Conditions: Pancreatic Cancer Pancreatic Adenocarcinoma Pancreas Ductal Adenocarcinoma
Keywords: Stereotactic Body Radiation Therapy Perioperative Therapy Resectable Pancreas Ductal Adenocarcinoma Borderline Resectable Pancreas Ductal Adenocarcinoma Nab-paclitaxel Abraxane Gemcitabine Neoadjuvant Therapy Adjuvant Therapy
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 48
Healthy volunteers: no

Brief summary:
The objective of this study is to estimate the R0 resection rate in patients with Resectable Pancreatic Ductal Adenocarcinoma (R-PDAC) as well as those with Resectable Pancreatic Ductal Adenocarcinoma (BR-PDAC) independently in response to neoadjuvant sequential therapy of combination nab-paclitaxel and gemcitabine followed by stereotactic body radiotherapy (SBRT).

Detailed description:
Patients in both cohorts will receive a total of 3 cycles of neoadjuvant combination chemotherapy of nab-paclitaxel and gemcitabine, followed by re-staging CT scan, if re-staging CT does not show evidence of metastatic disease. Patients will receive SBRT and definitive surgical resection. Subsequently, patients will receive 3 cycles of adjuvant combination chemotherapy of nab-paclitaxel and gemcitabine. Each cycle of combination chemotherapy will be a total of 4 weeks. Patients will be evaluated for response at completion of the 3 cycles of neoadjuvant combination chemotherapy with CT scans of chest, abdomen and pelvis. Patients will undergo surveillance CT scan at 3-month intervals until evidence of disease progression.

Arms:
arm 1: Nab-paclitaxel and gemcitabine, for R-PDAC patients enrolled in this trial, will be given in combination as neoadjuvant combination chemotherapy, followed by SBRT. This is will be followed up by surgical resection and an additional combination chemotherapy of nab-paclitaxel and gemcitabine as adjuvant chemotherapy. arm 2: Nab-paclitaxel and gemcitabine, for BR-PDAC patients enrolled in this trial, will be given in combination as neoadjuvant combination chemotherapy, followed by SBRT. This is will be followed up by surgical resection and an additional combination chemotherapy of nab-paclitaxel and gemcitabine as adjuvant chemotherapy.

Interventions: intervention 1: Nab paclitaxel intervention 2: Gemcitabine
Intervention descriptions: intervention 1: Nab-paclitaxel and gemcitabine, for R-PDAC patients, will be given in combination as neoadjuvant and adjuvant chemotherapy. Nab-paclitaxel will be administered by IV infusion at a dose of 125 mg/m2 over 30 minutes on Days 1, 8, and 15 of every 28-day cycle. Gemcitabine will be administered by IV infusion, immediately after the administration of nab-paclitaxel, at a dose of 1000 mg/m2 over 30 minutes on Days 1, 8 and 15 of every 28-day cycle. intervention 2: Nab-paclitaxel and gemcitabine, for BR-PDAC patients, will be given in combination as neoadjuvant and adjuvant chemotherapy. Nab-paclitaxel will be administered by IV infusion at a dose of 125 mg/m2 over 30 minutes on Days 1, 8, and 15 of every 28-day cycle. Gemcitabine will be administered by IV infusion, immediately after the administration of nab-paclitaxel, at a dose of 1000 mg/m2 over 30 minutes on Days 1, 8 and 15 of every 28-day cycle.

Protocol document:
Prot_SAP_ICF_000.pdf: 
 
 
 
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Protocol/COMIRB # 15-0150 
 
Version Date: 6.20.2017 
 
 
Title: 
 
Perioperative Therapy for Resectable and Borderline Resectable Pancreatic 
Adenocarcinoma with Molecular Correlates 
 
 
Lead Principal Investigator (“Lead PI”):  Colin D. Weekes – Harvard Cancer Center 
 
 
Translational Science Principal Investigator:  Lawrence Leichman – University of California San 
Diego 
 
Site Specific Principal Investigators (“PI”) 
 
Tanios Bekaii-Saab – Mayo Clinic - Arizona 
Aaron Scott – University of Arizona 
Wells Messersmith – University of Colorado 
Elliot Newman – New York University (NYU) 
 
Radiation Therapy Physician Coordinator:  Kevin Du - NYU 
 
Surgery Physician Coordinator:  Elliot Newman - NYU 
 
Gastroenterology Physician Coordinator:  Sachin Wani – University of Colorado 
 
Radiology Physician Coordinator:  Alec Megibow - NYU 
 
Statistician:  Judith Goldberg - NYU 
 
 
 


 
 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
This is an investigator-initiated study.  The lead principal investigator (PI), Colin D. Weekes, 
MD, PhD is conducting the study and acting as the sponsor.  As the sponsor-investigator, 
both the legal/ethical obligations of a PI and those of a sponsor will be followed. 
 
By my signature, I agree to personally supervise the conduct of this study and to ensure its 
conduct in compliance with the protocol, informed consent, Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) procedures, instructions from Sponsor 
representatives, the Declaration of Helsinki, International Conference on Harmonization 
(ICH) Good Clinical Practices (GCP) guidelines, and the applicable parts of the United States 
Code of Federal Regulations (CFR) or local regulations governing the conduct of clinical 
studies. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed 
about their obligations in meeting the above commitments.  
 
Study Protocol 
Number: 
COMIRB 15-0150 
Study Reference 
Number: 
AX-CL-PANC-AGICC-004253 
Study Protocol Title: 
Perioperative Therapy for Resectable and Borderline 
Resectable Pancreatic Adenocarcinoma with Molecular 
Correlates 
 
 
 
 
Sponsor-Lead Principal Investigator: 
 
 
 
 
Signature: ___________________________________ 
 
 
 
                   Colin D. Weekes, MD,PhD 
 
Date: _______ 
 
 
 
 
Site Principal Investigator: 
 
 
 
Signature: ___________________________________  
 
 
Printed Name: _______________________________ 
 
Date: _______ 
 
 
 
 
 
 
Protocol Synopsis 


 
 
 
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Study Rationale 
 
Pancreas Cancer. Despite accounting for only 3% of cancer incidence in the U.S. population, 
pancreas ductal adenocarcinoma (PDAC) was the 4th leading cause of cancer death in U.S. in 2012.1  
A successful, microscopically margin-negative R0 operation is the only potentially curative option for 
patients with PDAC.  However, only 20% of patients with this condition present with early stage 
disease amenable to curative resection. Even then, the 5-year overall survival rate after curative 
resection is approximately 20%.2  Thus, the overall 5-year survival rate for PDAC is 5-8%.   
 
Surgery.  Patients who are candidates for potentially R0 resections are now divided into two 
categories: “resectable” (R) or “borderline resectable” (BR).  Maurer et al first used the adjective 
“borderline” to describe PDACs that were between classically resectable and unresectable because 
of clear vascular invasion into critical arteries and veins.3   The clinical definition of borderline 
resectable pancreas ductal adenocarcinoma (BR-PDAC) has been largely based on multidetector 
computed tomography (CT).4  There is general agreement that the prognosis of BR-PDAC will be 
inferior to patients with resectable pancreas ductal adenocarcinoma (R-PDAC).5  Unfortunately, BR-
PDAC patients present more often than patients with classically R-PDAC.  While the definition of BR-
PDAC has been debated, for the purposes of this protocol, the 2014 NCCN guidelines will be utilized 
(see Eligibility Criteria). 
 
Adjuvant Therapy.  Postoperative gemcitabine or 5-Fluorouracil (5FU) improves the survival by a 
meager 10% after an R0 resection for patients with PDAC.6 Unfortunately, approximately 25% of 
patients do not receive any form of adjuvant treatment due to post-operative complications and/or 
poor performance status.  Moreover, 25% of patients who undergo curative surgery for resectable 
disease will experience rapid progression, which is a reflection of its aggressive tumor biology.  In 
this situation, these patients will not benefit from the extensive surgery for resection of their tumor. 
 
Neoadjuvant Therapy.  Neoadjuvant therapy offers advantages in the treatment paradigm of PDAC. 
The probability of delivering therapy prior to surgery is higher compared to initiation of adjuvant 
treatment. In a well-selected population, 90-100% of patients were able to complete the entire course 
of planned neoadjuvant treatment.7  Furthermore, neoadjuvant therapies may enhance the R0 
resection rates for the patient with BR-PDAC.8 This strategy also provides the opportunity to identify 
patients who would not benefit from curative R0 resection due to early disease progression during 
the short period of neoadjuvant therapy.9  Lastly, neoadjuvant therapy provides a window into 
effective postoperative therapy. 
      
 
Systemic Therapy.  Two combination chemotherapy programs have recently supplanted single-
agent gemcitabine in the treatment of patients with stage IV PDAC.  FOLFIRINOX, a three drug 
combination with 5FU, irinotecan and oxaliplatin improved survival for stage IV PDAC with 
performance status (PS) 0-1 by approximately 5 months over gemcitabine alone.10  The hematologic 
and clinical toxicities of FOLFIRINOX are formidable and most clinicians reserve this combination for 
patients younger than 70.  The combination of gemcitabine and nab-paclitaxel demonstrated a 
remarkably high response rate in association in prolonged median survival of 12.2 months in the 
phase II study.11 Interestingly, stromal SPARC was associated with longer OS when treated with this 
combination in the phase II trial (n=36).  Analysis of the subsequent phase III MPACT for stage IV 
PDAC patients with PS 0-2 demonstrated a response rate for gemcitabine and nab-paclitaxel of 23% 
with significant improvement in median overall survival (OS) compared to gemcitabine alone (8.5 
versus 6.7 months).12 A more accurate reflection of the value of stromal SPARC in survival outcomes 
and response rates will be informed by further analysis in the MPACT study.  Stromal SPARC was 


 
 
 
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neither prognostic nor correlated with response in the MPACT biomarker sample set (n=256), which 
was comprised primarily of metastatic tissue with only 11% of the samples from pancreatic lesions.13 
 
Stereotactic Body Radiation Therapy.  The role of radiation therapy in the treatment of locally 
advanced and postoperative adjuvant therapy for PDAC is controversial. Indeed, a current 
postoperative intergroup trial for PDAC patients who have undergone an R1 or R0 patients is testing 
6 cycles of gemcitabine alone versus 5 cycles of gemcitabine plus conventional radiation therapy.  
Conventional radiation therapy employs a relatively large field and treats patients to 5040 cGy over 
five weeks.14  The development of advanced imaging techniques has allowed for compensation for 
organ movement associated with respiration.  The administration of stereotactic body radiation 
therapy (SBRT) to extracranial organs is now feasible due to these advancements.15   
 
Modern studies have introduced multiple fractionation of dosing as well as decreasing the total 
administered dose.  Systemic chemotherapy has also been added to SBRT in an attempt to augment 
the survival benefit associated with SBRT.  Chuong et al. introduced the concept of dose-painting to 
SBRT.16  This strategy treats the tumor abutting the vessel with a higher dose (35-50 Gy) with the 
remainder of the tumor receiving 25-30 Gy over 5 fractions.  This SBRT strategy administered after 
neoadjuvant gemcitabine, taxotere and capecitabine in patients with borderline resectable tumors 
resulted in a 77% treatment response rate. The addition of 6 cycles of gemcitabine post SBRT of 24-
36 Gy administered in 3 fractions resulted in a local control rate of 78% with low frequency of GI 
toxicity (14% grade 3) and a median survival of 14.3 months.  Although SBRT has not been 
prospectively investigated in the setting of neoadjuvant therapy for PDAC  SBRT has been shown to 
safely facilitate margin-negative resection in patients with borderline resectable disease (96.9%) 
while maintaining high rate of local disease control in unresectable patients (1-year local control 
81%).16 
 
Treatment Strategy.  This protocol will evaluate the utility of perioperative therapy for patients with 
both R-PDAC and BR-PDAC, as two independent patient cohorts.  Patients will receive 3 cycles of 
neoadjuvant gemcitabine and nab-paclitaxel (Nab-paclitaxel®) chemotherapy and stereotactic body 
radiotherapy (SBRT) administered sequentially prior to definitive surgery followed by an additional 3 
cycles of adjuvant combination chemotherapy of gemcitabine and nab-paclitaxel.  The chemotherapy 
backbone of gemcitabine and nab-paclitaxel was chosen due to its favorable toxicity profile and its 
ability to modulate the stroma. 
 
Molecular Objectives 
Knowledge of appropriate molecular markers to guide therapy is essential for the development of 
appropriate modern cancer treatments. Such markers are needed, but lacking for patients with 
PDAC.  The neoadjuvant setting is ideal to compare tissue obtained pre-therapy with post-therapy 
tissue from the primary pancreatic adenocarcinoma.  For patients with PDAC, several intratumoral 
markers have been tested in attempts to identify predictive biomarkers of therapeutic response. 
Unfortunately, varying degrees of reproducibility have hampered reliability.  For example, the 
evaluation of intratumoral hENT-1 and cytidine deaminase have been linked to gemcitabine 
response. However, prospective evaluations of these markers have been unsatisfactory because of 
methodology issues that may have led to conflicting reports.  Attempts to link intratumoral SPARC 
evaluation with response to nab-paclitaxel (Nab-paclitaxel®) have been inconsistent as well.   
Recently, Commisso et al published data demonstrating a role for the degree of “macropinocytosis” 
in KRAS-mutated cells, which may explain the efficacy nab-paclitaxel in KRAS mutant PDAC.17 
 
SMAD4: The loss of function of the tumor suppressor gene SMAD4 (also known as deletion in 
pancreas cancer 4 (DPC4)), occurs as a late event 50% of pancreas adenocarcinomas.  SMAD4 


 
 
 
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forms a protein complex with receptor-specific SMADs to promote signal transduction of the 
transforming growth factor-b (TGF-b) and bone morphogenetic protein (BMP) pathways.18,19  The 
loss of function of SMAD for occurs by a combination of loss of heterozygosity (LOH) or intragenic 
mutation.20,21  The deletion of SMAD4 has been associated with a number of negative clinical 
implications.  Deletion of SMAD4 predicts for a poorer prognosis in patients with surgically resected 
pancreas adenocarcinoma.22,23  An evaluation of the relationship between SMAD4 deletion and site 
of recurrence failed to demonstrate a direct correlation between SMAD4 deletion and post-surgical 
recurrence site.24   In contrast, an analysis of site of disease at the time of death utilizing a rapid 
autopsy program demonstrated the 70% of patients will die of distant metastasis, whilst 30% die of 
complications of locally aggressive disease.  Seventy-five percent of patients with distant metastases 
harbored SMAD4 deletion analyzed by immunoassay in comparison to 22% of patients with local 
disease possessed a SMAD4 deletion.25 A prospective evaluation of the predictive nature of SMAD4 
deletion in patients receiving neoadjuvant therapy is yet to be completed. 
 
Circulating DNA Analysis of KRAS:  Mutations in KRAS is the most common genetic abnormality 
found in pancreas adenocarcinoma tumors, occurring in upward of 95%.26  KRAS is one of three 
human RAS genes (HRAS, NRAS and KRAS).  These are 21 k-Da small GTPases that function to 
transduce receptor mediated signals to activate the mitogen-activated protein kinase (MAP kinase, 
MAPK) pathway, amongst others.27  Mutated KRAS proteins in pancreas cancer are a result of one 
of three single point mutations at residues G12, G13 and Q61.  Oncogenic substitutions at G12 and 
G13 are activating mutations resulting in constitutive activation of Ras, which effectively results in 
receptor-independent stimulation downstream signal-regulating cellular functions such as increased 
proliferation, suppression of apoptosis, altered metabolism, metastasis and alterations of the tumor 
microenvironment.28  Q61 point mutations interfere with GTP hydrolysis.29  Recently it has been 
demonstrated that circulating DNA found in the peripheral blood possess representative genetic 
abnormalities originating from tumor DNA.30  These cell-free fragments of DNA (cfDNA) are shed into 
the bloodstream by cells undergoing apoptosis or necrosis and the load of circulating cell-free DNA 
correlates with tumor staging and prognosis.31 Techniques such as digital polymerase chain reaction, 
beads, emulsion, amplification and magnetics (BEAMing) or pryrophosphorylsis-activated 
polymerization (PAP) now allow for the enumeration of rare mutant variants in complex DNA 
mixtures.32-34  This approach has been used to follow dynamic changes in colorectal cancers in 
response to multimodality therapy.35  This observation supports the use of monitoring circulating 
tumor DNA a feasible biomarker of therapeutic response.   The use of circulating DNA as a dynamic 
biomarker of therapeutic response in pancreas cancer is appealing due to the difficult nature of 
biopsying pancreas tumors repetitively over the course of therapy.  Analysis of circulating DNA 
represents a minimally invasive way to evaluate therapeutic response in this patient population.  
Given the high frequency of KRAS mutations in pancreas adenocarcinoma, quantification of KRAS 
mutated circulating DNA in patients with a known existing KRAS mutation in the primary tumor may 
represent a feasible minimally invasive way to assess therapeutic response to therapy.  Since all 
patients will be undergoing surgical resection of their pancreas tumor, a comparison between levels 
of KRAS mutation in circulating DNA with the primary tumor will be possible to assess the 
concordance between alterations in circulating DNA KRAS frequency with pathologic response to 
therapy. 
 
Gene Expression and Mutational Analysis:  Next generation sequencing allows for increased base 
coverage of a DNA sequence, as well as higher sample throughput.  This technique also allows for 
the sequencing of RNA transcripts, which facilitates the evaluation of alternative gene splicing, post-
transcriptional modification, gene fusions and mutations.  Ingenuity pathway analysis (IPA) can be 
utilized to analyze the resultant RNA-Seq data to allow for interpretation of the data in terms of genetic 
pathways.  RNA-Seq will be performed from primary tumor samples obtained at baseline, completion 


 
 
 
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of chemotherapy as well as from the resected tumor.35  This strategy will provide insight into genetic 
pathways regulated in response to chemotherapy and radiation, respectively.  The RNA-Seq pathway 
analysis data will be evaluated with respect to clinical outcomes of pathologic response and survival 
estimates.   
 
SPARC: Secreted protein acid and rich in cysteine (SPARC) is frequently overexpressed in PDAC.  
SPARC both positively and negatively effects tumor growth properties.  Data shows that SPARC 
inhibits angiogenesis by inhibiting vascular endothelial growth factor (VEGF) function; whilst, 
promoting epithelial-to-mesenchymal transition (EMT) and invasion through altering matrix 
metalloprotease expression.36,37  These features are particularly intriguing in PDAC where SPARC 
overexpression in the stroma stands along with inhibition of angiogenesis and promotion of cancer 
cell invasion and metastasis.  SPARC also binds albumin.  In this context, intratumoral SPARC may 
serve as a cellular sink to enhance intratumoral accumulation and pharmacokinetic parameters of 
nab-paclitaxel.  Von Hoff et al have suggested that the effect of nab-paclitaxel’s effect with 
gemcitabine may rest with the former agent’s ability to reach the stroma and deplete SPARC.11 
Although SPARC expression in the stroma of metastatic tissues is not prognostic or predictive of 
response to nab-paclitaxel plus gemcitabine, it has been demonstrated that SPARC expression in 
primary pancreatic lesions is associated with poor prognosis and worse response to 
gemcitabine.13,38,39 Therefore, the correlation of SPARC expression with response to therapy will be 
evaluated in the resected primary tumor using the IHC assay developed for the MPACT trial.  
     
Macropinocytosis: Oncogenes such as Ras and its down-stream effector, BRAF, stimulate nutrient 
uptake by up regulation or translocation of nutrient transporters to the plasma membrane.40 
Macropinocytosis is an endocytic process that Ras-transformed cells utilize to internalize 
extracellular albumin.  In turn, albumin serves as a rich source of amino acids that drive cancer cell 
metabolism upon its degradation in the lysosome.41 In addition to its metabolic functionality, 
macropinocytosis has also been characterized as a drug delivery mechanism for various 
therapeutics, including nanoparticles.  More recently, it has been shown that macropinocytosis 
occurs in an oncogenic KRAS-mutated mouse model of PDAC.17 Indeed, fluorescent-labeled nab-
paclitaxel is selectively internalized into oncogenic K-Ras-expressing pancreatic cancer cells through 
macropinocytosis.42  The extent of macropinocytosis in cancer cell lines varies, therefore, we propose 
to study whether macropinocytic uptake in human tumors is predictive of clinical outcomes 
associated with nab-paclitaxel and gemcitabine treatment.  This analysis will be performed on fresh 
tumor specimens from patients at NYU in the laboratory of Dr. Dafna Bar-Sagi with NYU. 
 
Stromal Elasticity: Pancreas ductal adenocarcinoma is characterized by the extensive deposition 
of desmoplastic stroma.  The stroma functions to support the growth of the malignant pancreas cells.  
The dense stromal compartment results in an increase in intratumoral turgor pressure, which in turn 
collapses the tumor vasculature.  This phenomenon impairs the intratumoral pharmacokinetic 
properties of chemotherapy.  It has recently been demonstrated that the combination of gemcitabine 
and nab-paclitaxel denude the desmoplastic stroma resulting in increased intratumoral vasculature 
patency to promote increased chemotherapy intratumoral penetration.11  The dynamic change in the 
stroma architecture can be measured both by immunohistochemical staining as well as by 
endoscopic ultrasound (EUS).  Alvarez et al have utilized immunohistochemical analysis of type I 
collagen to demonstrate that nab-paclitaxel induces a reduced stromal content by the formation of 
low density collagen bundles comprised of disrupted and disorganized fibers.43  Concordantly they 
observed a decrease in tumor stiffness (increased tumor elasticity) as measured by EUS 
elastography in tumors responding to combination therapy with gemcitabine and nab-paclitaxel. 
 
 


 
 
 
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Study Design: 
 
The study is designed as a multi-institutional, open-label phase II trial to obtain safety and preliminary 
efficacy data for a new peri-operative treatment regimen consisting of neoadjuvant gemcitabine and 
nab-paclitaxel combined with stereotactic body radiation therapy (SBRT) in a sequential manner 
followed by surgical resection and adjuvant combination chemotherapy for two independent patient 
cohorts with previously untreated R-PDAC (20 patients) or BR-PDAC (30 patients). Neoadjuvant 
therapy will consist of 3 cycles of combination chemotherapy with gemcitabine and nab-paclitaxel.  
Patients without evidence of metastatic disease on restaging CT after completion of neoadjuvant 
chemotherapy will subsequently receive SBRT followed by definitive surgical resection.  Adjuvant 
therapy consisting of 3 cycles of gemcitabine and nab-paclitaxel will be administered to patients 
without evidence of metastatic disease, Figure 1.  Gemcitabine 1000 mg/m2 and nab-paclitaxel 125 
mg/m2 will be administered intravenously on days 1, 8 and 15 of a 28-day cycles in accordance to 
the dosing schedule in the completed phase III MPACT.12  SBRT will be administered at least 21 
days and no longer than 35 days after completion of the 3 cycles of neoadjuvant combination 
chemotherapy.  Ideal administration of SBRT will between 21 and 28 days after completion of 
neoadjuvant chemotherapy. 
 
Resectable Pancreas Ductal Adenocarcinoma.  R-PDAC is defined as having no evidence of 
distant metastasis and tumor mass showing no extension to superior mesenteric artery (SMA) and 
hepatic artery. There must be a clearly defined fat plane between SMA and celiac axis.  Patent 
superior mesenteric vein (SMV/portal vein (PV) with no distortion of venous architecture.  
 
Borderline Resectable Pancreas Ductal Adenocarcinoma.  BR-PDAC is defined as localized 
PDAC with 1 or more of the following features: a) an interface between the primary tumor and 
superior mesenteric vein (SMV)-portal vein (PV) measuring 180o or greater of the circumference of 
the vein wall, and/or b) short-segment occlusion of the SMV-PV with normal vein above and below 
the level of obstruction that is amenable to resection and venous reconstruction and/or c) short-
segment interface of any degree between tumor and hepatic artery with normal artery proximal and 
distal to the interface that is amenable to resection and arterial reconstruction , and/or d) an interface 
between the tumor and SMA or celiac trunk measuring less than 180o of the circumference of the 
artery wall.43   
 
Endpoints. The primary study endpoint is rate of R0 resection. Additionally upon completion of 
therapy, patient will be followed for survival with physical exam, CT scan, the serum biomarkers CEA 
and CA19.9 to estimate overall survival and disease-free survival. Study endpoints will be evaluated 
independently for each study cohort.  There is no intent to compare endpoints between treatment 
cohorts.  Patients will undergo EUS and biopsy at baseline and after 3 cycles of neoadjuvant 
combination chemotherapy as part of the SBRT fiducial marker placement procedure.  Biopsy 
samples will be utilized to assess molecular study endpoints. The planned biopsies performed by 
EUS are mandatory for study enrollment.  In addition, endoscopic elastography will be performed in 
a subset of patient to assess dynamic changes in stromal characteristics in response to 
chemotherapy. Serum and plasma will be obtained at baseline, upon completion of the 3 cycles of 
neoadjuvant chemotherapy, prior to and upon completion of postoperative chemotherapy to assess 
exploratory biomarkers. Macropinocytosis will be analyzed on tissue from surgical specimens. There 
is no intent to compare endpoints between treatment arms. 


 
 
 
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Patient Cohorts 
Patient Cohorts 


 
 
 
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between the tumor and SMA or celiac trunk measuring less than 180o of the circumference 
of the artery wall.”44  Please refer to 2014 NCCN PDAC Guidelines. 
5. Age > 18 years old 
6. ECOG performance status of 0 or 1 
7. Patients must have adequate bone marrow function:  
• 
Platelets >100,000 cells/mm3 
• 
Hemoglobin > 9.0g/dL 
• 
Absolute Neutrophil Count > 1,500 cells/mm3 
 
8. Patients must have adequate liver function:  
• 
AST and ALT < 2.5 X upper limit of normal 
• 
Alkaline phosphatase < 2.5 X upper limit of normal   
• 
Total bilirubin < 1.5 mg/dL 
 
9. Patients must have adequate renal function: creatinine <1.5 mg/dL is recommended; 
however, institutional norms are acceptable. Creatinine within institutional limits of normal or 
creatinine clearance (CrCl) > 50 mL/min calculated using the Cockcroft-Gault equation. 
10. Women of childbearing potential and sexually active males must use an effective 
contraception method during treatment and for three months after completing treatment. 
11. Negative serum or urine β-hCG pregnancy test at screening for patients of childbearing 
potential. 
12. Patients must have < Grade 2 pre-existing peripheral neuropathy (per CTCAE v. 4.03). 
13. Ability to understand and willingness to sign a written informed consent. 
 
Exclusion Criteria: 
 
1. Patients with locally advanced surgically unresectable PDAC. 
2. Patients with evidence of distant metastatic PDAC. 
3. Prior chemotherapy or radiation therapy of any kind for treatment of pancreas 
adenocarcinoma. 
4. Prior major surgery within 4 weeks of starting study drug administration. 
5. Patient unable or not willing to perform all study related biopsies and blood draws for 
exploratory endpoints will not be enrolled on study, as all study related procedures are 
mandatory. 
6. Concomitant treatment with full dose warfarin (coumadin) is NOT allowed.  However, 
treatment with low molecular weight heparin (LMWH) (such as enoxaparin or dalteparin) or 
rivaroxaban is allowed.  Patients on full dose warfarin (coumadin) must be transitioned to 
either LMWH or rivaroxaban prior to administration of any study related drugs.   


 
 
 
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7. Recent or ongoing clinically significant gastrointestinal disorder (e.g., malabsorption, 
bleeding, inflammation, emesis, diarrhea >grade 1).  
8. Patients with clinically significant cardiac disease (e.g. congestive heart failure New York 
Heart Association Class III or IV (see Appendix A), symptomatic coronary artery disease and 
cardiac arrhythmias not well controlled with medication), or myocardial infarction within the 
previous six months. 
9. Serious, uncontrolled, concurrent infection(s). 
10. Pregnant or breastfeeding women. Positive pregnancy test within 7 days of starting treatment. 
11. Treatment for other carcinomas within the last five years, except cured non-melanoma skin 
and treated in-situ cervical cancer. 
12. Participation in any investigational drug study within 4 weeks preceding the start of study 
treatment. 
13. Patients with external biliary drains. 
 
Statistical Analysis: 
 
Statistical Rationale: 
 
This Phase II study is designed to test the feasibility and safety of a new preoperative regimen for 
patients with R-PDAC and BR-PDAC.  The primary objective of the trial is to estimate the rate of R0 
resections.  All patients entered into each cohort will be included in the estimates of R0 resection 
rates (intent to treat) and progression-free survival, Overall survival will also be summarized. Specific 
molecular properties of the patient’s tumor that are thought to relate to therapeutic efficacy will be 
analyzed and correlated with clinical outcomes. The trial will also be monitored for grade III/IV 
hematologic toxicity.  
 
Assumptions: In the R-PDAC cohort, the trial will be considered to be successful if 81.6% or greater 
of R-PDAC patients entered on the trial have R0 resections; for the BR-PDAC cohort, the trial will be 
considered successful if R0 resection rate for this group of patients is ≥ 42%. See sample size and 
study design below. Target designs are Simon two-stage optimal phase II designs with 80% power 
and alpha of 0.05.   
 
Primary Analysis: 
The primary endpoint is the exact 95% confidence intervals for each cohort R0 resection rates by 
cohort. Secondary endpoints include Kaplan Meier curves for PFS and overall survival by cohort.  
Changes over time in biologic correlates using mixed effects models within and across cohorts to 
take into account incomplete longitudinal data.  
 
Sample Size: 
R-PDAC: 20 patients. This is based on a Simon optimal 2 stage design to test the null hypothesis 
that the rate of R0 resection rate is ≤50% versus the alternative that the R0 resection rate is ≥81.6%. 
If the regimen is not effective, there is a 2% probability of concluding that it is (target  =0.05). If the 


 
 
 
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regimen is actually effective, there is a 15% probability of concluding that it is not (target power = 
80%).  Based on this 2-stage design, if the regimen is tested on 9 patients in the first stage, if 4 or 
fewer patients go on to R0 resection, the trial be terminated at the end of the first stage. With a total 
of 20 patients, the regimen would be accepted for further study if 15 or more R0 resections are 
observed in the total group of 20 patients. 
 
BR-PDAC: 30 patients. This is based on a Simon optimal 2-stage Phase II design to test the null 
hypothesis that the R0 resection rate is ≤20% versus the alternative that the R0 resection rate is ≥ 
42%, if the regimen is not effective there is a 0.05 probability of concluding that it is (target α=0.05). 
If the regimen is actually effective, there is a 20% probability of concluding that it is not (power = 
91%, target power =80%).  Based on this 2-stage design, if the regimen is tested on 13 patients in 
the first stage, if 3 or fewer patients go on to R0 resection, the trial will be terminated. With a total of 
30 patients, the regimen would be accepted for further study if  or more R0 resections are observed 
in the total group of 30 patients.45 
 
Primary Endpoint:  
• 
R0 resection rates for patients with R-PDAC and BR-PDAC. 
 
