity 
  
Percent Stain 
Interpretation 
ACTION 
RRM1 
>=2+ 
AND 
>=50% 
HIGH 
No Gem 
RRM1 
>=2+ 
AND 
<50% 
MODERATE 
Gem 
RRM1 
<2 
  
? 
LOW 
Gem 
RRM1 
0 
  
  
NEGATIVE 
Gem 
ENT1 
>=2 
AND 
>=25% 
POSITIVE 
Gem 
ENT1 
<2 
OR 
<25% 
LOW 
Gem 
ENT1 
0 
  
  
NEGATIVE 
No Gem 
TYMS 
>=2 
AND 
>=30% 
HIGH 
No 5-FU 
TYMS 
>=2 
AND 
<30% 
MODERATE 
5-FU 
TYMS 
1+ 
AND 
>=25% 
MODERATE 
5-FU 
TYMS 
1+ 
AND 
<=25% 
LOW 
5-FU 
TYMS 
0 
  
  
NEGATIVE 
5-FU 
TOP1 
>=2 
AND 
>=30% 
HIGH 
Irinotecan 
TOP1 
<2 
OR 
<30% 
LOW 
No Irinotecan 
TOP1 
0 
  
  
NEGATIVE 
No Irinotecan 
ERCC1 
3 
 
 
HIGH 
No Plat 
ERCC1 
2 
AND 
>50% 
HIGH 
No Plat 
ERCC1 
2 
AND 
<50% 
LOW 
Platinum 
ERCC1 
0-1 
 
 
LOW 
Platinum 

June 28 2018, Amendment 18 
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SPARC 
>=2+ 
OR 
>=30% 
HIGH 
nab 
SPARC 
<2+ 
AND 
<30% 
LOW 
nab 
SPARC 
0 
  
  
NEGATIVE 
no nab 
SMAD4 
Intact 
  
  
POSITIVE 
No further therapy 
SMAD4 
Loss 
  
  
NEGATIVE 
Gem 
All patients who undergo neoadjuvant therapy and have disease stabilization or response, or do not 
progress to an inoperable state will undergo surgery.  Neoadjuvant therapy must be initiated within 0-4 
weeks after the enrollment consent is signed. 
 
 Adjuvant therapy will be administered as summarized in either Figure D (page 51) or  
Figure E (page 52).  Adjuvant therapy must be initiated within 4-12 weeks from date of surgery.  
Reference regimens will be used and no investigational treatments will be administered. If a molecular 
target cannot be identified by molecular profiling analysis, the patient will be treated with the best 
available therapies.   The recommended treatment will take into account input from the medical oncology 
investigators, patient performance status, co-morbidities, and contraindications. When necessary, other 
relevant factors concerning the patient’s clinical history and current medical literature will also be taken 
into consideration. The schema of biomarker and corresponding agents in Figures C (page Error! 
Bookmark not defined.), D (page 51) and E (page 52) will be periodically updated as methodologies and 
therapies are approved by the FDA. Each site will notify its respective IRB of changes made to the 
treatment strategies. 
 
Throughout treatment on this protocol, dose modifications, supportive care, and treatment of 
chemotherapy-related toxicity will be made at the physician’s discretion following manufacturer’s 
guidelines (see Appendix F) and standard supportive care (Appendix L).  If insurance denies coverage for 
the standard treatment that has been identified per the protocol, then another standard treatment will be 
identified by the investigator within the same schema pathway as the denied treatment (see Figure C, D or 
E). 
2.2.2. [Neoadjuvant] Pre-operative Pathway for Resectable Patients 
Patients with resectable pancreatic cancer will receive the following preoperative therapy:  (refer to Fig. 
A, p. 46) 
1. For resectable patients where molecular profiling is predictive: 

June 28 2018, Amendment 18 
22 
• 6-8 weeks of best profile-directed therapy   
• Restaging 
• In the absence of disease progression - surgery 
2. For resectable patients whose specimen is adequate but molecular profiling is not predictive (profile 
not predictive) or for inadequate specimens (target not identified): 
• Gemcitabine or Capecitabine-based chemo radiation  
• Restaging 
• In the absence of disease progression – surgery – which should occur 3-6 weeks after  
   Chemotherapy completion       
 
2.2.3. [Neoadjuvant] Pre-operative Pathway for Borderline Resectable Patients 
 
Patients with borderline resectable pancreatic cancer will receive the following preoperative therapy: 
(refer to Fig. B, page 47) * If at any restaging, unequivocal distant disease progression is identified on 
imaging patients will be considered to have progressive disease and proceed to off study follow-up. 
1. For borderline resectable patients where molecular profiling is predictive:  
• 6-8 weeks of best profile-directed systemic therapy   
• Restaging* 
• Chemo radiation  
• Restaging*   
• Surgery 
2. For borderline resectable patients whose molecular profiling is successful, but a target is not 
predicted. (profile not predictive):  
• Gemcitabine or Capecitabine-based chemo radiation  
• Restaging* 
• Surgery  
3. For borderline resectable patients with inadequate specimens (target not identified):  
• FOLFIRINOX (4 cycles)  
• Restaging* 
• Chemo radiation 
• Restaging* 

June 28 2018, Amendment 18 
23 
• Surgery which should occur 3-6 weeks after chemotherapy completion 
2.2.4. [Neoadjuvant] Preoperative Treatment 
2.2.4.1 [Neoadjuvant] Preoperative FNA Profiling Schema (Figure C page Error! Bookmark not 
defined.) 
2.2.4.2. [Neoadjuvant] Preoperative Treatment Regimens 
 
NOTE:  all pre-operative regimens (a-j) are identical to post-operative regimens (a-j); and post-
operative regimens (k-n) are not pre-operative options. 
 
When dose reductions are necessary, the treating physician will refer to current package 
inserts.  Dose reductions will be at the discretion of the treating physician who is expected to be in contact 
with the study team. 
a. Gemcitabine-based XRT Treatment Regimen: 
Chemotherapy: Gemcitabine 400mg/m2 IV at fixed dose rate, infused over 40 minutes on Day 1 (day -2 to 
+1), and then weekly x 6 during radiation therapy. 
Radiation: External-beam radiation therapy will be delivered 5 days/week over 5.5 weeks with  6-18-
MeV photons. Using 3D conformal or IMRT techniques, patients will receive a total dose of 50.4 Gy 
prescribed to the 95% isodose at 1.8 Gy/fraction (28 fractions).2 
b. Capecitabine-based XRT Treatment Regimen: 
Chemotherapy: Capecitabine 825 mg/m2 orally twice daily on Day 1 and continuing Monday through 
Friday during radiation. 
Radiation: External-beam radiation therapy will be delivered 5 days/week over 5.5 weeks with  6-18-
MeV photons. Using 3D conformal or IMRT techniques, patients will receive a total dose of 50.4 Gy 
prescribed to the 95% isodose at 1.8 Gy/fraction (28 fractions).13 
c. FOLFIRINOX Treatment Regimen: 
FOLFIRINOX:  On Day 1, oxaliplatin 85 mg/m2 IV infused over 120 minutes, irinotecan 180 mg/m2 IV 
infused over 90 minutes, leucovorin 400 mg/m2 IV infused over 120 minutes, followed by bolus 
fluorouracil (5-FU) 400 mg/m2 IV; followed by 5-FU 2,400 mg/m2 IV as a 46-hour continuous infusion, 
cycled every 2 weeks for a total of 2 months of therapy.14  
d. FOLFIRI Treatment Regimen: 
FOLFIRI: On Day 1, Irinotecan 180 mg/m2 IV infused over 90 minutes, leucovorin 400 mg/m2 IV infused 
over 120 minutes, followed by bolus fluorouracil (5-FU) 400 mg/m2 IV; then 5-FU 2,400 mg/m2 IV as a 
46-hour continuous infusion, cycled every 2 weeks for a total of 2 months of therapy. 
e. Gemcitabine w/irinotecan Treatment Regimen: 

