Clinical trial NCT02318095
Conditions: Resectable Pancreatic Cancers
Keywords: Cancer of the pancreas
Sponsor: Duke University
Start date: 2015-02-17; Completion date: 2022-11-14
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research protocol will evaluate the feasibility of administering neoadjuvant gemcitabine and nab-paclitaxel with hypofractionated, image guided, intensity modulated radiotherapy (HIGRT) in resectable and borderline resectable pancreatic cancer

Detailed description:
Pancreatic cancer is the fourth leading cause of cancer-related death in the United States and accounts for roughly 40,000 deaths each year. Despite the use of neoadjuvant and adjuvant therapies, little progress has been made in the the last three decades, and the search for more efficacious treatment continues.In patients with a good performance status the combination of effective systemic therapy with gemcitabine/nab-paclitaxel and high dose local radiotherapy may improve disease outcomes. This is a prospective, single arm study in patients in newly diagnosed, previously untreated pancreatic cancer who are planned to undergo surgical resection The primary objective of this study is to evaluate the toxicity of a neoadjuvant approach incorporating gemcitabine/nab-paclitaxel and Hypofractionated image guided intensity-modulated radiotherapy (HIGRT) prior to surgical resection. Eligible subjects will recieve standard neoadjuvant gemcitabine and nab-paclitaxel dosing is as follows:Nab-Paclitaxel (125mg/m2) days 1,8,15 every 28 days for 2 cycles Gemcitabine (1000mg/m2) days 1,8,15 every 28 days for 2 cycles followed by HIGRT and surgical resection.

Adjuvant chemotherapy may be given post surgery at the discretion of the treating medical oncologist.

Arms: arm 1: This is a single arm prospective study. All eligible subjects will recieve 2 cycles of neoadjuvant Gemcitabine/nab-Paclitaxel, followed by hypofractionated radiation therapy followed by surgical resection. Subjects may receive adjuvant chemotherapy post surgical resection at the clinical discretion of the medical oncologist.
Interventions: intervention 1: Gemcitabine/nab-Paclitaxel intervention 2: Radiation therapy intervention 3: Sugical resection intervention 4: Adjuvant chemotheapy
Intervention descriptions: intervention 1: Prospective, single arm study ; eligible subjects will recieve 2 cycles of neoadjuvant Gemcitabine/nab-Paclitaxel. All chemotherapy administered to study subjects is standard of care. The chemotherapy combination, gemcitabine/nab-paclitaxel, is considered to be a standard-of-care, non-investigational chemotherapy combination; chemotherapy dosing and treatment schedule will be managed by the treating medical oncologist. Restaging will be completed post chemotherapy. intervention 2: 5 fractions of hypofractionated IGRT or IMRT at 5Gy per fraction will be delivered before surgery. Restaging will be completed post radiation therapy. intervention 3: Surgical resection of the pancreas post radiation therapy intervention 4: Adjuvant chemotherapy may be given after surgery at the clinical discretion of the medical oncologist

Protocol documents:
Prot_SAP_000.pdf: 
Feasibility Study of Neoadjuvant Gemcitabine/nab-Paclitaxel and Hypofractionated 
Image-Guided Intensity Modulated Radiotherapy in Resectable and Borderline 
Resectable Pancreatic Cancer 
 
NCT02318095 
Version Date: May 6, 2019 
 
 
 
 
Sponsor: 
PI – Duke Cancer Institute 
 
 
Funding Source: 
Departmental Support 
 
 
Protocol Source: 
PI - Duke Cancer Institute 
 
 
Duke IRB#: 
Pro00058865 
 
 
IND#:(if required) 
000000 
 
Principal Investigator 
Manisha Palta, M.D. 
DUMC 3085 
Durham, NC 27710 
(919) 668-5640 
manisha.palta@dm.duke.edu  
 
Co- Investigators 
Brian Czito, M.D. 
brian.czito@dm.duke.edu 
 
Christopher Willett, M.D. 
christopher.willett@dm.duke.edu 
 
Collaborators 
James Abbruzzese, M.D. (medical oncologist) 
james.abbruzzese@dm.duke.edu 
 
Xuefeng Zhang, M.D. (Pathology) 
xuefeng.zhang@dm.duke.edu 
 
Dan Trey Blazer (Surgical Oncology) 
trey.blazer@duke.edu 
 
 
 
 
 
 