Secondary Endpoints: 
• 
To assess safety and feasibility of perioperative therapy with neoadjuvant gemcitabine and 
nab-paclitaxel (nab-paclitaxel®) chemotherapy followed by stereotactic radiotherapy before 
surgery in addition to adjuvant of gemcitabine and nab-paclitaxel. 
• 
To assess objective response rate to neoadjuvant chemotherapy and chemotherapy + 
radiotherapy.  
• 
To determine the R0 response rate in patients able to undergo surgical resection of pancreas 
adenocarcinoma.  
• 
To estimate the overall survival rate (OS) for all patients enrolled on this trial  
• 
To estimate the median progression-free survival (PFS) for all patients enrolled on this trial 
• 
To estimate the median disease-free survival (DFS) for all patients enrolled on this trial 
• 
To evaluate if histological response after neoadjuvant chemoradiotherapy is related to 
response to treatment and/or PFS and/or OS 
• 
To estimate the rate of patients not receiving surgical resection due to neoadjuvant therapy 
related adverse events. 
 
Exploratory Objectives: 
• 
To correlate post therapeutic macropinocytosis with other exploratory markers and estimates 
of clinical outcomes. 
• 
To correlate pathologic response rate after preoperative therapy with DFS and PFS stratified 
by ability to undergo surgery. 
• 
To correlate dynamic changes in stromal elasticity associated with chemotherapy 
administration and clinical outcomes. 
• 
To correlate change in serum CA19.9 and CEA levels with clinical outcomes. 
• 
To correlate basal and dynamic changes in biomarkers of tissue SPARC, SMAD4 deletion, 
circulating DNA analysis of KRAS and gene expression analysis with clinical outcomes. 


 
 
 
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List of Abbreviations and Definitions of Terms 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT (SGPT) 
Alanine Aminotransferase (SGPT) 
ANC 
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AST (SGOT) 
Aspartate Aminotransferase (SGOT) 
β-hCG 
Beta - human chorionic gonadotropin (hCG) 
BR-PDAC 
Borderline Resectable Pancreas Ductal Adenocarcinoma 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CA19-9 
Carbohydrate Antigen 19-9 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CMH 
Cochran-Mantel-Haenszel 
CONKO 
Charite Onkologie  
CrEL 
Cremophor-EL 
CRF 
Case Report Form 
CR 
Complete Response 
CRT 
Chemoradiation Therapy 
CT 
Computed Tomography 
CTC 
Circulating Tumor Cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
DFS 
Disease-Free Survival 
DHHS 
Department of Health and Human Services 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 


 
 
 
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DVT 
Deep Vein Thrombosis 
DY 
Diagnostic Yield 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGF 
Epidermal Growth Factor 
EMT 
Epidermal-Mesenchymal Transition 
EOS 
End of Study Treatment 
ES 
Endosonographer 
ESPAC 
European Study Group for Pancreatic Cancer 
EUS 
Endoscopic Ultrasound 
EUS-FNA 
Endoscopic Ultrasound Fine-Needle Aspiration 
EUS-FNB 
Endoscopic Ultrasound Fine-Needle Biopsy 
EUS-TA 
Endoscopic Ultrasound – Guided Tissue Acquisition 
5-FU 
5-Fluorouracil 
FDA 
Food and Drug Administration 
FOLFIRINOX 
5-FU, folinic acid, irinotecan and oxaliplatin combination chemotherapy 
GCP 
Good Clinical Practice(s) 
G-CSF 
Granulocyte Colony-Stimulating Factor 
GI 
Gastrointestinal  
GITSG 
Gastrointestinal Study Group 
Gy 
Gray 
HA 
Human Albumin 
hENT1 
human equilibrative nucleoside transporter 1 
Hgb 
Hemoglobin 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 


 
 
 
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IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous(ly) 
IVRS 
Interactive voice response system 
KRAS 
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LAP-07 
Locally Advanced Pancreas – 07 Clinical Trial 
LD 
Longest Diameter 
LMWH 
Low molecular weight heparin 
MBC 
Metastatic Breast Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Minor Response 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NA 
Not Applicable 
NCI 
National Cancer Institute 
NCCN 
National Comprehensive Cancer Network 
ND 
Not Done 
NIH 
National Institutes of Health 
OCE 
On-site cytopathologist evaluation 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PDAC 
Pancreas Ductal Adenocarcinoma 
PE 
Paraffin Embedded 
PET 
Positron-Emission Tomography 
PFS 
Progression-free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Prothrombin Time 


 
 
 
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PTT 
Partial Thromboplastin Time 
PV 
Portal Vein 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RI 
Reconstruction Interval 
ROS 
Reactive Oxygen Species 
R-PDAC 
Resectable Pancreas Ductal Adenocarcinoma 
RTOG 
Radiation Therapy Oncology Group 
PV 
Portal Vein 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RI 
Reconstruction Interval 
ROS 
Reactive Oxygen Species 
R-PDAC 
Resectable Pancreas Ductal Adenocarcinoma 
RTOG 
Radiation Therapy Oncology Group 
SAE 
Serious Adverse Event 
SBRT 
Stereotactic Body Radiation Therapy 
SD 
Stable Disease 
S.D. 
Standard Deviation 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SLD 
Sum of Longest Diameters 
SMA 
Superior Mesenteric Artery 
SMV 
Superior Mesenteric Vein 
SmPC 
Summary of Product Characteristics 
SPARC 
Secreted Protein Acidic and Rich in Cysteine (osteonectin) 
SUSAR(s) 
Suspected unexpected serious adverse reaction(s) 
SUV 
Standard Uptake Value 
TTF 
Time to Treatment Failure 
UE 
Unable to Evaluate 
ULN 
Upper Limit of Normal 
US 
United States 


 
 
 
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VEGF 
Vascular Endothelial Cell Growth Factor 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 


 
 
 
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Table of Contents 
Protocol/COMIRB # 15-0150 ............................................................................................................ 1 
Version Date:11.16.2016 .................................................................................................................. 1 
Title ....................................................................................................................................................... 1 
Protocol Synopsis .............................................................................................................................. 2 
List of Abbreviations and Definitions of Terms ............................................................................ 12 
 
1.0     BACKGROUND ..................................................................................................................... 22 
1.1     Pancreas Adenocarcinoma ............................................................................................. 22 
1.2    Radiation Therapy for Pancreas Cancer ........................................................................ 24 
1.2.1 Chemoradiation Therapy (CRT) .................................................................................. 24 
1.2.2 Stereotactic Body Radiation Therapy (SBRT) ........................................................... 25 
1.3    Endoscopic Ultrasound (EUS) ......................................................................................... 25 
1.3.1 Endoscopic Ultrasound (EUS) – Guided Tissue Acquisition ................................... 25 
1.3.2 Endoscopic Elastography ............................................................................................. 26 
1.4 Molecular Objectives ............................................................................................................. 26 
1.5    Study Conduct .................................................................................................................... 29 
 
2.0    STUDY HYPOTHESIS AND OBJECTIVES ...................................................................... 29 
2.1    Overarching Hypothesis .................................................................................................... 29 
2.2    Study Objectives ................................................................................................................ 29 
2.2.1 Primary Objective ........................................................................................................... 29 
2.2.2 Secondary Objectives .................................................................................................... 29 
2.2.3 Exploratory Objectives .................................................................................................. 29 
 
3.0    STUDY POPULATION .......................................................................................................... 30 
3.1    Inclusion Criteria ................................................................................................................. 30 
3.2    Exclusion Criteria: .............................................................................................................. 31 
 
4.0    STUDY DESIGN AND PLAN ............................................................................................... 31 
4.1    Study Design ....................................................................................................................... 31 
4.2    Study Chemotherapy Administration .............................................................................. 33 
4.2.1 Nab-paclitaxel (Abraxane®) ......................................................................................... 33 


 
 
 
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4.2.1.1 Nab-paclitaxel Product and Storage ........................................................................ 33 
4.2.1.2 Premedication .............................................................................................................. 33 
4.2.1.3 Administration .............................................................................................................. 34 
4.2.1.4 Drug Ordering and Storage ....................................................................................... 34 
4.2.2 Gemcitabine .................................................................................................................... 34 
4.2.2.1 Description ................................................................................................................... 34 
4.2.2.2 Premedication .............................................................................................................. 34 
4.2.2.3 Administration .............................................................................................................. 34 
4.2.2.4 Drug Ordering and Storage ....................................................................................... 34 
4.2.2.5 Regimen ....................................................................................................................... 34 
4.3    Rules for Dose Omission and Schedule Modification .................................................. 35 
4.3.1 Administration of Study Drug to Patients with Abnormal Hepatic Function .......... 35 
4.3.2 Dose Modification Tables .............................................................................................. 35 
4.3.2.1 Dose Modifications at Day 1 ..................................................................................... 36 
4.3.2.2 Dose Adjustments within a Treatment Cycle .......................................................... 37 
4.3.2.3 Peripheral Neuropathy ............................................................................................... 40 
4.3.2.4 Hypersensitivity Reactions ........................................................................................ 40 
4.3.2.5 Pulmonary Embolism ................................................................................................. 40 
4.3.2.6 Colony Stimulating Factor Administration ............................................................... 41 
4.3.2.7 Other Toxicities ........................................................................................................... 41 
4.4    Concomitant Medications .................................................................................................. 43 
4.5    Discontinuation ................................................................................................................... 43 
 
5.0    DETAILED DESCRIPTION OF STUDY DRUG MANAGEMENT AND 
ADMINISTRATION .......................................................................................................................... 44 
5.1    Nab-paclitaxel ..................................................................................................................... 44 
5.1.1 Packaging, Labeling, and Storage of Study Drug ..................................................... 44 
5.2    Gemcitabine ........................................................................................................................ 45 
5.2.1 Packaging, Labeling, and Storage of Study Drug ..................................................... 45 
5.3 Endocopic Ultrasound Procedures ..................................................................................... 46 
5.3.1 Endoscopic Ultrasound ................................................................................................. 46 
5.3.2 Cytopathologic assessment and final diagnosis ....................................................... 46 
5.3.3 Elastography ................................................................................................................... 47 
5.3.4 Fiducial markers placement .......................................................................................... 47 


 
 
 
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5.4 SBRT ....................................................................................................................................... 48 
5.5 Surgery .................................................................................................................................... 50 
5.5.1 Definitive Surgical Resection ........................................................................................ 50 
5.5.2 Specimen Orientation .................................................................................................... 50 
5.5.3 Operative Note ................................................................................................................ 50 
 
6.0    MEASUREMENTS AND EVALUATIONS ........................................................................... 51 
6.1    General Considerations ..................................................................................................... 51 
6.2    Central Laboratory and Central Imaging ........................................................................ 52 
6.3  Table 8: Study Calendar ................................................................................................... 53 
6.4    Baseline Evaluations ......................................................................................................... 56 
6.5 Treatment Phase Evaluations ............................................................................................. 57 
6.6   Molecular Marker Analyses ............................................................................................... 57 
6.7    Day 1 Assessments ........................................................................................................... 58 
6.8    Efficacy Response Assessments .................................................................................... 58 
6.9 Per Cycle Evaluations ........................................................................................................... 58 
6.10 End-of-Study (EOS) Evaluations ...................................................................................... 59 
6.11    Follow-up for Adverse Events ........................................................................................ 59 
6.12    Follow-up for Disease Progression ............................................................................... 60 
6.13  Follow-up for Overall Survival .......................................................................................... 60 
 
7.0 ADVERSE EVENTS MANAGEMENT GUIDELINES ........................................................... 61 
7.1 Background ............................................................................................................................ 61 
7.2 Definition of an Adverse Event (AE) ................................................................................... 61 
7.3 Definition of a Serious Adverse Event (SAE) .................................................................... 62 
7.4 Timeline for Consideration of AE/SAE Reporting Requirements ................................... 62 
7.5 Lack of Efficacy is not considered an AE or SAE ............................................................. 63 
7.6 Laboratory Results as Serious Adverse Events ............................................................... 63 
7.7 Patient Reporting of AEs and SAEs ................................................................................... 63 
7.8 Investigator Reporting of AEs and SAEs ........................................................................... 63 
7.8.1 Additional Investigator Responsibilities on Follow-up of SAEs ............................... 64 
7.8.2 IRB/EC Notification of SAEs ......................................................................................... 66 
7.8.3 Expedited Reporting by Principal Investigator to Celgene ...................................... 66 
7.8.4 Sponsor Notification of Post-Study SAEs ................................................................... 66 


 
 
 
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7.9 
Pregnancy ........................................................................................................................... 66 
7.9.1 Females of Childbearing Potential: ............................................................................. 66 
7.9.2 Male Subjects ................................................................................................................. 67 
7.10 Expedited Reporting of Adverse Events .......................................................................... 67 
Celgene Drug Safety Contact Information: .......................................................................... 67 
 
8.0 STATISTICAL METHODS ........................................................................................................ 67 
8.1    Statistical Considerations .................................................................................................. 67 
8.1.1 Brief Statistical Rationale: ............................................................................................. 67 
8.1.2 Sample Size .................................................................................................................... 68 
8.1.3 Statistical Analysis ......................................................................................................... 68 
8.2 Population Analysis ............................................................................................................... 69 
8.3 Demographics and Baseline Characteristics .................................................................... 69 
8.4 Patient Disposition ................................................................................................................. 69 
8.5 Prior and Concomitant Medications .................................................................................... 69 
8.6 Endpoints ................................................................................................................................ 69 
8.6.1 Safety Endpoints ............................................................................................................ 69 
8.6.2 Efficacy Endpoints .......................................................................................................... 70 
8.6.3 Exploratory Endpoints ................................................................................................... 70 
8.7 Criteria for Enrollment Termination ..................................................................................... 70 
8.8  Efficacy Assessments .......................................................................................................... 70 
8.9 Independent Data Monitoring Committee ........................................................................... 71 
 
9.0   REGULATORY CONSIDERATIONS .................................................................................... 72 
9.1 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) Approval . 72 
9.2 Ethical Conduct of the Study ................................................................................................ 73 
9.2.1 Informed Consent ........................................................................................................... 73 
9.3    Confidentiality ..................................................................................................................... 73 
9.4 Publication .............................................................................................................................. 74 
9.5 Investigator Documentation .................................................................................................. 74 
9.5.1 Form FDA 1572 .............................................................................................................. 74 
9.5.2 Curriculum Vitae ............................................................................................................. 74 
9.5.3 Financial Disclosure ....................................................................................................... 74 
9.5.4 Records Retention ......................................................................................................... 74 


 
 
 
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9.5.5 Protocol Deviations ........................................................................................................ 75 
 
10.0 APPENDICES .......................................................................................................................... 75 
Appendix A: New York Heart Association Classification ....................................................... 75 
Appendix B: Radiology Technical Manual ................................................................................ 75 
Appendix C:  RECIST CRITERIA 1.1 ....................................................................................... 75 
Appendix A: New York Heart Association Classification ....................................................... 76 
Appendix B: Radiology Technical Manual ................................................................................ 77 
Appendix C:  RECIST CRITERIA 1.1 ....................................................................................... 79 
 
11.0 REFERENCES: ....................................................................................................................... 85 
 
 
LIST OF TABLES 
 
Table 1: Drug Dosing Schedule…………….……………………………………………………………...33 
 
Table 2: Dose Levels……………………….………………………………………………………………34 
 
Table 3: Dose Modifications for Day 1 of Each Cycle (Hematologic Toxicity)………………………..34 
 
Table 4: Dose Modifications for Day 1 of Each Cycle (Non-Hematologic Toxicity)…………………..34 
 
Table 5: Dose Modifications Due to Hematologic Toxicity………….………………………………….36 
 
Table 6: Dose Modifications for Non-Hematological Toxicity within a Cycle……….…………………38 
 
Table 7: Use of G-CSF and Dose Reductions for Hematologic Toxicity……………………………...39 
 
Table 8: Study Calendar……………………………………………………………………………………51


 
 
 
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1.0     BACKGROUND 
1.1     Pancreas Adenocarcinoma  
 
Background. Pancreas Ductal Adenocarcinoma (PDAC) remains a devastating disease.  
Unfortunately upwards of 80% to 85% of patients diagnosed with this disease will have unresectable 
advanced disease at diagnosis.2  This precludes the vast majority of patients from receiving the only 
curative therapy of surgical resection.  Only approximately 20% of patients are candidates for resection 
of the cancer.  Approximately eighty percent of patients that undergo surgical resection for this disease 
will develop disease recurrence.2  As a result, the overall survival rate for this disease is less than 5% 
for all patients diagnosed with pancreas ductal adenocarcinoma.  In recent years, there has been a 
significant improvement in the understanding of the genetics and biology of this disease.  It is estimated 
that PDAC develops over a 20-year period with the clinical disease occurring in the last 2 to 3 years 
of the disease natural history.46  Furthermore, there appears to be central founder mutations that are 
common to all foci of PDAC whereas, passenger mutations appear to be differentiated by the site of 
disease.  Additional work demonstrates that pancreas cancer metastasis occurs as an early event in 
oncogenesis.47  These results may underpin the clinical observation in some patients who develop 
distant disease early after surgical resection of the primary tumor.  It also suggests that the majority of 
patients with resectable locally advanced disease possess a subclinical systemic component of their 
disease that is not treated by surgical resection.   These are some of the factors that may account for 
the overall poor long-term survival associated with surgical resection of the disease.   
 
Surgery.  Surgical resection of PDAC is a technically challenging surgery that is associated with a 
high rate of morbidity and mortality in inexperienced centers.48  However, in centers performing a large 
volume of these surgical procedures the surgery-related mortality rate is less than 3%, although 
complication remains a reality for a proportion of patients. Surgical resection for this disease can be 
accomplished by several surgical techniques depending on the location of the tumor within the 
pancreas. The approach to resect the pancreas head involves a pancreaticoduodenectomy (Whipple 
Procedure) in which the head of the pancreas along with the tumor, the common bile duct 
(choledochectomy), gall bladder and cystic duct (cholecystectomy), duodenum, proximal jejunum and 
regional lymph nodes are resected.  Reconstructive surgery then follows, consisting of 
pancreaticojejunostomy, hepaticojejunostomy and a gastrojejunostomy.  These procedures allow the 
digestive juices, bile and food to reach the gastrointestinal tract.  This procedure has been modified in 
several ways over the course of time to include a pylorous sparing procedure as well of the introduction 
of minimally invasive techniques such as a laparoscopic approach or the implementation of robotic 
assistance.  PDAC involving the body and tail of the pancreas generally are approached with a distal 
pancreatectomy with splenectomy.  A small minority of patients will undergo a total pancreatectomy to 
resect a pancreas tumor.   
 
The complexity of the surgical approach as well as the peri-pancreatic anatomy requires a deliberate 
approach to identify patients that may be surgical candidates.  Resectable PDAC is defined as 
patients having no evidence of distant metastasis and tumor mass showing no extension to superior 
mesenteric artery (SMA) and hepatic artery. There must be a clearly defined fat plane between SMA 
and celiac axis.  A patent superior mesenteric vein (SMV) / portal vein (PV) individually or at the 
SMV/PV confluence with no distortion of venous architecture is an additional requirement.  Locally 
advanced disease is characterized as either Borderline Resectable PDAC or Unresectable PDAC.  
The importance of this designation is that patients with BR-PDAC are treated on a curative intent 
paradigm with possibility of undergoing surgical resection in conjunction with perioperative therapy, 
whilst those deemed unresectable are destined for palliative therapy.  The definition of true borderline 
resectable disease remains controversial.  Katz et al published a definition to be incorporated into 
clinical trial standardization that has been adopted by the Intergroup pilot study (Alliance A021101) as 
well as the National Comprehensive Cancer Network (NCCN) Pancreatic Cancer Guidelines of 2014.44   


 
 
 
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In this protocol, BR-PDAC is defined as localized PDAC with 1 or more of the following features: a) an 
interface between the primary tumor and superior mesenteric vein (SMV)-portal vein (PV) measuring 
180o or greater of the circumference of the vein wall, and/or b) short-segment occlusion of the SMV-
PV with normal vein above and below the level of obstruction that is amenable to resection and venous 
reconstruction and/or c) short-segment interface of any degree between tumor and hepatic artery with 
normal artery proximal and distal to the interface that is amenable to resection and arterial 
reconstruction and/or d) an interface between the tumor and SMA or celiac trunk measuring less than 
180o of the circumference of the artery wall. The goal of surgical resection for this disease is to achieve 
R0 resection without any evidence of microscopic disease involving the surgical margins.  The natural 
history of the disease requires that all fit patients receive perioperative therapy; however, the 
appropriate perioperative remains controversial at this time and remains an active area of 
investigation.  Central radiologic review by Dr. Alex Megibow at New York University will be used to 
determine the eligibility and stratification of identified patients for study participation. 
 
Perioperative Therapies.  The primary controversial issues regarding perioperative therapy for 
pancreas ductal adenocarcinoma revolve around the timing of initiation of said therapy as well as 
defining the appropriate therapeutic modalities to be utilized in this setting.  Some groups have 
advocated for adjuvant therapy, whilst others have supported the use of neoadjuvant therapy.  The 
historical benefit of adjuvant therapy has been the removal of the tumor at an early stage in the 
absence of distant metastases and at a time when the patient is likely to be at an ultimate fitness level 
to withstand the surgery-associated morbidity.  Unfortunately, the enthusiasm for this approach has 
waned of late due to the high rate of both local and distant recurrence.  In contrast, neoadjuvant therapy 
affords the opportunity administer systemic therapy early in the treatment paradigm after identification 
of the primary tumors.  Additionally, neoadjuvant therapy can identify those patients that would not 
benefit from surgical resection due to rapid disease recurrence.  Indeed, approximately 30% to 40% 
of patients who initiate neoadjuvant therapy with the serial administration of chemotherapy and 
chemoradiation therapy discontinue therapy prior to surgical resection.49  The relative high attrition 
rate is due to a number of reasons including local progression, development of distant metastases, 
treatment-related toxicity and physical decompensation.  Those patients who complete neoadjuvant 
therapy and went onto to have surgical resection of their tumor tend to have a superior outcome to 
those patients receiving adjuvant therapy.50 
 
The role of perioperative chemotherapy alone or with the addition of radiation has also been a point of 
contention amongst a variety of research groups.  These arguments have persisted largely because 
of the ineffective chemotherapy options available to these patients.  Gemcitabine has remained the 
standard-of-care for this disease since a randomized trial demonstrated an overall survival benefit over 
5-fluorouracil (5-FU) in patients with metastatic pancreas adenocarcinoma.51   Postoperative adjuvant 
therapy with chemotherapy alone has been shown to improve overall survival.  The Charite Onkologie 
Clinical (CONKO-001) trial evaluated 6 cycles of adjuvant gemcitabine versus observation, 
demonstrating favorable associated survival of 22.8 months in comparison to 20.2 months in the 
observation arm.52  The long-term results of this trial demonstrate persistent benefit for chemotherapy 
with a 5-year overall survival of 20.7% compared to 10.4% for patients not receiving adjuvant therapy.53 
Although single-agent gemcitabine has been the standard of care for stage IV PDAC patients, the 
ESPAC-3 trial tested 5-fluorouracil versus gemcitabine in the postoperative adjuvant setting for PDAC 
patients. Overall survival was statistically the same for each agent.6  
 
A large series of therapeutic trials combining other cytotoxic chemotherapy agents, as well as biologic 
agents with gemcitabine have been completed in attempt to demonstrate a survival benefit over 
gemcitabine in the metastatic disease setting to no avail.  Recently two combination chemotherapy 
regimens have demonstrated improved overall survival in comparison to gemcitabine in the metastatic 
disease setting.  Both the combination of infusional 5-FU, leucovorin, irinotecan and oxaliplatin 
(FOLFIRINOX) as well as the combination of gemcitabine and nab-paclitaxel (Abraxane/Nab-
paclitaxel®) have demonstrated an improved median overall survival over gemcitabine of 11.7 and 8.5 


 
 
 
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months, respectively in comparison to 6.5 and 6.7 months, respectively for gemcitabine.10,12  The 
clinically significant impact of these observations is bore out by the reduction in rate of death of 43% 
and 28%, respectively associated with FOLFIRINOX and gemcitabine combined with nab-paclitaxel 
relative to gemcitabine.  Importantly when considering perioperative therapy, both regimens were 
associated with clinically significantly improved response rates and disease control rates in 
comparison to gemcitabine in the metastatic setting. Both therapies are overall tolerable but are 
associated with significant toxicities of bone marrow suppression and neuropathy, as well as GI toxicity 
and dehydration associated with FOLFIRINOX.  As a result, it is incumbent upon clinical researchers 
to demonstrate the safety of these regimens in the perioperative setting for the treatment of potentially 
curable PDAC.  The results of these clinical trials set the stage for the incorporation of effective 
combination chemotherapy into the perioperative setting for the management of PDAC. 
 
In this trial, we have selected gemcitabine and nab-paclitaxel as the perioperative systemic regimen.  
This doublet is generally well tolerated initially with cumulative bone marrow and neurotoxicity as the 
usual dose-limiting toxicities.  Gemcitabine and nab-paclitaxel can be administered to patients over 70 
with less initial concern and less initial dose modification than FOLFIRINOX.  The lead Principal 
Investigator (PI) at University of Colorado and the PI at New York University have had preliminary 
experience in this regimen with SBRT (see below) and have found the regimen safe.  Finally, our 
interest in potential molecular biomarkers such as SPARC and macropinocytosis made us consider 
gemcitabine and nab-paclitaxel as more compelling in the perioperative setting.    
 
1.2    Radiation Therapy for Pancreas Cancer 
 
1.2.1 Chemoradiation Therapy (CRT) 
 
The role of conventional combined chemotherapy and radiation (chemoradiation therapy, CRT) in the 
treatment of pancreas ductal adenocarcinoma remains controversial.  Support for this therapeutic 
modality in the adjuvant setting was initially demonstrated in 1985 by the Gastrointestinal Tumor Study 
Group (GITSG).14  A total of 43 patients were randomized to receive adjuvant chemoradiation with split 
course radiation and 5FU compared to observation.  Patients receiving CRT had a median survival 
rate of 20 months compared to 11 months for those in observation.  This was also associated with an 
improved 2-year survival of 42% versus 15% for those receiving CRT.  The role of conventional CRT 
was further evaluated in the European Study Group for Pancreatic Cancer-1 (ESPAC-1) trial used a 2 
x 2 design to test adjuvant chemotherapy alone versus CRT or observation.  The results of this study 
were highly controversial with chemotherapy demonstrating improved survival over observation of 20 
months versus 15 months.  However, chemoradiation demonstrated an inferior survival rate of 16 
months in comparison to 18 months for chemotherapy alone.  This study has been widely criticized for 
the lack of uniformity in the radiation administration both in terms of the technical aspects of the split 
course radiation and the total dose administered between sites.54   
 
Two additional studies have evaluated the role of adjuvant CRT in pancreas cancer therapy.  The 
Radiation Therapy Oncology Group (RTOG) trial RTOG 9704 explored the role of adding systemic 
chemotherapy to CRT.55  All patients received conventional external beam radiation therapy to 50.4 
Gy combined with 5FU 250 mg/m2 per day.  Subsequently, patients were randomize to receive either 
5FU or gemcitabine for one cycle prior to CRT and followed with 3 additional cycles post CRT.  
Ultimately, this study showed a non-statistically significant trend in survival favoring gemcitabine.  The 
LAP-07 trial results have been released, once again demonstrating no advantage of CRT over 
chemotherapy in the adjuvant setting.56  These results are likely a function of the fact that pancreas 
cancer is largely a systemic disease with most patients developing distant metastasis at the time of 
recurrence. 
 


 
 
 
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1.2.2 Stereotactic Body Radiation Therapy (SBRT) 
 
The development of advanced imaging techniques has allowed for compensation for organ movement 
associated with respiration.  The administration of stereotactic body radiation therapy (SBRT) to 
extracranial organs is now feasible due to these advancements.  The early use of SBRT for the 
treatment of pancreas cancer utilized the administration of a single fraction of high dose radiation of 
20-25 Gy.57  This was associated with a marginal survival benefit and delayed gastrointestinal toxicity.  
Work by a number of investigators has now demonstrated that several dosimetric parameters are 
predictive of toxicity including V15 (volume receiving 15 Gy or greater) > 9.1 cc, V20 > 3.3 cc and V25 > 
20 cc correlating with a 50% chance of intestinal toxicity.15  Dmax (Maximum dose received) Dmax of 35 
Gy and 38 Gy correlated with 5% and 10% rate of at least grade 3 GI toxicity.  As a result of these 
observations, more modern studies have introduced multiple fractionation of dosing, as well as 
decreasing the total administered dose.  Systemic chemotherapy has also been added to SBRT in an 
attempt to augment the survival benefit associated with SBRT.   
 
The addition of 6 cycles of gemcitabine post SBRT of 24-36 Gy administered in 3 fractions resulted in 
a local control rate of 78% with low frequency of GI toxicity (14% grade 3) and a median survival of 
14.3 months.58  The use of neoadjuvant gemcitabine for 2 cycles followed by SBRT resulted in a local 
control rate of 85% and a median survival of 20 months without acute grade 3 toxicity and minimal 
delayed grade 3 toxicity.59  SBRT has been integrated into the treatment cycle of gemcitabine to 
address the question of the necessity to delay the time between chemotherapy and SBRT 
administration.  In this study, SBRT was administered on the typical rest week of gemcitabine during 
cycle 1 when dosed weekly for 3 weeks with 1 week of rest.  The subsequent cycles of gemcitabine 
were administered without delay.  No grade 3 toxicities were observed with this strategy; thereby, 
demonstrating that a delay is not required between chemotherapy administration and SBRT.  Chuong 
et al introduced the concept of dose-painting to SBRT.16  This strategy treats the tumor abutting the 
vessel with a higher dose (35-50 Gy) with the remainder of the tumor receiving 25-30 Gy over 5 
fractions.  This SBRT strategy administered after neoadjuvant gemcitabine, taxotere and capecitabine 
for patients with BR-PDAC resulted in a 77% treatment response rate.  Ninety-seven percent of 
patients undergoing surgical resection attained an R0 resection with a pathologic complete response 
occurring 9% of patients.  Patients completing surgical resection had a median survival of 19.3 months 
versus 12.3 months. 
 
In summary, the use of radiation therapy in the management of PDAC remains controversial and 
remains under active investigation.  Conventional chemoradiation therapy possesses marginal benefit 
in comparison to single agent chemotherapy in the adjuvant setting.   This is likely due to the systemic 
nature of the disease.  Delayed initiation of systemic chemotherapy as a result of time required to 
administer CRT and CRT associated toxicity represent additional factors resulting in the marginal 
benefit of CRT in the adjuvant setting.  SBRT represent an efficient way to administer dose intense 
radiation therapy that does not delay chemotherapy administration.  Patients with BR-PDAC or locally 
recurrent disease may benefit the most from SBRT due to its ability to achieve a tumor response.  That 
said, the impact in terms of toxicity and efficacy of combining SBRT with modern combination 
chemotherapy in the perioperative setting for R-PDAC and BR-PDAC on R0 resection rate and survival 
remains to be defined. 
1.3    Endoscopic Ultrasound (EUS)  
 
1.3.1 Endoscopic Ultrasound (EUS) – Guided Tissue Acquisition 
 
Endoscopic Ultrasound - Guided Tissue Acquisition (EUS-TA) by fine-needle aspiration (EUS-FNA) 
and fine-needle biopsy (EUS-FNB) has become an integral to the diagnosis and staging of 
gastrointestinal malignancies.60  The common indications for EUS-TA include diagnosis and staging 


 
 
 
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of pancreaticobiliary, esophageal, gastric and rectal malignancies along with evaluation of GI 
subepithelial lesions and lymphadenopathy.  The ideal EUS-TA technique needs to be safe, accurate 
and achieve a high diagnostic yield (DY).   
 