June 28 2018, Amendment 18 
24 
Gemcitabine 1,000 mg/m2 IV infused over 30-40 minutes followed immediately by irinotecan 100 mg/m2 
IV infused over 90 minutes, both administered on Days 1 and 8 and cycled every 3 weeks for a total of 2 
cycles. 16 
f. Gemcitabine w/ oxaliplatin Treatment Regimen:  
Gemcitabine 1,000 mg/m2 IV infused over 30-40 minutes on Day 1 and a 2-hour infusion of oxaliplatin 
100mg/m2 IV on day 2, cycled every two weeks for a total of 3 cycles.17 
g. Gemcitabine w/ cisplatin Treatment Regimen: 
Gemcitabine 750 mg/m2 IV infused over 30-40 minutes and cisplatin 30 mg/m2 IV infused over 30 
minutes, cycled every 2 weeks for 3 cycles.18 
h. Gemcitabine/capecitabine Treatment Regimen: 
Gemcitabine 1000 mg/m2 IV infused over 30-40 minutes Days 1, 8 and 15 and capecitabine 825mg/m2 
orally twice daily on days 1- 21 cycled every 4 weeks for a total of 2 cycles.19 
i. Gemcitabine/nab-paclitaxel Treatment Regimen:  
Nab-paclitaxel 125 mg/m2 IV infused over 30-40 minutes (maximum infusion time not to exceed 40 
minutes) followed by gemcitabine 1000mg/m2 IV infused over 30-40 minutes on Days 1, 8, and 15, 
cycled every 28 days for a total of 2 cycles.21 
j. Capecitabine/nab-paclitaxel Treatment Regimen: 
Nab-paclitaxel 125 mg/m2 IV on day 1, 8 ) and capecitabine 825 mg/m2 PO BID days 1-14 on a Q3 week 
cycle.  Repeat for 3 cycles.22 
2.2.4.3. Disease Progression on Therapy 
 
If the patient has resectable disease that progressed locally, but remains resectable and had: 
 
  1.   Induction chemotherapy, then the patient may be given chemoXRT based on 
multidisciplinary review.  Restaging will be performed upon completion of therapy to assess 
resectability. 
 
  2.   ChemoXRT, then proceed to surgery. 
 3.   ChemoXRT with development of indeterminate liver or lung lesions and/or rising     
 
            CA19-9:  Add an additional 2 months of chemotherapy per PI discretion. 
  
            Restaging will be performed upon completion of therapy to assess resectability. 
 
If the patient had borderline resectable disease that progressed to locally advanced: 

June 28 2018, Amendment 18 
25 
 
  1.   Remove from treatment and place patient on survival follow up. 
 
If the patient has unequivocal metastatic disease on imaging studies: 
 
  1.   The patient will be considered inoperable, removed from treatment , and followed for 
survival. 
2.2.5. [Adjuvant] Pathways for all patients after Postoperative Restaging 
1. No evidence of disease, target is identified in surgical specimen, and molecular profiling is 
predictive:  
If neoadjuvant ChemoXRT has not been given: 2-4 months of best profile-directed therapy (See Figure D 
page 51). 
If neoadjuvant ChemoXRT has been given: 4 months of best profile-directed therapy.    (See Figure E 
page 52). 
 
2. No evidence of disease: target is not identified in the surgical specimen or target is identified in 
the surgical specimen and molecular profiling is not predictive:  
If neoadjuvant ChemoXRT has not been given:  
 2 months of Chemo/XRT or 
 2 months ChemoXRT and standard chemotherapy (See Figure D page 51). 
If neoadjuvant ChemoXRT has been given:  
4 months of systemic therapy – target not identified or SMAD4 loss or 
 No further therapy – SMAD4 intact (See Figure E page 52). 
 
3. 
Evidence of disease recurrence or metastasis:  
Off-treatment, and moved to follow-up (see Section 6.5 for Follow-up). 
2.2.6. [Adjuvant] Postoperative Treatment   
2.2.6.1  [Adjuvant] Postoperative Profiling Schema no prior XRT (Figure D page 51) 
2.2.6.2  [Adjuvant] Postoperative Profiling Schema when patient DID receive pre-operative XRT 
(Figure E page 52) 
2.2.6.3.  [Adjuvant] Postoperative Treatment Regimens 
 
NOTE:  all post-operative regimens (a-j) are identical to pre-operative regimens (a-j); and post-
operative regimens (k-n) are not pre-operative options: 
a. Gemcitabine-based XRT Treatment Regimen: 

June 28 2018, Amendment 18 
26 
Chemotherapy: Gemcitabine 400mg/m2 IV at fixed dose rate, infused over 40 minutes on Day 1 (day -2 to 
+1), and then weekly x 6 during radiation therapy. 
Radiation: External-beam radiation therapy will be delivered 5 days/week over 5.5 weeks with  6-18-
MeV photons. Using 3D conformal or IMRT techniques, patients will receive a total dose of 50.4 Gy 
prescribed to the 95% isodose at 1.8 Gy/fraction (28 fractions).2 
b. Capecitabine-based XRT Treatment Regimen: 
Chemotherapy: Capecitabine 825 mg/m2 orally twice daily on Day 1 and continuing Monday through 
Friday during radiation. 
Radiation: External-beam radiation therapy will be delivered 5 days/week over 5.5 weeks with  6-18-
MeV photons. Using 3D conformal or IMRT techniques, patients will receive a total dose of 50.4 Gy 
prescribed to the 95% isodose at 1.8 Gy/fraction (28 fractions). 13 
c. FOLFIRINOX Treatment Regimen: 
FOLFIRINOX:  On Day 1, oxaliplatin 85 mg/m2 IV infused over 120 minutes, irinotecan 180 mg/m2 IV 
infused over 90 minutes, leucovorin 400 mg/m2 IV infused over 120 minutes, followed by bolus 
fluorouracil (5-FU) 400 mg/m2 IV; followed by 5-FU 2,400 mg/m2 IV as a 46-hour continuous infusion, 
cycled every 2 weeks for a total of 2 months of therapy.14  
d. FOLFIRI Treatment Regimen: 
FOLFIRI: On Day 1, Irinotecan 180 mg/m2 IV infused over 90 minutes, leucovorin 400 mg/m2 IV infused 
over 120 minutes, followed by bolus fluorouracil (5-FU) 400 mg/m2 IV; then 5-FU 2,400 mg/m2 IV as a 
46-hour continuous infusion, cycled every 2 weeks for a total of 2 months of therapy.20 
e. Gemcitabine w/ irinotecan Treatment Regimen: 
Gemcitabine 1,000 mg/m2 IV infused over 30-40 minutes followed immediately by irinotecan 100 mg/m2 
IV infused over 90 minutes, both administered on Days 1 and 8 and cycled every 3 weeks for a total of 2 
cycles. 16    
f.. Gemcitabine w/ oxaliplatin Treatment Regimen:  
Gemcitabine 1,000 mg/m2 IV infused over 30-40 minutes on Day 1 and a 2-hour infusion of oxaliplatin 
100mg/m2 IV on day 2, cycled every two weeks for a total of 3 cycles. 17  
g. Gemcitabine w/ cisplatin Treatment Regimen: 
Gemcitabine 750 mg/m2 IV infused over 30-40 minutes and cisplatin 30 mg/m2 IV infused over 30 
minutes, cycled every 2 weeks for 3 cycles. 18  
h. Gemcitabine/capecitabine Treatment Regimen: 

June 28 2018, Amendment 18 
27 
Gemcitabine 1000 mg/m2 IV infused over 30-40 minutes Days 1, 8 and 15 and capecitabine 825mg/m2 
orally twice daily on days 1- 21, cycled every 4 weeks for a total of   2 cycles.  19 
i. Gemcitabine/nab-paclitaxel Treatment Regimen:  
Nab-paclitaxel 125 mg/m2 IV infused over 30-40 minutes (maximum infusion time not to exceed 40 
minutes) followed by gemcitabine 1000mg/m2 IV infused over 30-40 minutes on Days 1, 8, and 15, 
cycled every 28 days for a total of 2 cycles. 21 
j.  Capecitabine/nab-paclitaxel Treatment Regimen: 
Nab-paclitaxel 125 mg/m2 IV on day 1, 8  and  
capecitabine 825 mg/m2 PO BID days 1-14 on a Q3 week cycle.  Repeat for 3 cycles.22 
k. Gemcitabine alone Treatment Regimen: 
Gemcitabine 1000 mg/m2 IV infused over 30-40 minutes, cycled every week times 3 weeks; 1 week off 
and then 3 more weeks for a total of 6 cycles. 23 
l. Capecitabine alone Treatment Regimen:  
Oral capecitabine 1,250 mg/m(2) administered twice daily (2,500 mg/m(2)/d) in 3-week cycles consisting 
of 2 weeks of treatment followed by 1 week without treatment. 24 
m. 5FU alone Regimen:  
Give per physician discretion standard of care. 15,24 
n. No further treatment recommended:  
 Molecular profiling suggests that no further targets are identified.  
2.2.7. Outcome Measures 
 
Disease status will be assessed at each restaging evaluation (clinical parameters, CT and/or MRI 
imaging, tumor markers). If progression is not observed at the end of study therapy, patients will be 
assessed every 3 months (plus or minus a 1 month window) for the first 18 months after study therapy has 
ended and then every 6 months until 5 years after enrollment/registration. PFS and OS will be reported.  
Adverse events will be monitored and collected in a summary format summary format as delineated in the 
study calendar (sections 6.6 and 6.7). See Sections 8.1 and 8.2 for adverse event reporting details. 
 