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1 Table of Contents 
2 
LIST OF ABBREVIATIONS ....................................................................................................................... 6 
3 
PROTOCOL SYNOPSIS AND RESEARCH SUMMARY ............................................................................... 8 
3.1 
Purpose ......................................................................................................................................... 8 
3.2 
Background and Significance ........................................................................................................ 8 
3.3 
Design and Procedure ................................................................................................................. 10 
3.4 
Selection of Subjects ................................................................................................................... 10 
3.5 
Duration of study ........................................................................................................................ 10 
3.6 
Data Analysis and Statistical Considerations .............................................................................. 10 
4 
INTRODUCTION ................................................................................................................................... 10 
4.1 
Study Disease .............................................................................................................................. 10 
4.2 
Radiation Therapy ....................................................................................................................... 10 
4.2.1 
Clinical experience .............................................................................................................. 11 
4.2.2 
Study Drug ........................................................................................................................... 12 
4.2.3 
Pre-clinical and clinical experience of study drug alone ..................................................... 12 
4.2.4 
Clinical experience with combination of study drug and radiation therapy ...................... 12 
4.3 
Study Purpose/Rationale ............................................................................................................ 12 
5 
OBJECTIVES AND ENDPOINTS ............................................................................................................. 12 
6 
STUDY SCHEMA ................................................................................................................................... 15 
7 
SUBJECT ELIGIBILITY ............................................................................................................................ 15 
7.1 
Inclusion Criteria ......................................................................................................................... 15 
7.2 
Exclusion Criteria ......................................................................................................................... 15 
8 
INVESTIGATIONAL PLAN ..................................................................................................................... 16 
8.1 
Study Design................................................................................................................................ 16 
8.1.1 
Dose Escalation ................................................................................................................... 16 
8.1.2 
Definition of Dose-Limiting Toxicity (DLT) .......................................................................... 16 
8.1.3 
Dose Modification ............................................................................................................... 16 
8.1.4 
Safety Considerations ......................................................................................................... 17 
8.1.5 
Treatment Interruptions during RT ..................................................................................... 17 
8.1.6 
Concomitant Medications/Therapies ................................................................................. 17 
8.2 
Rationale for Selection of Dose, Regimen, and Treatment Duration ......................................... 18 


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8.3 
Rationale for Correlative Studies ................................................................................................ 18 
8.4 
Definition of Evaluable Subjects, On Study, and End of Study ................................................... 18 
8.5 
Early Study Termination .............................................................................................................. 18 
9 
RADIATION THERAPY .......................................................................................................................... 18 
9.1 
Type, Classification, Location, and Short Description ................................................................. 18 
9.2 
Equipment ................................................................................................................................... 18 
9.3 
Dose Specifications ..................................................................................................................... 18 
9.4 
Localization, Simulation, and Immobilization ............................................................................. 18 
9.5 
Imaging ........................................................................................................................................ 18 
9.6 
Treatment Planning/Target Volumes ......................................................................................... 19 
9.7 
Dose Limitations for Normal Tissue ............................................................................................ 19 
9.8 
Treatment Verification ................................................................................................................ 19 
9.9 
Quality Assurance of Dose Distribution ...................................................................................... 19 
10 
STUDY DRUG ................................................................................................................................... 19 
11 
PATIENT ASSESSMENTS................................................................................................................... 19 
11.1 
Pretreatment Evaluations/Management .................................................................................... 20 
11.2 
Screening Examination ................................................................................................................ 21 
11.3 
Treatment Period ........................................................................................................................ 21 
11.4 
End of Treatment ........................................................................................................................ 21 
11.5 
Follow-up Period ......................................................................................................................... 21 
11.6 
End of Study ................................................................................................................................ 21 
11.7 
Early Withdrawal of Subject(s) .................................................................................................... 21 
11.7.1 
Criteria for Early Withdrawal .............................................................................................. 21 
11.7.2 
Follow-up Requirements for Early Withdrawal .................................................................. 22 
11.7.3 
Replacement of Early Withdrawal(s) .................................................................................. 22 
11.8 
Study Assessments ...................................................................................................................... 22 
11.8.1 
Medical History ................................................................................................................... 22 
11.8.2 
Physical Exam ...................................................................................................................... 22 
11.8.3 
Correlative Assessment ....................................................................................................... 22 
12 
SAFETY MONITORING AND REPORTING ......................................................................................... 22 
12.1 
Adverse Events ............................................................................................................................ 22 
12.1.1 
AEs of Special Interest ......................................................................................................... 23 


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12.1.2 
Reporting of AEs .................................................................................................................. 23 
12.2 
Serious Adverse Events ............................................................................................................... 23 
12.2.1 
Reporting of SAEs ................................................................................................................ 23 
12.3 
Other Reportable Information .................................................................................................... 23 
12.4 
Special Warnings and Precautions .............................................................................................. 23 
12.5 
Safety Oversight Committee (SOC) ............................................................................................. 24 
12.6 
External Data and Safety Monitoring Board (DSMB) .................................................................. 24 
13 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................................................. 24 
13.1 
Monitoring .................................................................................................................................. 24 
13.2 
Audits .......................................................................................................................................... 24 
13.3 
Data Management and Processing ............................................................................................. 25 
13.3.1 
Study Documentation ......................................................................................................... 25 
13.3.2 
Case Report Forms (CRFs) ................................................................................................... 25 
13.3.3 
Data Management Procedures and Data Verification ........................................................ 25 
13.3.4 
Coding ................................................................................................................................. 26 
13.3.5 
Study Closure ...................................................................................................................... 26 
14 
STATISTICAL METHODS AND DATA ANALYSIS ................................................................................ 26 
14.1 
Analysis Sets ................................................................................... Error! Bookmark not defined. 
14.2 
Patient Demographics and Other Baseline Characteristics ........... Error! Bookmark not defined. 
14.3 
Treatments ..................................................................................... Error! Bookmark not defined. 
14.4 
Primary Objective........................................................................... Error! Bookmark not defined. 
14.4.1 
Variable .................................................................................. Error! Bookmark not defined. 
14.4.2 
Statistical Hypothesis, Model, and Method of Analysis ......... Error! Bookmark not defined. 
14.4.3 
Handling of missing values, censoring, and discontinuations Error! Bookmark not defined. 
14.5 
Secondary Objectives ..................................................................... Error! Bookmark not defined. 
14.5.1 
Key Secondary Objective ........................................................ Error! Bookmark not defined. 
14.5.2 
Other Secondary Objectives .................................................. Error! Bookmark not defined. 
14.6 
Exploratory Objectives ................................................................... Error! Bookmark not defined. 
14.6.1 
Key Exploratory Objective ...................................................... Error! Bookmark not defined. 
14.6.2 
Other Exploratory Objectives ................................................. Error! Bookmark not defined. 
14.7 
Sample Size Calculation ................................................................. Error! Bookmark not defined. 
15 
ADMINISTRATIVE AND ETHICAL CONSIDERATIONS ........................................................................ 28 