The key relevant outcomes of EUS-TA include specimen adequacy, DY, accuracy, and adverse 
events. There are several limitations and technical challenges associated with this procedure. Low DY 
(false-negative diagnoses) is the most important pitfall with the potential to negatively impact patient 
outcomes by inappropriate patient care.  A recent review reported a false-negative diagnoses rate of 
4-45% in solid pancreatic masses, 21-53% in pancreatic cystic neoplasms, and 6-14% in lymph 
nodes.61  This usually is a result of sampling errors [related to improper EUS-TA, errors in image 
recognition, experience of the endosonographer (ES) and lesion characteristics].60-63 There are several 
variables that have been studied to optimize outcomes associated with EUS-TA.  These include 
performance of EUS-FNA versus FNB, needle gauge, use of a stylet and suction, number of passes, 
sampling technique, presence of an on-site cytopathologist evaluation (OCE) during the procedure 
and the skill and experience of the ES and the cytopathologist. 
 
A recent review of the literature by Wani et al to assess the technical aspects of EUS-TA to optimize 
EUS-TA for tissue acquisition has identified the following parameters to optimize the safety, accuracy 
and diagnostic yield of the procedures:  the routine use of a stylet during EUS-FNA; the use of suction 
during EUS-FNA of a pancreas mass; the use of a 25-g needle is associated with a higher DY 
compared to 22-g needle in patients undergoing EUS-FNA of pancreas mass; the high-definition FNB 
needle (Echo Tip Procure™) is highly effective for acquisition of core specimens; the routine use of 
the “capillary” technique is preferable to standard suction and should be utilized for EUS-FNB for 
histologic specimens.   This study will employ these parameters to optimally and safely administer 
repetitive EUS-TA to assess the dynamic change in tissue specific biomarkers to correlate with clinical 
outcome. 
 
1.3.2 Endoscopic Elastography 
 
Endoscopic elastography has been developed as a noninvasive method to characterize pancreas 
masses of benign and malignant etiologies.  This technique utilizes real-time assessment of the tissue 
elasticity distribution calculation with subsequent representation in fundamental B-mode imagining.  
An Elastography Score ranging from 1 to 5 is assigned to the pancreas masses.  Score 1 is a 
homogeneous soft mass (green) associated with normal pancreas.  Score 2 remains a soft (green, 
yellow or red) mass that has become heterogeneic corresponding to fibrosis.  Score 3 masses are 
hard (blue) with minimal heterogenicity that correspond to small early pancreas adenocarcinoma (< 
25mm).  Score 4 mass possess a hypoechoic core with green appearance surrounded by hard (blue) 
tissue, corresponding with hypervascular lesion such neuroendocrine tumor or pancreas metastasis.  
Score 5 is associated with advanced pancreas adenocarcinoma are primarily blue with a soft tissue 
(green, red) core.   Dynamic changes in elastography characteristics of a pancreas may represent a 
novel modality to assess tumor response to therapy.  Indeed Alvarez et al have now demonstrated 
that increased elasticity (decrease tumor stiffness) is associated with response to combination 
gemcitabine and nab-paclitaxel chemotherapy.  This trial will gather preliminary data on the effects of 
preoperative chemotherapy on the Elastography Score on a cohort patients enrolled in the trial.   
1.4 Molecular Objectives 
 
Knowledge of appropriate molecular markers to guide therapy is essential for the development of 
appropriate modern cancer treatments. Such markers are needed, but lacking for patients with PDAC.  
The neoadjuvant setting is ideal to compare tissue obtained pre-therapy with post-therapy tissue from 
the primary pancreatic adenocarcinoma.  For patients with PDAC, several intratumoral markers have 
been tested in attempt to serve as predictive biomarkers of therapeutic response with varying degrees 
of reproducibility.  Attempts to link intratumoral SPARC evaluation with response to nab-paclitaxel 


 
 
 
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(Nab-paclitaxel®) also remain inconsistent.   Recently, Commisso et al published data demonstrating 
the role “macropinocytosis” in KRAS-mutated cells, which may explain the efficacy nab-paclitaxel in 
KRAS mutant PDAC.17 
 
SMAD4: The loss of function of the tumor suppressor gene SMAD4 (also known as Deletion in 
Pancreas Cancer 4 (DPC4)), occurs as a late event 50% of PDACs.  SMAD4 forms a protein complex 
with receptor-specific SMADs to promote signal transduction of the transforming growth factor-b (TGF-
b) and bone morphogenetic protein (BMP) pathways.18,19  The loss of function of SMAD4 occurs either 
by a combination of loss of heterozygosity (LOH) or intragenic mutation.20,21  The deletion of SMAD4 
has been associated with a number of negative clinical implications.  Deletion of SMAD4 predicts for 
a poorer prognosis in patients with surgically resected pancreas adenocarcinoma.22,23  An evaluation 
of the relationship between SMAD4 deletion and site of recurrence failed to demonstrate a direct 
correlation between SMAD4 deletion and post-surgical recurrence site.24   In contrast, an analysis of 
site of disease at the time of death utilizing a rapid autopsy program demonstrated the 70% of patients 
will die of distant metastasis, whilst 30% die of complications of locally aggressive disease.  Seventy-
five percent of patients with distant metastases harbored SMAD4 deletion analyzed by immunoassay 
in comparison to 22% of patients with local disease possessed a SMAD4 deletion.25  A prospective 
evaluation of the predictive nature of SMAD4 deletion in patients receiving neoadjuvant therapy is yet 
to be completed.  Hence, we will evaluate the basal and dynamic SMAD4 loss of function in tumors of 
patients. 
 
Circulating DNA Analysis of KRAS:  Mutations in KRAS is the most common genetic abnormality 
found pancreas adenocarcinoma tumors, occurring in upward of 95%.26  KRAS is one of three human 
RAS genes (HRAS, NRAS and KRAS).  These are 21 k-Da small GTPases that function to tranduce 
receptor mediated signals to activate the mitogen-activated protein kinase (MAP kinase, MAPK) 
pathway, amongst others.27  Mutated KRAS proteins in pancreas cancer are a result of one of three 
single point mutations at residues G12, G13 and Q61.  Oncogenic substitutions at G12 and G13 are 
activating mutations resulting in constitutive activation of Ras, which effectively results in receptor-
independent stimulation downstream signal-regulating cellular functions such as increased 
proliferation, suppression of apoptosis, altered metabolism, metastasis and alterations of the tumor 
microenvironment.28  Q61 point mutations interfere with GTP hydrolysis.29  Recently it has been 
demonstrated that circulating DNA found in the peripheral blood possess representative genetic 
abnormalities originating from tumor DNA.30  These cell-free fragments of DNA (cfDNA) are shed into 
the bloodstream by cells undergoing apoptosis or necrosis and the load of circulating cell-free DNA 
correlates with tumor staging and prognosis.31 Techniques such as digital polymerase chain reaction, 
beads, emulsion, amplification and magnetics (BEAMing) or pryrophosphorylsis-activated 
polymerization (PAP) now allow for the enumeration of rare mutant variants in complex DNA 
mixtures.32-34  This approach has been used to follow dynamic changes in colorectal cancers in 
response to multimodality therapy.35  This observation supports the use of monitoring circulating tumor 
DNA a feasible biomarker of therapeutic response.   The use of circulating DNA as a dynamic 
biomarker of therapeutic response in pancreas cancer is appealing due to the difficult nature of 
biopsying pancreas tumors repetitively over the course of therapy.  Analysis of circulating DNA 
represents a minimally invasive way to evaluate therapeutic response in this patient population.  Given 
the high frequency of KRAS mutations in pancreas adenocarcinoma, quantification of KRAS mutated 
circulating DNA in patients with a known existing KRAS mutation in the primary tumor may represent 
a feasible minimally invasive way to assess therapeutic response to therapy.  Since all patients will be 
undergoing surgical resection of their pancreas tumor, a comparison between levels of KRAS mutation 
in circulating DNA with the primary tumor will be possible to assess the concordance between 
alterations in circulating DNA KRAS frequency with pathologic response to therapy. 
 
Gene Expression and Mutational Analysis:  Next generation sequencing allows for increased base 
coverage of a DNA sequence, as well as higher sample throughput.  This technique also allows for 


 
 
 
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the sequencing of RNA transcripts, which facilitates the evaluation of alternative gene splicing, post-
transcriptional modification, gene fusions and mutations.  Ingenuity pathway analysis (IPA) can be 
utilized to analyze the resultant RNA-Seq data to allow for interpretation of the data in terms of genetic 
pathways.  RNA-Seq will be performed from primary tumor samples obtained at baseline, completion 
of chemotherapy as well as from the resected tumor.35  This strategy will provide insight into genetic 
pathways regulated in response to chemotherapy and radiation, respectively.  The RNA-Seq pathway 
analysis data will be evaluated with respect to clinical outcomes of pathologic response and survival 
estimates.   
 
SPARC: Secreted protein acid and rich in cysteine (SPARC) is frequently overexpressed in PDAC.  
SPARC both positively and negatively effects tumor growth properties.  It has been shown to inhibit 
angiogenesis by inhibiting vascular endothelial growth factor (VEGF) function whilst, promoting 
epithelial-to-mesenchymal transition (EMT) and invasion through altering matrix metalloprotease 
expression.36,37  These features are particularly intriguing in PDAC where SPARC overexpression in 
the stroma stands along with inhibition of angiogenesis and promotion of cancer cell invasion and 
metastasis.  SPARC also binds albumin.  In this context, intratumoral SPARC may serve as a cellular 
sink to enhance intratumoral accumulation and pharmacokinetic parameters of nab-paclitaxel.  Von 
Hoff et al have suggested that the effect of nab-paclitaxel with gemcitabine may rest with the former 
agent’s ability to reach the stroma and deplete SPARC.11 Although SPARC expression in the stroma 
of metastatic tissues is not prognostic or predictive of response to nab-paclitaxel plus gemcitabine, it 
has been demonstrated that SPARC expression in primary pancreatic lesions is associated with poor 
prognosis and worse response to gemcitabine.13,38,39 Therefore, the correlation of SPARC expression 
with response to therapy will be evaluated in the resected primary tumor using the IHC assay 
developed for the MPACT trial.  
     
Macropinocytosis: Oncogenes such as Ras and its down-stream effector, BRAF, stimulate nutrient 
uptake by up regulation or translocation of nutrient transporters to the plasma membrane.40 
Macropinocytosis is an endocytic process that Ras-transformed cells utilize to internalize extracellular 
albumin.  In turn, albumin serves as a rich source of amino acids that drive cancer cell metabolism 
upon its degradation in the lysosome.41 In addition to its metabolic functionality, macropinocytosis has 
also been characterized as a drug delivery mechanism for various therapeutics, including 
nanoparticles.  More recently, it has been shown that macropinocytosis occurs in an oncogenic Ras 
model of PDAC.17 Indeed, fluorescent-labeled nab-paclitaxel is selectively internalized into oncogenic 
K-Ras-expressing 
pancreatic 
cancer 
cells 
through 
macropinocytosis.42 
 The 
extent 
of 
macropinocytosis in cancer cell lines varies therefore, we propose to study whether macropinocytic 
uptake in human tumors is predictive of clinical outcomes associated with nab-paclitaxel and 
gemcitabine treatment.  Fresh tumor specimens from patients will be analyzed on patients at NYU and 
in the laboratory of Dr. Dafna Bar-Sagi at NYU. 
 
Stromal Elasticity: Pancreas ductal adenocarcinoma is characterized by the extensive deposition of 
desmoplastic stroma.  The stroma functions to support the growth of the malignant pancreas cells.  
The dense stromal compartment results in an increase in intratumoral turgor pressure, which in turn 
collapses the tumor vasculature.  This phenomenon impairs the intratumoral pharmacokinetic 
properties of chemotherapy.  It has recently been demonstrated that the combination of gemcitabine 
and nab-paclitaxel denude the desmoplastic stroma resulting in increased intratumoral vasculature 
patency to promote increased chemotherapy intratumoral penetration.11  The dynamic change in the 
stroma architecture can be measured both by immunohistochemical staining as well as by endoscopic 
ultrasound (EUS).  Alvarez et al have utilized immunohistochemical analysis of type I collagen to 
demonstrate that nab-paclitaxel induces a reduced stromal content by the formation of low density 
collagen bundles comprised of disrupted and disorganized fibers.43  Concordantly they observed a 
decrease in tumor stiffness (increased tumor elasticity) as measured by EUS elastography in tumors 
responding to combination therapy with gemcitabine and nab-paclitaxel. 
 


 
 
 
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1.5    Study Conduct 
 
This study will be conducted in compliance with the protocol approved by the Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC), and in accordance with Good Clinical Practice 
(GCP) standards.  No deviation from the protocol will be implemented without the prior review and 
approval of the IRB/IEC except where it may be necessary to eliminate an immediate hazard to a 
research patient.  In such a case, the deviation will be reported to the IRB or IEC as soon as possible. 
 
 
2.0    STUDY HYPOTHESIS AND OBJECTIVES  
2.1    Overarching Hypothesis 
 
Effective preoperative combination chemotherapy plus SBRT prior to surgery combined with effective 
postoperative combination chemotherapy will improve overall survival for patients with R-PDAC and 
BR-PDAC. 
2.2    Study Objectives 
 
2.2.1 Primary Objective 
 
1. The primary efficacy objective of this study is to estimate the R0 resection rate in patients with 
resectable PDAC as well as those with borderline resectable PDAC independently in response 
to neoadjuvant sequential therapy of combination gemcitabine and nab-paclitaxel followed by 
SBRT.  
 
2.2.2 Secondary Objectives 
 
1. To assess safety and feasibility of perioperative therapy with neoadjuvant gemcitabine and 
nab-paclitaxel (nab-paclitaxel®) chemotherapy followed by stereotactic radiotherapy before 
surgery in addition to adjuvant of gemcitabine and nab-paclitaxel. 
 
2. Estimation of objective response rate in response to neoadjuvant therapy.   
 
3. Estimation of overall survival: overall survival, defined as the time from study treatment initiation 
until death from any cause. 
 
4. Estimation of progression-free survival: progression-free survival (PFS), defined as the time 
from study treatment initiation to the first occurrence of documented disease progression, as 
determined by the PI review of tumor assessments using RECIST v1.1, or death from any 
cause during the study.  
 
5. Estimation of disease-free survival: disease-free survival, defined as the time from first 
postoperative CT scan demonstrating no evidence of malignancy to the time of documented 
disease progression, as determined by the PI review of tumor assessments using RECIST 
v1.1, or death from any cause during the study.  
 
6. Estimation of the histopathologic response rate to neoadjuvant therapy and correlate it to 
survival outcomes.   
 
2.2.3 Exploratory Objectives 
 


 
 
 
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1. Correlate the post therapeutic macropinocytosis with other exploratory markers and estimates 
of clinical outcomes.  
 
2. Correlate pathologic response after neoadjuvant therapy with PFS stratified by ability to 
undergo surgical resection.   
 
3. Correlate dynamic changes in stromal elasticity associated with chemotherapy administration 
and clinical outcomes.  
 
4. Correlate changes in serum CA19.9 and CEA levels in response to therapy will be correlated 
with outcomes. 
 
5. To correlate basal and dynamic changes in biomarkers of tissue SPARC, SMAD4 deletion, 
circulating DNA analysis of KRAS and gene expression analysis with clinical outcomes. 
 
 
3.0    STUDY POPULATION 
3.1    Inclusion Criteria 
 
1. Histologically confirmed resectable or borderline resectable pancreatic adenocarcinoma. 
Pathology Report Form. 
 
2. No evidence of distant metastasis representing stage IV metastatic disease. 
3. R-PDAC: No evidence of distant metastasis and tumor mass showing no extension to superior 
mesenteric artery (SMA) and hepatic artery. There must be a clearly defined fat plane between 
SMA and celiac axis.  Patent superior mesenteric vein (SMV/portal vein (PV) with no distortion 
of venous architecture.  Please refer to 2014 NCCN PDAC Guidelines. 
4. BR-PDAC: defined as localized PDAC with 1 or more of the following features:  a) an interface 
between the primary tumor and superior mesenteric vein (SMV)-portal vein (PV) measuring 
180o or greater of the circumference of the vein wall, and/or b) short-segment occlusion of the 
SMV-PV with normal vein above and below the level of obstruction that is amenable to 
resection and venous reconstruction and/or c) short-segment interface of any degree between 
tumor and hepatic artery with normal artery proximal and distal to the interface that is amenable 
to resection and arterial reconstruction and/or d) an interface between the tumor and SMA or 
celiac trunk measuring less than 180o of the circumference of the artery wall.  Please refer to 
2014 NCCN PDAC Guidelines. 
5. Age > 18 years old 
6. ECOG performance status of 0 or 1 
7. Patients must have adequate bone marrow function:  
• 
Platelets >100,000 cells/mm3  
• 
Hemoglobin > 9.0 g/dL 
• 
Absolute Neutrophil Count > 1,500 cells/mm3 
 
8. Patients must have adequate liver function:  
• 
AST and ALT < 2.5 X upper limit of normal 
• 
Alkaline phosphatase < 2.5 X upper limit of normal  
• 
Total bilirubin < 1.5 mg/dL 
 
9. Patients must have adequate renal function: creatinine <1.5 mg/dL is recommended; however, 
institutional norms are acceptable. Creatinine within institutional limits of normal or creatinine 
clearance (CrCl) > 50 mL/min calculated using the Cockcroft-Gault equation. 


 
 
 
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10. Women of childbearing potential and sexually active males must use an effective contraception 
method during treatment and for three months after completing treatment. 
11. Negative serum or urine β-hCG pregnancy test at screening for patients of childbearing 
potential. 
12. Patients must have < Grade 2 pre-existing peripheral neuropathy (per CTCAE 4.03). 
13. Ability to understand and willingness to sign a written informed consent. 
 
3.2    Exclusion Criteria: 
 
1. Patients with locally advanced surgically unresectable PDAC. 
2. Patients with evidence of distant metastatic PDAC. 
3. Prior chemotherapy or radiation therapy of any kind for treatment of pancreas adenocarcinoma. 
4. Prior major surgery within 4 weeks of starting study drug administration. 
5. Patient unable or not willing to perform all study related biopsies and blood draws for 
exploratory endpoints will not be enrolled on study as all study related procedures are 
mandatory. 
6. Concomitant treatment with full dose warfarin (coumadin) is NOT allowed.  However, treatment 
with low molecular weight heparin (LMWH) (such as enoxaparin or dalteparin) or rivaroxaban 
is allowed.  Patients on full dose warfarin (coumadin) must be transitioned to either LMWH or 
rivaroxaban prior to administration of any study related drugs.   
7. Recent or ongoing clinically significant gastrointestinal disorder (e.g., malabsorption, bleeding, 
inflammation, emesis, diarrhea >grade 1).  
8. Patients with clinically significant cardiac disease (New York Heart Association Classification 
III or IV (see Appendix A) and cardiac arrhythmias not well controlled with medication), or 
myocardial infarction within the previous six months. 
9. Serious, uncontrolled, concurrent infection(s) requiring antibiotics. 
10. Pregnant or breastfeeding women: positive pregnancy test within 7 days of starting treatment. 
11. Treatment for other carcinomas within the last five years, except cured non-melanoma skin 
and treated in-situ cervical cancer. 
12. Participation in any investigational drug study within 4 weeks preceding the start of study 
treatment. 
13. Patients with external biliary drains. 
 
 
4.0    STUDY DESIGN AND PLAN 
4.1    Study Design 
 
The study is a multi-institutional, open-label phase II trial to assess the safety and obtain preliminary 
efficacy data for a new perioperative treatment regimen consisting of gemcitabine and nab-paclitaxel 
combined with SBRT in a sequential manner followed by surgical resection and adjuvant combination 
chemotherapy of gemcitabine and nab-paclitaxel for two independent patient cohorts: R-PDAC and 
BR-PDAC.   The study will accrue 20 R-PDAC patients and 30 BR-PDAC patients  
 
Patients will receive a total of 3 cycles of combination neoadjuvant chemotherapy followed by SBRT 
if restaging CT does not show evidence of metastatic disease. Upon completion of SBRT patients will 
receive definitive surgical resection. Subsequently, patients will receive 3 cycles of adjuvant 
combination chemotherapy, Figure 1.  Each cycle of combination chemotherapy will be a total of 4 
weeks. Gemcitabine and nab-paclitaxel will be administered according to the dosing schema utilized 
in the phase III MPACT study. Gemcitabine 1000 mg/m2 IV (following nab-paclitaxel 125 mg/m2) 
administered weekly for 3 weeks with one week off before the next cycle.  


 
 
 
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study of this combination in patients with metastatic pancreas adenocarcinoma.12  This regimen will 
be administered for a total of 3 cycles in the neoadjuvant (preoperative) and adjuvant (postoperative) 
settings.  Patient will undergo restaging CT scan upon completion of combination chemotherapy.  
Patients will undergo EUS and biopsy at baseline and upon completion of 3 cycles of neoadjuvant 
combination chemotherapy as part of SBRT fiducial marker placement procedure.   
   
SBRT will commence 21 days and no longer than 35 days after completion of the third cycle of 
neoadjuvant chemotherapy.  The rationale of this therapy is to deliver highly conformal radiation at 
higher fractional doses than conventional radiation.  The planned radiation dose per fraction will range 
from 5 Gy to 12 Gy per fraction depending on approximation of radiation field to adjacent bowel.  This 
will result in the total delivered radiation dose ranging from 24 to 36 Gy. 
 
Surgery will take place between four and six weeks after SBRT is complete.  Adjuvant chemotherapy 
will be administered six to 12 weeks after surgery.  A restaging CT scan will be obtained prior to 
initiating adjuvant chemotherapy to assess for evidence of disease recurrence.   
 
In the post-therapy follow-up period, patients will be followed every three months with follow-up 
physical exam, serum CEA/CA19.9 and CT scans for two years.  Follow-up after two years will occur 
at least every six months with physical exam, serum CEA/CA19.9 and CT scans at 6-month intervals 
for the next 3 years to complete 5 years of follow up.   
 
Disease status will be assessed using RECIST version 1.1.  In this trial, accrual will be halted after 10 
patients are entered to analyze safety following the entire protocol.  If more than three of the first 10 
patients experience preoperative toxicity that prevents surgery, the trial will be halted.  If more than 
20% of the patients taken to surgery die of treatment-related complications, the trial will be halted.  The 
determination to continue therapy will be made in concert with the PIs from each institution participating 
in this trial.    
4.2    Study Chemotherapy Administration 
 
4.2.1 Nab-paclitaxel (Abraxane®) 
 
4.2.1.1 Nab-paclitaxel Product and Storage 
 
Nab-paclitaxel for Injectable Suspension (also known as ABI-007, nab-paclitaxel, paclitaxel protein-
bound particles for injectable suspension) is an albumin-bound form of paclitaxel with a mean particle 
size of approximately 130 nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous 
state. Nab-paclitaxel is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 
20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single-use vial 
contains 100 mg of paclitaxel and approximately 900 mg of human albumin. Each milliliter (mL) of 
reconstituted suspension contains 5 mg paclitaxel.   
 
Nab-paclitaxel vials must be stored in original cartons at controlled 20°C–25°C.  Vials must be retained 
in the original cartons to protect from bright light.  For further details, see the Nab-paclitaxel Prescribing 
Information or Summary of Product Characteristics.  Nab-paclitaxel is free of solvents.   The active 
agent in nab-paclitaxel is paclitaxel.  
 
4.2.1.2 Premedication 
Patients do not require premedication prior to nab-paclitaxel administration, as hypersensitivity 
reactions are not expected, though initial antiemetic prophylaxis is recommended due to administration 
of gemcitabine following nab-paclitaxel treatment. 


 
 
 
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If a hypersensitivity reaction occurs, the infusion should be stopped and not restarted. If felt to be in 
the patient’s best interests, at the PI’s discretion, treatment may continue on subsequent cycles using 
the premedication regimen the institution typically uses for Taxol. 
 
4.2.1.3 Administration 
 
Nab-paclitaxel must be administered immediately before gemcitabine administration.  Nab-paclitaxel 
should be administered by IV infusion at a dose of 125 mg/m2 over 30 minutes on Days 1, 8, and 15 
of every 28-day cycle according to institutional standard. 
 
4.2.1.4 Drug Ordering and Storage 
 
Nab-paclitaxel vials must be stored in original cartons at controlled 20°C–25°C.  Vials must be retained 
in the original cartons to protect from bright light.  For further details, see the Nab-paclitaxel Prescribing 
Information or Summary of Product Characteristics. 
 
4.2.2 Gemcitabine 
 
4.2.2.1 Description 
 
Gemcitabine is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine HCl is 2´-
deoxy-2´,2´-difluorocytidine monohydrochloride (-isomer). For further details, see the Gemcitabine 
Prescribing Information or Summary of Product Characteristics. 
 
4.2.2.2 Premedication 
 
Please see gemcitabine prescribing information for recommended premedication strategies. 
 
4.2.2.3 Administration 
 
Gemcitabine must be administered immediately after nab-paclitaxel.  Gemcitabine should be 
administered by IV infusion at a dose of 1000 mg/m2 over 30 minutes on Days 1, 8 and 15 of every 
28-day cycle according to institutional standard. 
 
4.2.2.4 Drug Ordering and Storage 
 
Gemcitabine will be obtained commercially.  Gemcitabine must be stored at 20°C–25°C. For further 
details, see the Gemcitabine Prescribing Information or Summary of Product Characteristics. 
 
4.2.2.5 Regimen 
 
Patients will be treated on an outpatient basis with nab-paclitaxel plus gemcitabine.   
 
Patients receiving nab-paclitaxel plus gemcitabine will receive nab-paclitaxel 125 mg/m2 as a 30- to 
40-minute infusion (maximum infusion time not to exceed 40 minutes) followed by 1000 mg/m2 
gemcitabine as a 30- to 40-minute infusion (maximum 40 minutes) weekly for 3 weeks followed by a 
week of rest.  Patients will receive 3 cycles in total as neoadjuvant therapy.  The patients will receive 
an additional 3 cycles of the combination chemotherapy as adjuvant therapy post-surgical resection of 
pancreas ductal adenocarcinoma (see Table 1). 
 
 


 
 
 
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   Table 1: Drug Dosing Schedule 
 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Nab-paclitaxel/Gemcitabine 
Cycle 1-3 
X 
X 
X 
- 
X 
X 
X 
- 
X 
X 
X 
- 
 
Supportive care per the institution’s normal standard of care including concomitant medications can 
be provided at the PI’s discretion (see Section 4.2). 
4.3    Rules for Dose Omission and Schedule Modification 
 
Day 1 dose missed: 
 
If the dose held or missed was to be given on Day 1 of the next cycle, that next cycle will not be 
considered to start until the day the first dose is actually administered to the patient (i.e., 1-2-3-Rest, 
X-1-2-3-Rest, etc.). 
 
 
Day 8 dose is missed: 
 
Cycle continues per protocol, with one dose not given (i.e., 1-2-3-Rest, 1-X-3-Rest, 1-2-3-Rest, etc.).  
Day 8 is administered as per cycle calendar if counts and chemistries permit.  NOTE: The same applies 
to any intracycle dose of Cycle 1 of gemcitabine single agent (Days 8, 15, 22, 29, 36, 43): the cycle 
continues with 1 dose not given. 
 
Day 15 dose missed: 
 
That week becomes the week of rest.  Next dose (if counts and chemistries permit) becomes Day 1 of 
a new cycle, and the patient is considered to have had a x2q3 (21-day) cycle (i.e., 1-2-3-Rest, 1-2-X, 
1-2-3-Rest, etc.). 
 
NOTE: The maximum delay between a missed scheduled dose and the next one (whichever dose was 
missed) should not be longer than 14 days (except for peripheral neuropathy; see Section 4.3.2.3). 
 
4.3.1 Administration of Study Drug to Patients with Abnormal Hepatic Function 
 
Study drug should only be administered if hepatic function is within the parameters established in the 
eligibility criteria.  Hepatic toxicity from taxanes may occur but it is uncommon.  Therefore, hepatic 
dysfunction that occurs while the patient is on study should prompt an evaluation to determine the 
cause, including the possibility of progressive metastatic disease and hepatotoxicity from concurrent 
medications. 
 
4.3.2 Dose Modification Tables 
 
Doses will be reduced for hematologic and other toxicities.  Dose adjustments are to be made according 
to the system showing the greatest degree of toxicity.  Toxicities will be graded using the NCI CTCAE 
Version 4.0. 
Two levels of dose modifications are permitted according to the criteria below.  If a toxicity requiring 
dose modification occurs following the second dose reduction of either study drug, further treatment 
should be discontinued.  Any further dose modification requires prior Celgene approval. 


 
 
 
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  Table 2: Dose Levels 
 
Dose Level 
Nab-paclitaxel Dose (mg/m
2)
A 
Gemcitabine (mg/m
2)
A 
Study Dose 
125 
1000 
-1 
100 
800 
-2
B 
75 
600 
A. Dose reductions may or may not be concomitant.  Please refer to Table 3 and Table 4 for specific 
recommendations regarding dose modifications for Day 1 of each cycle for hematologic and non-hematologic 
toxicity, respectively.  Please refer to Table 5 and Table 6 for specific recommendations regarding dose 
modifications within a cycle for hematologic and non-hematologic toxicities, respectively. 
B.     A maximum of 2 dose level reductions are allowed. 
 
 
Patients experiencing study drug-related toxicities that require a delay in scheduled nab-
paclitaxel or gemcitabine dosing for 21 days will be discontinued from further treatment in this 
study (except for peripheral neuropathy; see Section 4.3.2.3). When a dose reduction is 
required, no dose re- escalation will be permitted for the duration of study treatment (with the 
exception mentioned in Table 5, namely: on Day 15, re-escalation with granulocyte-colony 
stimulating factor (G-CSF) support is permitted, after a previous dose reduction on Day 8 of 
the same cycle). 
 
 
4.3.2.1 Dose Modifications at Day 1 
 
In the event dose modifications are required at the beginning of a cycle due to AEs or hematologic 
toxicities, doses of nab-paclitaxel and gemcitabine may be adjusted as detailed in Table 3 and Table 
4 as presented below: 
 
  
  Table 3: Dose Modifications for Day 1 of Each Cycle (Hematologic Toxicity) 
 
Treatment day counts and toxicity 
ANC 
Platelets 
Timing 
³ 1.5 x 109/L 
And 
³ 100 x 109/L 
Treat on time 
<1.5 x 109/L 
Or 
<100 x 109/L 
Delay by 1 week intervals until 
recovery 
Key: ANC = Absolute neutrophil count. 
 
 
 


 
 
 
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Table 4: Dose Modifications for Day 1 of Each Cycle (Non-Hematologic Toxicity) 
 
Non Hematologic Toxicity and/or Dose Hold with Previous Cycle 
Toxicity/dose held 
Gemcitabine and Nab-paclitaxel dose this cycle 
Grade 0, 1 or 2 toxicity 
Same as Day 1 of previous cycle (except for Grade 2 cutaneous toxicity 
where doses of gemcitabine and nab-paclitaxel should both be reduced to 
next lower dose level) 
Grade 3 toxicity
A 
Decrease gemcitabine and nab-paclitaxel to next lower dose level
A 
Grade 4 toxicity
BA, B  
Off protocol treatment
B 
Dose held in 2 previous consecutive cycles 
Decrease gemcitabine to next lower dose level and continue throughout the 
rest of treatment 
Key: CTCAE = Common terminology criteria for adverse events. 
 