 
 

June 28 2018, Amendment 18 
28 
3. PATIENT SELECTION 
3.1. Screening and Eligibility Criteria 
To be eligible to sign a screening consent (see Appendix I: Eligibility Checklist) patients must: 
• 
Have adenocarcinoma of the pancreas or highly suspicious for pancreas adenocarcinoma per CT 
or MRI 
• 
18 years of age or older 
• 
Able to understand and provide written informed consent or have Legally Authorized 
Representative (LAR) 
To be eligible to sign enrollment consent, the patient must have a confirmed diagnosis of pancreatic 
adenocarcinoma. After enrollment consent is signed, treatment eligibility is confirmed. If treatment 
eligibility is not met, the patient will be treated off study and will not be followed on study. 
3.1.1. Treatment Eligibility Criteria:  
• Enrollment consent must have been signed. 
• Have an ECOG performance status < 2  
• Have biopsy-proven, resectable (defined in Section 3.1.2) or borderline resectable (defined in 
Section 3.1.3) adenocarcinoma of the pancreas based on CT or MRI findings as detailed in Sections 
3.1.2 and 3.1.3.  Biopsy must be / have been completed within 2 months prior to molecular 
profiling. 
• Have adequate organ and bone marrow function as defined by:   
o  total leukocytes >3 x103/μL 
o  absolute neutrophil count (ANC) >1.5x 103/μL 
o  hemoglobin >9 g/dL  
o  platelets >100 x 10e3/μL 
o  creatinine clearance >60 mL/min or creatinine <1.5 mg/dL 
o  bilirubin < 2 mg/dL:  At two weeks from biliary decompression, if the subject’s serum 
bilirubin remains greater than two, but has demonstrated a progressive decline, the subject 
may be enrolled into the trial and appropriate modification and dose adjustments will be 
made to the predicted regimen. Eligibility of subjects whose bilirubin levels remain elevated 
above 2, without demonstrating a downward trend, will be determined at the discretion of the 
trial PIs and their treatment assignment. 
o  aspartate transaminases (AST/SGOT)  <3 x ULN 
o  alanine transaminases (ALT/SGPT)  <3 x ULN 

June 28 2018, Amendment 18 
29 
•  Female patients must be post-menopausal for > 1 year, surgically sterile, or have a negative 
pregnancy test and used at least one form of contraception for 4 weeks prior to Day 1 of the study, 
during study treatment and during the first 4 months after study treatment is discontinued. Male 
patients must be surgically sterile or use barrier contraception during the study and for 4 months 
after the last dose of any study drug. 
 
3.1.2.Definition of Resectable Pancreatic Cancer includes all of the following: 
• No evidence of extra pancreatic disease 
• No evidence of tumor-arterial abutment (celiac, SMA [superior mesenteric artery] or HA [hepatic 
artery]) 
• If tumor induced narrowing of the SMV [superior mesenteric vein], PV [portal vein] or SMV-PV 
[superior mesenteric-portal vein] confluence is present, it must be <50% of the diameter of the 
vessel 
•   Ca 19-9 <5000, when bilirubin is <2 
3.1.3. Definition of Borderline Resectable Pancreatic Cancer 
 
To include at least one of the following: 
• Tumor abutment <180° of the SMA or celiac axis 
• Tumor abutment or encasement of a short segment of the HA 
•  Tumor induced narrowing of SMV, PV or SMV-PV of >50% of the diameter of the vessel. 
• Short segment occlusion of the SMV, PV or SMV-PV with a suitable PV above and SMV below, for 
reconstruction 
• CT or MRI findings suspicious for, but not diagnostic of, metastatic disease (based on review at each 
site’s weekly multidisciplinary pancreatic cancer conference)  
• Biopsy proven N1 disease (regional lymph nodes involved) from pre-referral biopsy or EUS-guided 
FNA 
• Resectable tumor and CA 19-9 >5000 
3.1.4. Definition of Locally Advanced   
• Artery:  Tumor encasement (> 180°) of SMA or celiac artery 
• Vein  Occlusion of SMV, PV or SMV-PV without suitable vessels above and below the tumor to 
allow for reconstruction (no distal or proximal target for vascular reconstruction) 

June 28 2018, Amendment 18 
30 
• Extra pancreatic disease:  No evidence of peritoneal, hepatic, or extra-abdominal metastases 
3.1.5. Definition of Metastatic Disease 
• Evidence of peritoneal or distant metastases 
3.2. Exclusion Criteria 
 
Any patient with one or more of the following will be excluded:  
• Have received chemotherapy or chemoradiation within  5 years prior to study enrollment 
• Have any previous history of another malignancy (other than cured basal or squamous cell 
carcinoma of the skin or cured in-situ carcinoma of the cervix) within 5 years of study enrollment 
• Uncontrolled co morbidities including, but not limited to, ongoing or active serious infection, 
symptomatic congestive heart failure, unstable angina, unstable cardiac arrhythmias, psychiatric 
illness, excessive obesity, or situations that would limit compliance with the study requirements or 
the ability to willingly give written informed consent 
• Known HIV, HBV, or HCV infection 
• Pregnant or breast-feeding patients or any patient with child-bearing potential not using 
contraception 4 weeks prior to treatment 
4. INFORMED CONSENT 
 
The principles of informed consent will be strictly adhered to as dictated by the policies and 
procedures of the local approving IRB. Screening consent for tumor biopsy and enrollment consent for 
participation in the study will be obtained and documented. Patients who develop metastatic disease may 
choose to participate in additional translational correlative studies and will be asked to sign a separate 
consent for tissue procurement and molecular analysis. 
5. SCREENING AND ENROLLMENT 
 
Investigators or their appropriate designees will identify potentially eligible patients from their 
clinics, patient self-referrals, or referrals from other clinicians. Inclusion/exclusion criteria will be 
reviewed and patient eligibility will be confirmed after both screening and enrollment consents are signed 
and screening is complete.  Globally, it is expected that approximate 288 patients will sign screening 
consents; 168 will sign enrollment consents.  Of those 168, we expect 38patients to exclude before 
treatment starts and 130 will start study treatment globally. Of these global patients,  up to 10 patients will 
sign screening consents and up to 6 will sign enrollment consents at our participating site, the University 
of Cincinnati.  Of those it is expected that up to 4-6 will start treatment at the University of Cincinnati. 

June 28 2018, Amendment 18 
31 
 
If the patient (or LAR, legally authorized representative) agrees to study participation, first, he/she 
must provide signed informed consent for study screening.  After signing a screening consent form, each 
patient will be assigned a unique subject number. The investigator will then request a biopsy (EUS/FNA 
preferred) to obtain a tumor sample for the study if not already available. The tumor biopsy must be 
performed within 2 months prior to analysis, and the patient must not have any intervening anticancer 
treatment between the time of the biopsy and the IHC and microarray analysis. 
 
When histology from the tumor biopsy confirms pancreatic adenocarcinoma, the patient will sign the 
enrollment consent and be evaluated for all inclusion/exclusion criteria. If all criteria are met, the subject 
will undergo study treatment.   Neoadjuvant treatment must be initiated 0-4 weeks after signing the 
enrollment consent form. 
6. CLINICAL MEASUREMENTS AND PROCEDURES 
6.1. Methodology for Obtaining FNA Specimen 
 
Patients, who do not have biopsy-confirmed diagnosis of pancreatic cancer and a cell block available 
for molecular analysis, or, who have specimens that are inadequate for molecular characterization, 
mayundergo an EUS/FNA biopsy. During EUS/FNA, extra passes will be obtained for processing into 
cell blocks that will be utilized for molecular profiling.  
 