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15.1 
Regulatory and Ethical Compliance ............................................................................................ 28 
15.2 
DUHS Institutional Review Board and DCI Cancer Protocol Committee .................................... 28 
15.3 
Informed Consent ....................................................................................................................... 28 
15.4 
Study Documentation ................................................................................................................. 28 
15.5 
Privacy, Confidentiality, and Data Storage ................................................................................. 29 
15.6 
Data and Safety Monitoring ........................................................................................................ 30 
15.7 
Protocol Amendments ................................................................................................................ 30 
15.8 
Records Retention ....................................................................................................................... 30 
15.9 
Conflict of Interest ...................................................................................................................... 30 
15.10 
Registration Procedure ........................................................................................................... 30 
16 
REFERENCES .................................................................................................................................... 31 
 
 
 
 


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2. LIST OF ABBREVIATIONS 
Use this list as a starting point for abbreviations used in your protocol. 
 
3D                  
3 Dimensional 
5-FU              5 fluoro-uracil 
AE                 Adverse events 
ANC              Absolute Neutrophil Count 
AP/PA           Anterior to Posterior, Posterior to Anterior 
APC               Argon Plasma Coagulation 
BED               Biologically Equivalent Dose 
BID                Twice Daily 
CBC               Complete Blood Count 
CBCT            Cone Beam Computed Tomography 
CDDP            Cisplatin 
Chemo           
Chemotherapy 
CPC               Cancer Protocol Committee 
CRT              Chemoradiotherapy 
CT                Computed Tomography 
CTCAE        Common Terminology Criteria for Adverse Events 
CTEP           Cancer Therapy Evaluation Program 
CTV             Clinical Tumor Volume 
D10cc           Minimum dose to the 10 milliliters of any volume receiving the highest dose 
D2cc             Minimum dose to the 2 milliliters of any volume receiving the highest dose 
DCI              Duke Cancer Institute 
DLT             Dose Limiting Toxicity 
Dmax            Maximum dose to any voxel within a volume 
DUHS           Duke University Health System 
ECOG           Eastern Cooperative Oncology Group 
EFRT            Extended Field Radiotherapy 
EQD2           Equivalent dose at 2 Gray per fraction 
FIGO            International Federation of Gynecology and Obstetrics 
G3 or G4      Grade 3 or Grade 4 toxicity 
GCP              Good Clinical Practice 
GOG             Gynecologic Oncology Group 
GTV             Gross Tumor Volume 
GU               Genitourinary 
GY               Gray 
HDR            High Dose Rate 
ICRU            International Commission on Radiation Units and Measurement 
ID                 Identification  
IMRT           Intensity Modulated Radiation Therapy (including Volumetric Modulated Arc Therapy) 
IRB              Institutional Review Board 
KPS             Karnofsky Performance Scale 
kVOBI 
      Kilovoltage on-board imaging 
LDR             Low Dose Rate 
LINAC         Linear Accelerator 
LRC             Loco-regional control 
MRI             Magnetic Resonance Imaging. 


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MTD            Maximum Tolerated Dose 
MV              Megavoltage 
NCI             National Cancer Institute 
OS               Overall Survival 
PA               Para-aortic 
PET             Positron Emission Tomography 
PI                Primary Investigator 
PTV            Planning Target Volume 
RTOG         Radiation Therapy Oncology Group 
SOC            Safety Oversight Committee 
TD5/5         Toxic dose of 5% at 5 years 
V18             Partial volume receiving greater than or equal to 18 Gray 
WAI            Whole abdominal irradiation 
WPRT         Whole Pelvic Radiotherapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3. PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
 
3.1 
Purpose 
This research protocol will evaluate the feasibility and acute toxicity of administering neoadjuvant 
gemcitabine and nab-paclitaxel with hypofractionated, image guided, intensity modulated 
radiotherapy (HIGRT) in resectable and borderline resectable pancreatic cancer.  
 
Primary Objective 
To determine if neoadjuvant gemcitabine/nab-paclitaxel and HIGRT is feasible in patients with 
potentially resectable pancreatic cancer and associated with Grade 3+ acute non-hematologic 
toxicity rate of <50% (excluding fatigue and alopecia).  
 