A. If the toxicity only affects neuropathy, then only Nab-paclitaxel should be reduced (please see Section 
  4.3.2.3). 
B. Pulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or a symptomatic, will be exempt from 
  this requirement (please see Section 4.3.2.5). 
 
 
 
4.3.2.2 Dose Adjustments within a Treatment Cycle 
 
In the event that patients must have treatment delayed within a treatment cycle due to toxicities, 
those doses held during a cycle will not be made up. 
Dose modifications due to hematologic toxicity (as represented by the blood counts and toxicities, 
below) within a treatment cycle should be adjusted as outlined in Table 5. 
 
 
 


 
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 Table 5: Dose Modifications Due to Hematologic Toxicity 
 
Day 8  
Blood Counts 
Day 8  
nab-paclitaxel 
Day 8 
Gemcitabine 
Day 15  
Blood Counts 
Day 15 
 nab-paclitaxel 
Day 15 
Gemcitabine 
Any Day 
nab-paclitaxel 
Any Day 
Gemcitabine 
ANC >1000 
And 
Platelets 
≥75,000 
100% 
100% 
ANC >1000 and 
Platelets ≥75,000 
100% 
100% 
ANC 500-1000 or 
Platelets 50,000- 
74,999 
Full Dose (treat 
on time) 
+ G-CSF
A 
Full Dose (treat 
on time) +  
G-CSF
A 
ANC <500 or 
Platelets <50,000 
Hold + G-CSF
A 
Hold + G-CSF
A 
ANC 500- 1000
a,c 
or Platelets 
50,000-74,999 
Decrease dose 
by 1 level (treat 
on time) 
Decrease dose 
by 1 level (treat 
on time) 
ANC >1000 and 
Platelets ≥75,000 
Return to 
Previous Dose 
level (treat on 
time) + G-CSF
A 
Return to 
Previous Dose 
Level (treat on 
time) + G-CSF
A 
ANC 500-1000 or 
Platelets 50,000- 
74,999 
Same Dose (as 
Day 8, treat on 
time) + G-CSF
A 
Same Dose (as 
Day 8, treat on 
time) + G-CSF
A 
ANC <500 or 
Platelets <50,000 
Hold + G-CSF
A 
Hold + G-CSF
A 
ANC <500
b 
or Platelets 
<50,000 
Hold 
Hold 
ANC >1000 and 
Platelets ≥75,000 
Decrease Day 8 
dose by 1 level 
(treat on time) + 
G-CSF
A 
Decrease Day 8 
dose by 1 level 
(treat on time) + 
G-CSF
A 
ANC 500-1000 or 
Platelets 50,000- 
74,999 
Decrease Day 8 
dose by 1 level 
(treat on time) 
+ G-CSF
A 
Decrease Day 8 
dose by 1 level 
(treat on time) 
+ G-CSF
A 


 
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Page 39 of 89 pages 
 
 
Protocol/COMIRB # 15-0150 – PI: Weekes – Version Date: 11.16.2016 
 
 
Day 8 
Blood Counts 
Day 8 
Nab-paclitaxel 
Day 8 
Gemcitabine 
Day 15 
Blood Counts 
Day 15 
Nab-paclitaxel 
Day 15
Gemcitabine 
Any Day 
Nab-paclitaxel 
Any Day 
Gemcitabine 
ANC <500 or 
Platelets <50,000 
Hold + G-CSF
A 
Hold + G-CSF
A 
Febrile Neutropenia 
(Grade 3 or 4)
C 
Hold.  Upon 
resuming dosing, 
decrease to next 
lower level and do 
not re-escalate 
throughout the 
rest of treatment. 
Hold.  Upon 
resuming dosing, 
decrease to next 
lower dose level 
and do not 
re-escalate 
throughout the 
rest of treatment. 
Recurrent Febrile 
Neutropenia (Grade 
3 or 4)
B 
Decrease to next 
lower dose level 
and do not 
re-escalate 
throughout the 
rest of treatment. 
Decrease 2 dose 
levels (to 600 
mg/m
2) and do 
not 
re-escalate 
throughout the 
rest of treatment. 
Abbreviations:  ANC = Absolute neutrophil count; G-CSF = Granulocyte colony stimulating factor. 
A. G-CSF is optional if descent only affects platelets. 
B. If patients do not experience resolution of neutropenia within 21 days, despite uninterrupted G-CSF treatment, study 
treatment will be discontinued. 
C. Febrile patients (regardless of neutrophil count) should have their chemotherapy treatment interrupted.  A full sepsis 
diagnostic work-up should be performed while continuing broad spectrum antibiotics.  If cultures are positive, the antibiotic 
may or may not be changed, depending on the sensitivity profile of the isolated organism.  Patients with persisting fever 
after 3 weeks, despite uninterrupted antibiotic treatment, will discontinue study treatment.  Febrile neutropenic patients can 
also receive G-CSF, in addition to antibiotic treatment, to hasten the resolution of their febrile neutropenia (following current 
institutional guidelines).  In all cases, blood counts must have returned to baseline levels before resuming chemotherapy 
treatment. 
 
Note:  for Gemcitabine Cycle 1 (of 8 weeks duration), intracycle dose modifications should be managed by either holding the dose, or reducing the dose, at the 
physician’s discretion and based on the nature and severity of the hematologic toxicity.  For doses held, the criteria specified in Section 4.2.3.2 should be followed.  
For dose reductions, the criteria specified for Day 8 gemcitabine in Table 5 should be followed.  For subsequent (weekly x 3 every 4 weeks) gemcitabine 
monotherapy cycles, Table 5 criteria for both Days 8 and 15 apply. 


 
 
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Dose modifications may also be made for non-hematological toxicity within a cycle as specified 
in Table 6. 
 
Table 6: 
Dose Modifications for Non-Hematological Toxicity within a Cycle 
 
CTCAE Grade 
Percent of Day 1 
Nab-paclitaxel and Gemcitabine Dose 
0-2 (and Grade 3 nausea/vomiting and alopecia) 
3 (except nausea/vomiting and alopecia) 
 4 
100%
A 
 
  Hold either one or both drugs to ≤Grade 1.  Then resume  
treatment at the next lower dose level. 
Hold
B,C 
 
Abbreviations: CTCAE = Common terminology criteria for adverse events.  
A. Except for cutaneous toxicity. 
B. This decision as to which drug should be modified will depend upon the type of non-hematologic toxicity 
  seen and which course is medically most sound in the judgment of the physician/investigator. 
C. Pulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, will be exempt 
  from this requirement (please see Section 4.3.2.5). 
 
4.3.2.3 Peripheral Neuropathy 
 
Nab-paclitaxel should be withheld in patients who experience ³ Grade 3 sensory neuropathy.  
Treatment may be resumed at the next lower dose level (see Table 2) in subsequent cycles after 
the sensory neuropathy improves to £ Grade 1. The time to resolution to Grade £ 1 should be the 
adverse event duration used for adverse event reporting.  In those patients who experience Grade 
4 sensory neuropathy, study drug should be withheld, and treatment resumed at a reduction of 2 
dose levels (Dose Level -2; see Table 2) in subsequent cycles after the sensory neuropathy 
improves to £ Grade 1.  Note: the PI may elect to dose modify for Grade 3 sensory neuropathy. 
 
4.3.2.4 Hypersensitivity Reactions 
 
Hypersensitivity reactions rarely occur.  If they do occur, minor symptoms such as flushing, skin 
reactions, dyspnea, lower back pain, hypotension, or tachycardia may require temporary interruption 
of the infusion.  However, severe reactions, such as hypotension requiring treatment, dyspnea 
requiring bronchodilators, angioedema or generalized urticaria require immediate discontinuation of 
study drug administration and aggressive symptomatic therapy.  Patients who experience a severe 
hypersensitivity reactions to nab-paclitaxel should not be re-challenged. 
 
4.3.2.5 Pulmonary Embolism 
 
Asymptomatic or clinically mild pulmonary embolism can be treated with low-molecular-weight 
heparin without interruption of therapy.  Moderate to severe pulmonary embolism will require 
permanent discontinuation of treatment. 


 
 
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4.3.2.6 Colony Stimulating Factor Administration 
Colony stimulating factors may be given according to institutional guidelines for the treatment of 
neutropenic fever or infections associated with neutropenia and for the prevention of febrile 
neutropenia in patients with an ANC <500 cells/µL (as per Table 7).  Patients not experiencing 
resolution of neutropenia within 21 days, despite uninterrupted G-CSF treatment, will discontinue 
study treatment. 
 
G-CSF Administration 
For QW study drug administration administer G-CSF 5 mcg/kg/day (rounded to the nearest vial size 
per PI/institution’s standard of care) 24 hours after chemotherapy and hold 48 hours prior to the next 
dose 
Table 7:  Use of G-CSF and Dose reductions for Hematologic Toxicity 
Adverse Event 
Occurrence 
Action to be Taken 
ANC < 500 cells/mm3 (nadir 
count) with neutropenic fever > 
38° 
OR 
Delay of next cycle due to 
persistent neutropenia (ANC < 
1500 cells/mm3) 
OR 
For patients on weekly treatment 
whose next treatment within the 
cycle (Day 8 or Day 15) is omitted 
due to persistent neutropenia 
(ANC < 1000 cells/mm3). 
OR 
Neutropenia < 500 cells/mm3 for > 
1 week 
Any 
Occurrence 
At the first occurrence of a hematological toxicity (as 
outlined in the Adverse Event column), the same dose 
is maintained and G-CSF is given as outlined below.  In 
the event that a hematological toxicity re-occurs in the 
face of G-CSF, dose reduction to the next lower level 
will be required for subsequent cycles once ANC is ³ 
1500 cells/mm3.  
 
If G-CSF is given concurrently with weekly NAB-
PACLITAXEL, administration may begin the day after 
NAB-PACLITAXEL is given and should stop at least 48 
hours prior to when NAB-PACLITAXEL is given the 
following week.   
Thrombocytopenia Grade 3 or 
Grade 4* 
1st 
Occurrence 
Dose reduction to next lower level 
Recurrence 
Dose reduction to next lower level 
*See NCI Toxicity Criteria Scale for definition of Grade 3 and Grade 4 events. 
 
4.3.2.7 Other Toxicities 
If toxicities are ³ grade 3, except for anemia, treatment should be withheld until resolution to £ grade 
1 or baseline if baseline was greater than grade 1, then reinstituted, if medically appropriate, at the 
next lower dose level (see Table 2). 
 
4.3.2.8 Pulmonary Toxicity 
There are case reports in the literature of an interstitial pulmonary inflammation or fibrosis thought 
to be secondary to gemcitabine.  If the patient develops dyspnea with a bilateral infiltrate not due to 


 
 
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infection or tumor with a 10% drop in O2 saturation, they may come off study.  This condition has 
been treated successfully in some cases with high dose steroids. The pulse oximeter test for O2 
saturation should be done every third cycle. Compare it to the O2 saturation level taken at the initial 
visit. 
 
Interstitial pneumonitis has been observed in ~1% during nab-paclitaxel monotherapy and in ~1% 
during combination treatment with nab-paclitaxel and carboplatin.  However, the risk has been higher 
for the combination of nab-paclitaxel with gemcitabine.  Pneumonitis has been reported at a rate of 
4% with the use of nab-paclitaxel in combination with gemcitabine.  Monitor patients closely for signs 
and symptoms of pneumonitis.  After ruling out infectious etiology, and upon making a diagnosis of 
pneumonitis, permanently discontinue treatment with nab-paclitaxel and gemcitabine and promptly 
initiate appropriate treatment and supportive measures. 
 
Prevention, Surveillance and Management of Interstitial Pneumonitis 
 
a. 
Before starting treatment with nab-paclitaxel candidates should be evaluated for familial, 
environmental or occupational exposure to opportunistic pathogens: do not enroll patients 
with a history of slowly progressive dyspnea and unproductive cough, or pulmonary 
conditions such as sarcoidosis, silicosis, idiopathic pulmonary fibrosis, hypersensitivity 
pneumonitis or multiple allergies. 
 
b. 
During treatment with nab-paclitaxel episodes of transient or repeated dyspnea with 
unproductive persistent cough or fever should be paid attention to. Radiographic evaluation 
with chest X-rays and computed tomography (CT) scans (normal or high resolution) may be 
indicated to look for infiltrates ground-glass opacities or honeycombing patterns. Pulse 
oximetry and pulmonary function tests can show respiratory and ventilation compromise. 
 
c. 
Infections should be ruled out with routine microbiological and/or immunologic methods. 
Transbronchial lung biopsy is not recommended, given its limited value and risk of 
pneumothorax and hemorrhage, and should be reserved for cases with unclear etiology. 
 
d. 
Upon a diagnosis of interstitial pneumonitis nab-paclitaxel should be permanently 
discontinued. After ruling out an infectious etiology, intravenous high-dose corticosteroid 
therapy should be instituted without delay, with appropriate premedication and secondary 
pathogen coverage. Patients with an added immunological component may also require 
immune modulation with azathioprine or cyclophosphamide. Appropriate ventilation and 
oxygen support should be used when required. 
 
4.3.2.9 Sepsis 
 
Sepsis has been reported in less than 1% during monotherapy and fatalities attributed to these 
events have been rare. However, the risk was appreciably higher in patients with advanced or 
metastatic pancreatic cancer receiving nab-paclitaxel in combination with gemcitabine with a rate of 
5% in patients in patients with or without neutropenia receiving nab-paclitaxel combined with 
gemcitabine. Complications due to the underlying pancreatic cancer, especially biliary obstruction 
or presence of biliary stent, were identified as significant contributing factors. The increased risk of 
sepsis in the setting of advanced or metastatic cancer in combination with gemcitabine could be 
managed with prophylactic antibiotic treatment in febrile patients (regardless of neutrophil count) 
and dose reduction, and with G-CSF treatment in neutropenic patients.  If a patient becomes febrile 
(regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile 
neutropenia, withhold nab-paclitaxel and gemcitabine until fever resolves and ANC ≥ 1500, then 


 
 
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resume treatment at reduced dose levels. 
 
4.4    Concomitant Medications 
 
Supportive care, including but not limited to anti-emetic medications, may be administered at the 
discretion of the PI.  Concurrent treatment with bisphosphonates is allowed.  Erythropoietin and G-
CSF may be administered at the discretion of the PI, consistent with institutional guidelines.  
4.5    Discontinuation 
A patient may voluntarily discontinue study participation at any time.  The PI may also, at his/her 
discretion discontinue the patient's study participation at any time.  In the event of discontinuation, 
the patient should return to the study site as soon as feasible to have the EOS assessments 
performed and the appropriate follow-up evaluations should occur.  Patients must discontinue 
study treatment if any of the following occurs: 
• 
Progressive disease with evidence of distant metastasis as determined by CT scans 
or MRIs. CA19-9 will not be used to determine disease progression or as a criterion 
for patient withdrawal from the study.   
• 
Development of toxicity that is unacceptable in the opinion of the PI. 
• 
Patient develops moderate to severe pulmonary embolism. 
• 
Patient declines to continue therapy (ie, withdraws consent). 
• 
If following the second dose reduction there is a recurrence of Grade 4 
neutropenia, or any other Grade 3 or 4 hematologic toxicity or non-
myelosuppressive AE, unless per the PI there is evidence of continuing benefit to 
the patient that outweighs the risk of recurrent toxicity, and after consultation with 
the Celgene. 
• 
Patient does not experience resolution of Grade 4 neutropenia within 21 days, 
despite uninterrupted G-CSF treatment. 
• 
Initiation of other anticancer therapy. 
• 
In the PI’s judgment, it is in the patient’s best interest to discontinue the study 
treatment. 
 
Responders and stable disease patients may continue on study treatment unless they develop an 
unacceptable toxicity. 
Patients who discontinue study treatment secondary to a laboratory abnormality or adverse event 
should be followed as outlined in Section 6.10. 
Patients who discontinue study treatment or active participation in the study should still be followed 
up for safety, disease progression and OS as described in Section 6.10, Section 6.11, and Section 
6.12, respectively.  Only if a patient withdraws consent for any further follow-up or contact should 
he or she be discontinued from the study. 
 


 
 
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5.0    DETAILED DESCRIPTION OF STUDY DRUG MANAGEMENT AND 
ADMINISTRATION 
5.1    Nab-paclitaxel 
 
5.1.1 Packaging, Labeling, and Storage of Study Drug 
 
Availability 
 
Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin. 
Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel.  
 
Storage and Stability 
 
Storage: Store the vials in original cartons at 20 ºC to 25 ºC (68 ºF to 77 ºF). Retain in the original 
package to protect from bright light.  
 
Stability: Unopened vials of nab-paclitaxel are stable until the date indicated on the package when 
stored between 20 ºC to 25 ºC (68 ºF to 77 ºF), in the original package. Neither freezing nor 
refrigeration adversely affects the stability of the product.  
 
Stability of Reconstituted Suspension in the Vial  
 
Reconstituted nab-paclitaxel should be used immediately, but may be refrigerated at 2 ºC to 8 ºC 
(36 ºF to 46 ºF) for a maximum of 4 hours if necessary. If not used immediately, each vial of 
reconstituted suspension should be replaced in the original carton to protect it from bright light. 
Discard any unused portion.  
 
Stability of Reconstituted Suspension in the Infusion Bag  
 
The suspension for infusion prepared as recommended in an infusion bag should be used 
immediately, but may be stored at ambient temperature (approximately 25 ºC) and lighting conditions 
for up to 4 hours.  
 
Study Medication Administration 
 
Nab-paclitaxel is injected into a vein [intravenous (I.V.) infusion] over 30 minutes.  The use of an in-
line filter is not recommended.  
 
Reconstitution and use of Nab-paclitaxel (ABRAXANE) 
 
1. Calculate the patient’s body surface area (BSA) at the beginning of the study and if the 
weight changes by > 10% by using the Hosteler BSA formula. 
2. Calculate the total dose (in mg) to be administered by:  
• 
Total Dose (mg) = BSA x (study dose mg/m2 ) 
3. Calculate the total number of vials required by: 
Total Number of Vials = Total Dose (mg) 
                             
100 (mg/vial) 


 
 
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Round up the number of vials to be reconstituted to the next higher whole number when 
a fractional number of vials is obtained by the above formula (e.g., if the total number of 
vials = 4.05 or 4.5, then 5 vials would be reconstituted).  
4. Using sterile technique, prepare the vials for reconstitution. 
5. Swab the rubber stoppers with alcohol. 
6. Aseptically, reconstitute each ABRAXANE vial by injecting 20 mL of 0.9% Sodium 
Chloride Injection, USP.  
• 
Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 
1 minute, using the sterile syringe directing the solution flow onto the inside wall of 
the vial. 
• 
DO NOT INJECT the 0.9% Sodium Chloride Injection, USP solution directly onto the 
lyophilized cake as this will result in foaming. 
• 
Once the injection is complete, allow the vial to sit for a minimum of 5 (five) minutes 
to ensure proper wetting of the lyophilized cake/powder.   
• 
Gently swirl and/or invert the vial slowly for at least 2 minutes until complete 
dissolution of any cake/powder occurs.  Avoid generation of foam.  Rapid agitation 
or shaking will result in foaming. 
• 
If foaming or clumping occurs, stand solution for at least 15 minutes until foam 
subsides. 
• 
Each ml of reconstituted product will contain 5 mg of paclitaxel. 
7. Calculate the exact total dosing volume of 5 mg/ml suspension required for the patient: 
• 
Dosing volume (ml) = Total dose (mg) / 5 (mg/ml) 
8. The reconstituted suspension should be milky and homogeneous without visible 
particulates.  If particulates or settling are visible, the vial should be gently inverted again 
to ensure complete resuspension prior to use.  Discard the reconstituted suspension if 
precipitates are observed.  
9. Once the exact volume of reconstituted ABRAXANE has been withdrawn from the vials, 
discard any excess solution left over in accordance with standard operating procedures. 
10. Further dilution is not necessary. Inject the calculated dosing volume of reconstituted 
ABRAXANE suspension into an empty sterile, standard PVC IV bag using an injection 
port.  Inject perpendicularly into the center of the injection port to avoid dislodging plastic 
material into the IV bag.   
11. Administer the calculated dosing volume of reconstituted ABRAXANE suspension by IV 
infusion over 30 minutes.  The use of in-line filters is not recommended because the 
reconstituted solution may clog the filter.  
5.2    Gemcitabine 
 
5.2.1 Packaging, Labeling, and Storage of Study Drug 
 
Description 
For complete details on drug administration, storage, clinical pharmacology, and the human 
pharmacokinetics of gemcitabine, please see the gemcitabine package insert. 
 


 
 
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Formulation 
Gemcitabine (difluorodeoxycytidine) is a pyrimidine antimetabolite, which is an analogue of 
deoxycytidine.  It was initially synthesized as a potential antiviral drug but selected for anticancer 
development because of its activity in in-vivo and in vitro tumors.  Gemcitabine is approved for the 
treatment of patients with pancreatic cancer and will be obtained commercially and relabeled 
as clinical supplies.  Gemcitabine should be stored, reconstituted and administered according to 
the manufacturer’s recommendation. 
 
Instructions for Storing Gemcitabine 
 
Store unopened vials per the gemcitabine product label.  Preparation and administration of 
gemcitabine should be per the gemcitabine package insert. 
 
Instructions for Use/Handling of Gemcitabine 
Use/handling of gemcitabine should be per the gemcitabine package insert. 
 
5.3 Endocopic Ultrasound Procedures 
 
5.3.1 Endoscopic Ultrasound 
 
Many patients with suspected pancreatic cancer will undergo endoscopic ultrasound (EUS) 
examinations and EUS-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) as indicated to 
confirm the diagnosis of pancreatic adenocarcinoma. Procedures will be performed by experienced 
endosonographers; each having performed >1000 cases. The curvilinear array echoendoscopes 
(GF-UC140P or GF-UCT140, Olympus) will be used and the procedures will be performed with the 
patients in the left lateral position or prone position under moderate-deep sedation with 
midazolam/fentanyl and/or intravenous propofol. The location (head, genu, body and tail of 
pancreas), size, shape, margins (regular, irregular, well defined, poorly defined) and echogenicity of 
the lesions will be recorded. In addition, endosonographers will document evaluation for vascular 
invasion. This evaluation will be standardized among all endosonographers and documented in a 
case report form. After localizing the lesion, a 22 or 25-guage needle (EUS N-3/ProCore Biopsy 
Needle, Cook Medical, Winston Salem, N.C.) will be used for FNA/FNB under EUS guidance. The 
use of a stylet and suction during the procedure will be at the discretion of the endosonographer. It 
is routine practice to perform these procedures in the presence of an on-site cytopathologist in the 
endoscopy unit to render an opinion regarding adequacy of the specimen and preliminary diagnosis 
of the aspirate. 
 
5.3.2 Cytopathologic assessment and final diagnosis 
Each procedure will be performed with a cytopathologist or cytotechnologist in the room. After each 
pass, the sample from the needle will be expressed using a 10 mL air-filled syringe onto a glass 
slide until no further material could be expressed. Then using another glass slide the sample will be 
spread out to make two slides. These slides will be numbered according to the number of the pass. 
One slide will be air dried and stained with Diff-Quik stain for immediate on-site interpretation. The 
other slide will be fixed in alcohol (95% ethanol) and stained later with Papanicolaou stain. The 
residual contents of the needle after every pass will be flushed with 5-10 ml of sterile saline solution 
into the Saccomano or cytolyte solution. After flushing the needle, the exterior of the needle will be 
wiped with sterile gauze soaked in saline solution to reduce cross contamination between the 
passes. The on-site evaluation of smears will be performed to assess cellular adequacy and to 
assess the need for any additional passes. The overall number of passes will be at the discretion of 


 
 
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the endosonographer as clinically indicated. Based on institutional experience and published 
literature, four EUS-FNA passes are required to confirm the diagnosis of malignancy. Two additional 
EUS-FNA/FNB passes will be made and collected for biomarker studies. Experienced 
cytopathologists will evaluate cytology slides. The slides for each pass were assessed using strict 
predefined criteria for the following: cellularity, adequacy of specimen, contamination, amount of 
blood, and diagnosis. The final diagnosis of malignancy will be made by reviewing all the slides 
prepared from the lesion and the cell block. The results will be entered in a case report form and 
then transferred to a database.     
 
5.3.3 Elastography 
 
Endoscopic elastography has been developed as a noninvasive method to characterize pancreas 
masses of benign and malignant etiologies.  This technique utilizes real-time assessment of the 
tissue elasticity distribution calculation with subsequent representation in fundamental B-mode 
imagining.  An Elastography Score ranging from 1 to 5 is assigned to the pancreas masses.  Score 
1 is a homogeneous soft mass (green) associated with normal pancreas.  Score 2 remains a soft 
(green, yellow or red) mass that has become heterogeneic corresponding to fibrosis.  Score 3 
masses are hard (blue) with minimal heterogenicity that correspond to small early pancreas 
adenocarcinoma (< 25mm).  Score 4 mass possess a hypoechoic core with green appearance 
surrounded by hard (blue) tissue, corresponding with hypervascular lesion such neuroendocrine 
tumor or pancreas metastasis.  Score 5 is associated with advanced pancreas adenocarcinoma are 
primarily blue with a soft tissue (green, red) core.   Dynamic changes in elastography characteristics 
of a pancreas may represent a novel modality to assess tumor response to therapy.  Indeed Alvarez 
et al have now demonstrated that increased elasticity (decrease tumor stiffness) is associated with 
response to combination gemcitabine and nab-paclitaxel chemotherapy.  This trial will gather 
preliminary data on the effects of preoperative chemotherapy on the Elastography Score of selected 
patients enrolled in the trial. 
 
5.3.4 Fiducial markers placement 
 
After completion of three cycles of gemcitabine and nab-paclitaxel in 12 weeks, repeat EUS will be 
performed. The protocol described above will be used to evaluate the pancreatic lesion. In addition, 
two EUS-FNA/FNB biopsies will be obtained and specimens will be collected for biomarker studies. 
After EUS-FNA/FNB, fiducial markers will be placed by experienced endosonographers using a 19-
gauge EUS-FNA needle (Cook Endoscopy, Winston-Salem, NC). Traditional fiducials (gold/carbon 
measuring 5 mm in length, 0.8 mm in diameter) will be used for this study. Fiducial marker placement 
involves first backloading the FNA needle with one fiducial marker at a time. The stylet of the EUS 
needle is withdrawn approximately 2-3 cm and the fiducial is backloaded into the needle tip by using 
sterile techniques. The needle tip of the EUS needle is then sealed with sterile bone wax to prevent 
unintended loss of the fiducial while advancing the needle through the therapeutic channel of the 
echoendoscope. The needle will then be inserted into the target lesion under EUS guidance. The 
stylet of the EUS needle will be advanced to maximal insertion, thus pushing the fiducial out of the 
needle and into the lesion. The EUS needle will then be withdrawn from the echoendoscope and 
reloaded with a new fiducial, and the technique will be repeated until a total of three fiducials are 
placed into the lesion in different planes. The goal will be to provide ample distance and angulation 
for image guided radiation therapy. The use of fluoroscopy will be at the discretion of the 
endosonographer. Intraprocedural intravenous antibiotics (Unasyn 3 gm or ciprofloxacin 400 mg) 
will be administered prophylactically in all patients. Technical difficulty and success along with the 
number of fiducials placed will be documented in a case report form. 


 
 
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5.4 SBRT  
5.4.1 Radiation Schedule 
Patients will undergo CT simulation within 2 weeks of completion of chemotherapy and no more than 3 
weeks prior to the first SBRT fraction. SBRT will be started between 3-5 weeks of completion of 
chemotherapy.  
5.4.2 Radiation Simulation 
Prior to simulation patients will undergo endoscopic fiducial marker placement (as described above.)  
Simulation will occur at least 1 day following fiducial placement to allow settling of the markers.  Ideally, 
3 fiducial markers will be placed in the pancreatic tumor. In the event of fiducial migration, the migrated 
fiducial will not be used if the marker position does not allow for accurate localization. A treatment 
planning CT scan preferably with IV contrast (unless contraindicated) and oral contrast (20 minutes 
before CT to opacify the duodenum) will be required to define clinical and planning target volumes and 
the critical organs at risk (OAR). The treatment planning CT will be acquired with the subject set up in 
the same position as for daily treatments. 4-dimensional CT (4D-CT) simulation tracking respiratory 
motion will be performed.  Target volumes will be contoured based on the maximum tumor excursion, 
for example on maximum intensity projection image. Normal structures will be contoured based on 
average image intensity projection image. 
Each subject will be positioned in the supine position. A stereotactic body frame will be used to minimize 
set-up variability. Abdominal compression may be used at the discretion of the treating physician. Oral 
and intravenous contrast agents are recommended but not required. The CT scan of the abdomen 
should start at or above the mid-thoracic spine and continue through the mid-lumbar spine.  All tissues 
to be irradiated must be included in the CT scan. CT scan thickness should ideally be 1.0 – 3.0 mm 
through the region that contains the target volumes. It is advised that extreme gastric filling not be 
present at the time of the planning CT scan. The target volumes and normal tissues must be outlined 
on all CT slices in which the structures exist.  
5.4.3 Radiation Planning 
The definition of volumes will be in accordance with the ICRU Report #50 and 62: The Gross Tumor 
Volume (GTV) is the extent of disease based on available diagnostic imaging (including PET/CT) and 
CT simulation images.  The Clinical Target Volume (CTV) is the gross tumor volume plus areas 
considered to contain microscopic disease. Elective lymph node regions will not be included in the CTV. 
The Internal Target Volume (ITV) includes the CTV with a margin to account for physiological patient 
movements (mostly breathing motion), based on the maximum tumor excursion on 4D-CT. The 
Planning Target Volume (PTV) will provide a margin around the ITV to compensate for the variability of 
treatment set up. Ideally a 2mm margin in all directions around the ITV will define the PTV as long as 
not prohibitive for the OAR. To maintain OAR constraints, the PTV may be cropped back from the 
duodenum and stomach. The treatment plan used for each subject will be based on an analysis of the 
volumetric dose including dose-volume histogram (DVH) analyses of the PTV and critical normal 
structures. DVHs must be generated for all critical normal structures and the unspecified tissues. 
Megavoltage equipment is required with effective photon energies ≥ 6 MV. Treatment may be delivered 
with Image Guided Intensity Modulated Radiation Therapy (IMRT) or Image Guided Volumetric 
Modulated Arc Therapy (VMAT). 
 


 
 
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Target Dose 
The prescribed dose to the PTV will be 33Gy. The dose per fraction will be 6.6Gy. Treatment will be 
prescribed such that 95-100% of the PTV receives the prescription dose. 
 