The study laboratory manual describes the methodology to be followed by the endoscopist for 
obtaining FNA specimens. See Laboratory Manual: Section 2:  Fine Needle Aspirate Sample Collection 
(Appendix J). The endoscopist may alter the procedure as required for clinical purposes as technology 
evolves.  
6.2. Methodology for Processing FNA Specimen and Shipping to Coordinating Site 
 
The cell blocks will be made at the site where the subject is enrolled. Slides will also be made at 
either the participating site or the coordinating site. The participating site will ship cell blocks and, if 
available, slides to the coordinating site. The study laboratory manual describes the methodology to be 
followed for processing FNA specimens and shipping. See Laboratory Manual (Appendix J). Laboratory 
procedures may be revised as required to maximize processing quality. 
6.3. Characterization of Specimen 
6.3.1. Overview 
 
After a diagnosis of pancreatic adenocarcinoma has been histologically confirmed, the remaining cell 
block will be used to perform further characterization of the tumor using IHC for the targets of interest.   

June 28 2018, Amendment 18 
32 
6.3.2. Immunohistochemistry 
 
Immunohistochemical staining for MASPIN, S100P, RRM1, ENT1, TYMS, TOP1, ERCC1, SPARC, 
and SMAD4 will be performed using the available cell block.  The antibodies will be purchased from 
commercially available sources and the staining procedure has been optimized on retrospective cell 
blocks. IHC evaluation will be made using appropriate positive and negative controls.  (See Table 1 (page 
20)  for interpretation of staining intensity and percent stain).26  
6.3.3. Molecular Analysis 
 
If adequate specimen is available, RNA and/or DNA will be extracted from the available cell blocks.  
Gene expression will be done on the following genes:   RRM1, ENT1, TYMS, TOP1,ERCC1, and 
SPARC. Expression levels will be normalized to GUSB which is a housekeeping control 
gene.  Mutational analysis is done using a single pool of primers to perform multiplex PCR for 
preparation of amplicon libraries from genomic "hot spot" regions and/or all-exon coverage of genes that 
are frequently mutated in human cancer genes. (See the study Lab Manual for a representative list of these 
genes). 
6.3.4 Communication with treating physicians regarding STREET profiled therapy 
 
The staining pattern of the STREET panel will be reviewed in a multi-disciplinary conference at 
the coordinating site and a final treatment plan determined.  The treatment plan will be communicated to 
the Principal Investigator or his/her designee at the participating site and to treating physicians. 
6.3.5 Radiation Therapy Data Review  
 
Unique to this study is that patients have been able to receive the nonsurgical components of 
their treatment either here at Froedtert and the FMLH/MCW affiliates or at outside institutions.  There 
is interest in reviewing all of the radiation therapy data for quality, including adherence to the protocol 
radiation dose/volume guidelines as well as reviewing contouring of targets and organs at risk, dose 
volume histograms, and dose distributions, and correlating this with outcome.  There is data from 
national cooperative postoperative radiation trials, used for the treatment of pancreatic cancer, which 
reveal the difference in local control and survival that adherence to protocol parameters and radiation 
quality can make.  We would like the opportunity to extend this review to this protocol and specifically 
focus on the quality of the radiation delivered both here at FMLH/MCW and outside of our institution.  
This will entail obtaining all of the radiation treatment planning records from the participants in the 
study with review of the contours, dose distribution, dose volume histograms, and patterns of 
recurrence to support the impact on local control and survival that the quality of the radiation delivered 
in the neoadjuvant and adjuvant setting can make. 
6.4. Study Assessments 
 
Patients will be evaluated as outlined in the study schema (see Sections 6.6 and 6.7).  
1.   Prior to neoadjuvant therapy 

June 28 2018, Amendment 18 
33 
2.   After 2 months of neoadjuvant therapy if 4 months of neoadjuvant therapy are planned     
(responding or stable disease) 
3.   Prior to surgery with assessment of disease status (responding or stable disease) or progressing 
but still operable. 
4.   1-3 months after surgery / prior to adjuvant treatment with assessment of disease status.  
5.   After 2 months of adjuvant therapy if 4 months of adjuvant therapy are planned.  
6.   After final study therapy is complete with assessment of disease status.  
7.   Hematology will include CBC with differential including platelet count and hemoglobin. 
Biochemistry will include ALT/SGPT, AST/SGOT, total bilirubin, and GFR or creatinine.  
Tumor markers will include Ca 19-9 (for patients who express Ca 19-9), and CEA. 
6.5. Follow-up 
 
If a subject discontinues for any reason, molecular profile results will be given to the subject’s 
physician to consider alternative therapies. 
• Patients with inoperable disease progression will come off treatment and be followed for survival 
every 6 months. 
• For patients without inoperable disease progression at the end of therapy, tumor assessments are to 
be undertaken every 3 months (plus or minus a 1 month window) for the first 18 months, then every 
6 months for years until 5 years from enrollment on study.  
 
 

November 24, 2015, Amendment 13 
 
34 
 
 
Visit Number:
1
2
3
4
5
6
~7
~8
~9
~10
11-17+
NA
Visit Name:
Screen                   0-
3 weeks
Enroll / Stage     
0-4 wks
Chemo or ChemoXRT  
5-12 weeks
#1          Restage   
0-6 weeks
Surgery          one 
day             
#2          Restage   
4-12 weeks
Chemo             
5-12 weeks
#3          Restage   
0-6 weeks
Chemo or ChemoXRT  
5-12 weeks
#4          Restage   
0-6 weeks
On Study      FU q 
12 weeks x 6,  
then q 6 mos
Survivial FU       q  
6 mos
X
X
X
X
X
X
X
X
X
(X)
(X)
(X)
(X)
(X)
(X)
 
X
X
X
X
X
X
X
X
X
Multidisciplinary 
Review  
X
X
X
X
X
X
Demographics
Medical History 
Phys Exam
X 
X 
X 
X 
Tumor markers
Ca 19-9, CEA
X
X
X
X
Hematology
X
X
X
X
Biochemistry
X
X
X
X
Pregnancy test - as per standard †
X†
X†
X†
ECOG Performance Status  !!
!!  X
X
X
X
X
X
Confirm weekly that scheduled treatment is on track (patients being treated outside MCW system only
X
X
X
X
X
X
X
X
Survival assessment 
X
X
◘     MRI abd/pelvis using a 3.0 Tesla see Section 7.2.3.       PET & MRI at Baseline & for  RESECTABLE at restage 1; for  BORDERLINE at restage 1 and/or  restage  2.
     When it is determined a patient's disease has progressed, the patient will move to off-study follow-up.
*       Pre-study tests and examinations are required within 6 weeks prior to treatment onset unless otherwise specified.
!!       ECOG must be < 2 at onset of initial treatment;                                                                ECOG above 2 after onset of initial treatment is captured in AE assessment.
    Physical Exam to include: vital signs, weight, review of systems, symptom assessment, and should be completed at least once from one staging to the next.
  Bilirubin must be < 2 when measuring Ca19-9. Only necessary for patient who express the CA19-9.
~       RESECTABLE patients On Study will participate in Visits 1, 2, 3, 4, 5, 6 & 11-17+.            Visits 7, 8, 9 & 10 may or may not occur depending on the molecular profile. 
confirm inclusion just prior to onset of tx
Inclusion Checklist
dALT/SGPT, AST/SGOT, AlkP, total 
bilirubin, GFR or creatinine
X 
X† 
X 
X 
*Standard           
Care                  
Activities
Most 
Recent
CBC with differential including 
platelet count and hemoglobin 
X 
Staging determined; when applicable, protocol-directed 
standard care tx recommendations provided to treating MD
 X 
X 
X 
 ◘Imaging:  PET & MRI  (per MD discretion)  (standard care activity)
STREET Profiling of tissue
6.6 Schedule of Visits, Procedures and 
Laboratory Tests 
Resectable Arm Schedule of Events
SCREENING CONSENT
X 
Adverse event assessment    
Imaging:      CT abd & pelvis    with    Chest CT or Chest Xray (standard care activ
ENROLLMENT CONSENT sign after bx confims diagnosis; pt may still exclude la
X 
biopsy must not be older than 2 months at 
time of molecular profiling
Obtain tissue                             
and ship to central site 
collect prior to start of therapy                                 
(x) = may collect at OR and/or at any restage
AT Coordinating SITE ONLY           
Blood for research                         