Secondary Objectives 
1. To evaluate grade ≥2 acute toxicity  
2. To assess number of patients who undergo surgical resection 
3. To assess R0 resection rate 
 
Exploratory Objectives 
1. To assess perioperative surgical complications (i.e. wound complications/infections, delayed 
gastric emptying, pancreatic leak, estimated blood loss, operative times)  
2. To assess for late toxicity (greater than 6 month post neoadjuvant therapy) 
3. To evaluate locoregional control and rate of distant metastasis  
4. To evaluate median progression free survival (PFS) 
5. To evaluate median overall survival (OS) 
6. To evaluate pathologic complete response (pCR) and percentage of viable tumor in surgical 
specimen with this neoadjuvant regimen  
7. To evaluate radiographic response after receipt of neoadjuvant gemcitabine/nab-paclitaxel and 
HIGRT  
8. To explore the effects of this neoadjuvant regimen on markers of tumor perfusion and hypoxia 
9.  To evaluate cross-sectional measurements of muscle, visceral fat and subcutaneous fat at a 
consistent L3 vertebral body level on pre-treatment and follow-up scans to assess for patterns 
that predict mortality. 
 
 
Hypotheses 
1. The administration of neoadjuvant gemcitabine/nab-paclitaxel and HIGRT will be feasible and 
associated with <50% rate of grade 3+ acute non-hematologic toxicity (excluding fatigue and 
alopecia). The secondary and exploratory objectives are hypothesis-generating and to power future 
prospective trials in this area of study.  
 
3.2 
Background and Significance 
Pancreatic cancer is the fourth leading cause of cancer-related death in the United States and accounts 
for roughly 40,000 deaths each year. 1 Patients generally present with locally advanced or metastatic 
disease that precludes cure since symptoms frequently prompt the diagnosis in the absence of effective 
screening strategies. Even among patients who present with localized disease, the 5-year overall survival 
(OS) is approximately 20%, but potentially higher in patients with complete surgical resection (R0) and 
uninvolved lymph nodes. 2, 3 Local and/or distant recurrence is common following resection, highlighting 
the importance of adjuvant therapy. 4, 5 Despite the use of neoadjuvant and adjuvant therapies, little 


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progress has been made in the last three decades, and the search for more efficacious treatment 
continues.6 
In 2011, published results of a randomized control trial compared a multi-drug regimen of 5-fluorouracil 
(5-FU), leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) to gemcitabine. Three hundred forty two 
patients < 76 years old with ECOG performance status of 0 or 1 were randomized with primary endpoint 
of overall survival. Median survival in the FOLFIRNOX group was 11.1 months compared to 6.8 months in 
the gemcitabine group. Objective tumor response was observed in nearly 30% of patients receiving 
FOLFIRINOX. Quality of life was also improved in the FOLFIRINOX arm despite higher rates of Grade 3 or 
4 adverse events. 7 These median survival results are comparable to survival amongst patients with 
locally advanced, non-metastatic pancreatic cancer. 8-10 
Given the encouraging results of FOLFIRINOX in the metastatic setting, a number of single institution 
retrospective series have demonstrated reasonable toxicity rates and R0 resections in patients with 
borderline and locally advanced pancreatic tumors typically treated with a modified FOLFIRINOX 
regimen. 11-14 In a series from Pittsburgh of 25 patients (13 unresectable and 12 borderline resectable), 
33% of patients went to surgery after FOLFIRINOX and 5 patients had a significant pathologic response. 
14 At Massachusetts General, 22 patients with locally advanced pancreatic cancer received FOLFIRINOX. 
The objective response rate was 30% (in line with the randomized data) and 5 patients were able to 
undergo R0 resection after combination FOLFIRINOX and chemoradiotherapy (CRT). 13 
Some major concerns regarding the neoadjuvant administration of FOLFIRINOX are the associated 
toxicities. These have prompted many clinicians to deliver a modified FOLFIRINOX regimen, however, no 
standardization of dose modifications exist. Also unclear is how these drug/dose modifications affect the 
chemotherapeutic efficacy. In addition, the generalizability of this regimen to pancreatic cancer patients 
who are typically older and of poorer performance status makes this regimen less ideal. Given liver 
function inclusion criteria, the breakdown of pancreatic tumor location does not represent the majority 
of patients who present with pancreatic head lesions.  
In addition to FOLFIRINOX, a randomized control trial demonstrated the superiority of combination 
gemcitabine with nab-paclitaxel compared to gemcitabine alone in patients with metastatic pancreatic 
cancer. This study of 861 patients with Karnofsky performance status score of 70 or more randomized 
patients to nab-paclitaxel (125mg/m2) followed by gemcitabine (1000mg/m2) days 1,8,15 every 4 weeks 
or gemcitabine monotherapy. The median overall survival was 8.5 months in the nab-
paclitaxel/gemcitabine group compared with 6.7 months in the gemcitabine group (HR 0.72). The 
combination of gemcitabine/nab-paclitaxel resulted in reasonable toxicity profile with the most 
common adverse side effects of neutropenia/leukopenia, alopecia, nausea/diarrhea, fatigue and 
neuropathy. 15 
This trial had no age exclusion and more borderline performance status patients were enrolled 
compared to studies utilizing FOLFIRINOX, potentially making a regimen of gemcitabine/nab-paclitaxel 
more generalizable to newly diagnosed pancreatic cancer patients. Given the modest toxicity, the 
backbone of gemcitabine and nab-paclitaxel is felt to be ideal for the incorporation of additional or 
novel systemic agents.  
Coinciding with alternative chemotherapy regimens to improve outcomes in pancreatic cancer patients, 
radiotherapy techniques to treat this patient group have evolved. High dose, image guided radiotherapy 
(HIGRT also called stereotactic body radiotherapy [SBRT] when a coordinate system is implemented) 
utilizes rigid patient immobilization and image guidance in an effort to deliver high doses of 
radiotherapy in a small number of fractions. Prospective data of SBRT in the subgroup of locally 
advanced, unresectable patients generally indicates high rates of freedom from local progression with 
reasonable acute and late toxicity with a variety of dose fractionation regimens. 16-18 A large 
retrospective study included patients with locally advanced and borderline resectable cancers again 
demonstrating high rates of local control with reasonable acute and late toxicities.18 One single 