OAR Constraints 
Duodenum (contoured 1cm above and below the PTV): V15 Gy < 9cc; V20 Gy < 3cc; V33 Gy 
< 1cc 
Proximal Stomach: V15 Gy < 9cc; V20 Gy < 3cc; V33 Gy < 1cc 
Kidneys: V12 Gy < 75% 
Liver: V12 Gy < 50% 
Spinal Cord: Max Dose 8 Gy 
 
5.4.4 Radiation Treatment Delivery 
SBRT will be delivered over a total of 5 fractions delivered on 5 consecutive days, Monday through 
Friday over an elapsed time of 1-2 weeks. Occasionally, treatment breaks will be necessary due to 
patient tolerance, weather, departmental schedule or treatment machine maintenance. These 
treatment breaks should be avoided if possible, but if they occur should be documented and reported. 
Daily target localization with kV and cone beam CT will be performed prior to radiation delivery, with 
adjustments in table position so that target volumes treated correspond to those planned to within 2 
mm.  Details of the administration of radiation therapy will be recorded as outlined in CRF in Appendix 
A. 
5.4.5 Radiation Administration Minor Deviations And Major Deviations 
 
1. Prescribed Dose 
 
a. Minor deviation: Less than 95% of the PTV receives at least 95% of the protocol 
specified dose. 
 
b. Major deviation: Less than 95% of the PTV receives at least 90% of the protocol 
specified dose. 
 
2. Volume 
 
a. Minor deviation: Margins less than specified or fields excessively large as deemed by the 
study coordinator. 
b. Major deviation: Margins transect the GTV, CTV or ITV. 
 
3. Treatment Interruptions 
 
a. No deviation: No unplanned treatment interruptions. 
b. Minor deviation: Unplanned treatment interruptions of 1-2 days. 
c. Major deviation: Unplanned treatment interruption of > 2 days. 


 
 
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5.5 Surgery 
 
5.5.1 Definitive Surgical Resection  
 
Diagnostic laparoscopy should involve simple laparoscopy to assess for small volume metastatic 
disease, which can be missed on conventional cross sectional imaging.  Laparoscopy should include 
general assessment of abdominal cavity to include liver, peritoneal surfaces and extra pancreatic 
sites. Any suspicious implants should be biopsied. Cytologic washings will not be acquired due to 
its unclear significance in disease outcome.  
 
Pancreatic resections (pancreaticodudenectomy for uncinate and head lesions, distal 
pancreatectomy +/- splenectomy for neck, body and tail lesions) will be performed in either an open 
or minimally invasive manner. For pancreaticoduodenectomy patients, either classic or pylorus-
preserving pancreaticoduodenectomy may be performed. Surgical drains and enteral tubes (e.g. 
gastrostomy and/or jejunostomy tubes) may be placed at the discretion of the operating surgeon. 
Exploration of the peritoneal cavity, laparoscopically or open, should include evaluation for 
radiologically occult macroscopic peritoneal or hepatic metastases. Biopsy proof of any metastatic 
disease (by frozen section assessment) is required prior to aborting planned procedure. Cytologic 
washings are not to be performed. Regional adenopathy is not a contraindication to resection if in 
the normal resection field for the planned operation. For pancreaticoduodenectomy operations, the 
retroperitoneal dissection along the medial edge of the uncinate process and the right lateral border 
of the superior mesenteric artery is the retroperitoneal margin to be inked and assessed by pathology 
for classification of R0 or R1 resections. If gross disease is left behind the procedure is deemed an 
R2 resection.  
 
All soft tissue to the patients right of the superior mesenteric artery (SMA) should be removed. This 
requires exposure and dissection along the right lateral border of the SMA. For distal 
pancreatectomy operations, dissection should continue lateral to the celiac axis and include the 
retroperitoneal tissues to the patients left of the celiac axis. Vascular resections (venous, and hepatic 
arterial) should be performed when indicated to achieve resection of all gross disease but not SMA 
resections, which have poor survival outcomes.64 Frozen section evaluation of the pancreatic 
parenchymal bile duct margins should be performed intraoperatively. In the event of a positive frozen 
section margin, further resection in an effort to achieve microscopically negative margins should be 
performed if possible. The retroperitoneal SMA margin should be evaluated on permanent section.  
 
5.5.2 Specimen Orientation  
 
The surgeon should ensure that the specimen is oriented for the surgical pathologist especially 
identifying the retroperitoneal SMA margin. In addition, pancreatic parenchymal margin, bile duct 
margin and if appropriate vascular resection margins need to be properly marked. It is advisable for 
the operating surgeon to personally orient the specimen with the pancreatic pathologist upon 
removing the specimen and before fixation.  
 
5.5.3 Operative Note  
 
The operative report should contain:  
1. A section detailing the operative findings with respect to the extent of disease and the primary 
tumor anatomy  
 


 
 
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2. A comment on the status of resection (R0/R1 (all gross disease resected) vs R2 (gross 
disease left behind). When the final pathology is available, an addendum should be dictated 
to further clarify R0 or R1 resection. 
 
The definitions for the resection classification that should be utilized in operative notes include:  
R0 – Macroscopically complete tumor removal with negative microscopic surgical margins  
(bile duct, pancreatic parenchyma, and SMA margins)  
R1 – Macroscopically complete tumor removal with any positive microscopic surgical margin 
(bile duct, pancreatic parenchyma, or SMA margins)  
R2 – Macroscopically incomplete tumor removal with known or suspected residual gross disease.  
 
 
6.0    MEASUREMENTS AND EVALUATIONS 
6.1    General Considerations 
Informed consent will be obtained prior to any study procedures being performed.  Each participant 
will be given a copy of the signed ICF.  The ICF must be approved by an Institutional Review Board 
(IRB)/Ethics Committee (EC) and by a Celgene or other sponsor-nominated representative. 
A complete medical history (including specific information regarding any prior anthracycline- related 
cardiac abnormality) and physical examination will be conducted on each patient for a review of 
systems and determination of any concurrent symptoms or conditions prior to the first dose of study 
drug. 
Routine study evaluations will be conducted to monitor for existing adverse events and the 
development of new adverse events.  Study site personnel will ask patients the following questions: 
6.1.1 Have you had any (other) medical problems since your last study visit? 
6.1.2 Have you taken any new prescribed or over-the-counter medicines or 
herbal/vitamin preparations, other than those given to you for this study, 
since your last study visit? 
6.1.3 Have any new procedures been performed since your last study visit? 
In addition, patients are to be encouraged to call the site to report any unexpected symptoms or 
problems they encounter between study visits. 
Medical symptoms or conditions present at or before study drug administration that manifest with 
the same intensity or frequency subsequent to study drug administration do not need to be recorded 
as adverse events in the CRF.  However, any pre-existing condition that presents with increased 
intensity or increased frequency following study drug administration, or any exacerbation of an event 
that is present at the time of study drug administration, should be considered an adverse event.  All 
adverse events occurring from initial dosing through study end, inclusive, should be followed as 
outlined in Section 6.10.  All adverse events must be completely and promptly recorded in the 
patient's source document (e.g., patient hospital records, patient clinic charts, and laboratory reports) 
and on the CRF (see Section 6.10).  Note that individual signs/symptoms should not be recorded in 
the CRF as adverse events.  If a unifying diagnosis is known, it is the diagnosis that should be 
recorded as the adverse event. 
Clinically significant laboratory abnormalities present at the Baseline visit will be recorded as 
pretreatment signs and symptoms.  After study treatment administration, laboratory abnormalities 


 
 
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will not be recorded as adverse events unless considered clinically significant by the PI, and clinically 
significant laboratory abnormalities will not be recorded as serious adverse events unless the event 
meets the definition of serious. 
Each PI is responsible for assessing the clinical significance of all abnormal laboratory values using 
the NCI CTCAE Scale version 4.03 (see  http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-
06-14_QuickReference_5x7.pdf), where applicable).  It is also the responsibility of the PI to assess 
the clinical significance of all abnormal laboratory values as defined by the list of normal values 
provided by the local laboratory.  All abnormal laboratory tests that are judged to be at least 
possibly drug related, or clinically relevant abnormal laboratory tests of uncertain causality, must 
be repeated.  Any abnormal values that persist should be followed at the discretion of the PI.  In 
some cases, significant changes within the range of normal values will require similar judgment. 
6.2    Central Laboratory and Central Imaging 
Central laboratory, central imaging, and central SPARC and other molecular biomarkers testing will 
be utilized for this study. 
6.2.1 Central Imaging 
Dr. Alec Megibow, based at New York University, will act as a central imaging reviewer and will 
provide an independent review of disease categorization in terms of resectable versus borderline 
resectable disease.  Patient treatment cohort allocation will be based on this central review of 
screening radiologic imaging (CT or MRI).  Turnaround time for patient allocation will be within 24 
hours of electronic receipt of the pertinent images.  Dr. Justin Ream at New York University will be a 
back-up reviewer if Dr. Megibow is not available.  The central imaging reviewer will also assess 
response and progression to therapy for all patients enrolled into the study in a blinded fashion that 
is independent of institutional evaluation assessment of therapeutic response.  Prospective collection 
of all on-study CT/MRI scans for all patients enrolled in the study will be included as part of the 
review. 
Films or electronic copies should be collected by the investigative sites and sent to the central image 
reader. Complete details regarding image handling and submission can be found in the Radiology 
Technical Manuals (Appendix B). 
Patients who are discontinued from treatment in the absence of disease progression (e.g., patients 
removed for unacceptable toxicity or patient/PI discretion) should undergo repeat imaging and tumor 
response assessments until disease progression is documented.  CT scans should be continually 
performed into follow-up every 12 weeks (at any time during that week), regardless of regimen. 
If a patient starts a new anti-cancer therapy prior to disease progression, then repeat imaging and 
tumor response assessments should be discontinued. 
6.2.2 Central Laboratory.  
An overview of the schedule of study assessment is provided in Study Calendar, Table 8. 
The laboratory of Colin Weekes will serve as central laboratory for sample processing to obtain 
molecular objectives.  Batched samples will be processed according to procedures outlined on the 
specimen collection forms.  Individual sites will be provided with necessary kits for initial on-site 
processing and storage prior to batched samples being delivered to the central laboratory.   Samples 
are not to be shipped on Fridays. 
Macropinocytosis assay will be performed on pancreatic specimens obtained only at New York 
University due to assay requirements to perform the assay on fresh samples.  The macropinocytosis 
assay will be performed in the laboratory of Dafna Bar-Sagi, Ph.D. according to procedures published 
by Commisso et. al.61 


 
 
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6.3  Table 8: 
Study Calendar 
 
 
NeoAdjuvant Chemotherapy 
SBRT 
Surgery 
Adjuvant Chemotherapy 
Surv.
17  
EOS
18 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
 
 
Assessment 
 
Days 
Days 
Days 
 
 
 
Days 
Days 
 
 
 
Baseline 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
 
 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
 
 
Informed 
Consent
1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent
2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History
3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Physical Exam
4 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Toxicity 
Evaluation
5 
 
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 
X 
Height and 
Weight
6 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
BSA 
Calculations
6 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
Prior/Concomitant 
Medication
7  
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 
X 
X 
Concurrent 
Procedures 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Peripheral 
Neuropathy 
Evaluation
3 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Vital Signs
3,9 
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 
X 
X 
ECOG
3,10 
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 
X 
X 
X 
X 
ECG (12 lead)
3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis
3  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Serum β-HCG
3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 
Panel
3,11 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
CBC
3.12 
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 
X 
X 
PT, PTT
3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum CA19.9
3,13 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
Serum CEA
3,13 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
Plasma 
Biomarker
3,13 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
CT Scan
3,14 
X
14 
 
 
 
 
 
 
 
 
 
 
 
X
14 
 
 
X
14 
 
 
 
 
 
 
 
 
 
 
X
14 
X
14 
X
14 
Radiology 
Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
EUS 
X
2 
 
 
 
 
 
 
 
 
 
 
 
 
X
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SBRT
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery
16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Chemotherapy 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
Biopsy 
X
2 
 
 
 
 
 
 
 
 
 
 
 
 
X
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
Informed Consent to be obtained for study participation.  Must be performed within 21 days of the initiation of study related treatments on cycle 1 day 1. 
2. 
Informed Consent to use diagnostic tumor biopsy specimens for molecular marker analysis.  Must be obtained within 1 week prior to performing initial tumor 
biopsy by endoscopic ultrasound.   Consent for EUS procedure will be obtained within 1 week of procedure as per standard operating procedure within 
respective endoscopic laboratory.  Elastography will be performed in patients consenting to this procedure at institutions possessing facilities to perform the 
endoscopic assay. 
3. 
Medical History.  This will be performed as part of screening evaluation for study participation within 21 days of study initiation.  This will also include all 
procedures and labs associated with screening evaluation. 
4. 
Physical exam.  This will be performed as part of screening evaluation for study participation within 21 days of study initiation and on days of response 
assessment.  Response assessment can occur + 7 days of cycle 3 day 28 of “Neoadjuvant Chemotherapy” and “Adjuvant Chemotherapy”. 
5. 
Toxicity Examination.  Unless otherwise specified, visits are to be performed within + 2 days of planned visit date.   
6. 
Body Surface Area (BSA) Calculation.  Height and weight will be obtained on dates of chemotherapy administration for purposes of BSA calculation for 
chemotherapy dosing. 
7. 
Prior/Concomitant Medications.  Medications and vitamins/supplements that the patient is taking in addition to study medications will be reviewed at each time 
point of either physical examination or toxicity examination. 
8. 
Peripheral Neuropathy.  Sensory neuropathy will be assessed at baseline.  Preexisting peripheral neuropathy at baseline must be < grade 1 according to 
CTCAE version 4.0.  This will be assessed on days of study drug administration prior to dosing. 
9. 
Vital Signs.  Will be assessed at baseline and prior to study drug administration and with every physical examination or toxicity examination. 
10. ECOG Performance Status.  Must be 0 or 1 at time of study enrollment.  Will be assessed prior to study drug administration and with every physical 
examination or toxicity examination  
11. Chemistry Panel (CMP).  Will be assessed at baseline, at day 1 of each chemotherapy cycles as well as response assessments and end of study visits. 
Baseline examination can occur within 21 days of cycle 1 day 1. Serum chemistry panel includes: Sodium (Na), Potassium (K), Bicarbonate (CO2), 
Chloride (Cl), Blood Urea Nitrogen (BUN), Creatinine (Cr), Serum Glucose, Alkaline Phosphatase (Alk Phos), Total Bilirubin (TBili), Aspartate 
Aminotransferase (AST),  Alanine Aminotransferase (ALT), Total Protein (TP) and Albumin (Alb). 
12. Complete Blood Count (CBC).  Will be assessed at baseline and at each day of chemotherapy administration as well as response assessments and end of 
study visits. Baseline examination can occur within 21 days of cycle 1 day 1.  The CBC includes: Total white blood cells (WBC), Hematocrit (Hct), 
Hemoglobin (Hgb), Platelet Count (Plt), white blood cell count differential to allow for calculation of Absolute Neutrophil Count (ANC).  
13. Serum Tumor Markers and Biomarkers.  CEA and CA19.9 and plasma biomarkers will be assessed at baseline, cycle 1 day 1 of “Adjuvant Chemotherapy” 
and at completion of cycle 3 day 28 of both “Neoadjuvant Chemotherapy” and “Adjuvant Chemotherapy” and at end of study visit. Baseline examination 
can occur within 21 days of cycle 1 day 1. CEA and CA19.9 will also be assessed as part of the surveillance evaluation. 
14. Radiologic Imaging.  CT scan of chest, abdomen and pelvis with oral and intravenous (IV) contrast is preferred imaging modality for radiologic evaluation 
cancer burden and therapeutic response.  Magnetic Resonance Imaging (MRI) is an acceptable alternative for those patients with a contraindication for CT 
IV contrast.  These assessments will be obtained within 21 days of cycle 1 day 1 of study treatment and again at cycle 3 day 28 of “Neoadjuvant 
Chemotherapy” and within 1 week prior of cycle 1 day 1 and cycle 3 day 29 of “Adjuvant Chemotherapy”.  Patients in the surveillance component of the 
clinical trial will have CT scan at 12 week intervals.  All radiologic images will undergo central review for allocation of treatment cohort, assessment of 
response to therapy and on study cancer staging. 
15. Stereotactic Body Radiation Therapy (SBRT).  SBRT will be initiated between weeks 3 and 5 from last dose of chemotherapy administered during cycle 3 
of “Neoadjuvant Chemotherapy”.  Patients will have physical examination and toxicity evaluation as dictated per the standard operating procedures of 
Radiation Oncology Department administering SBRT. 
16. Surgical Resection of Primary Pancreas Ductal Adenocarcinoma.   
17. Surveillance examination.  Patients who have completed all therapy will enter into surveillance phase of clinical trial.  Patients will be evaluated at 12-week 
intervals for 2 years.  Those patients that survive beyond 2 years beyond completion of all therapy will undergo surveillance examination at 6-month 
intervals, unless clinical circumstances warrant more frequent examinations.  Surveillance examination will include medical history, physical examination, 


 
 
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ECOG performance status assessment, concomitant medication reconciliation and laboratory evaluation to include CMP, CBC, CEA and CA19.9.  
Radiologic imaging will be obtained within 1 week prior to surveillance examination. 
18. End of Study (EOS) Examination.  EOS examination will occur within 30 days of patients who do not complete the treatment phase of the clinical trial due 
to either disease progression or study-related toxicity.  EOS examination will include medical history, physical examination, ECOG performance status 
assessment, concomitant medication reconciliation and laboratory evaluation to include CMP, CBC, CEA, CA19.9 and plasma biomarker. 


 
 
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6.4    Baseline Evaluations 
Baseline evaluations will be performed for all patients to determine study eligibility.  These 
evaluations must be obtained ≤21 days prior to initiating of therapy (see Section 6.5).  Any 
questions regarding patient eligibility should be directed to the Criterium-nominated 
Project Manager or designee for review Lead PI Dr. Colin Weekes or PI for Translational 
Science, Dr. Lawrence Leichman and written approval. 
The following clinical evaluations will be performed at Baseline after informed consent has 
been obtained: 
• 
Medical history (including specific information regarding any prior 
therapy and cardiac abnormality); 
• 
Physical examination; 
• 
Height and weight assessment; 
• 
Urinalysis (a urine dipstick may be used); 
• 
Prior medication evaluation; 
• 
Vital signs; 
• 
ECOG performance status score.  
• 
Serum β-HCG pregnancy test (for women of childbearing-potential only) 
will be conducted within 72-hours prior to first study drug administration 
(negative results required for study drug administration); 
• 
ECG (12 lead); 
• 
Clinical chemistry panel (to include, but not limited to, sodium, potassium, 
chloride, glucose, BUN, alkaline phosphatase, AST/SGOT, ALT/SGPT, 
serum albumin, and total bilirubin and creatinine); 
• 
CBC, differential and platelet count; 
• 
PT, PTT coagulation studies (local lab results allowed to confirm patient 
eligibility); 
• 
CEA and CA19.9 and plasma biomarkers; 
• 
CT scan (or MRI if patient is allergic to contrast agent) within 14 days prior 
to Cycle 1 Day 1; 
• 
Peripheral Neuropathy Assessment; 
• 
Consent to use diagnostic tumor biopsy (archival tissue) for 
molecular marker analysis. 
The PI will account for all patients who are screened for this study.  Although CRFs will 
not be completed for patients who fail screening, source documents will be reviewed by the 
Criterium-designated study monitor for completion and accuracy.  All appropriate CRF 
pages must be completed for enrolled patients. 


 
 
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6.5 Treatment Phase Evaluations 
All Baseline testing must be completed within 21 days of initiating therapy.  Following 
completion of Baseline testing, patients will receive study-mandated treatment.  Patients 
should return within 3 days to begin Cycle 1 of study drug dosing.  Unless otherwise 
specified, visits where response assessments are not performed must occur within ± 2 
days of the planned visit date.  CT scans should be performed at Baseline (within 21 days 
prior to Cycle 1 Day 1), Cycle 3 Day 28 of neoadjuvant chemotherapy, Cycle 1 Day 1 of 
adjuvant chemotherapy, Cycle 3 Day 28 of adjuvant chemotherapy and every 12 weeks 
during the surveillance phase (at any time during that week), and EOS.  CT scans may 
be obtained within 7 days prior of scheduled day during the treatment phase and for 
unscheduled imaging studies outlined in Section 6.7.   
If the PI suspects a drug-related toxicity, an extra-unscheduled visit with additional 
laboratory tests may be performed.  Nab-paclitaxel and gemcitabine should be 
administered as specified in Section 4.2.The same mode of imaging for target lesions must 
be used at Baseline and throughout the study. CT image preparation will follow the 
specifications provided in the RECIST response guidelines. 
 
6.6   Molecular Marker Analyses 
 
In those cases where tumor samples from patients treated on study are available and 
informed consent has been obtained, paraffin-embedded (PE) tumor blocks or newly 
sectioned, unstained slides will be sent for immunohistochemistry (IHC) analysis.  
Immunohistochemical stains will include, but not be limited to, SPARC and hENT1 and 
will be performed in a central, Clinical Laboratory Improvement Amendments (CLIA) - 
approved laboratory.  All tissue samples will be run blinded with respect to the treatment 
assignment and to the patient response to treatment.  It is preferred that fixed tissue 
samples from patients are shipped as PE blocks so that slides from each specimen can 
be generated at the central testing laboratory for IHC analysis.  However, in cases where 
PE blocks may not be released from the custody of the site, the sections may be prepared 
at the site.  At least 10 slides (1 section per slide) should be prepared using super frost plus 
slides and left to AIR DRY.  Thickness of the sections should be at 4-5 micron.  Specimen 
collection kits, including super frost plus slides and return shipping containers, will be 
provided by the central laboratory to each of the specimen collection sites. 
 
Serum CA19-9 and Plasma biomarker.  Blood samples for the evaluation of the CA19-9 
and molecular biomarkers will be collected on Day 1 of each chemotherapy cycles with 
a maximum of 6 cycles including both neoadjuvant and adjuvant combination 
chemotherapy for both treatment arms.  CA19-9 and SPARC are further discussed in 
Section 8.3.5. Plasma molecular biomarkers will be obtained at baseline, within 1 week of 
cycle 3 day 28 of neoadjuvant chemotherapy, cycle 1 day 1 of adjuvant chemotherapy 
and within 1 week of cycle 3 of day 28 of adjuvant chemotherapy. 
Macropinocytosis Analysis. 


 
 
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6.7    Day 1 Assessments 
The following assessments will be performed on Day 1 of each treatment cycle: 
• 
Physical examination; 
• 
Height and Weight assessment; 
• 
BSA calculations (Day 1 of Cycle 1, and recalculated per the site’s 
standard of care, or if body weight changes by more than 10%); 
• 
Urinalysis (a urine dipstick may be used); 
• 
Concomitant medication evaluation; 
• 
Concurrent procedures; 
• 
Peripheral Neuropathy Assessment; 
• 
Vital signs (prior to dosing); 
• 
ECOG Performance Score 
• 
Clinical chemistry panel; 
• 
CBC, differential and platelet count; 
• 
Adverse event evaluation; 
• 
Serum CA19-9 and CEA (Day 1 of each chemotherapy cycles with a 
maximum of 6 cycles including both neoadjuvant and adjuvant combination 
chemotherapy); 
 
Day 1 evaluations for Cycle 1 may be omitted if Baseline evaluations are performed 
within 72 hours of Cycle 1, Day 1. 
6.8    Efficacy Response Assessments 
The following efficacy response assessments will be performed: 
 
CT scans should be performed at Baseline (within 14 days prior to Cycle 1 Day 1), Cycle 
3 Day 28 of neoadjuvant chemotherapy, Cycle 1 Day 1 of adjuvant chemotherapy, 
Cycle 3 Day 28 of adjuvant chemotherapy and every 12 weeks during the surveillance 
phase (at any time during that week), and EOS (if required per the defined study imaging 
schedule). 
6.9 Per Cycle Evaluations 
On Days 8 and 15 of each cycle, the following assessments will be performed: 
• 
Height and Weight Assessments 
• 
BSA calculations  
• 
Concomitant medication evaluation; 
• 
Vital signs (prior to dosing); 
• 
ECOG Performance Status 


 
 
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• 
CBC, differential and platelet count; 
• 
Adverse event evaluation. 
The following assessments will be performed during the rest week of each cycle: 
• 
Concomitant medication evaluation; 
• 
Vital signs; 
• 
ECOG Performance Status 
• 
CBC, differential and platelet count; 
• 
Adverse event evaluation. 
 
6.10 End-of-Study (EOS) Evaluations 
An EOS evaluation should be performed for all patients who end treatment.  The following 
procedures will be completed at the EOS Visit: 
• 
Physical examination; 
• 
Height and Weight assessment; 
• 
Concomitant medication evaluation; 
• 
Concurrent procedures; 
• 
Peripheral Neuropathy Assessment; 
• 
Vital signs; 
• 
ECOG Performance Status  
• 
Clinical chemistry panel; 
• 
CBC, differential and platelet count; 
• 
CA19.9, CEA and plasma biomarker 
• 
CT scan (or MRI if patient is allergic to contrast agent) only if required 
per the defined study imaging schedule; 
• 
Adverse event evaluation. 
The PI must follow all SAEs observed during the study until these events have resolved, 
the patient is lost to follow-up, or the events are otherwise explained.  The PI should report 
these SAEs in accordance with the procedures described in Section 7.  Clinical laboratory 
tests may be repeated during the post-treatment period if clinically indicated. 
6.11    Follow-up for Adverse Events 
Any AE or SAE whose onset occurred between the signing of the informed consent form 
to 30 days after the last dose of study drug or EOS (whichever is later) will be collected. 
The PI should report SAEs in accordance with the procedure described in Section 7. 
 


 
 
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Adverse event follow-up will be conducted as follows: 
• 
Non-serious adverse events, other than neuropathy, will be followed for 30 
days after the patient’s last dose of study drug. 
• 
Neuropathy will be followed until improvement to Grade 1 occurs, or at 
least 3 months have elapsed without improvement or worsening, or the 
patient initiates any other anticancer therapy during follow-up.  For patients 
taking nab-paclitaxel and gemcitabine, if nab-paclitaxel is discontinued but 
gemcitabine is continued, this should be considered as continuation of the 
study regimen and AE follow-up should continue. 
• 
All serious adverse events (regardless of relationship to study drug) will be 
followed until resolution. 
Clinical laboratory tests may be repeated during follow-up if clinically indicated. 
 
Follow-up evaluations include studies necessary to document the resolution or persistence 
of any unresolved AEs and could include: 
• 
Physical examination, weight; 
• 
Concomitant medication evaluation; 
• 
Concurrent procedures; 
• 
Vital signs; 
• 
ECOG performance status score.  Only one observer is required at these time 
points; 
• 
CBC, differential, platelet count, and clinical chemistries; 
• 
Peripheral neuropathy assessment (physician). 
 
6.12    Follow-up for Disease Progression 
Patients who are discontinued from treatment in the absence of disease progression (e.g., 
patients removed for unacceptable toxicity or patient/PI discretion) should undergo repeat 
imaging and tumor response assessments until disease progression is documented.  
Imaging studies (CT scans) should be continually performed into follow-up every 8 weeks 
(at any time during that week), regardless of regimen.  It is recommended that subsequent 
therapy not be instituted until disease progression is documented. 
If a patient starts a new anti-cancer therapy prior to disease progression, then repeat 
imaging and tumor response assessments should be discontinued.  For patients taking 
nab-paclitaxel and gemcitabine, if nab-paclitaxel is discontinued but gemcitabine is 
continued, this should be considered as continuation of the study regimen and imaging 
should continue. 
6.13  Follow-up for Overall Survival 
Post-study, overall survival status will be monitored on a monthly basis for 6 months and 
then every 3 months thereafter until death, the study closes or 3 years have elapsed since 
subject discontinuation from treatment.  This evaluation may be by record review and/or 


 
 
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telephone contact with the patient’s treating physician. 
 
 
7.0 ADVERSE EVENTS MANAGEMENT GUIDELINES 
7.1 Background 
These adverse event management guidelines are intended to ensure the safety of each 
patient while attempting to characterize the safety and tolerability of the test products.  In 
agreeing to the provisions of this protocol, the PI accepts all legal responsibilities 
for prompt notification of SAEs to Celgene Drug Safety.  Celgene in turn will be 
responsible for reporting the SAEs to the appropriate regulatory authorities. 
Adverse events occurring during the study will be graded according to the NCI CTCAE 
Scale, where applicable.  Adverse events that are not included on the toxicity scale will be 
designated as Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life 
threatening, and Grade 5 = death. 
The PI should evaluate all adverse events and should make an immediate effort to 
determine their etiology.  Adverse events that are determined not to be possibly, probably, 
or definitely related to study drug may not require further evaluation but will need to be 
recorded on the CRFs.  Study medications may be interrupted for an adverse event at the 
discretion of the PI.  Patients requiring toxicity management should be assessed and 
evaluated at least weekly as indicated by the severity of the event. 
7.2 Definition of an Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a patient receiving a marketed 
pharmaceutical product or in a patient who is participating on a clinical trial who is receiving 
an investigational or non-investigational pharmaceutical agent.  The AE does not 
necessarily have a causal relationship with the patient’s treatment. Therefore, an 
adverse event can be any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered to 
be related to the medicinal product. In cancer clinical trials, many AEs are in fact related 
to progression of the patient’s underlying malignancy. 
 
An adverse event includes: 
7.2.1 An exacerbation of a pre-existing illness; 
7.2.2 An increase in frequency or intensity of a pre-existing episodic event or condition; 
7.2.3 A condition detected or diagnosed after study drug administration even though 
it may have been present prior to the start of the study; 
7.2.4 
Continuously persistent disease or symptoms that were present at Baseline and 
worsen following the start of the study. 
 
An adverse event does not include: 
7.2.5 A medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
or transfusion); however, the condition that leads to the procedure is an 


 
 
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adverse event. 
 