June 28 2018, Amendment 18 
35 
 
Visit Number:
1
2
3 ~
4 ~
5
6
7
8
9~
10~
11~
12~
13-19+
NA
Visit Name:
Screen                   0-
3 weeks
Enroll / Stage     
0-4 weeks
Chemotherapy   
8-12 weeks
#1          Restage   
0-2 weeks
Chemo XRT        5-
7 weeks
#2          Restage   
3-6 weeks
Surgery          one 
day             
#3          Restage   
4-12 weeks
Chemotherapy   
8-12 weeks
#4          Restage   
0-2 weeks
Chemotherapy   
8-12 weeks
#5          Restage   
0-2 weeks
On Study      FU q 
12 weeks x 6,  
then  q  6 mos
Survival     FU   q  
6 mos
X
X
X
Adverse event assessment  
X
X
X
X
X
X
X
(X)
(X)
(X)
(X)
(X)
(X)
(X)
X
X
X
X
X
X
X
X
X
X
X
Multidisciplinary 
Review  
X
X
X
X
X
X
X
Demographics
Medical History 
Phys Exam
X
X
X
X
X
Tumor markers
Ca 19-9, CEA
X
X
X
X
X
Hematology
X
X
X
X
X
Biochemistry
X
X
X
X
X
Pregnancy test - as per standard †
X†
X†
X†
X†
ECOG Performance Status 
!!  X
X
X
X
X
X
X
Confirm weekly scheduled treatment is on track (patients beingtreated outside MCW system on
X
X
X
X
X
X
X
X
X
X
 
Survival assessment
X
X
 Bilirubin must be < 2 when measuring Ca19-9. Only necessary for patients who express the CA19-9.
ENROLLMENT CONSENT sign after bx confirmed diagnosis; pt may still exclude l
Imaging:      CT abd & pelvis    with    Chest CT or Chest Xray (standard care activ
 Physical Exam to include: vital signs, weight, review of systems, symptom assessment, and should be completed at least once from one staging to the next.
~       BORDERLINE patients On Study will participate in Visits 1, 2, 5, 6, 7, 8, 13-19+.     Visits 3,4,9,10,11,& 12 may or may not occur depending on the molecular profile. 
 ◘     MRI abd/pelvis using a 3.0 Tesla see Section 7.2.3.       PET & MRI at Baseline & for  RESECTABLE at restage 1; for  BORDERLINE at restage 1 and/or  restage  2.
 When it is determined a patient's disease has progressed, the patient will move to off-study follow-up.
*       Pre-study tests and examinations are required within 4 weeks prior to treatment onset unless otherwise specified.
!!       ECOG must be < 2 at onset of initial treatment;                                                                ECOG above 2 after onset of initial treatment is captured in AE assessment.
confirm inclusion just prior to onset of tx
Inclusion Checklist
 X† 
STREET Profiling of tissue
X 
6.7  Schedule of Visits, Procedures and 
Laboratory Tests 
Borderline Resectable Arm
SCREENING CONSENT
Obtain tissue                             
and ship to central site 
biopsy must not be older than 2 months at 
time of molecular profiling
 X 
Staging determined; when applicable, protocol-directed 
standard care tx recommendations provided to treating MD
X 
*Standard           
Care     
Activites
Most 
Recent
CBC with differential including 
platelet count and hemoglobin 
dALT/SGPT, AST/SGOT, AlkP, total 
bilirubin, GFR or creatinine
     X 
X 
X 
X 
 X 
 X 
collect prior to start of therapy                                 
(x) = may collect at OR and/or at any restage
AT Coordinating SITE ONLY           
Blood for research                         
   ◘Imaging:  PET & MRI  (per MD discretion) (standard care activity) 

November 24, 2015, Amendment 13 
36 
 
7. ASSESSMENT OF ACTIVITY 
7.1. Definition of Treatment Response 
 
Response to neoadjuvant therapy will be assessed at the time of restaging and recorded as: 
1.  Clinical benefit: defined as stable or improved performance status 
2.  Biochemical benefit:  defined as a stable or lower Ca19-9 in those patients whose Ca19-9    was 
abnormal at the start of therapy 
3.  Radiographic benefit:  the absence of disease progression and a primary tumor which is  smaller 
(as assessed by measurement of the maximum transverse diameter of the tumor) 
All patients who receive at least 2 treatment cycles and undergo at least one on-study disease 
assessment or experience early progression will be considered evaluable for response.  
7.2. Evaluation of Treatment Response 
7.2.1. CT Imaging 
 
Imaging studies will be reviewed at the respective site by abdominal imaging specialists. Tumors will 
be assessed at the established staging intervals by CT scan of the abdomen/pelvis and CT of chest or 
Chest X-ray. Treatment response will be classified by the RECIST version 1.1 criteria (see Appendix G). 
In addition, tumors will be assessed for conversion of tumor from borderline resectable to resectable 
based on previously defined criteria.  For progression that is operable vs. inoperable progression see 
sections 3.1.2., 3.1.3., and 3.1.4.  
7.2.2. PET-Scan Imaging 
 
18F-FDG PET scans from the coordinating site will be evaluated semi quantitatively by SUV analysis. 
SUV’s normalized to injected activity, patient's body weight and hyper metabolic activity in the 
cerebellum will be calculated from the mean activity concentration in the tumor VOIs between 40 and 70 
min after injection, which is the last time frame of the dynamic scan. A volume-weighted mean value of 
each PET scan will be derived from all lesions to give one average SUV (SUVavg) for each PET scan. The 
percentage change in SUV between the 18F-FDG PET at baseline and at completion of neoadjuvant 
therapy will be calculated.  PET scans are per physician discretion.   
7.2.3. Diffusion Weighted MRI Imaging 
 
At the coordinating site, diffusion-weighted MRI of the abdomen will be performed by a 
commercially available 3.0 tesla MRI system with a coil combination as appropriate for patient body 
habitus. The protocol will include standard T1 and T2 weighted sequences, in and out of phase imaging, 
and pre- and post-contrast imaging with the standard gadolinium-based contrast agents used in abdominal 

June 28 2018, Amendment 18 
37 
imaging. A power injector will be used for the intravenous administration of the contrast agent to ensure 
correct timing of the early arterial, late arterial/parenchymal and venous phase. Diffusion weighted 
imaging will also be performed. Apparent diffusion coefficient (ADC) maps will be generated by the 
console from the diffusion weighted imaging data. The ADC map will be used to determine the hyper 
cellular/malignant portions of the tumor. Tumor response assessments will be made based on the 
anatomic and functional comparison of the tumors before and after therapy.  MRI’s per physician 
discretion. 
7.2.4. Biochemical Testing 
 
Ca19-9 will be evaluated serially in all patients with documented elevated Ca19-9 at initial screening. 
The Ca19-9 value documented at study inclusion and subsequent staging is considered reliable 
(evaluable) when bilirubin is <2. 
7.3. Survival  
 
PFS will be calculated only in patients who underwent resection, from the date of cytologic or 
histologic diagnosis until the date of recurrence or the last date at which the patient was known to be free 
of disease.  OS will be calculated from the date of cytologic or histologic diagnosis until the date of death 
or last contact.  
 
OS and PFS will be calculated on all treated patients. Patients without disease progression at 5 years 
will be censored at that time. Patients lost to follow-up without documented disease progression will be 
censored at the time of last contact.  This is also true of patients discontinuing due to toxicity. Patients 
undergoing post-study therapeutic surgery/resection or radiation prior to progression will be censored at 
the initiation of that therapy if all macroscopic evidence of the tumor was resected. The date of 
progression will be the earlier of the dates of progression determined by CT or MRI imaging (increased 
lesion size, new metastases, new arterial/venous involvement) and rising Ca19-9 if the patient produces 
Ca19-9.  
8. ASSESSMENT OF SAFETY, RISKS, AND BENEFITS 
8.1. Adverse Events 
8.1.1 Recording Adverse Events 
 
An adverse event is defined as any untoward medical occurrence temporally associated with any 
study procedure or treatment, regardless of whether it is considered related to the study procedure or 
treatment. This includes changes in laboratory parameters. The National Cancer Institute Common 
Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.0 will be used to grade adverse events (see 

June 28 2018, Amendment 18 
38 
Appendix C). All unexpected grade 3 and all grade 4-5 adverse events (AE) occurring during the study 
protocol will be recorded, noting severity and causality. AE’s will be collected in a summary format as 
delineated in the study calendar (sections 6.6 and 6.7). 
8.1.2 Reporting Adverse Events (AE) 
 