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institution, prospective study of SBRT has been performed to date in patients with resectable disease. 
Fifteen patients with resectable pancreatic cancer were treated on a Phase I dose escalation study with 
hypofractionated proton beam therapy with concurrent capecitabine. The dose used was 5 Gy per 
fraction x5 fractions.  Eleven patients went on to surgery (progression of disease in those who did not go 
to surgery) with no associated perioperative complications. Pathologic assessment demonstrated 
significant fibrosis- 75% fibrosis as opposed to viable tumor. 19 
Given the high rates of both local and distant failure in potentially resectable pancreatic cancer patients, 
a combination of effective systemic therapy and local therapy is needed. In patients with a good 
performance status the combination of effective systemic therapy with gemcitabine/nab-paclitaxel and 
high dose local radiotherapy may improve disease outcomes. The primary objective of this study is to 
evaluate the toxicity of a neoadjuvant approach incorporating gemcitabine/nab-paclitaxel and HIGRT 
prior to surgical resection.  
 
3.3 
Design and Procedure 
Prospective, single arm study in patients in newly diagnosed, previously untreated pancreatic cancer 
who are planned to undergo surgical resection 
 
3.4 
Selection of Subjects  
Patients potentially eligible for study enrollment will be identified in the Radiation Oncology and GI 
oncology clinics. The treating radiation oncologist, medical oncologist or surgical oncologist (or their 
extenders) will introduce the study to patients and if the patient is interested he/she will meet with one 
of our clinical trials nurses for further details and consent.  
 
3.5 
Duration of Study 
Patients will be on study therapy for approximately 6 months. The end of study participation will be 
60 days post surgery. Thereafter patients will continue to be followed by the treating medical oncologist 
and/or radiation oncologist as per standard of care for follow up care. 
 
3.6 
Data Analysis and Statistical Considerations  
   Please see section 14 below for this information 
 
4.  INTRODUCTION 
4.1 
Study Disease 
See Background and Significance section  
 
4.2 
Radiation Therapy 
Simulation: Patients will undergo CT and/or MRI simulation utilizing customized immobilization. If 
patient is able to tolerate, respiratory motion management will be implemented (i.e. breath-holding 
technique, abdominal compression). Administration of IV and oral contrast is preferred for target and 
normal tissue delineation but at the discretion of the treating physician. A pretreatment renal scan to 
assess kidney differential may be performed at the discretion of the treating physician prior to initiation 
of treatment.  
Treatment planning:  
Gross Tumor Volume (GTV): tumor volume will be defined on the basis of endoscopic procedures, CT, 
and/or MRI imaging.  
Clinical Target Volume (CTV):  
The CTV should include the primary tumor and involved nodal areas with margin for microscopic disease 
extension. Additionally the following nodal regions are suggested based on tumor location as follows:  


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Pancreatic head: peri-pancreatic, para-aortic (celiac/SMA) 
Pancreatic body: peri-pancreatic, para-aortic (celiac/SMA)  
Pancreatic tail: peri-pancreatic, para-aortic (celiac/SMA) and splenic hilum 
Portal and pancreaticoduodenal lymph nodes will not routinely be included unless concern for gross 
disease in this region. For the para-aortic nodes the most proximal 1-1.5cm of the celiac axis and 
proximal 2.5-3cm of the SMA from the take-off of the aorta should be contoured. These contours should 
be expanded by 1-1.5cm for the CTV.   
Planning Target Volume (PTV): per treating physician discretion but typically CTV +0.5-1cm.  
The following normal tissues will be contoured: Liver, stomach, duodenum, small bowel (peritoneal 
space (bowel bag), rather than bowel loops), right kidney, left kidney, and spinal cord.  
Treatment Planning and Delivery:  
Normal Tissue Constraints: At the discretion of the treating physician, however, the following 
constraints/prioritizations are recommended:  
PTV
95% PTV covered by 95% Rx dose
Kidney
70% one kidney less than 15Gy
Liver
70%<24Gy
Spinal Cord
20Gy max
Small bowel
25Gy max
Duodenum
25Gy max
Stomach
25Gy max
 
3D conformal, IMRT or volumetric arc therapy (VMAT) are all permissible techniques for treatment 
delivery.  
Dose: A dose of 5Gy x 5 fractions= 25Gy in total will be administered to the PTV.  
Ideally, treatment will be delivered over 5 consecutive days for 5 total treatments. Treatment must be 
completed within a 10 day time period (inclusive of weekends/holidays).  
Prior to each fraction of treatment, image guidance will be utilized to confirm positioning. kVOBI and 
cone beam CT (CBCT) will be utilized.  Patients will be assessed weekly during radiation therapy as per 
standard of care.  
 