[Procedures that occur during the trial should be recorded on the 
Concurrent Procedure CRF]; 
7.2.6 Pre-existing diseases, conditions, or laboratory abnormalities present or 
detected at the start of the study that do not worsen; 
7.2.7 Hospitalizations or procedures that are done for elective purposes not related to 
an untoward medical occurrence (e.g., hospitalizations for cosmetic or elective 
surgery or social/convenience admissions); 
7.2.8 
The disease being studied or signs/symptoms associated with the disease; 
7.2.9 Overdose of study drug without any clinical signs or symptoms. 
7.3 Definition of a Serious Adverse Event (SAE) 
A serious adverse event (SAE) is defined as any untoward medical occurrence at any dose 
that: 
7.3.1 Is fatal; 
7.3.2 Is life-threatening (defined as an immediate risk of death from the event 
as it occurred); 
7.3.3 
Results in persistent or significant disability or incapacity; 
7.3.4 Requires in-patient hospitalization or prolongs an existing hospitalization. 
(Exception: Hospitalization for elective treatment of a pre-existing condition that 
did not worsen during the study is not considered an adverse event.  NOTE: 
Complications that occur during hospitalization are adverse events and if a 
complication prolongs hospitalization, then the event is serious); 
7.3.5 Is a congenital anomaly/birth defect in the offspring of a patient who 
received medication; 
7.3.6 Conditions not included in the above definitions that may jeopardize the patient 
or may require intervention to prevent one of the outcomes listed above unless 
clearly related to the patient’s underlying disease. 
The PI should exercise medical and scientific judgment when deciding whether expedited 
reporting is appropriate in other situations not strictly meeting the criteria outlined above.  
Examples of important medical events which may also meet the definition of a SAE include: 
intensive treatment in an emergency room or at home for a reversible condition that did not 
result in hospitalization (e.g., allergic bronchospasm or convulsions), certain laboratory 
abnormalities (eg, blood dyscrasias), or development of drug dependency or drug abuse.  
If there is any question, please consult the relevant Medical Monitor. 
7.4 Timeline for Consideration of AE/SAE Reporting Requirements 
The PI is responsible for recording, reporting and following all adverse events, regardless 
of causality, observed during the study period, starting with signing of the informed 
consent form and ending at the time the patient goes off study or 30 days after patient’s 
last dose of study drug and those made known to the PI at any time thereafter that are 
suspected of being related to investigational product, whichever is later.  Events occurring 
within 30 days prior to study drug administration should be recorded as pre-treatment 


 
 
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signs and symptoms. 
7.5 Lack of Efficacy is not considered an AE or SAE 
“Lack of efficacy” (progressive disease) is not considered an adverse event and 
therefore should not be captured as an adverse event or serious adverse event. 
7.6 Laboratory Results as Serious Adverse Events 
According to the NCI CTCAE system of adverse event grading, laboratory values of Grade 
3 or 4 are described as “severe” or “life-threatening.” For example, an absolute neutrophil 
count (ANC) <500/mm3 would meet laboratory criteria as Grade 4 (“life-threatening”).  This 
description is not always synonymous with the assessment of the “serious” criteria of an 
AE as “life-threatening”.  In order for adverse events to be considered serious by “life-
threatening” 
criteria, it must be medically judged as possessing “an immediate risk of death from the 
event as it occurred,” not because of the theoretical potential for life-threatening 
consequences.  In the case of a neutrophil count <500/mm3, the AE would be captured 
as an AE of Grade 4 
neutropenia, but it would not automatically be considered a SAE unless the investigational 
physician determined this represented an immediately life-threatening event for the patient 
or another serious criterion was met.  Specifically, uncomplicated Grade 4 neutropenia 
should not be reported as a SAE.  Neutropenia associated with fever, infection, or 
hospitalization should be reported as a SAE.  
7.7 Patient Reporting of AEs and SAEs 
Patients are to be encouraged to call the site to report any unexpected symptoms or 
problems they encounter between office visits.  These events should be considered in the 
same fashion as if they had been reported at a scheduled office visit.  At each scheduled 
office visit, after the patient has had an opportunity to spontaneously mention any 
problems, the site Investigator should inquire about adverse events by asking the following 
standard questions: 
7.7.1 Have you had any (other) medical problems since your last clinic visit? 
7.7.2 Have you taken any new prescribed or over-the-counter medicines or 
herbal/vitamin preparations, other than those given to you in this study, since 
your last visit/assessment? 
7.7.3 Have any new procedures been performed since your last study visit? 
7.8 Investigator Reporting of AEs and SAEs 
The PI or designee must completely and promptly record each adverse event in the source 
documentation and in the appropriate CRF, regardless of relationship to study drug as 
determined by the PI.  The PI must assess AE/SAE causality for any patients treated 
at his/her site.  The PI should attempt, if possible, to establish a diagnosis based on the 
patient's signs and symptoms.  When a diagnosis for the reported signs or symptoms is 
known, the PI should report the diagnosis, not the symptoms, as the adverse event. 
Clinically significant laboratory abnormalities present at the Baseline visit will be recorded 
as pre-treatment signs and symptoms.  After study treatment administration, laboratory 


 
 
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abnormalities will not be recorded as adverse events unless considered clinically 
significant by the PI, and clinically significant laboratory abnormalities will not be recorded 
as serious AEs unless the event meets the definition of serious. 
AEs and SAEs should be reported on the appropriate CRFs.  Any AE that meets a criterion 
for an SAE requires the completion of an SAE Report Form in addition to being recorded 
on the AE page/screen of the CRF.  In addition, all SAEs must be reported to Celgene 
Drug Safety within 24 hours of the PI’s knowledge of the event by facsimile, or other 
appropriate method, using the SAE Report Form, or approved equivalent form.  This 
instruction pertains to initial SAE report as well as any follow-up reports. 
The PI is required to ensure that the data on these forms is accurate and consistent. 
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the 
study (from the time of initial study drug administration to 30 days after the last dose of IP, 
and those made known to the PI at any time thereafter that are suspected of being related 
to IP. 
The SAE report should provide a detailed description of the SAE and include summaries 
of hospital records and other relevant documents.  If a subject died and an autopsy has 
been performed, copies of the autopsy report and death certificate are to be sent to 
Celgene Drug Safety as soon as these become available. Any follow-up data should be 
detailed in a subsequent SAE Report Form, or approved equivalent form, and sent to 
Celgene Drug Safety. 
 
7.8.1 Additional Investigator Responsibilities on Follow-up of SAEs 
The PI and supporting personnel responsible for patient care should institute any 
supplemental investigations of SAEs based on their clinical judgment of likely causative 
factors. This may include extra clinical laboratory tests, discharge summary, physical 
examinations or consulting an appropriate specialist.  Celgene Drug Safety may also 
request the PI to conduct supplemental assessments.  The results of any additional 
assessments conducted must be reported to Celgene Drug Safety.  If a patient dies during 
participation in the study and an autopsy is performed, a copy of the report must be 
submitted to Celgene Drug Safety.  If during the follow-up period for a SAE, a patient 
dies due to another event unrelated to the SAE being followed, the event causing 
the death will be reported as a separate SAE. 
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) 
business days. Urgent queries (e.g. missing causality assessment) may be handled by 
phone. 
 
Report of Adverse Events to the Institutional Review Board 
 
The PI is required to notify his/her Institutional Review Board (IRB) of a serious adverse 
event according to institutional policy.   
 
Principal Investigator Reporting to the FDA 
 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 


 
 
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brochure, or reference safety information document should be reported promptly to the 
Food and Drug Administration (FDA) by telephone or by fax.  Fatal or life threatening SAEs 
that meet the criteria for reporting to the FDA must be reported to the FDA within 7 
calendar days after awareness of the event.  All other SAEs that meet the criteria for 
reporting to the FDA must be reported to the FDA within 15 calendar days after awareness 
of the event.  A clear description of the suspected reaction should be provided along with 
an assessment as to whether the event is drug or disease related.    
If this is a multicenter trial, suggest including language indicating that participating study 
sites should NOT report SAEs to the FDA.  Rather, participating sites should report SAEs 
to Celgene and the primary study site, and the primary site will be responsible for reporting 
to FDA. 
 
Adverse event updates/IND safety reports 
 
Criterium Inc. shall notify the PI via an IND Safety Report of the following information: 
• 
Any AE associated with the use of drug in this study or in other studies that is both 
serious and unexpected. 
• 
Any finding from tests in laboratory animals that suggests a significant risk for 
human 
subjects 
including 
reports 
of 
mutagenicity, 
teratogenicity, 
or 
carcinogenicity. 
 
The PI shall notify his/her IRB/EC promptly of these new serious and unexpected AE(s) 
or significant risks to subjects. 
The PI must keep copies of all AE information, including correspondence with Celgene 
and the IRB/EC, on file. 
IND Annual Reports 
 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an 
annual report is provided to the FDA within 60-days of the IND anniversary date.  21 CRF 
312.33 provides the data elements that are to be submitted in the report.  The Annual 
Report should be filed in the study's Regulatory Binder, and a copy provided to Celgene 
Corporation as a supporter of this study as follows. 
 
Celgene Corporation 
Attn: Medical Affairs Operations 
Connell Corporate Park  
400 Connell Drive Suite 700 
Berkeley Heights, NJ  07922 
 
All adverse experience reports must include the patient number, age, sex, weight, severity 
of reaction (e.g. mild, moderate, severe), relationship to drug (e.g., probably related, 
unknown relationship, definitely not related), date and time of administration of test 
medications and all concomitant medications, and medical treatment provided.   The PI is 
responsible for evaluating all adverse events to determine whether criteria for “serious” 
and as defined above are present.  The PI is responsible for reporting adverse events to 
Celgene as described below. 
 


 
 
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7.8.2 IRB/EC Notification of SAEs 
The PI is responsible for promptly notifying the IRB/EC of the SAE, including any follow-
up information, occurring at his/her site and any SAE regulatory reports and Investigational 
New Drug Safety Reports that he/she receives from Celgene Drug Safety (see Section 
7.8 for Guidelines for Reporting Adverse Events). 
 
7.8.3 Expedited Reporting by Principal Investigator to Celgene 
 
Serious adverse events (SAE) are defined above.  The PI must inform Celgene in writing 
using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours of 
being aware of the event.  The written report must be completed and supplied to Celgene 
by facsimile within 24 hours/1 business day.  The initial report must be as complete as 
possible, including an assessment of the causal relationship between the event and the 
investigational product(s), if available.  Information not available at the time of the initial 
report (e.g., an end date for the adverse event or laboratory values received after the 
report) must be documented on a follow-up report.  A final report to document resolution 
of the SAE is required.  The Celgene tracking number (AX-CL-PANC-AGICC-004253) and 
the institutional protocol number should be included on SAE reports (or on the fax cover 
letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE report to 
Celgene should be attached to the SAE and retained with the patient records. 
 
7.8.4 Sponsor Notification of Post-Study SAEs 
 
The PI should notify Celgene of any death or SAE occurring after a patient has withdrawn 
from the study, when such death or SAE may reasonably be related to the medication 
used in the study.  However, PIs are not obligated to actively seek adverse events in former 
study participants. 
7.9 Pregnancy 
 
7.9.1 Females of Childbearing Potential: 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless 
of age or disease state) of a female subject occurring while the subject is on IP, or within 
30 days of the subject’s last dose of IP, are considered immediately reportable events.  IP 
is to be discontinued immediately.  The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, using the Pregnancy Initial Report Form or approved equivalent form. 
The PI will follow the female subject until completion of the pregnancy, and must notify 
Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent 
form. 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), 
the site Investigator should report the abnormal outcome as an AE. If the abnormal 
outcome meets any of the serious criteria, it must be reported as an SAE to Celgene Drug 
Safety by facsimile, or other appropriate method, within 24 hours of the PI’s knowledge of 
the event using the SAE Report Form, or approved equivalent form. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard 


 
 
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to causality, as SAEs. In addition, any infant death after 28 days that the PI suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
by facsimile, or other appropriate method, within 24 hours of the PI’s knowledge of the 
event using the SAE Report Form, or approved equivalent form. 
 
7.9.2 Male Subjects 
If a female partner of a male subject taking IP becomes pregnant, the male subject taking 
IP should notify the PI, and the pregnant female partner should be advised to call their 
healthcare provider immediately. 
7.10 Expedited Reporting of Adverse Events 
For the purpose of regulatory reporting, Criterium Inc. will determine the expectedness of 
events suspected of being related to study medication based on the Investigator Brochure 
for nab-paclitaxel and clinical experience with gemcitabine. 
 
Criterium Contact Information: 
 
Lawrence Reiter, PhD 
Director, Clinical Operations & Quality Assurance 
Tel: 416-277-9630   
Fax: 518-583-0384 
Office: 518-583-0095 
 
Celgene Drug Safety Contact Information: 
 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
 
 
8.0 STATISTICAL METHODS 
8.1    Statistical Considerations 
 
8.1.1 Brief Statistical Rationale:  
This is a Phase II study with two primary aims: 1) to estimate the rate of R0 resection in 
each of the two cohorts separately; 2) to test the feasibility and safety of a new preoperative 
regimen for patients with R-PDAC and BR-PDAC.  All patients entered into each cohort will 
be included in the estimates of R0 resection rates (intent to treat). Secondary 
objectives include estimation of Progression-free survival and Overall Survival in each 
cohort (strata). Outcomes will be examined in relation to the correlative biomarkers for 
each patient’s tumor. The trial will also be monitored for grade III/IV hematologic toxicity. 
Although dose reductions for chemotherapy are written into the protocol, as part of their 
charter, the Steering Committee will develop criteria for safety evaluation for all portions of 


 
 
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the clinical trial (chemotherapy, SBRT and surgery). 
 
In the R-PDAC cohort, the trial will be considered to be successful if 81.6% or greater of 
R- PDAC patients entered on the trial have R0 resections; for the BR-PDAC cohort, the 
trial will be considered successful if 42% of patients or greater have a R0 resection. See 
sample size and study design below. Each of the designs is a Simon optimal two stage 
phase II design with 80% power and alpha of 0.05. 
 
8.1.2 Sample Size 
R-PDAC: 20 patients. This is based on a Simon optimal 2 stage design to test the null 
hypothesis that the rate of R0 resection rate is ≤50% versus the alternative that the R0 
resection rate is ≥81.6%. If the regimen is not effective, there is a 2% probability of 
concluding that it is (target  =0.05). If the regimen is actually effective, there is a 15% 
probability of concluding that it is not (target power = 80%).  Based on this 2-stage design, 
if the regimen is tested on 9 patients in the first stage, if 4 or fewer patients go on to R0 
resection, the trial be terminated at the end of the first stage. With a total of 20 patients, 
the regimen would be accepted for further study if 15 or more R0 resections are observed 
in the total group of 20 patients. 
 
BR-PDAC: 30 patients. This is based on a Simon optimal 2-stage Phase II design to test 
the null hypothesis that the R0 resection rate is ≤20% versus the alternative that the R0 
resection rate is ≥ 42%, if the regimen is not effective there is a 0.05 probability of 
concluding that it is (target α=0.05). If the regimen is actually effective, there is a 20% 
probability of concluding that it is not (power = 80%, target power =80%).  Based on this 
2-stage design, if the regimen is tested on 13 patients in the first stage, if 3 or fewer 
patients go on to R0 resection, the trial will be terminated. With a total of 30 patients, the 
regimen would be accepted for further study if 10 or more R0 resections are observed in 
the total group of 30 patients. [Calculations from PASS 2014, NCSS, J. Hintze, Kaysville, 
Ut] 45 
 
8.1.3 Statistical Analysis  
 
Within each cohort, patient and disease characteristics will be summarized using 
descriptive statistics (means, standard deviations, medians, etc.) for continuous variables 
and frequency distributions for qualitative variables. Each of the biomarkers measured 
at the pretreatment biopsy (e.g., SPARC and collagen deposition) will be described similarly 
in each cohort. Macropinocytosis activity will be summarized in a similar manner. For the 
primary endpoint of R0 resection, resection rates for each cohort will be estimated with 
exact 95% confidence intervals at the completion of the trial. 
Biomarkers and R0 Resection Rates. To evaluate the influence of the biomarker levels and 
other characteristics on R0 resection rates in each cohort, logistic regression models will 
be used to evaluate the role of each of these biomarkers individually and in combination 
in predicting response to treatment.  Further, the association between R0 resection 
(yes/no) and macropinocytosis activity will be estimated using odds ratios. From these 
analyses, we will estimate the odds of R0 resection as a function of each of the biomarkers 
alone, macropinocytosis alone, or in combination as well as the area under the curve 
(AUC) for the Receiver Operating Characteristic Curve (ROC). From the ROC curves 
associated with each of these biomarkers (univariate analyses and multivariable analyses), 
we can estimate the sensitivity and specificity for various cut-points of each of the 


 
 
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biomarkers individually and in combination with 95% confidence intervals. To frame these 
analyses, for a single biomarker (e.g., macropinocytosis activity), we can detect an odds 
ratio of 2.8 if the observed R0 rate is 50% for a one standard deviation change above the 
mean activity with 58 patients in the BRPDAC cohort (3.5 in the 20 patient RPDAC 
cohort). [Calculations from PASS 2014, NCSS, J. Hintze, Kaysville, Ut].45 The contributions 
of additional biomarkers to classification of R0 resection will be evaluated by the increases 
in AUC for the ROC curves in each cohort. We note that to be useful, the AUC should be 
at least 75%. Two- sided z tests will be used to test the increases in AUC with 
additional biomarkers. Validation studies will be undertaken if these initial studies 
support the utility of these biomarkers to predict response to the chemotherapy regimen. 
Safety. All adverse experiences will be summarized within cohort by body system and 
grade. Summary tables will be provided that indicate the proportions of patients with one 
or more specified AEs in these classes. 
Other Endpoints. Progression-free survival and survival will be estimated separately for 
each cohort of patients with Kaplan Meier curves and estimates of median survival 
with 95% confidence intervals. Exploratory analyses will be undertaken to evaluate the 
prediction of PFS and OS based on measured biomarkers using Cox regression methods 
with a strategy similar to that used above for response prediction with logistic regression 
methods. 
8.2 Population Analysis 
 
All efficacy analyses will be based on the ITT population. Unless otherwise specified, the 
treated population includes all who received at least 1 dose of study drug, will be the 
analysis population for all safety/ tolerability analyses.  In addition, overall-survival, 
progression-free survival and disease-free survival analysis will be stratified based 
upon the ability to have tumor resection or resection outcome (R0 or no-R0). 
8.3 Demographics and Baseline Characteristics 
Patient characteristics including demographics, disease duration and extent at Baseline, 
and relevant medical history will be summarized for the purpose of characterizing the 
patient population and establishing baseline comparability of the treatment regimens. 
8.4 Patient Disposition 
 
Patient disposition including reason for discontinuation of therapy will be summarized by 
treatment regimen. Patient disposition also will be summarized by study site. 
8.5 Prior and Concomitant Medications 
All concomitant medications and prior medications taken within 30 days of first study drug 
administration will be coded to therapeutic drug classes and generic drug names using the 
World Health Organization (WHO) Drug Classification.  The incidence of prior and 
concomitant medication usage will be summarized by therapeutic drug class and generic 
drug names. 
8.6 Endpoints 
 
8.6.1 Safety Endpoints 
 


 
 
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Safety endpoints include AEs, SAEs, physical examination, vital signs, clinical laboratory 
testing and ADA testing.  Safety endpoints will be analyzed using the safety population. 
 
Adverse Events 
 
All reported AEs will be mapped to standard coding terms of the MedDRA, grouped by 
system organ class and preferred terms and tabulated by dose groups. The incidence of 
AEs in each dose group will be tabulated by seriousness, severity, and relationship to 
study drug.  The incidence of DLTs will be summarized by dose group. 
 
ECOG Performance Status and Physical Examination 
 
ECOG performance status and physical examination data at baseline and follow-up will be 
listed by patient for each dose group. 
 
8.6.2 Efficacy Endpoints 
 
Efficacy endpoints include R0 rate, overall survival, disease-free survival, progression-free 
survival and tumor marker CA 19-9. Efficacy endpoints will be analyzed using the ITT 
Population. 
 
8.6.3 Exploratory Endpoints 
 
Exploratory endpoints include blood biomarkers, tumor biomarkers and endoscopic 
elastography (optional).  These endpoints will be analyzed using the ITT Population.  The 
correlation of predictive biomarkers with efficacy endpoints for study treatment will be 
explored. 
8.7 Criteria for Enrollment Termination 
 
Enrollment will be terminated when the predetermined number of patients has completed 
treatment on study.   
8.8  Efficacy Assessments 
 
Patients will undergo tumor assessments as outlined in Section 4.1. 
 
Any evaluable and measurable disease must be documented at screening and reassessed 
at each subsequent tumor evaluation.  The Investigator, as well as Central Reviewer will 
assess response per RECIST v1.1 for patients with measurable disease (see Appendix 
C). Tumor assessments should generally be performed during the last week of cycles in 
which they are required, before the start of treatment 
in the next cycle.  Tumor 
assessments may also be performed at any time if progressive disease is suspected. 
 
Screening assessments should include CT scans of the chest and abdomen.  Spiral CT or 
MRI may be performed instead.  A bone scan is required to assess for bone metastases. 
CT scan of the pelvis and/or brain scan (CT or magnetic resonance imaging [MRI]) should 
be performed if 
clinically indicated.  For subsequent tumor assessments, the same 


 
 
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imaging methods used at screening must be used for each patient to assess disease 
documented at baseline. Other methods of assessment of measurable disease may be 
used per RECIST v1.1.  Assessments of the tumor marker CA 19-9 should be performed 
on the same schedule as imaging studies. Radiographic assessment should be the main 
source in determining the treatment benefit and tumor progression in this study. 
 
Survival data including the date of death and the cause of death will be collected. 
8.9 Independent Data Monitoring Committee 
 
Monitoring and Oversight 
 
The Lead Principal Investigator (Lead PI) will be responsible for overseeing the safety and 
efficacy of the trial, executing the DSM plan, and complying with all reporting 
requirements. This oversight will be accomplished through additional oversight from the 
Data and Safety Monitoring Committee (DSMC) at the University of Colorado Cancer 
Center (CU Cancer Center).  The DSMC is responsible for ensuring data quality and 
patient safety for all clinical studies at the CU Cancer Center.   A summary of the DSMC’s 
activities is as follows: 
 
• 
Ongoing review of all serious adverse events (SAEs), unanticipated problems 
(UAPs) and reportable adverse events (AEs) 
• 
Has the authority to close and/or suspend trials for safety or trial conduct issues 
• 
May submit recommendations for corrective actions to the CU Cancer Center’s 
Executive Committee 
 
Per the CU Cancer Center Institutional DSM Plan, SAEs, UAPs and reportable AEs are 
reported to the DSMC, IRB and the sponsor per protocol.  All SAEs, UAPs and reportable 
AEs are to be reported to the DSMC within 5 business days of the Lead PI receiving 
notification of the occurrence. 
 
Each subject’s treatment outcomes will be discussed by the site’s investigators and staff 
at regularly scheduled disease-oriented working group meetings.  Data regarding number 
of subjects, significant toxicities, dose modifications, and treatment responses will be 
discussed and documented in the meeting’s minutes. 
 
The Lead PI will provide a DSM report to the CU Cancer Center DSMC on a six month 
basis. The DSM report will include a protocol summary; current enrollment numbers; 
summary of toxicity data to include specific SAEs, UAPs and AEs; any dose modifications; 
all protocol deviations; and protocol amendments. The DSM report to the DSMC will also 
include, if applicable, the results of any efficacy data analysis conducted, as well as any 
internal DSMB reports. Results and recommendations from the review of this six month 
report by the DSMC will then need to be submitted by the site to the IRB of record at the 
time of continuing review. 
 
As the sponsor-investigator in this multi-site trial, the Lead PI is responsible for organizing 
and conducting monthly teleconferences with all participating sites.  The Lead PI will also 
be responsible for including data from all of the participating sites within the overall trial’s 
six month DSM report to the DSMC to include minutes from monthly PI teleconferences.  
Each participating site will be responsible for submitting the results and recommendations 


 
 
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from the DSMC’s six month review to their IRB of record at the time of continuing review. 
 
Quality Control and Quality Assurance 
Site monitoring visits will be performed by the Lead PI’s authorized representative on a 
regular basis, pursuant to the Monitoring Plan. During these visits, information recorded 
on the CRFs will be verified against source documents. After the CRFs are received by 
the Lead PI’s authorized representative, they will be reviewed for safety information, 
legibility, completeness, accuracy and logical consistency. The data will be entered into a 
database. Additional computer programs that identify selected Protocol deviations, out-of-
range data, and other data errors may be used to help monitor the study. As necessary, 
requests for clarification or correction will be sent to the appropriate Investigator. 
 
Independent auditors from the Lead PI’s authorized representative will be allowed by the 
Investigator to audit previously monitored data. In addition, audits may be conducted at 
any time by appropriate regulatory authorities. 
 
Steering Committee 
The conduct of this trial will be overseen by a Steering Committee, presided by the Lead 
PI and representative PIs from the individual sites participating in this multi-center study.  
Functions of the Steering Committee include, but are not limited to, assessing reports 
provided on compliance with the protocol by participating sites, monitoring patient 
enrollment, and evaluating the appropriateness of continuing or stopping the study.   
The Steering Committee will meet periodically by teleconference to discuss the progress of 
the study, as well as based on need.  The Steering Committee meetings shall include the 
Lead PI or his designee and require two-thirds of its constituency to be present in order to 
approve recommendations affecting the study.  Note: the Steering Committee is separate 
from the independent Data Monitoring Committee described in Section 8.5. 
 
9.0   REGULATORY CONSIDERATIONS 
9.1 Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
Before study initiation, this protocol and informed consent form will be submitted for review 
and approval to the IRB/EC charged with this responsibility.  In addition, any form of 
proposed advertising and advertising text for patient recruitment must be reviewed and 
approved by Celgene prior to submission to the IRB/EC.  The PI will forward to Celgene 
or sponsor-nominated designee a copy of the IRB/EC’s approval of this protocol, any 
amendments informed consent form, and any modifications to the informed consent, based 
on the US Food and Drug Administration (FDA) regulations set forth in 21 Code of Federal 
Regulations (CFR) 56, as well as those of the applicable regulatory bodies in all other 
participating countries outside of the US. 
In addition, the PI will be responsible for forwarding to Celgene or sponsor-nominated 
designee a description of the IRB/EC board members (including profession and affiliation) 
or a US Department of Health and Human Services (DHHS) General Assurance number 
and expiration date.  If neither of these is available, the chairperson must submit a 
statement indicating that the members of the board responsible for the review meet FDA 


 
 
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and other appropriate regulatory requirements.  In addition, the labeling for all approved 
study drugs should be submitted to the IRB/EC for informational purposes. 
Clinical supplies will not be shipped to the clinical site until IRB/EC approval is obtained 
for the protocol and the informed consent form.  Any existing amendments, informed 
consent, and photocopies of the approved documents must be received by Celgene or 
other sponsor- nominated designee prior to drug shipment. 
The PI will be responsible for obtaining annual approval/renewal of the IRB/EC throughout 
the duration of the study.  Copies of the PI’s reports and the IRB/EC’s continuance of 
approval must be sent to Celgene. 
9.2 Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
Guidelines of the International Conference on Harmonization (ICH) of Technical 
Requirements for Registration of Pharmaceuticals for Human Use, and in full compliance 
with the World 
Medical Association Declaration of Helsinki and its most recent 
amendments. 
 
9.2.1 Informed Consent 
Written informed consent of the patient to participate in the study must be obtained and 
documented by the PI in accordance with the FDA Regulations set forth in 21 CFR 50 as 
well as the applicable regulatory bodies in all other participating countries outside the 
United States. 
 
The PI must provide the patient with a copy of the consent form, which is in a language 
understandable to the patient.  Written consent should be obtained before any protocol-
required procedures are performed, including any procedure not part of normal patient 
care (e.g., withdrawal of current medications). 
9.3    Confidentiality 
The PI and any other study personnel involved in this study shall not disclose, or use for 
any purposes (other than for the performance of this study), any data, records, or other 
information (hereinafter collectively “information”) disclosed to the PI or other study 
personnel.  Such information shall remain the confidential and proprietary property of 
Celgene, and shall be disclosed only to the PI or other designated study personnel.  The 
obligation of non-disclosure shall not apply to the following: 
• 
relevant disclosure to potential study participants for the purpose 
of obtaining informed consent; 
• 
information after such time that it is or becomes publicly available through 
no fault of the PI or other study personnel; and, 
• 
information after such time that it is disclosed to the PI by a third party 
entitled to disclose such information. 
In order to comply with the applicable privacy laws, the PI will ensure that the patient 
consents to the use of data by Celgene and its designees for the purposes of regulatory 
submissions, study publications and drug approval. 
In compliance with ICH GCP Guidelines, it is required that the PI and institution permit 


 
 
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authorized representatives of the company, of the regulatory agency(s), and the IRB/EC 
direct access to review the subject’s original medical records for verification of study 
related procedures and data.  Direct access includes examining, analyzing, verifying, and 
reproducing any records and reports that are important to the evaluation of the study.  The 
PI is obligated to inform and obtain the consent of the subject to permit named 
representatives to have access to his/her study-related records without violating the 
confidentiality of the subject. 
9.4 Publication 
Data from any individual center must not be published or presented until the complete 
multicenter study has been published or presented in full.  Any subsequent publications 
should refer to the published multicenter findings.   
9.5 Investigator Documentation 
 
9.5.1 Form FDA 1572 
This study meets all of the requirements for exemption from the IND regulations. An IND 
is not required to conduct this investigation and a fully executed Form FDA 1572 is also 
not required. Alternately, the PI will provide Celgene with a listing of principal and sub-
investigators and all updates when applicable.  
 
9.5.2 Curriculum Vitae 
The PI must provide Celgene with his/her current dated curriculum vitae and a current 
dated curriculum vitae for each sub-Investigator listed on the study.  Current dated 
curriculum vitae is defined as updated within 2 years of study start up. 
 
9.5.3 Financial Disclosure 
The PI and Sub-Investigator(s) must complete a Clinical Investigator Financial 
Certification/Disclosure Statement to report financial interests and arrangements that may 
be of concern to FDA in accordance with 21 CFR 54. 
 
9.5.4 Records Retention 
Essential documents must be retained by the PIs for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the IP.  The PI must retain these 
documents for the time period described above or according to local laws or requirements, 
whichever is longer. Essential documents include, but are not limited to, the following: 
9.5.4.1 
Signed informed consent documents for all subjects; 
9.5.4.2 
Subject identification code list, screening log (if applicable), and enrollment 
log; 
9.5.4.3 
Record of all communications between the PI and the IRB/EC; 
9.5.4.4 
Composition of the IRB/EC; 
 
9.5.4.5 
Record of all communications between the PI, Celgene, and their authorized 
representative(s); 


 
 
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9.5.4.6 
List of Sub-investigators and other appropriately qualified persons to whom 
the PI has delegated significant study-related duties, together with their 
roles in the study, curriculum vitae, and their signatures; 
9.5.4.7 
Copies of CRFs (if paper) and of documentation of corrections for all subjects; 
9.5.4.8 
IP accountability records; 
9.5.4.9 
Record of any body fluids or tissue samples retained; 
9.5.4.10 
All other source documents (subject records, hospital records, 
laboratory records, etc.); 
9.5.4.11 
All other documents as listed in Section 8 of the ICH consolidated guideline 
on GCP (Essential Documents for the Conduct of a Clinical Trial). 
The PI must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified 
period. The PI must obtain approval in writing from Celgene prior to destruction of any 
records. If the PI is unable to meet this obligation, the PI must ask Celgene for permission 
to make alternative arrangements.  Details of these arrangements should be documented. 
All study documents should be made available if required by relevant health authorities. 
PI/Institution should take measures to prevent accidental or premature destruction of 
these documents. 
 
9.5.5 Protocol Deviations 
Apart from the regulatory requirements, it is vital to the success of the study that the PI 
adheres to the details of the protocol and thus holds to a minimum the number of cases, 
which may be later classified as “incomplete,” “unusable,” or “not evaluable.” 
 
 
10.0 APPENDICES 
Appendix A: New York Heart Association Classification 
Appendix B: Radiology Technical Manual 
Appendix C:  RECIST CRITERIA 1.1 
 
 
 
 


 
 
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Appendix A: New York Heart Association Classification 
 
NYHA 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical 
activity, e.g., no shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g., walking short distances (20-100 m). Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
 
 
 


 
 
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Appendix B: Radiology Technical Manual 
1. Imaging: 
Every attempt should be made to assure that imaging studies used for determination 
of eligibility for this protocol are obtained with a “pancreas protocol”. While the details 
of this will vary from site to site, important components are given below. Please note, 
that MOST sites will easily meet these requirements.  
 
a. CT 
 
1. CTs should be performed on a multidetector scanner with 16 slice capability 
as a minimum requirement. 
 
2. All scans MUST be IV contrast enhanced 
 
3.   2-phase acquisition is preferable with images taken during a “pancreatic 
parenchymal” 
      phase (approximately 40 seconds following initiation of contrast bolus) and a 
portal 
      venous phase (approximately 70-80 seconds following initiation of contrast 
bolus).  
 
b. MRI 
 
1. Studies should be obtained using a phased array body coil 
 
2. IV gadolinium gradient recalled echo sequences through the liver and 
pancreas should be obtained during arterial, early portal venous, and portal 
venous phases. 
 