AEs will be recorded in OnCore and an alert of a new AE will be sent to the multicenter study 
coordinator.  AE reporting to the IRB will be per policy of the approving IRB (for the coordinating site, 
see Appendix D Medical College of Wisconsin Office of Research SOP Requirements for Reporting to 
the IRB).  See Appendix N for the communication plan for participating site reporting of SAE’s to 
the coordinating site. 
8.2. Serious Adverse Events (SAEs) 
 
All SAEs, whether or not considered related to a study procedures or treatments, occurring during the 
study protocol or within 24 hours of coming off protocol, will be recorded. An SAE is any untoward 
medical occurrence that results in: (1) death including all deaths occurring within 4 weeks of the last 
treatment administration, (2) life-threatening events, (3) events requiring hospitalization or prolonged 
hospitalization, or (4) events which are incapacitating, or permanently disabling. Medically important 
events that may not be immediately life-threatening, or result in death or hospitalization, but may 
jeopardize the patient or require intervention to prevent one of the other listed above outcomes, will be 
considered serious. If the patient dies, any post-mortem findings including histopathology must be 
provided. SAE reporting to the IRB will be per policy of the approving IRB. See Appendix N for the 
communication plan for participating site reporting of SAE’s to the coordinating site.  
8.3. Study Risks 
 
The known risk associated with participating in this study is similar to the risk of standard care. All 
activities of the study are standard care except for the risks of obtaining extra passes during the EUS/FNA 
(at screening), and obtaining up to 10 blood draws of 30 cc of extra blood at several time points during 
the study.  Research blood will be obtained only for subjects enrolled at the coordinating site. 
8.3.1. Known Risks 
The slight risk of extra passes during FNA represents an increase in the already standing risks 
associated with EUS/FNA. Because this study takes extra samples during the routine FNA procedure, the 
extra risks of the research are the additional side effects that could occur because the procedure will last a 
few minutes longer and because the FNA will require several additional samples.  

June 28 2018, Amendment 18 
39 
 
Less frequent side effects related to EUS include drug reaction from medication for sedation, 
irritation and/or tenderness at the site of sedative injection, including the rare chance of clotting at the 
vein. A rare side effect of EUS is perforation of the GI tract requiring surgical repair.  
 
Less frequent side effects of FNA include infection. Rarely, pancreatitis can occur and usually 
resolves with conservative treatment within a few days. Very rarely, surgery would be required for 
pancreatitis. Another rare side effect of FNA is minor bleeding where the needle is passed through the gut 
wall. Very rarely, unusual bleeding may require hospitalization and/or blood transfusion and/or surgery.  
8.3.2. Risk Discussion 
 
This study is assessing a treatment approach. It is not assessing safety or efficacy of the individual 
therapies. This study is isolating a prescriptive approach (molecular profiling) that relies on clinical 
application of the results of studies involving tumor biomarkers (targets) to identify best treatments.  The 
major risk is that conclusions from recent scientific studies (focused on treating the individual pancreatic 
tumor based on biomarkers specific to the tumor itself) will not support treatment decisions equally or 
better than the earlier scientific studies that were focused on the treatment response of groups of patients 
and that are currently used by many oncologists as the basis of their prescriptive decisions. The 
prescriptive approach that is the focus of this study is currently used as standard care by some clinicians 
(such as academicians who stay current with recent research), yet this prescriptive use is disparate within 
the larger oncology community, thus requiring future research. 
 
The discussion of risk (other than the risks of blood draw and extra passes during FNA), therefore, 
falls to the oncologist’s standard discussion of risk with his/her patient when prescribing the FDA-
approved treatment that is identified as the appropriate treatment.  
8.4. Study Benefits 
 
This is a new treatment approach, and the exact degree of efficacy is unknown. The patient may 
benefit from participating in this study by having a better chance of successful resection of his/her tumor.  
The knowledge gained from this study may benefit future patients with pancreatic adenocarcinoma. 
9. PATIENT DISCONTINUATION 
 
If an investigator removes a patient from the study or if the patient declines further participation, a 
final assessment of the patient’s disease status should be performed prior to any therapeutic intervention. 
These results, along with a reason for study discontinuation will be recorded. The status of a patient who 
is discontinued for purposes other than recurrent or metastatic disease should be monitored in on-study 
follow-up (see Section 6.5) whenever possible as long as the patient agrees. Patients will discontinue 

June 28 2018, Amendment 18 
40 
treatment if any of the following occur: (1) recurrent or metastatic disease, (2) unacceptable toxicity, (3) 
patient withdrawal of consent, (4) investigator decision, or (5) non-compliance. 
10. DISCONTINUATION OF THE STUDY 
 
The entire trial will be stopped if evidence has emerged that makes the study continuation 
unnecessary or unethical or when the stated objectives are achieved.  
11. STATISTICAL METHODS 
 
Assumptions: 
1.  60% of the patients are borderline resectable 
2.  Resectable patients have a resectability rate of 80% 
3.  Borderline resectable patients have a resectability rate of 60% 
4.  Two-sided 5% significance level, 80% power 
 
Assumptions for effect on survival 
1. The median survival is 40 months for those who are resected, and 12 months for those who are not 
resected.  
2.   Exponentially distributed survival time for resected and non-resected patients. 
 
Some implications: 
1.   The overall resectability rate is 69% 
2.   Median survival of all resectable patients is 23.7 months 
3.   Median survival of all borderline resectable patients is 18.3 months 
4.   Median survival of all patients is 20.2 months 
5.   170 historical controls  
6.   120 study subjects  
7.   Primary outcome: resectability rate 
8.   Secondary outcomes: overall survival, progression-free survival 
 
     The proportion of patients whose tumors are successfully resected will be compared between the 
historical controls and the experimental group via a Mantel-Haenszel test with two strata: resectable 
tumors and borderline resectable tumors. We expect 60% of the patients to fall into the borderline 

June 28 2018, Amendment 18 
41 
resectable stratum. With 170 control patients and 120 patients in the experimental group the study will 
have an 80% power to detect an increase in resectability if the true odds ratio is 2.35.. This corresponds to 
an increase of resectability from 60% to 78% for borderline resectable patients, and from 80% to 90% for 
resectable patients, and a 85% overall rate of resectability. 
 
Assuming that all the gains for survival will be from moving patients from the non-resected to the 
resected group, and that survival has an exponential distribution, the median survival should improve 
from 23.7 months to 30.7 months among resectable patients, from 18.3 months to 24.5 among borderline 
resectable patients, and from 20.2 months to 26.8 months overall. 
      Overall survival will be calculated from the date of cytologic or histologic diagnosis until the date of 
death or last contact; time to progression will be calculated only in patients who underwent resection, 
from the date of cytologic or histologic diagnosis until the date of recurrence or the last date at which the 
patient was known to be free of disease. The survival curves will be estimated using the Kaplan-Meier 
method, and the two groups will be compared via a stratified log-rank test at a two-sided 5% significance 
level. 
12. ADJUNCT TRANSLATIONAL STUDIES at Coordinating Site only 
12.1. Generation of Direct Xenograft Tumors 
12.1.1. Rationale 
     The identification of the molecular targets prior to treatment allows for the selection and early delivery 
of optimal therapeutic regimens. While response to therapies may be guided by molecular phenotypes, it 
is still unclear which individual targets may be of greatest therapeutic value. In order to address this 
problem, we propose to implant human pancreas tumors in mice. By establishing a renewable xenograft 
model from resected human tumors, tumor samples can be expanded and characterized in depth at the 
genetic and epigenetic levels. The major advantage of utilizing human pancreatic xenografts lies in the 
ability of the tumor to maintain an identical genetic and morphological phenotype to the primary tumor. 
In addition, it appears that no major variations in the status principal genes are mutated through early 
passaging of carcinoma in mice, suggesting that the fundamental pathogenetic elements remain 
stable.25This murine model can be used to apply, test, and validate novel treatment regimens. Therefore, 
the efficacy and pharmacodynamic effect of multiple single treatments or combination of treatments on a 
single tumor may be examined in manner which may not be feasible in a clinical trial setting. 
Furthermore, the xenograft models may be used to study other aspects of tumor biology including 
angiogenesis, tumor microenvironment, and cancer stem cells. 