4.2.1 
Clinical experience  
HIGRT, also called stereotactic body radiotherapy [SBRT], when a coordinate system is implemented) 
utilizes rigid patient immobilization and image guidance in an effort to deliver high doses of 
radiotherapy in a small number of fractions. This was first implemented in the treatment of brain 
metastases and there are now data for treatment of a variety of extracranial sites. Prospective data of 
HIGRT in the subgroup of locally advanced, unresectable pancreatic patients generally indicates high 
rates of freedom from local progression with reasonable acute and late toxicity with a variety of high 
dose fractionation regimens. 16-18 A large retrospective study included patients with locally advanced and 
borderline resectable cancers again demonstrating high rates of local control with reasonable acute and 
late toxicities. 19 One single institution, prospective study of SBRT has been performed to date in 
patients with resectable disease. Fifteen patients with resectable pancreatic cancer were treated on a 
Phase I dose escalation study with hypofractionated proton beam therapy with concurrent capecitabine. 
Eleven patients went on to surgery (progression of disease in those who did not go to surgery) with no 
associated perioperative complications.19  
 


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4.2.2 
Study Drug 
There is no investigational study drug. All chemotherapy administered to study subjects is standard of 
care. 
4.2.3 
Pre-clinical and clinical experience of study drug alone 
Not applicable (please see above).  
 
4.2.4 
Clinical experience with combination of study drug and radiation therapy 
Not applicable (please see above).  
 
4.3 
Study Purpose/Rationale 
Given the high rates of both local and distant failure in potentially resectable pancreatic cancer patients 
a combination of effective systemic therapy and local therapy is needed. In patients with a good 
performance status the combination of effective systemic therapy with gemcitabine/nab-paclitaxel and 
high dose local radiotherapy may improve disease outcomes. 
 
Chemotherapy 
Standard neoadjuvant gemcitabine and nab-paclitaxel dosing is as follows: 
Nab-Paclitaxel (125mg/m2) days 1,8,15 every 28 days for 2 cycles 
Gemcitabine (1000mg/m2) days 1,8,15 every 28 days for 2 cycles  
Starting dose of gemcitabine/nab-paclitaxel may be modified per treating physician discretion. Cycles 
are repeated every 4 weeks and therapy will be administered for a maximum of 2 cycles. Adjustments to 
dosing schedules and/ or dose modifications may be determined by the treating physician’s clinical 
assessment. Gemcitabine/nab-paclitaxel will be commercially supplied. 
 
Chemotherapy Agents 
In this study, there is no investigational medicinal product. The chemotherapy combination, 
gemcitabine/nab-paclitaxel, is considered to be a standard-of-care, non-investigational combination 
medicinal product. The components of gemcitabine/nab-paclitaxel will be obtained from standard 
commercial sources and stored, formulated, and administered according to institutional standards and 
the respective product package inserts, when applicable.  
Pre-medications (anti-emetics, hydration, antihistamines, corticosteroids, etc.), dosage, and 
administration for chemotherapy should be according to institutional standards and the respective 
product package insert(s), when applicable. 
 
5. OBJECTIVES AND ENDPOINTS 
Objective
Endpoint
Analysis
Primary
To determine if
neoadjuvant 
gemcitabine/nab-paclitaxel 
and hypofractionated 
image guided intensity-
modulated radiotherapy 
(HIGRT) is feasible in 
patients with potentially 
resectable pancreatic 
cancer. 
The neoadjuvant regimen will be 
considered feasible if (a) the trial can 
accrue 25 patients in no more than 3 
years, (b) if at least 17 of the 25 
patients adhere to the neoadjuvant 
regimen, and (c) the acute grade 3+ 
non-hematologic acute toxicity is 
less than 50% (excluding fatigue and 
alopecia) 
 
See Section 3.6
Key Secondary
1. To evaluate grade ≥2
acute toxicity  
1. CTCAE version 4 will be used 
for all toxicity assessments. The 
See Section 3.6


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2. To assess resection rate 
 
 
3. To assess R0 resection 
rate 
acute toxicity rate, defined as any 
non-hematologic grade 2+ 
toxicity occurring during HIGRT 
treatment through 60 days post-
treatment, will be estimated with 
its exact 80% confidence interval. 
Likewise, we will determine the 
rate of grade 2+ hematologic 
toxicity occurring during 
treatment through 60 days post 
treatment and the proportion of 
patients requiring treatment 
breaks longer than 5 days.   
 
 
2. Patients who undergo surgical 
resection will be documented 
 
3. Pathologic review will 
determine if an R0 resection has 
been performed.  
  
Exploratory
1. To assess perioperative 
surgical complication 
rates (i.e. wound 
complications/infections, 
delayed gastric 
emptying, pancreatic 
leak, estimate blood 
loss, operative time) 
 
2. To assess late toxicity 
with this neoadjuvant 
regimen  
 
 
 
 
3. To evaluate local control 
and rate of distant 
metastasis with this 
neoadjuvant regimen  
 
4. To evaluate median 
progression free survival 
(PFS) 
 
 
1. Perioperative surgical 
complications (within 60 days 
post surgery) will be recorded. 
 
 
 
 
 
2. CTCAE version 4 will be used to 
assess late grade 3+ non-
hematologic toxicity or Grade 4+ 
hematologic toxicity occurring 6 
months or more after the 
completion of neoadjuvant 
therapy.  
 