3. Other sequences will be obtained including some form of T2 weighted 
sequence, non contrast T1 sequences. Most sites will acquire diffusion 
weighted images. MRCP  sequences are NOT a requirement for determining 
resectability. 
 
*For patients who present with imaging studies not performed at participating sites, 
eligibility will be at the discretion of the PI. Every attempt will be made to avoid 
having the patient repeat the study; however, this may not be possible in all cases. 
 
2. Transferring of Images. 
Images should be collected on a CD. For CT studies, please ask your technologists to 
include the “THIN SECTION” data as well as the conventional reconstructed images. 
The thin sections are important to visualize the vascular structures, which are critical 
for determining resectability status. MRI studies, by virtue of the way in which they are 
acquired, do NOT require additional thin section images to be sent.   
 
For research purposes, please also include the site radiologist’s report on the study.  
The CD should be anonymized and named for the site and the sequence of the study 
sent (e.g. NYU_1, NYU_2…NYU_n). Reports should have names redacted.  Once the 


 
 
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CD is created, please use overnight mail (labels will be provided) and send to: 
 
 
Alec J. Megibow, MD, MPH 
 
Department of Radiology, NYU-Langone Medical Center 
 
550 First Avenue, ROOM HCC 232 
 
New York, NY 10016 
 
3. Image interpretation 
Determination of protocol eligibility will be based on 2014 NCCN guidelines for 
resectability.  The central PI will communicate to the site PIs with a simple email stating 
that the patient is eligible or ineligible. If the site disputes the central PI determination, 
a more detailed analysis of the case will be sent to the site.  Please be certain that the 
site’s PI email address is included with the packet in which the CD is sent.  
 
 


 
 
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Appendix C:  RECIST CRITERIA 1.1 
Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference 
ELIGIBILITY 
• 
Only patients with measurable disease at baseline should be included in protocols 
where objective tumor response is the primary endpoint. 
Measurable Disease – the presence of at least one measurable lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should 
be confirmed by cytology/histology. 
Measurable Lesions – lesions that can be accurately measured in at least one 
dimension with the minimum size of: 
• 
10 mm by CT scan or MRI (no less than double the slice thickness and a 
minimum of 10 mm). 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-
measureable). 
• 
15 mm for nodal disease in short axis 
• 
20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
• 
Malignant lymph node: 15 mm in short axis when assessed by CT scan 
(CT scan slice thickness no greater than 5 mm). At baseline and in follow-
up only the short axis is to be followed. 
Non-Measurable Lesions – all other lesions, including small lesions (longest 
diameter <10 mm or pathological lymph nodes with >10 to <15 mm short axis) as 
well as truly non-measurable lesions. Lesions considered truly non-measurable 
include leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques, and nodal disease that is 10 to 
<15 mm in short axis. 


 
 
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Special Considerations Regarding Lesion Measurability: Bone lesions, cystic 
lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
• 
Blastic bone lesions are non-measurable. 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion. Study protocols should detail the 
conditions under which such lesions would be considered measurable. 
Measurement of Lesions 
• 
All measurements should be taken and recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 28 days before the 
beginning of the treatment. 


 
 
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Methods of Measurement 
• 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and at each subsequent 
response assessment. Imaging based evaluation should always be done rather than 
clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical examination. 
• 
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
• 
CT is the best currently available and reproducible method to measure target lesions 
selected for response assessment. The CT scan slice thickness should be 5 mm or 
less. When the CT scans have a slice thickness that is greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable. Eisenhauer et al. (2009) for more details concerning the use of CT 
scan and MRI. 
• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
• 
Ultrasound (US) should not be used to measure tumor lesions. The utilization of 
endoscopy and laparoscopy for objective tumor evaluations is not advised. 
• 
FDG-PET can be used to determine a new lesion if the lesion was absent at baseline 
on FDG PET. 
• 
Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in 
complete response when all lesions have disappeared. 
• 
Cytology and histology can be used to differentiate between PR and CR in rare 
cases (e.g., after treatment to differentiate between residual benign lesions and 
residual malignant lesions in tumor types such as germ cell tumors). 
Baseline Documentation of “Target” and “Non-Target” Lesions 
• 
All measurable lesions up to a maximum of two lesions per organ and 5 lesions in 
total, representative of all involved organs should be identified as target lesions and 
recorded and measured at baseline. 
• 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves accurate repeated measurements. 


 
 
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• 
A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum diameters. The baseline sum diameters will be used as 
reference by which to characterize the objective tumor. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added to the sum. 
• 
If a target lesion becomes too small to measure, a default value of 5 mm is assigned. 
If the lesion disappears, the measurement is recorded at 0 mm. 
• 
If extranodal target lesions fragment, the LDs of the fragmented portions are added 
in the sum. If targets lesions coalesce and cannot be distinguished, the LD of the 
coalesced lesion is added to the sum. 
• 
For a patient with SD or PR, a lesion which disappears and then reappears will 
continue to be measured and added to the sum. Response will depend upon the 
status of the other lesions. For a patient with CR, reappearance of a lesion is 
considered PD. 
• 
New lesions should be unequivocal and not attributable to differences in scanning 
technique or findings which may not be tumor. If a new lesion is equivocal, repeat 
scans are needed to confirm. If confirmed, PD is assessed from the date of the first 
scan. 
• 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not 
required, but the presence or absence of each or in rare case unequivocal 
progression should be noted at each subsequent response assessment. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
* Complete Response 
(CR): 
Disappearance of all target lesions. Any pathological lymph node 
(whether target or non-target) must have reduction in short axis to <10 
mm 
* Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters 
* Progressive Disease 
(PD): 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 
mm. The appearance of one or more new lesions is also considered 
progression. 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 


 
 
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Evaluation of Non-Target Lesions 
* Complete Response 
(CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (i.e., <10 
mm short axis) 
* Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits 
* Progressive Disease 
(PD): 
Unequivocal progression of the existing non-target lesions. The 
appearance of one or more new lesions is also considered progressive 
disease. 
Note: Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, 
the opinion of the PI should prevail. 
 
Evaluation of Overall Response 
The overall response is assessed according to the following table. 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
• 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
• 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it 
is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) 
to confirm the complete response status. If described in the clinical protocol, FDG-
PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. 


 
 
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Confirmation 
Confirmation of PR or CR to deem either one the ‘best overall response’ is only 
needed in non-randomized trials if response is the primary endpoint. 
REPORTING OF RESULTS 
• 
All patients included in the study must be assessed for response to treatment, even if 
there are major protocol treatment deviations or if they are ineligible. Each patient 
will be assigned one of the following categories: 1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) inevaluable for response: 
specify reason such as early death from malignant disease, early death from toxicity, 
tumor assessments not repeated/incomplete, or other (specify) 
 
 
 


 
 
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11.0 REFERENCES: 
 
1. American Cancer Society: Cancer Facts and Figures 2013. Atlanta, GA: 
American Cancer Society, 2013. 
 
2. Yeo CJ, Yeo TP, Hruban RH, Kern SE et al.  Cancer of the Pancreas. In De Vita 
VT, ed. Principles and Practice of Oncology, 7th Edition. Philadelphia: Lippincott 
Williams & Wilkins pp 945-986, 2000. 
 
3. Maurer CA, Zgraggen K, Buchler MW.  Pancreatic carcinoma. Optimizing therapy 
adjuvant and neoadjuvant therapy?  Zentralb Chir 124 (5): 401-7 (in German), 
1999. 
 
4. Tempero MA, Behrman S, Ben-Josef E, et al.  Pancreatic adenocarcinoma: 
Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 3(5) 589-626, 
2005.  
 
5. Papavasilious P, Chun YS, Hoffman JP et al.  How to define and manage 
borderline resectable pancreas cancer.  Surg Clin N Am 93:663-674, 2013. 
 
6. Neoptolemos JP, Stocken DD, Bassi C et al.  Adjuvant chemotherapy with 
fluorouracil plus folinic acid vs gemcitabine following pancreas cancer resection: 
a randomized controlled trial. JAMA. 304(10):1073-81, 2010. 
 
7. Ohigashi H, Ishikawa O, Eguchi H et al. Feasibility and efficacy of combination 
therapy with preoperative full-dose gemcitabine, concurrent three dimensional 
conformal radiation, surgery, and postoperative liver perfusion chemotherapy for 
T3-pancreas cancer. Ann Surg 250:88 –95, 2009. 
 
8. Laurence JM, Tan PD, Morarji K et al.  A systematic review and meta-analysis of 
survival and surgical outcomes following neoadjuvant chemoradiotherapy 
forpancreatic cancer.  J. Gastrointest. Surg 15: 2059-2069, 2011.   
 
9. Heinrich S, Schafer M, Weber A et al. Neoadjuvant chemotherapy generates a 
significant tumor response in resectable pancreas cancer without increasing 
morbidity: results of a prospective phase II trial. Ann Surg 248:1014 –1022, 2008. 
 
10. Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus Gemcitabine for 
Metastatic Pancreatic Cancer.  N Engl J Med 364:1817-1825, 2011. 
 
11. Von Hoff DD, Ramanathan RK, Borad MJ et al.  Gemcitabine plus nab-paclitaxel 
is an active regimen in patients with advanced pancreatic cancer: a phase I/II 
trial.  J Clin Oncol. 29(34):4548-54, 2011. 
 
12. Von Hoff DD, Ervin T, Arena FP et al.  Increased Survival in Pancreatic Cancer 
with nab-Paclitaxel plus Gemcitabine.  N Engl J Med 369:1691-1703, 2013. 
 
13. Hidalgo M, Plaza C, Illei PB, et al. SPARC analysis in the phase III MPACT trial 
of nab-paclitaxel plus gemcitabine vs gem alone for patients with metastatic 
pancreatic cancer. Oral presentation at: 16th World Congress on Gastrointestinal 


 
 
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Cancer; June 25-28, 2014; Barcelona, Spain [abstract O-0004]. 
 
14. Kaiser MH, Ellenberg SS.  Pancreatic Cancer: Adjuvant Combined Radiation and 
Chemotherapy Following Curative Resection.  Arch Surg. 120(8):899-903, 1985. 
 
15. Trakul N, Koong AC and Chang DT.  Stereotactic body radiotherapy in the 
treatment of pancreatic cancer.  Semin Radiat Oncol 24(2):140-7, 2014. 
 
16. Chuong MD, Springett GM, Frelich JM et al.  Stereotactic body radiation therapy 
for locally advanced and borderline resectable pancreatic cancer is effective and 
well tolerated.  Int J Radiat Oncol Biol Phys 86(3):516-522, 2013. 
 
17. Commisso C, Davidson SM, Soydaner-Azeloglu RG, et al. Macropinocytosis of 
protein is an amino acid supply route in Ras-transformed cells.  Nature 2013 497: 
633-637.   
 
18. Malkoski SP, Wang XJ.  Two sides of the story? Smad4 loss in pancreatic cancer 
versus head-and-neck cancer.  FEBS Lett. 2012 Jul 4;586(14):1984-92. 
 
19. Massagué J, Seoane J, Wotton D.  Smad transcription factors.  Genes Dev. 2005 
Dec 1;19(23):2783-810. 
 
20. Hahn SA, Schutte M, Hoque AT, et al.  DPC4, a candidate tumor suppressor 
gene at human chromosome 18q21.1.  Science. 1996 271(5247):350-353. 
 
21. Blackford A, Serrano OK, Wolfgang CL, et al.  SMAD4 gene mutations are 
associated with poor prognosis in pancreatic cancer.  Am J Hum Genet. 1976 
(1):9-17. 
 
22. Singh P, Srinivasan R, Wig JD.  SMAD4 genetic alterations predict a worse 
prognosis in patients with pancreatic ductal adenocarcinoma.  Pancreas. 2012 
41(4):541-6. 
 
23. Winter JM, Tang LH, Klimstra DS, et al.  Failure patterns in resected pancreas 
adenocarcinoma: lack of predicted benefit to SMAD4 expression.  Ann Surg. 
2013 258(2):331-5. 
 
24. Iacobuzio-Donahue CA, Fu B, Yachida S, et al.  DPC4 gene status of the primary 
carcinoma correlates with patterns of failure in patients with pancreatic cancer.  J 
Clin Oncol. 2009 27(11):1806-13. 
 
25. Cox AD_and Der CJ.  Ras history: the saga continues. Small GTPases 2010 1:2-
27. 
 
26. Karnoub AE. And Weinberg RA.  Ras oncogenes: split personalities.  Nat. Rev. 
Mol. Cell Biol. 2008 9:517-531 
 
27. Scheffzek k. et al.  The Ras-RasGAP complex: structural basis for GTPase 
activation and its loss in oncogenic Ras mutants.  Sci. 1997 277:333-338. 
 


 
 
© 2015 AGICC / Criterium Inc     PROPRIETARY & CONFIDENTIAL 
Page 87 of 89 pages 
Template Final Ver. 7JAN2015 
Protocol/COMIRB # 15-0150 – PI: Weekes – Version Date: 11.16.2016 
 
 
28. Scheidig AJ et al.  The pre-hydrolysis state of p21(ras) in complex with GTP: new 
insights into the role of water molecules in the GTP hydrolysis reaction of ras-like 
proteins.  Structure. 1999 7:1311-1324. 
 
29. Diaz LA and Bardelli A.  Liquid Biopsies: Genotyping circulating tumor DNA.  J 
Clin Oncol. 2014 32(6):579-586. 
 
30. Bettegowda C, Sausen M, Leary RJ, et al.  Detection of circulating tumor DNA in 
early- and late-stage human malignancies.  Sci. Transl. Med. 2014 
6(224):224ra24   
 
31. Vogelstein B and Kinzler KW.  Digital PCR.  Proc. Natl. Acad. Sci. 1999 96:9236-
9241. 
 
32. Dressman D, Yan H, Traverso G et al.  Transforming single DNA molecules into 
fluorescent magnetic particles for detection and enumeration of genetic 
variations.  Proc. Natl. Acad. Sci. 2003 100:8817-8822. 
 
33. Liu Q and Sommer S.  Pyrophosphorolysis-activated polymerization (PAP): 
application to allele specific amplification.  Biotechniques.  2000 29:1072-1076, 
1078, 1080. 
 
34. Diehl F, Schmidt K, Choti MA, et al.  Circulating mutant DNA to assess tumor 
dynamics.  Nat. Med. 2008 14(9):985-990. 
 
35. Xu W1, Seok J, Mindrinos MN, et al.  Human transcriptome array for high-
throughput clinical studies.  Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3707-
12. 
36. Kupprion C, Motamed K, Sage EH et al. SPARC  (BM-40, osteonectin) inhibits 
the mitogenic effect of vascular endothelial growth factor.  J Biol Chem 1994;273 
(45): 29635-29640.  
 
37. Barker TH, Baneyx G, Cardo-Vila M et al. SPARC  regulates extracellular matrix 
organization through its modulation of integrin-linked kinase activity. J Biol Chem 
2005; 280 (43): 36483-36493.  
 
38. Infante JR, Matsubayashi H, Sato N et al. Peritumoral Fibroblast SPARC 
Expression and Patient Outcome With Resectable Pancreatic Adenocarcinoma, 
J Clin Oncol, 2007 25(3):319-25. 
 
39. Sinn M, Sinn BV, Striefler JK et al. SPARC expression in resected pancreatic 
cancer patients treated with Gemcitabine: results from the CONKO-001 study. 
Annals of Oncology, 2014 25:1025-32. 
 
40. Yun J, Rago C, Cheong I et al. Glucose deprivation contributes to the 
development of KRAS pathway mutations in tumor cells.  Science 2009; 325 
155-1559.  
 


 
 
© 2015 AGICC / Criterium Inc     PROPRIETARY & CONFIDENTIAL 
Page 88 of 89 pages 
Template Final Ver. 7JAN2015 
Protocol/COMIRB # 15-0150 – PI: Weekes – Version Date: 11.16.2016 
 
 
41. Bar-Sagi D, Feramisco JR.  Induction of membrane ruffling and fluid-phase 
pinocytosis in quiescent fibroblasts by ras proteins.  Science 1986; 233: 1061-
1068.  
 
42. Commisso C, Flinn RJ and Bar-Sagi D.  Determining the macropinocytic index of 
cancer cells through a quantitative image-based assay.  Nat Protoc 9:182-192, 
2014. 
 
43. Alvarez R, Musteanu M, Garcia-Garcia M et al.  Stromal disrupting effects of nab-
paclitaxel in pancreatic cancer.  Br J Cancer. 109(4):926-33, 2013. 
 
44. Katz MHG, Marsh R, Herman JM, et al. Borderline resectable pancreatic cancer: 
need for standardization and methods for optimal clinical trail design.  Ann Surg 
Oncol 20: 2787-2795, 2013. 
 
45. Sample size calculations from PASS 2014, NCSS.  J. Hintze, Kaysville UT. 
 
46. Yachida S and Iacobuzio-Donahue CA.  Evolution and dynamics of pancreatic 
cancer progression.  Oncogene 32:5253-5260, 2013. 
 
47. Rhim AD, Mirek ET, Aiello NM et al.  EMT and dissemination precede pancreatic 
tumor formation.  Cell 148)1-2):349-61, 2012. 
 
48. Nathan H, Cameron JL, Choti MA et al. The volume-outcomes effect in Hepato-
pancreato-biliary surgery:  hospital versus surgeon contributions and specificity of 
the relationship.  J Am Coll Surg 208(4):528-538, 2009. 
 
49. Evans DB, Varadhachary GR, Crane CH et al. Peroperative gemcitabine-based 
chemoradiation for patient with resectable adenocarcinoma of the pancreatic 
head.  J Clin Oncol 26(21):3496-3502, 2008. 
 
50. Katz MH, Wang H, Fleming JB et al.  Long-term survival after multidisciplinary 
management of resected pancreatic adenocarcinoma.  Ann Surg Oncol 16(4):836-
847, 2009. 
 
51. Burris HA III, Moore MJ, Andersen J et al.  Improvements in survival and clinical 
benefit with gemcitabine as first-line therapy for patients with advanced pancreas 
cancer: a randomized trial. J Clin Oncol 15(6):2403-2413, 1997. 
 
52. Oettle H, Post S, Neuhaus P et al.  Adjuvant chemotherapy with gemcitabine vs 
observation in patients undergoing curative-intent resection of pancreas cancer: 
a randomized controlled trial. JAMA. 297(3):267-77, 2007. 
 
53. Oettle H, Neuhaus P, Hochhaus A et al.  Adjuvant Chemotherapy with 
gemcitabine and long-term outcomes among patients with resected pancreatic 
cancer:  The CONKO-001 Randomized Trial.  JAMA 310(14):1473-1481, 2013. 
 
54. Neoptolemos JP, Stocken DD, Friess H et al.  A randomized trial of 
chemoradiotherapy and chemotherapy after resection of pancreatic cancer.   N 
Engl J Med 350:1200-1210, 2004. 


 
 
© 2015 AGICC / Criterium Inc     PROPRIETARY & CONFIDENTIAL 
Page 89 of 89 pages 
Template Final Ver. 7JAN2015 
Protocol/COMIRB # 15-0150 – PI: Weekes – Version Date: 11.16.2016 
 
 
 
55. Regine WF, Winter KA, Abrams RA et al.  Fluorouracil vs gemcitabine 
chemotherapy before and after fluorouracil-based chemoradiation following 
resection of pancreatic adenocarcinoma.  JAMA 299(9):1019-1026. 
 
56. LAP 007 Trial 
 
57. Koong AC, Christofferson E, Le QT et al.  Phase I study of stereotactic 
radiosurgery in patients with locally advanced pancreatic cancer.  Int J Radiat 
Oncol Biol Phys 58(4):1017-1021, 2004. 
 
58. Mahadevan A, Jain S, Goldstein M et al.  Stereotactic body radiotherapy and 
gemcitabine for locally advanced pancreatic cancer.  Int J Radiat Oncol Biol Phys 
78(3):735-742, 2010. 
 
59. Mahadevan A, Miksad R Goldstein M et al.  Induction gemcitabine and stereotactic 
body radiotherapy for locally advanced pancreatic cancer.  Int J Radiat Oncol Biol 
Phys 81(4):e615-e622, 2011. 
 
60. Dumonceau JM, Polkowski M, Larghi A, et al. Indications, results, and clinical 
impact of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: 
European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. 
Endoscopy 43:897-912, 2011. 
 
61. Fuji LL, Levy MJ. Pitfalls in EUS FNA. Gastrointest Endosc Clin N Am 24:125-142, 
2014. 
 
62. Orell SR. Pitfalls in fine needle aspiration cytology. Cytopathology 14:173-82, 
2003. 
 
63. Woolf KM, Liang H, Sletten ZJ, et al. False-negative rate of endoscopic ultrasound-
guided fine-needle aspiration for pancreatic solid and cystic lesions with matched 
surgical resections as the gold standard: one institution's experience. Cancer 
Cytopathol 121:449-58, 2013. 
 
64. Mollberg N1, Rahbari NN, Koch M, et al.  Arterial resection during pancreatectomy 
for pancreatic cancer: a systematic review and meta-analysis.  Ann Surg. 254:882-
93, 2011. 
 


Consent and Authorization Form
Principal Investigator:
Wells A. Messersmith, MD, FACP
COMIRB No:
15-0150
Version Date:
January 4, 2021
Study Title:
Perioperative Therapy for Resectable and Borderline Resectable 
Pancreatic Adenocarcinoma with Molecular Correlates
You are being asked to be in a research study.  This form provides you with information about 
the study. A member of the research team will describe this study to you and answer all of your 
questions. Please read the information below and ask questions about anything you don’t 
understand before deciding whether or not to take part. 
Why is this study being done?
This study plans to learn more about pancreatic cancer. We will study the safety and 
effectiveness of a new treatment for patients with a type of pancreatic cancer called operable 
and borderline operable pancreatic ductal adenocarcinoma. This treatment is a combined 
chemotherapy and radiation therapy. The treatment will be given to patients before they have 
surgery (preoperative) and again after they have surgery (postoperative). 
We hope to learn how well this combination of chemotherapy and radiation therapy works to 
shrink tumors before surgery. This way, the tumors can be safely and more completely removed 
during surgery. Patients in this study have operable, non-metastatic (no spread to other organs) 
pancreatic adenocarcinoma. The main goal of this study is to find out the rate at which surgery 
may remove all visible cancer from the study patients. The study researchers will look at the 
harm that this treatment might cause patients. The researchers will also look at the tumor 
markers of the disease found in tumor tissue and blood samples.
Standard treatment therapies that are used to treat patients with pancreatic cancer include 
surgery, chemotherapy, and radiation therapy. Generally, surgery comes first, followed by 
chemotherapy and radiation. In this study, patients will first be given a combination of two 
chemotherapy drugs that are intended to help stop the growth and spread of cancer. Next, they 
will receive radiation, then have their surgery, and again receive the combination chemotherapy. 
In this study receiving chemotherapy before and after surgery is considered investigational. 
The two chemotherapy drugs are nab-paclitaxel (abraxane) and gemcitabine (gemzar). These 
drugs will be given through a vein (intravenously, or “IV”). Throughout the rest of this form, 
when these drugs are referenced by themselves they will be called “abraxane” and 
“gemcitabine”. When referenced together in combination use they will be called the 
“study drugs”.
Abraxane has been approved by the United States Food and Drug Administration (FDA) for the 
treatment of advanced, inoperable pancreatic cancer that has spread to other organs. However, 
the use of abraxane to treat patients whose pancreatic cancer can be removed by surgery 
(resectable or operable) or partly removed by surgery (borderline resectable or borderline 
operable) is considered “investigational”. This means this study drug has not been approved by 
the FDA for this use. 
Gemcitabine has been approved by the FDA for the treatment of all pancreatic cancer at all 
stages and is not considered investigational.  
COMIRB
APPROVED
For Use
29-Jan-2021
10-Nov-2021


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COMIRB: 15-0150
PI:  Messersmith
Version Date:  01/04/2021
Page 2 of 24
You are being asked to be in this research study because we are only studying this treatment in 
patients who have not yet been treated for pancreatic cancer, and whose disease is non-
metastatic. Your doctor has reviewed your computerized tomography (CT) or Magnetic 
Resonance Images (MRI) and believes you are eligible to take part in this study. 
Other people in this study
Up to 15 people from your area will participate in the study. 
Up to 50 people around the country will be in the study.  Two patient groups (cohorts) will be 
taking part in this study: 

Up to 20 people will be in Cohort 1: Resectable (Operable) tumors
In general “resectable” pancreatic cancers are those which can be removed 
because they do not touch major blood vessels.  

Up to 30 people will be in Cohort 2: Borderline Resectable (Borderline Operable) 
tumors
“Borderline resectable” generally includes those which touch the major arteries 
and/or veins that take blood to or from the pancreas or its surrounding tissues.
What happens if I join this study?
If you join the study, you will be asked to sign this consent form before you receive any study 
related tests or procedures. Some of these procedures are the same as you would receive as 
standard of care treatment even if you did not participate in this trial.
There are three parts to this study:
1.
Screening (before the study)
2.
Treatment
3.
After Treatment Follow-up
Below is a general description of these three parts of this study, including which therapies, tests, 
and procedures will be given and when.  It is also an overview of what will be expected of you if 
you decide to take part in this study. 
1.  SCREENING
Once you sign this consent form the following will be done to see if you can be in this study. In 
the next section “Study Procedures” will give a description of these and other procedures you 
can expect to have if you take part in this study.

Medical History 

Physical exam 

Height and weight

Body Surface Area calculation (for chemotherapy dosing)

Review of medications (those you are allergic to or taking including, vitamins, herbs 
or over-the-counter medications) 

Review of other medical procedures you may be having done

Peripheral neuropathy evaluation


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
Vital signs

ECOG performance status

ECG

Urine test

Blood tests (including a complete blood count (CBC), a complete chemistry panel 
(CMP), serum pregnancy, coagulation, and tumor markers known as serum CA19-9, 
serum CEA, and a plasma biomarker.

CT with contrast or MRI (chest, abdomen and pelvis)

Radiology review

Endoscopic Ultrasound (EUS) with diagnostic tumor biopsy. You will sign a separate 
consent form when you have this procedure. Tumor tissue that is taken during this 
procedure and not needed for your diagnosis and standard treatment would normally 
be thrown away, but we will use this left-over tumor tissue in this study to do a 
molecular tumor analysis (this may also include looking to see if the tumor tissue is 
hard or soft).

Archived tumor tissue
2.  TREATMENT
The study treatment consists of:

3 months (12 weeks) of chemotherapy (the study drugs)

5 days of Stereotactic Body Radiation Therapy (SBRT)

surgery (4 to 6 weeks after SBRT) to remove any operable cancerous tumors

3 months (12 weeks) of chemotherapy. 
The chemotherapy you receive before your operation and after your operation will be the same.  
A. STUDY DESIGN
Below is a chart that shows the order in which procedures will take place in this study. Below 
the chart is a description of each procedure, but in the chart some of the procedures are show 
using abbreviations that mean the following:
EUS means an Endoscopic Ultrasound.
CT means a Computed Tomography Scan
MRI means a Magnetic Resonance Imaging Scan
SBRT means Stereotactic Body Radiation


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COMIRB: 15-0150
PI:  Messersmith
Version Date:  01/04/2021
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EUS and possible biopsy*
                EUS 
                                                             radiation marker placement and biopsy
               CT
         CT
            CT
                    CT
                 (or MRI) 
     (or MRI) 
        (or MRI)                                (or MRI)
B. STUDY PROCEDURES 
Archived Tumor Tissue
If you also had surgery in the past, you must allow us to request tumor tissue from your prior 
biopsy to be used for this study. We will contact the institution where you had your surgery 
and ask them to send us a portion of your tumor tissue that they have stored so that it may 
be used this research. We will also do molecular tumor testing on this tumor tissue.
Body Imaging Studies (CT or MRI)
Body imaging studies such as Computerized Tomography (CT) Scans and Magnetic 
Resonance Imagining (MRI) will be used to determine your eligibility for this trial. Your 
doctor will make the choice which test is appropriate for you. These tests are routine for 
patients with pancreas cancer. They will help determine if you are eligible for this study. 
They will also show the size of your tumor and whether the size changes during treatment.  
Since these are standard tests, your doctor and/or radiologist will describe this procedure 
including the side effects you might experience. 
Blood Tests
We will take approximately 2 tablespoons of blood for a variety of tests to check your kidney 
and liver function and to look for tumor markers. A pregnancy test will also be done for 
women of childbearing potential.
ECOG performance status score 
This is a scale used to assess how a patient's disease is progressing, and how the disease 
affects a patient’s daily living abilities. It helps determine appropriate treatment and 
prognosis.
Gemcitabine 
1
Gemcitabine 
1
SBRT 
- 
Surge
ry – 4 


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PI:  Messersmith
Version Date:  01/04/2021
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Electrocardiogram (ECG)
An ECG is a simple, noninvasive procedure that makes a recording of the electrical activity 
of the heart. Electrodes are placed on the skin of the chest and connected in a specific order 
to a machine. Output usually appears on a long scroll of paper that displays a printed graph.
Peripheral Neuropathy Assessment
When your medical history is reviewed, your doctor will also do an evaluation about 
peripheral neuropathy. This is numbness, tingling, pain, or lack of feeling in your arms, legs, 
hands, or feet. This is done to see how well you may tolerate the treatment.
Endoscopic ultrasound (EUS) and Diagnostic Tumor Biopsy 
This is a minimally invasive procedure done to assess many things, including cancer of the 
pancreas.  Under light sedation, an experienced, well trained physician will pass a thin 
flexible tube into your stomach and duodenum to visualize the pancreas and your tumor.  It 
uses high-frequency sound waves to produce detailed images of the lining and walls of your 
digestive tract, chest, and nearby organs, such as the pancreas, liver, and lymph nodes.  An 
EUS is a formal outpatient surgery that allows your doctor to sample (biopsy) tissue from 
your pancreatic tumor.  This procedure will also include tumor marker testing. Your doctor 
will give you specific instructions to prepare for your EUS which may include asking you to:

Fast before the EUS procedure, to make sure your stomach is empty.

Stop taking certain medications, such as blood thinners. Blood thinners may 
increase your risk of bleeding if a biopsy is performed during EUS. If you 
have chronic conditions, such as diabetes or high blood pressure, your doctor 
will give you specific instructions about your medications.

Plan ahead for your recovery, if you will be sedated before EUS. Most people 
who have EUS are given medication to relax them. You should arrange for 
someone to drive you home after the procedure.
This study requires 2 endoscopic evaluations of your pancreatic tumor.  During the second 
evaluation, radiation markers (tiny gold seeds) will be placed to help guide your radiation 
oncologist for Stereotactic Body Radiation Therapy (SBRT). A doctor trained in analyzing 
biopsies (pathologist) will report the test results if you have fine-needle aspiration. Your 
doctors will discuss any important findings and next steps with you.
Molecular Marker Analysis
Molecular markers (also called biomarkers) are substances such as genetic material (DNA 
and RNA) and proteins found in blood and tumor tissue. These can show if a patient with 
cancer will or will not respond to a treatment. Currently, no such markers are available for 
patients with your type of pancreas cancer. In this study we will be testing your blood and 
tumor tissue (from your biopsy) before treatment is started and after chemotherapy is 
completed. The biopsy and the blood needed for this testing will be taken prior to the start of 
chemotherapy and prior to the start of SBRT (most likely at the time of radiation marker 
placement). 