June 28 2018, Amendment 18 
42 
 
This protocol provides us with an opportunity to assess the feasibility of generating xenografts of 
resected and metastatic tumors. To generate human pancreatic cancer xenografts we would utilize a 
previously described method, which reported engraftment rates ranging from 20-100%.3 In this model, 
fresh human tumors are either implanted into immunodeficient mice in an orthotopic or heterotopic 
fashion. The tumors are then expanded and may be stored for further use. The primary determinants of 
successful tumor engraftment are related to the viability, sterility, and processing time of the specimen. 
This protocol will allow us the opportunity to implement and further refine the procurement and 
processing of resected tumors to optimize xenograft engraftment.  
12.1.2. Murine Model 
 
NOD/SCID mice will be utilized in the generation of xenograft tumors as this model has been 
demonstrated to have superior efficiency of tumor formation. The mice will be housed in specific 
pathogen-free conditions to prevent sickness and infectious outbreak. After implantation the mice will be 
monitored regularly for general health and weekly body weights will be obtained. All animal-related 
protocols will be submitted for the Institutional Animal Care and Use Committee (IACUC) review and 
approval. See Laboratory Manual: Section 3 for details of tumor engraftment and expansion (Appendix 
J).  Laboratory procedures may be revised as required to maximize processing quality. 
12.2. Characterization of Resected Primary & Metastatic Tumors 
12.2.1. Rationale 
 
The expected CR response after neoadjuvant chemo radiotherapy for pancreatic cancer is 
approximately 1%. Even in the setting of favorable clinicopathologic features such as node negativity and 
negative margins, the majority of pancreatic cancers will recur. Following completion of neoadjuvant 
therapy, the residual viable tumor present in the resected primary specimen may represent a population of 
cells which are resistant to the administered therapy. Further characterization of the residual primary 
tumor may improve future treatment options for inevitably recurrent disease. 
 
Patients who develop metastatic disease may be candidates for biopsy or resection of these 
lesions. Further analysis of metastatic lesions may potentially provide important information regarding 
the pathogenesis of genetic alterations which are associated with pancreatic cancer metastases or 
molecular biologic correlates of adjuvant therapy failure. Importantly, unlike previous rapid autopsy 
series, resection of evolving metastatic lesions allow for further insight into the temporal sequence of 
genetic alterations leading to cancer metastases and death. This protocol will allow patients to have 
repeated characterization of primary and metastatic tumors. 
12.2.2. Molecular Characterization of Primary Resected and Metastatic Tumors 

June 28 2018, Amendment 18 
43 
 
Residual and metastatic tumors will be assessed for phenotypic changes in histology. In addition, 
using IHC and quantitative real-time polymerase chain reaction (qRT PCR), the resected tumors will 
undergo molecular characterization of the previously tested targets: SPARC, RRM1, ERCC1, TYMS, 
TOP1 and hENT1. The initial tumor molecular phenotype will be compared to the subsequent resected 
tumor molecular phenotype to evaluate for changes suggestive of new chemotherapeutic resistance. 
12.2.3. Biomarkers in peripheral blood 
 
Inherent in the tumor biology of cancer, cells or cell components may be found within the blood 
stream prior to gross identification of metastatic disease either with radiographic techniques or at the time 
of surgery. We hypothesize that prior to the development of metastatic disease, circulating tumor cells or 
exosomes may be identified.  Using peripheral blood samples from patients at different stages of 
treatment, we plan to assess for changes in circulating tumor cell numbers.  In addition, we will evaluate 
changes in exosomal microRNA expression within patient serum as it relates to treatment and prognosis.  
Finally, we seek to be able to identify the presence of cell-free DNA as a marker of tumor stage and 
prognosis from patient plasma. 
13. ADMINISTRATION  
13.1. Training 
 
Investigator and staff training will be conducted to share information regarding study design, study 
requirements and amendments subsequent to study onset. 
13.2. Multi-site Approval and Activation 
The Multi-Site Research Coordinating Office is responsible for oversight of regulatory documentation for 
each Participating Institution(s).  Documents should be provided to the MCW CTO Coordinating Office 
either via the OnCore Clinical Trials Management System (CTMS) or by Fax (414) 805-9025.  For 
questions, please call (414) 805-9001.  See address and contact information; 
 
 
CCCTO Multi-Site Research Coordinating Office  
Medical College of Wisconsin/Cancer Center 
9200 W. Wisconsin Avenue 
Milwaukee, WI  53226 
Phone-(414)805-9001 Fax- (414) 805-9025 
E-mail-kjensik@mcw.edu 
 

June 28 2018, Amendment 18 
44 
See Appendix N for Procedures related to Multi-site Approval, Activation, Site Monitoring, and Ongoing 
Management 
13.2.1 Site Initiation 
 
Site initiation will be performed to assure that each Investigator and his/her staff understand the 
protocol, applicable regulations, human subject protections requirements, and the Investigator’s 
obligations.  The site initiation process will ensure that required documentation with the appropriate 
approval is in place prior to subject enrollment. 
13.2.2 Monitoring 
 
The Medical College of Wisconsin Cancer Center Clinical Trials Office will provide monitoring for 
this study.  The monitor(s) is qualified by training and experience to oversee the progress of the study at 
the participating site to ensure continuing adequacy of facilities and adherence to the clinical study 
protocol, and applicable regulations and laws that pertain to the conduct of the clinical study.  The 
monitor(s) will review the data collection and source documentation, the timely submission of accurate 
records to the Sponsor, and the maintenance of proper records.  A report will be written following site 
monitoring and a follow-up letter will be provided with a summary of findings. 
13.3 Modification of the Protocol 
 
Amendments to the study that could adversely affect patient safety, alter the scope of the 
investigation, the quality of the study, design, duration of therapy, number of patients or selection criteria 
must be made only after consultation with the Principal Investigators. These amendments must be 
submitted to and approved by the MCW IRB in accordance with MCW regulations.  Subsequently, the 
amended protocol must be submitted by the participating site to its local IRB for approval. 
13.4. Completion of Case Report Forms 
 
Case report forms will be used to collect and enter the data into an electronic database. Source 
documents, original reports and films, will remain in each respective institution’s medical records for 
future reference. Data will be collected according to research activities specified in Protocol Sections 6.6 
and 6.7. 
13.5 Access to Source Data and Study Documents  
 
Subject-specific Research Files (SsRF), maintained on site, will include study-specific source 
documents such as the Enrollment Checklist, the original signed consent and any additional source notes 
obtained by research personnel.  In addition, the SsRF will include copies of source documents (such as 
copies of lab or imaging reports or copies of Medical Record notes) as specified in Appendix N.  (See 
Appendix N for procedures regarding maintenance of Subject Research File). 

June 28 2018, Amendment 18 
45 
 
All study records and source data will be available for inspection by the study Coordinating 
monitor(s), IRB and other regulatory authorities.  The coordinating site and the participating site will 
record data associated with assessment of the primary objective; certain data associated with secondary 
objectives may be collected for patients enrolled only at the coordinating site (as noted by asterisks in 
Section 2.1.2 Secondary Objectives).  Once entered, data will be evaluated to ensure that it is complete, 
consistent and logically sound.  If changes to the data are required, all changes, reason for changes and 
persons making the changes will be documented. 
13.6. Data Safety Monitoring 
 
This study will be monitored by the FH/MCW Cancer Center Data Safety Monitoring Committee 
(FH/MCW CC DSMC).  A record of the membership of the FH/MCW CC DSMC will be maintained in 
the study research file and updated when membership changes. The FH/MCW CC DSMC will review 
DSM reports from the study PI semi-annually or more frequently if needed.  
 
Patients will be monitored throughout the course of therapy for toxicity. Safety evaluations will 
consist of physicians and/or their designees’ assessments and examinations and laboratory measurements 
prior to initiating each cycle of chemotherapy. For purposes of DSMB reporting, adverse events will be 
described and graded according the NCI Common Toxicity Criteria version 4.03 (see Appendix C). 
A summary of the FH/MCW CC DSMC activities are as follows:  
• 
Review the clinical trial for data integrity and safety.  
• 
Review all unexpected grade 3, and all grade 4, and 5 adverse events, as well as any others 
requiring expedited reporting as defined in this protocol. (Grades 4 & 5 events must be reported 
to the DSMC within 5 calendar days of study staff’s knowledge.)  
• 
Grade 4 (life threatening) hematologic toxicities are reported every 6 months. All other grade 4 
toxicities (life threatening) are reported within 5 calendar days.   
• 
Review all DSM reports.  
• 
Submit a summary of any recommendations related to study conduct.  
• 
Terminate the study if deemed unsafe for patients.  
 
A copy of the MCWCC Data and Safety Monitoring Plan and membership roster will be maintained in 
the study research file and updated as membership changes. The committee will review reports from the 
study PI twice annually (or more frequently if needed) and provide recommendations on trial 
continuation, suspension or termination as necessary.  
 