3. Local control and distant 
metastasis rate will be assessed 
at standard of care follow up 
appointments 
 
4. Disease progression will be 
assessed at standard of care 
follow up appointments 
 
 
See Section 3.6


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5. To evaluate median 
overall survival with this 
neoadjuvant regimen 
 
6. To evaluate pathologic 
complete response 
(pCR), percentage of 
viable tumor, percent 
fibrosis and histologic 
grading of treatment 
response in surgical 
specimen with this 
neoadjuvant regimen 
compared to historical 
control rates with 
chemoradiation (CRT) 
alone and neoadjuvant 
SBRT.  
 
7. To evaluate 
radiographic response 
after receipt of 
neoadjuvant 
gemcitabine/nab-
paclitaxel and HIGRT in 
the neoadjuvant setting
 
8. To explore the effects 
of this neoadjuvant 
regimen on markers of 
tumor perfusion and 
hypoxia 
 
 
9. To evaluate cross-
sectional area 
measurements of 
muscle, visceral fat and 
subcutaneous fat at a 
consistent L3 vertebral 
body level on pre-
treatment and follow-
up scans to attempt to 
assess for patterns that 
predict mortality. 
 
5. Death (due to any cause will be 
recorded).  
 
 
6. Response will be assessed at 
the time of pathologic review and 
appropriate data collected.  
 
 
 
 
 
 
 
 
 
 
 
 
7. Radiographic response will be 
assessed by tumor 
measurements 
 
 
 
 
 
8. Blood and urine will be 
obtained at baseline, prior to 
HIGRT, after HIGRT, and 
postoperatively. Urine will be 
collected in order to measure 
isoprostanes. 
 
9. Cross sectional measurements 
will be obtained using existing 
staging CT scans. 
 


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6 STUDY SCHEMA 
 
 
 
7 SUBJECT ELIGIBILITY 
7.1 
Inclusion Criteria 
1. Patient has signed informed consent and is willing to comply with the protocol 
2. Histologically or cytologically proven adenocarcinoma of the pancreas (within the last 90 days) 
3. Either resectable or borderline resectable as determined on staging imaging (as defined by National 
Comprehensive Cancer Network [NCCN])  
4. Patient is 18 years or older 
5. Karnofsky performance status 70 or greater 
6. The ANC count ≥ 1500, the platelet count ≥ 100,000 and hemoglobin ≥ 9g/dL 
7. Laboratory values meet the following constraints: Bilirubin less than or equal to 2 mg/dL; AST and 
ALT less than or equal to 3 x ULN (stenting to improve biliary obstruction is permitted)   
8. No evidence of metastatic disease based on imaging of the chest, abdomen and pelvis. 
 
7.2 
Exclusion Criteria 
1. Metastatic disease on pretreatment imaging  
2. Prior systemic therapy 
3. Prior abdominal radiation. Any prior radiation must be approved by the Radiation Oncology PI 
4. Previous treatment for pancreatic cancer 
Resectable  
Borderline Resectable (NCCN criteria) 
2 cycles 
Gemcitabine/nab-Paclitaxel 
SBRT 
5 frac ons (5Gy no chemo) 
Surgery 
Adjuvant chemotherapy                  
(at discre on of trea ng medical 
oncologist) 
Restaging imaging/labs 
with no evidence of 
metasta c disease 
~3-6 weeks Restaging imaging/labs  
Ac ve therapy  
period 
KPS ≥ 70 
Staging 
CA 19-9/CEA 
Con nued 
follow up 


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5. Patients with any serious/poorly controlled medical or psychological conditions that would be 
exacerbated by treatment, would complicate protocol compliance 
6. Pregnant or lactating. Adequate birth control must be used if of child bearing potential per 
institutional policy. Negative pregnancy test in female patients of child-bearing potential per 
institutional policy. Post-menopausal women must have had amenorrhea for at least 18 months to 
be considered non-child bearing 
7. Clinically significant peripheral vascular disease 
8. Presence of active or chronic infection 
9. Clinically significant atherosclerotic cardiovascular disease including patients with New York Heart 
Class II/III/IV CHF, ventricular arrhythmias requiring medication, myocardial infarction, 
cerebrovascular accident, transient ischemic attack, coronary artery bypass grafting, angioplasty, 
cardiac or other vascular stenting within the past 6 months 
10. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess within six months 
prior to treatment start 
11. History of collagen vascular disease or inflammatory bowel disease (Crohn’s or ulcerative colitis) 
12. Current grade 2 or higher peripheral neuropathy 
13. Anticoagulation with warfarin 
14. History of arterial thromboembolic events or symptomatic pulmonary embolism within the past 6 
months 
15. Active bleeding diathesis or history of major bleeding, CNS bleeding, or significant hemoptysis within 
the past 6 months 
 
9. INVESTIGATIONAL PLAN 
8.1 
Study Design 
Please refer to study schema in section 6. Eligible subject population is outlined in section 3.4. Forty 
patients will be accrued to this prospective, single arm study in 5 years . Treatment duration is as 
outlined in scheme in section 6. Serum, plasma and urine will be collected as indicated in 
exploratory analysis (section 3.6). 
 