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Version Date:  01/04/2021
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The intent of the treatment used in this study is to make your operation more successful, but 
the biopsies and blood draws for biomarker analysis will not be used to determine your 
treatment in this study. Instead they will be analyzed after all enrollment in this trial is 
complete. You will not receive the results of these analyses.
Chemotherapy (the Study Drugs)
Cancer chemotherapy is designed to safely kill tumor cells while doing less harm to normal 
cells. The next section of this consent form will tell you about the known side effects of the 
chemotherapy that you will receive.  Chemotherapy prior to surgery is designed to kill both 
tumor cells in your pancreas and other invisible cells that might have escaped the pancreas 
to invade other parts of your body.  This is called “preoperative chemotherapy.” 
In this trial you will receive two chemotherapeutic agents (two drugs) by intravenous (IV) 
infusion. These are gemcitabine and abraxane.  These drugs are FDA approved to be given 
to patients with advanced pancreas cancer. However, they are not FDA approved to be 
given to patients before or after an operation for pancreas cancer.  These drugs are given 
on the same day.  This study visit procedure will last several hours so you can receive the 
drugs safely and with medication to prevent nausea or vomiting.
Gemcitabine is a type of chemotherapy known as anti-metabolites which 
prevents cells from making DNA, to stop cell growth and cause cells to die. You 
will receive gemcitabine through a tube in your vein (IV infusion) for 3 cycles 
before your surgery and for 3 cycles after your surgery.  Each cycle will consist of 
an IV infusion each week for 3 consecutive weeks with one week off.  The 3 
cycles will take approximately 12 weeks.  
Abraxane is paclitaxel bound to a protein called albumin.  This allows the 
abraxane to be given without the other medicine, which lowers the risk of an 
allergic reaction. Abraxane is a type of chemotherapy drug known as a taxane. It 
works on cells when they undergo the part of cell division known as mitosis.  
Because cancer cells divide faster than normal cells, they are more likely than 
normal cells to be affected by this drug. In this study, abraxane will be given for 3 
cycles before the surgery and for 3 cycles after the surgery.  Each cycle will 
consist of an IV infusion each week for 3 consecutive weeks with one week off.  
The 3 cycles will take approximately 12 weeks.  This is the same schedule we 
will use for gemcitabine. 
Stereotactic Body Radiation Therapy (SBRT) and Radiation Marker Placement 
Radiation Therapy 
This is a standard of practice in the United States for many patients after they 
have had a successful operation for pancreatic cancer. 
Stereotactic body radiation therapy (SBRT) 
This is a type of radiation therapy in which a few high doses of radiation are 
delivered to small, well-defined tumors. The goal is to deliver a radiation dose 
that is high enough to kill the cancer, while minimizing exposure to healthy 
tissues and organs nearby. SBRT is typically used to treat small, early-stage 
tumors, or isolated recurrences or spread from various types of cancer. SBRT 


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Version Date:  01/04/2021
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has been used successfully to treat early-stage pancreatic cancer and metastatic 
cancers. SBRT begins with one or more sessions of treatment planning. This 
planning uses imaging (such as a CT scan, or MRI) to map the exact position of 
the tumor to be treated. These images are then used to create customized 
treatment plans. During treatment, high-level computerized devices point several 
radiation beams of different intensities at different angles, so that the radiation is 
directed precisely to the tumor. 
SBRT Delivery: In this study, SBRT will be given 5 times, on 5 consecutive days.
Radiation Marker Placement
This is now considered standard practice to place radiation markers for a 
SBRT. Radiation markers are tiny gold seeds that are placed into the pancreas.  
The radiation markers will be placed during the second study EUS. A radiation 
marker is placed in the view of an image that is created when a CT or MRI 
imaging system is used. The radiation marker is used as a point of reference or 
measure to help doctors pinpoint the exact location of a tumor. The doctor will 
aim the radiation beam in the way that will concentrate its energy on the tumor 
and not the nearby tissue. This procedure will be performed under anesthesia 
and the doctor performing the procedure will discuss the risks with you and give 
you a separate consent form.  The risks will also be discussed in the next section 
of this consent form.
Surgery
Surgery to remove a tumor offers the best chance for long-term control of all types of 
pancreatic cancer.  If a tumor is able to be removed with surgery, it is called resectable.
Different types of surgery are performed depending on the location of the tumor within the 
pancreas:

Whipple Procedure (Pancreaticoduodenectomy)

Distal Pancreatectomy

Total Pancreatectomy
The Whipple Procedure, or pancreaticoduodenectomy, is the most common 
surgery to remove tumors in the pancreas.  In a standard Whipple procedure, the 
surgeon removes the head of the pancreas, the gallbladder, part of the 
duodenum (the uppermost portion of the small intestine), the pylorus (a small 
portion of the stomach), and the lymph nodes near the head of the pancreas.  
The surgeon then reconnects the rest of the pancreas and digestive organs so 
that pancreatic digestive enzymes, bile, and stomach contents will flow into the 
small intestine during digestion.  
A distal pancreatectomy is generally performed if a tumor is located in the body 
or tail portion of the pancreas.  The surgeon removes the body and tail of the 
pancreas, and sometimes the spleen.  All other organs are left in place.  


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PI:  Messersmith
Version Date:  01/04/2021
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A total pancreatectomy is performed when the tumor is situated in such a way 
that requires the entire pancreas to be removed.  It may also be performed when 
there are multiple tumors spread throughout the pancreas.  Similar to a Whipple 
procedure, the gallbladder, part of the duodenum, the bottom portion of the 
stomach and local lymph nodes are removed along with the entire pancreas.  
The spleen may also be removed.  
Within 2 months of surgery, you will begin postoperative chemotherapy using the same study 
drugs you received pre-operatively. Once again, you will have 3 cycles of chemotherapy. In 
each cycle, you will receive an IV infusion of the study drugs each week for three weeks with 
one week off. 
When you finish the postoperative chemotherapy, the treatment portion of the study is done and 
you will be given a guide to follow-up examinations and studies. 
The treatment portion of this study will take about 8 months. We will continue to follow up with 
you about every 12 weeks for 5 years. 
C. STUDY VISITS
Preoperative Chemotherapy
Cycle 1, Day 1

Physical exam 

Toxicity (adverse events) evaluation

Height and weight

Body Surface Area calculation (for chemotherapy dosing) 

Review your medications 

Review other medical procedures you may be having 

Peripheral neuropathy evaluation

Vital signs

ECOG performance status

Urine test

Blood tests 

Chemotherapy infusion
Cycle 1, Day 8 and Day 15

Toxicity (adverse events) evaluation

Height and weight

Body Surface Area calculation (for chemotherapy dosing)

Review your medications 

Vital signs

ECOG performance status

Blood tests 

Chemotherapy infusion
Cycle 1, Day 22

Toxicity (adverse events) evaluation

Review your medications 


Consent and Authorization Form
COMIRB: 15-0150
PI:  Messersmith
Version Date:  01/04/2021
Page 9 of 24

Vital signs

ECOG performance status

Blood tests
Cycle 2, Day 1

Toxicity (adverse events) evaluation

Height and weight

Body Surface Area calculation (for chemotherapy dosing)

Review your medications 

Review other medical procedures you may be having 

Peripheral neuropathy evaluation

Vital signs

ECOG performance status

Urine test

Blood tests

Chemotherapy infusion
Cycle 2, Day 8 and Day 15

Toxicity (adverse events) evaluation

Height and weight

Body Surface Area calculation (for chemotherapy dosing)

Review your medications

Peripheral neuropathy evaluation 

Vital signs

ECOG performance status

Blood tests 

Chemotherapy infusion
Cycle 2, Day 22

Toxicity (adverse events) evaluation

Review your medications 

Vital signs

ECOG performance status

Blood tests 
Cycle 3, Day 1

Toxicity (adverse events) evaluation

Height and weight

Body Surface Area calculation (for chemotherapy dosing)

Review your medications 

Review other medical procedures you may be having

Peripheral neuropathy evaluation 

Vital signs

ECOG performance status

Urine test

Blood tests  

Chemotherapy infusion


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Cycle 3, Day 8 and Day 15

Toxicity (adverse events) evaluation

Height and weight

Body Surface Area calculation (for chemotherapy dosing)

Review your medications

Vital signs

ECOG performance status

Blood tests 

Chemotherapy infusion
Cycle 3, Day 22

Physical exam

Toxicity (adverse events) evaluation

Review your medications 

Vital signs

ECOG performance status

Blood tests –  which will include tumor marker testing

CT or MRI
Radiation (SBRT) and Surgery
SBRT

Physical exam 

ECOG performance status

Radiology review

Endoscopic Ultrasound (EUS) 

SBRT

Tumor biopsy 
Surgery

Physical exam 

ECOG performance status

Surgery
Postoperative Chemotherapy
Cycle 1, Day 1

Physical exam 

Toxicity (adverse events) evaluation

Height and weight

Body Surface Area calculation (for chemotherapy dosing)

Review your medications

Review other medical procedures you may be having 

Peripheral neuropathy evaluation

Vital signs

ECOG performance status

Urine test

Blood tests – which will include tumor marker testing


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
CT or MRI

Chemotherapy infusion
Cycle 1, Day 8 and Day 15

Toxicity (adverse events) evaluation

Height and weight

Body Surface Area calculation (for chemotherapy dosing)

Review your medications  

Vital signs

ECOG performance status

Blood tests 

Chemotherapy infusion
Cycle 1, Day 22

Toxicity (adverse events) evaluation

Review your medications 

Vital signs

ECOG performance status

Blood tests 
Cycle 2, Day 1

Physical exam

Toxicity (adverse events) evaluation

Height and weight

Body Surface Area calculation (for chemotherapy dosing)

Review your medications 

Review other medical procedures you may be having

Peripheral neuropathy evaluation 

Vital signs

ECOG performance status

Urine test

Blood tests 

Chemotherapy infusion
Cycle 2, Day 8 and Day 15

Toxicity (adverse events) evaluation

Height and weight

Body Surface Area calculation (for chemotherapy dosing)

Review your medications 

Vital signs

ECOG performance status

Blood tests 

Chemotherapy infusion
Cycle 2, Day 22

Toxicity (adverse events) evaluation

Review your medications 


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
Vital signs

ECOG performance status

Blood tests 
Cycle 3, Day 1

Toxicity (adverse events) evaluation exam

Height and weight

Body Surface Area calculation (for chemotherapy dosing)

Review your medications

Review other medical procedures you may be having 

Peripheral neuropathy evaluation 

Vital signs

ECOG performance status

Urine test

Blood tests 

Chemotherapy infusion
Cycle 3, Day 8 and Day 15

Toxicity (adverse events) evaluation

Height and weight

Body Surface Area calculation (for chemotherapy dosing)

Review your medications 

Vital signs

ECOG performance status

Blood tests 

Chemotherapy infusion
Cycle 3, Day 22 – End of Treatment 

Physical exam

Toxicity (adverse events) evaluation

Review your medications 

Vital signs

ECOG performance status

Blood tests – which will include tumor marker testing 

CT or MRI

Radiology review
3.  AFTER TREATMENT FOLLOW-UP 
Surveillance Evaluations
If you complete all therapy you will enter into the surveillance phase of the study. We will 
evaluate you at least every 12 weeks (3 months) for 2 years. If your disease does not progress 
after 2 years, then we will evaluate you every 6 months. We will examine you more often if 
needed for clinical reasons. 
Surveillance examination will include the following assessments:


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
Medical History

Physical Exam

Toxicity (adverse events) evaluation 

Review your medications

Height and weight

Vital signs

ECOG performance status

Blood tests

CT or MRI with radiology review within 1 week prior to this visit.
End-of-Study (EOS) Evaluations
An EOS evaluation will be performed for all subjects who end treatment after the surveillance 
period.  The following procedures will be completed at the EOS Visit:

Medical history

Physical exam 

Toxicity (adverse events) evaluation 

Height and weight

Review other medications you are taking

Review other medical procedures you are having

Peripheral neuropathy evaluation

Vital signs

ECOG performance status

Blood tests - which will include tumor marker testing

CT or MRI with radiology review 
What are the possible discomforts or risks?
Discomforts you may experience while in this study include those listed below:
Risks from the Study Drugs
You may have side effects while you are in this study, but you will be carefully checked by the 
study doctor for any problems. There may be risks or side effects of the study drugs that are 
unknown at this time. You should tell the study doctor/ staff about anything that is bothering you 
or any side effects you have, even if you do not think they are related to the study drug.
Gemcitabine
Most Common Side Effects of Gemcitabine

A decrease in white blood cells that fight infection. You may be more susceptible 
to bacterial infections.

A decrease in platelets that assist in blood clotting.  You may experience excess 
bruising or bleeding. 

A decrease in red cells (anemia) that carry oxygen to your tissues. This may 
cause fatigue or the sense of being tired.  

Overall fatigue may occur from the weekly IV infusions of gemcitabine


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
Flu-like symptoms may occur.  This includes headaches, muscle aches, fever 
with shivering.  

Mild swelling of your hands or feet.  

A skin rash over the chest and extremities, especially the legs may occur.  It may 
cause itching.  

Nausea

Diarrhea
Less Common Side Effects of Gemcitabine

Muscle aches

Vomiting

Constipation

Change in liver function tests that could cause jaundice (yellowing of the skin)

Change in kidney function tests

Excess protein in the urine

Shortness of Breath 
Rare but Serious Side Effects of Gemcitabine

A severe skin reaction called Stevens-Johnson syndrome, a painful red or 
purplish rash that spreads and blisters causing the top layer of skin to die and 
shed

Inflammation or scarring of the lung leading to shortness of breath and cough

Kidney and liver failure

Cardiac dysfunction such as heart attack, congestive heart failure (heart unable 
to pump enough blood throughout the body), and atrial fibrillation (problem with 
speed or rhythm of the heartbeat). 
Abraxane
The following is a list of the most medically significant or most common side effects 
reported in completed studies considered to be related to abraxane. In some cases, side 
effects can be serious, long-lasting, or can cause death. Some side effects go away 
soon after you stop the study drug/ therapy and some may never go away. The study 
doctor may alter the dosage regimen of abraxane (if allowed by the study) or give you 
medicines to help lessen the side effects. This is not a complete list of all side effects 
that may occur. For more information about risks and side effects, please ask the study 
doctor.
Very Common Side Effects of Abraxane 
(a 10% or more chance that this will happen)

Anemia (a decrease in the number of red blood cells, which may make you feel 
weak or tired)

Low number of white blood cells with or without fever (that may make it easier to 
get infections). A decrease in the number of platelets, the cells that help your 
blood to clot (which may lead to unusual bleeding or bruising under the skin).  

Constipation

Diarrhea

Nausea


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
Vomiting  

Stomach pain

Pain, swelling, or sores on the inside of the mouth

Neuropathy, a disorder of the nerves which can cause tingling or numbness, with 
weakness or decreased sensation or movement

Dizziness

Headache

Feeling tired or weak

Pain (including muscle, joints, bone, and chest pain)

Swelling caused by fluid held in the tissues, especially of the ankles, feet, or 
fingers

Fever

Chills

Decreased appetite

Change in taste

Weight loss

Difficulty sleeping

Depression

Cough

Shortness of breath

Hair loss  

Rash, possibly red, bumpy, or generalized

Itchiness

Changes in nails, including discoloration or separation from nailbed

Abnormal liver function test results

Dehydration (loss of water and minerals in the body)

Nosebleed

Decreased potassium levels in the body
Common Side Effects of Abraxane
(between a 1% to less than 10% chance that this will happen)

Bone marrow depression, which is a severe reduction of red or white blood cells 
and platelets (at nearly the same time) which can cause weakness, bruising, or 
make infections more likely

Infections, including pneumonia or of the lung, mouth, gallbladder, urinary tract, 
nail, or hair follicle (which may be bacterial, fungal or viral)

A very severe infection of the blood, which may include a decrease in blood 
pressure

Inflammation of the lung passages

Thickening, inflammation, or scarring in the lungs which may cause 
breathlessness or cough

Inflammation of the bowel causing abdominal pain or diarrhea

Blockage of the intestine

Trouble swallowing

Indigestion or upset stomach

Abnormal chemistry or electrolyte blood test results

Abnormal kidney function test results


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
Acute kidney failure

Blood in the urine

Lack of muscle coordination

Muscle weakness

Anxiety

Nasal congestion

Mouth or throat pain

Dry mouth, nose, and throat

Coughing up blood or bloody sputum

Blood clot in the lungs or in deep vein

Fluid in the chest cavity

Red or flushed skin

Dry skin

Hand-foot syndrome, involving reddening, swelling, numbness, and peeling of 
palms and soles of feet

High blood pressure

Low blood pressure

A decrease in the heart’s ability to pump blood to all parts of the body and 
possibly heart failure

Faster heartbeat

Watery eyes

Changes in vision or blurry vision

Infusion site reactions (described as discomfort, bleeding or bruising/ swelling at 
the needle site, and in some instances infection or leaking of IV fluid outside of 
blood vessel into the surrounding tissue

Localized swelling due to buildup of lymph fluid
Uncommon Side Effects of Abraxane
(between a 0.1% to less than 1% chance that this will happen)

Irregular or slow heartbeat

Stopping of the heart

Allergic reaction (may include skin inflammation, rash, trouble breathing, trouble 
speaking, fever), sometimes fatal

Syndrome involving abnormal blood clotting with decreased platelets, bruising 
(including tiny red or purple spots under the skin), and possibly leading to blood 
clots

Edema/ swelling and cyst formation of the macular area of the retina.

Irritation and redness of the thin membrane covering the eye

Inflammation of the cornea 

Too much fluid in the body

Feeling unwell

Sleepiness

Scaly or peeling skin

Potentially life-threatening allergic reaction of the skin and oral mucous 
membranes (may include lesions in the mouth, itching and blistering skin.

Hives

A loss of nerve function in the muscles of the face 


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Additional side effects observed during post-marketing surveillance of abraxane, not 
otherwise noted above include:

Lack of movement in the vocal cords with possible voice changes

Skin sensitivity to sunlight

Potentially life-threatening allergic reaction (may include skin rash with skin 
blistering)

Skin or tissue damage from prior radiation therapy can become damaged again, 
when a person receives chemotherapy after having had radiation therapy. This is 
referred to as radiation recall and may involve redness, peeling, pain, and 
swelling. Skin changes have been noted to range from mild redness to tissue 
death. Radiation recall may also occur in the lungs and other internal organs.
Elderly Subjects  

In subjects 65 years old or older with metastatic breast cancer who received 
abraxane monotherapy, a higher incidence of nose bleed, diarrhea, dehydration 
(loss of water and minerals in the body), feeling tired or weak and swelling 
caused by fluid held in the tissues, especially of the ankles, feet, or fingers has 
been reported.
Abraxane in Combination with Gemcitabine

In subjects with metastatic pancreatic cancer, who received the combination of 
abraxane and gemcitabine, there may be an increase of blood infections. Contact 
your study doctor immediately if you develop a fever. Your study doctor will evaluate 
if your fever is an early sign of a serious infection, which may require treatment.

A particular lung illness, known as pneumonitis (thickening, inflammation, or scarring 
in the lungs with breathlessness or cough) appears to occur more often (4%) when 
the two drugs are given together. This lung illness requires early detection and 
treatment as it may be life-threatening or even fatal. Therefore, it is important that 
you promptly tell your study doctor if you have worsening shortness of breath, 
difficulty breathing, fever, or a dry cough (not productive), for further evaluation and 
possible treatment.

Acute renal or kidney failure and hemolytic uremic syndrome (a syndrome involving 
abnormal blood clotting, with decreased platelets, bruising including tiny red or 
purple spots under the skin, and possibly leading to blood clots) have been reported 
commonly and uncommonly, respectively, in combination of abraxane with 
gemcitabine.

A very rare condition known as Posterior Reversible Encephalopathy Syndrome that 
causes leaking of fluid outside of blood vessels has occurred when gemcitabine is 
given alone or in combination with other chemotherapy medications. Therefore, you 
should tell your doctor if you have one or more of the following symptoms: 
o
headache; 
o
abnormal shaking of the body; 
o
sleepiness; 
o
increased blood pressure; 
o
feeling confused; 


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o
abnormal vision including loss of vision; 
o
loss of muscle control or muscle weakness, numbness, or tingling in 
extremities.

A very rare condition known as Capillary Leak Syndrome that causes leaking of fluid 
outside of blood vessels has occurred when gemcitabine is given alone or in 
combination with other chemotherapy medications. Therefore, you should tell your 
study doctor if you have one or more of the following symptoms: 
o
fatigue; 
o
lightheadedness or fainting; 
o
pain in arms, legs, stomach, or all over body; 
o
swelling in face or body; difficulty breathing; low blood pressure.
Elderly Subjects

In subjects 65 years old or older, who received abraxane and gemcitabine, a higher 
incidence of diarrhea, decreased appetite, dehydration (loss of water and minerals in 
the body) and of nose bleed has been reported compared to subjects less than 65 
years old. 

In subjects 75 years old or older, a higher incidence of serious adverse reactions and 
adverse reactions leading to treatment discontinuation has been reported.
Risks of Having Blood Taken
In this study we will need to get about a half-cup of blood from you. We will get blood by 
putting a needle into one of your veins and letting the blood flow into a glass tube.  You may 
feel some pain when the needle goes into your vein.  A day or two later, you may have a 
small bruise where the needle went under the skin. 
Risk of Pregnancy
Females:
Abraxane can cause harm to an unborn child if it is given to a pregnant woman. You cannot 
take part in this study if you are pregnant or breast-feeding. Because of the possible risks to 
an unborn child, if you are a female who can become pregnant, you will be asked to take a 
pregnancy test prior to starting study drug treatment and throughout your study participation.
If you decide to take part in this study, you should avoid becoming pregnant while receiving 
study medication. You must commit to abstinence from heterosexual contact, or agree to 
use medical doctor-approved contraception throughout the study without interruption, while 
receiving study medication or for a longer period if required by local regulations. If you 
become pregnant while receiving study medication, you must tell the study doctor right 
away. If this happens, the study medication will be discontinued. The study doctor will follow 
you and your pregnancy to completion.
Males: 
If you have a partner of childbearing potential, you should avoid fathering a child while 
receiving study medication and for 6 months after your last dose of study medication. You 
must agree to complete abstinence from heterosexual contact or use a condom during 


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sexual contact with a female of childbearing potential while receiving study medication and 
within 6 months after your last dose of study medication. If your partner becomes pregnant 
while you are receiving study medication or within 6 months after you took your last dose of 
study medication, you must tell the study doctor right away.
The principal investigator may ask for your partner’s permission to collect information about 
the outcome of her pregnancy and the health of her baby.  You will be given a contact form 
to share with your partner. This form will allow her to reach out to the study team if she is 
interested in providing information about her pregnancy and the health of her baby.  By 
sharing the contact form with your partner, your partner will become aware of your 
participation in this study.
Risks of loss of confidentiality:
There is a risk that people outside of the research team will see your research information.  We 
will do all that we can to protect your information, but it cannot be guaranteed.
Other possible risks include:
While you take part in this study, you will have tests and procedures that are standard of care 
for your disease. These include CT scans, MRIs, endoscopic ultrasound (EUS) with diagnostic 
biopsy, and stereotactic body radiation therapy (SBRT). There are risks associated with these 
procedures. You should talk to your study doctor about any questions you may have about 
these risks.   
The study may include risks that are unknown at this time. 
What are the possible benefits of the study?
This study is designed for the researcher to learn more about pancreatic cancer.  However, 
there is no guarantee that your health will improve if you join this study.  Also, there could be 
risks to being in this study.  If there are risks, these are described in the section describing the 
discomforts or risks.
Are there alternative treatments? 
There may be other ways of treating your pancreatic cancer. Instead of taking part in this study:

You may choose to receive treatment with another experimental therapy

You may choose to receive treatment with another approved therapy

You may choose to receive comfort/palliative care

You could also choose to get no treatment at all
You should talk to your doctor about your choices.  Make sure you understand all of your 
choices before you decide to take part in this study.  You may leave this study and still have 
these other choices available to you. 


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Who is paying for this study? 
Celgene Corporation is providing a grant of funding support for this research. Celgene 
Corporation manufactures abraxane. Dr. Wells Messersmith is the Investigator-Sponsor of this 
study. The research study will only pay for procedures not considered standard of care. This 
may include a biopsy, if the most recent biopsy you had before you start the study (at screening) 
was obtained outside the time allowed for this study. If this is the case, a research biopsy may 
be required.
Will I be paid for being in the study?  
You will not be paid to be in the study. 
Will I have to pay for anything?
You and/or your health insurance may be billed for the costs of medical care during this study, if 
these expenses would have happened even if you were not in the study, or if your insurance 
agrees in advance to pay.  If you have health insurance, the cost of these services will be billed 
to your insurance company.  If your insurance does not cover these costs, or you do not have 
insurance, these costs will be your responsibility.
Is my participation voluntary?
Taking part in this study is voluntary.  You have the right to choose not to take part in this study.  
If you choose to take part, you have the right to stop at any time.  If you refuse or decide to 
withdraw later, you will not lose any benefits or rights to which you are entitled. 
If you leave this study, you will still receive your normal medical care.  The only medical care 
that you will lose is the medical care you are getting as part of this study.  You might be able to 
get that same kind of medical care outside of the study.  Ask your study doctor. 
 
If there are any new findings during the study that may affect whether you want to continue to 
take part, you will be told about them.
Can I be removed from this study?
The study doctor may decide to stop your participation without your permission if the study 
doctor thinks that being in the study may cause you harm, or for any other reason. Also, the 
sponsor may stop the study at any time.
What happens if I am injured or hurt during the study? 
If you have an injury while you are in this study, you should call Dr. Messersmith immediately.  
His phone number is 303-724-0747 (clinic hours) or 720-848-0300 (24 hours). 
We will arrange to get you medical care if you have an injury that is caused by this research.  
However, you or your insurance company will have to pay for that care. 


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Who do I call if I have questions?
The researcher carrying out this study is Wells A. Messersmith, MD. You may ask any 
questions you have now. If you have questions, concerns, or complaints later, you may call Dr. 
Messersmith at 303-724-0747 (clinic hours) or 720-848-0300 (24 hours). You will be given a 
copy of this form to keep.  
You may have questions about your rights as someone in this study. You can call Dr. 
Messersmith with questions.  You can also call the responsible Institutional Review Board 
(COMIRB).  You can call them at 303-724-1055. 
A description of this clinical trial will be available on http://www.clinicaltrials.gov as required by 
U.S. law. This Web site will not include information that can identify you. You can search this 
Web site at any time.
Who will see my research information?
The University of Colorado Denver (UCD) and its affiliated hospital(s) have rules to protect 
information about you.  Federal and state laws including the Health Insurance Portability and 
Accountability Act (HIPAA) also protect your privacy.   This part of the consent form tells you 
what information about you may be collected in this study and who might see or use it.  
The institutions involved in this study include: 

University of Colorado Denver

University of Colorado Hospital
We cannot do this study without your permission to see, use and give out your information.  You 
do not have to give us this permission.  If you do not, then you may not join this study.  
We will see, use and disclose your information only as described in this form and in our Notice 
of Privacy Practices; however, people outside the UCD and its affiliate hospitals may not be 
covered by this obligation.
We will do everything we can to maintain the confidentiality of your personal information but 
confidentiality cannot be guaranteed. 
The use and disclosure of your information has no time limit.  You can cancel your permission to 
use and disclose your information at any time by writing to the study’s Principal Investigator (PI), 
at the name and address listed below.  If you do cancel your permission to use and disclose 
your information, your part in this study will end and no further information about you will be 
collected.  Your cancellation would not affect information already collected in this study.  
Wells A. Messersmith, MD
University of Colorado Cancer Center
12801 E. 17th Ave, RC-1 South, Room 8121
Mail Stop 8117
Aurora, Colorado 80045
Both the research records that identify you and the consent form signed by you may be looked 
at by others who have a legal right to see that information, such as:  


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
Federal offices such as the Food and Drug Administration (FDA) and the Office of 
Human Research Protections (OHRP) that protect research subjects like you

People at the Colorado Multiple Institutional Review Board (COMIRB)

The study doctor and the rest of the study team

Celgene Corporation, who is the manufacturer of abraxane and the company 
providing a grant of funding support.

Academic Gastrointestinal Cancer Consortium (AGICC)

Officials at the institution where the research is conducted and officials at other 
institutions involved in this study who are in charge of making sure that we follow all 
of the rules for research
We might talk about this research study at meetings.  We might also print the results of this 
research study in relevant journals.  But we will always keep the names of the research 
subjects, like you, private. 
You have the right to request access to your personal health information from the Investigator. 
The investigator (or staff acting on behalf of the investigator) will use your information 
for the research outlined in this consent form. They will also make all or some of the 
following health information about you collected in this study available to:  

Criterium, Inc., a Contract Research Organization who is assisting with the 
management and monitoring of this study

Other participating sites including: 
o
Harvard Cancer Center
o
Mayo Clinic - Arizona
o
New York University
o
University of Arizona
o
University of Kansas
Information about you that will be seen, collected, used and disclosed in this study:

Name and Demographic Information (age, sex, ethnicity, address, phone number, 
etc.).

Your social security number

Portions of your previous and current Medical Records that are relevant to this study, 
including but not limited to Diagnosis(es), History and Physical, laboratory or tumor 
tissue studies, radiology studies, procedure results

Research Visit and Research Test records

Tumor Tissue samples and the data with the samples. 

Billing or financial information


Consent and Authorization Form
COMIRB: 15-0150
PI:  Messersmith
Version Date:  01/04/2021
Page 23 of 24
What happens to Data, Tumor Tissue, Blood and Specimens that are collected in 
this study? 
Scientists at the University of Colorado Denver and the hospitals involved in this study work to 
find the causes and cures of disease.  The data, tumor tissue, blood and specimens collected 
from you during this study are important to this study.  If you join this study:

The data, tumor tissue, blood, or other specimens given by you to the investigators 
for this research no longer belong to you.  

Both the investigators and Celgene Corporation may study your data, tumor tissue, 
blood, or other specimens collected from you.

If data, tumor tissue, blood, or other specimens are in a form that identifies you, UCD 
or the hospitals involved in this study may use them for future research only with 
your consent or Institutional Review Board (IRB) approval.

Any product or idea created by the researchers working on this study will not belong 
to you.

There is no plan for you to receive any financial benefit from the creation, use or sale 
of such a product or idea. 
[SIGNATURES ON NEXT PAGE]


Consent and Authorization Form
COMIRB: 15-0150
PI:  Messersmith
Version Date:  01/04/2021
Page 24 of 24
Agreement to be in this study and use my data
I have read this paper about the study or it was read to me.  I understand the possible risks and 
benefits of this study.  I understand and authorize the access, use and disclosure of my 
information as stated in this form.  I know that being in this study is voluntary.  I choose to be in 
this study. I will get a signed and dated copy of this consent form.
Signature: 
Date: 
Print Name: 
Consent form explained by: 
Date: 
Print Name: 
Witness Signature: 
Date: _________
Witness Print Name: 
Witness of Subject Signature

Witness of Consent Process