Any available DSMC letters will be submitted to the IRB of record as required. 
 
The participating site will submit DSMB reports to the Coordinating site, and the Coordinating site 
will forward all reports to the DSMB. 

June 28 2018, Amendment 18 
46 
 
13.7. Retention of Study Documentation 
 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. The patient’s involvement in the study 
should be clearly documented in the clinical records. Details are to include the protocol number, the 
patient’s identification number, the patient’s consent(s) to take part in the study, the date of all study visits 
and the dates of treatment. Copies of CRFs must be retained by investigators, for as long as legally 
required after completion of the study. All study data including master files, CRFs, source data, and 
correspondence with the Coordinating site, an IRB, or study subject will be stored for at least 10 years 
according to MCW Office of Research SOP (see Appendix E). 
 
Clinical study records will not be disposed of, nor custody of the records transferred, without prior 
Coordinating site approval. 
13.8. Ethics Consideration 
 
The study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines and the Office of Human Research Protection. The investigators will inform the 
IRB of subsequent protocol amendments. 
 
The investigator must inform the patient about the background and present knowledge of treatment 
via molecular profiling. The investigator must ensure the following items are discussed:  
1.   The patient must be provided the patient information and informed consent form consistent with 
the protocol version used and approved by the IRB. The patient must be informed that this is a new 
treatment approach and that the exact degree of efficacy is unknown, and that treating him/her will 
contribute to further knowledge. 
2.   The patient will be given time to discuss his/her participation with the investigator and members of 
their family. Before the patient is entered into the study, the patient’s written consent must be 
obtained. A copy of the signed consent form will be provided to the patient and the original scanned 
into the electronic database created for this study. 
3.   The patient may refuse to provide a biopsy or may refuse treatment proposed in the context of the 
study before or at any time during the study. Refusal to participate will involve no penalty or loss 
of benefits to which the patient is otherwise entitled. 
4.   An explanation of whom to contact for answers to pertinent questions about the research and the 
patient’s rights, and who to contact in the event of a research-related injury must be given to the 
patient. 

June 28 2018, Amendment 18 
47 
13.9. Publication Policy 
 
All the results are the property of the Principal investigators. Investigators may not submit for 
publication or presentation study results without allowing the PIs 30 working days to review and 
comment on the pre-publication manuscript. Co-authorship will be discussed and mutually agreed upon 
before submission of a manuscript to a publisher. 
 
 

November 24, 2015, Amendment 13 
48 
 
Figure A 
 

June 28 2018, Amendment 18 
49 
Figure B 
 

June 28 2018, Amendment 18 
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Figure C 
 

June 28 2018, Amendment 18 
51 
 
 
 
Resection Profiling (previous neoadj XRT) 
TYMS high & RRM1 high or 
hENT1- or Target not Identified 
Gem(-)/5FU(-) 
TYMS low & RRM1 high or hENT1 - 
Gem(-)/5FU(+) 
GTYMS high & RRM1 low & hENT1 + 
Gem(+)/5FU(-) 
Gem/Platin 
FOLFIRINOX 
Gem/nab 
Figure D 
FOLFIRI 
5-FU 
Gem/Irino 
Gem 
Profile Not Predictive 
ERCC 
expressn 
- 
+ 
TOPO 
expressn 
- 
+ 
SPARC 
expressn 
- 
+ 
ERCC 
expressn 
- 
+ 
TOPO 
expressn 
- 
+ 
SPARC 
expressn 
- 
+ 
Cape/nab 
SMAD 
expressn 
- 
+ 
Gem/Cape 
No further 
Rx 
Target not identified: 4 mo Gem/Cape  
TYMS low & RRM1 low & hENT1 + 
Gem(+)/5FU(+) 
Gem/Cap 
FOLFIRINOX 
ERCC 
expressn 
- 
+ 
SPARC 
expressn 
- 
+ 
Gem/nab 
TOPO 
expressn 
- 
+ 
FOLFIRI vs. 
Gem/Irino 

June 28 2018, Amendment 18 
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Figure E
 

November 24, 2015, Amendment 13 
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Appendices A – M (see separate Appendices document) 
 
 

June 28 2018, Amendment 18 
54 
14. REFERENCES 
 
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Evans DB. Long-term survival after multidisciplinary management of resected pancreatic 
adenocarcinoma. Ann Surg Oncol. 2009; 16(4):836-4 
2. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based 
chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin 
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3. Akita H, Zheng Z, Takeda Y et al. Significance of RRM1 and ERCC1 expression in 
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6. Rejiba S, Bigand C, Parmentier C et al. Gemcitabine-based chemogene therapy for 
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7. Iacobuzio-Donahue Christine A, Fu Baojin, et al.  DPC4 Gene Status of the Primary 
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8. Crane Christopher H, Varadhachary, Gauri R, et al.  Phase II Trial of Cetuximab, 
Gemcitabine, and Oxaliplatin Followed by Chemoradiation With Cetuximab for Locally 
Advanced (Tr) Pancreatic Adenocarcinoma:  Correlation of Smad4 (Dpc4) 

June 28 2018, Amendment 18 
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Immunostaining With Pattern of Disease Progression.  J Clin Oncol. 2011;29(22):3037-
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9.  Katz MHG, Pisters PWT, Evans DB et al.  Borderline resectable pancreatic cancer: the 
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adenocarcinoma (MPA): Preplanned interim analysis results of the PRODIGE 
4/ACCORD 11 trial. J Clin Oncol 28:15s, 2010 (suppl; abstr 4010). 

June 28 2018, Amendment 18 
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15. Van Rijswijk RE, Jeziorski K, Wagener DJ, Van Laethem JL, Reuse S, Baron B, Wils J, 
Weekly High-Dose 5-fluorouracil and Folinic Acid in Metastatic Pancreatic Carcinoma :  
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18. Varadhachary GR, Wolff RA, Crane CH et. al. Preoperative gemcitabine and cisplatin 
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19. Herrmann R, Bodoky G, Ruhstaller T et al. Gemcitabine plus capecitabine compared 
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cooperative oncology group. J Clin Oncol 2007; 25(16):  2212-2217. 
20. C. Neuzillet, O. Hentic, B. Rousseau, V. Rebours, L. Bengrine-Lefèvre, E. Raymond, P. 
Ruszniewski, C. Louvet, P. Hammel; Hôpital Saint Antoine, Paris, France; Hôpital 
Beaujon, Clichy, France.  FOLFIRI Regimen As Second-/Third-line Chemotherapy in 
Patients With Advanced Pancreatic Adenocarcinoma Refractory to Gemcitabine and 

June 28 2018, Amendment 18 
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Platinum Salts :  A Retrospective Series of 70 Patients. .J Clin Oncol 29: 2011 (suppl 4; 
abstr 272)Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz 
JJ. J Clin Oncol. 2002;20(1):160. 
21. Von Hoff DD, Ramanathan R, Borad M et al. SPARC correlation with response to 
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22. Somer BG, Schwartzbert, LS, Arena F, Epperson A, Fu D, Bortner B.V.  Phase II Trial of 
nab-paclitaxel (nanoparticle albumin-bound paclitaxel (ABX)) + capecitabine (XEL) in 
first-line treatment of metastatic breast cancer (MBC).  Journal of Clinical Oncology, 
2007 ASCOAnnual Meeting Proceedings Part 1. Vol25, No. 18S (June 20 Supplement), 
2007: 1053 
23. Burris HA, Moore MJ, Anderson J et al. Improvements in survival and clinical benefit 
with gemcitabine as first-line therapy for patients with advanced pancreatic cancer. J Clin 
Oncol 1997; 15(6): 2403-13. 
24. DeCaprio JA, Mayer RJ, Gonin R, Arbuck SG.   Fluorouracil and high-dose leucovorin in 
previously untreated patients with advanced adenocarcinoma of the pancreas :  results of 
a phase II trial.  J Clin Oncol. 1991;9(12):2128.   
25. Kamikozuru H, Kuramochi H, Hayashi K et al. ERCC1 codon 118 polymorphism is a 
useful prognostic marker in patients with pancreatic cancer treated with platinum-based 
chemotherapy. Internat J of Oncol. 2008; 32:  1091-1096. 
26. Friboulet L, Olaussen K, Pignon J,et al.  ERCC1 Isoform Expression and DNA Repair in 
Non-Small-Cell Lung Cancer.  N Engl J Med. (2013). 

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