8.1.1 
Dose Escalation  
Not applicable 
 
8.1.2 
Definition of Dose-Limiting Toxicity (DLT) 
Not applicable 
 
8.1.3 
Dose Modification. 
Dose Modifications and Toxicity Management of Chemotherapy 
Treatment Parameters for Day 1 of Each Cycle 
Treatment on day one of each cycle should be delayed until: 
 
Absolute neutrophil count (ANC) is > 1,500/mm3 and hemoglobin is > 9g/dL 
 
Recovery to grade ≤ 1 from any clinically significant treatment-related non-hematologic 
toxicity. Subjects may continue drug with grade 2 toxicity if not considered clinically 
significant by treating physician (i.e. alopecia).  
 
Laboratory only abnormalities are permitted but must meet the following criteria:  
1. Not considered clinically significant in the treating physician’s judgment (with the 
exception of ANC and hemoglobin)  
2. No clinical symptoms 
3. Do not require treatment modifications or delays or result in a medical intervention.  


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However, caution is needed to ensure re-treatment is considered safe and in the interest of the 
subject.   
 
Investigators should be vigilant and alert to early and overt signs of myelosuppression, infection, febrile 
neutropenia and related events, so that these complications can be promptly and appropriately 
managed. Appropriate dose modifications should be made by treating physician. Suggested dose 
modification levels for each agent are noted below. Patients should be made aware of these signs and 
encouraged to seek medical attention at the earliest opportunity.  
 
No dose reductions for gemcitabine/nab-paclitaxel are required for Grade 1 and 2 toxicities, except for 
those considered clinically significant, intolerable to the patient due to prolonged duration or adverse 
effects on quality of life.  
 
For Grade 2-3 or persistent intolerable Grade 2 non-hematologic toxicity (e.g., fatigue, diarrhea, nausea, 
vomiting, neuropathy, respiratory symptoms, etc), refer to gemcitabine/nab-paclitaxel prescribing 
information for dose modification guidance which is at the treating physician’s discretion. If the 
initiation of a cycle is delayed for ≥ 4 weeks, continuation of treatment must be discussed with the 
principal investigator. 
 
Potential Dose Level Modifications for Each Agent  
Agent  
Initial Dose
Level –1 
Level –2 
Level –3
Nab-Paclitaxel 
125mg/m2
100mg/m2
75mg/m2
Discontinue
Gemcitabine
1000 mg/m2
800mg/m2
600mg/m2
Discontinue
 
Chemotherapy toxicity assessment will be performed at the standard of care visits (typically days 1,8,15 
during systemic therapy). During the course of radiotherapy, acute toxicity will be assessed at the 
standard treatment visit. Given the short duration of radiation treatment it is unlikely that dose 
modifications will be made. Radiotherapy treatments may be discontinued at the discretion of the 
treating physician for any reason.  
 
8.1.4 
Safety Considerations 
To further evaluate the safety and toxicity profile of the therapy combination, an interim safety 
analysis will be performed after the first five patients in have completed study therapy. Accrual 
will not be halted during this analysis.  All grade 4-5 AEs will be tabulated and reviewed.  If > 
20% of patients experience treatment-related grade 4-5 AEs, a decision will be made to either 1) 
halt the trial and all further accrual, 2) amend the protocol for more aggressive dose 
modification and/or 3) institute additional clinical monitoring.   
 
8.1.5 
Treatment Interruptions during RT 
Although we do not anticipate side effects resulting in a break in treatment there is the low 
possibility of duodenal/bowel perforation or bleeding secondary to radiation treatment. Prior 
prospective studies in resectable and unresectable pancreatic patients have not reported acute 
duodenal/bowel perforation. At the discretion of the treating physician radiotherapy will be 
discontinued.  
 
8.1.6 
Concomitant Medications/Therapies  
No concomitant therapy. Gemcitabine/nab-Paclitaxel will be administered first followed by 
HIGRT alone. Supplemental medications during chemotherapy and radiation will be 


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administered per institutional polices.  Growth factor support is allowed on this protocol at the 
treating physicians’ discretion and per institutional policy.  
 
8.2 
Rationale for Selection of Dose, Regimen, and Treatment Duration 
See section 4.1 
 
8.3 
Rationale for Correlative Studies 
Blood and urine will be collected for future correlative studies. Specimens will be banked in a -80° 
freezer in locked facilities in the Radiation Oncology Department. Please see section 11.8.3 for 
further information. 
 
 Definition of Evaluable Subjects, On Study, and End of Study 
Patient enrolled on the study who initiates planned therapy will be evaluable. Patient are “on study” 
during neoadjuvant gemcitabine/nab-Paclitaxel and HIGRT. End of study is defined as 60 days post 
surgery. We will continue to collect patient data for 2 years after diagnosis or until death. For the 
purposes of the primary endpoint of feasibility a patient who has received 2 cycles of 
gemcitabine/nab-paclitaxel (regardless of dose reductions) and HIGRT will be considered to have 
completed the neoadjuvant regimen.  
 
8.4 
Early Study Termination 
This study can be terminated at any time for any reason by the PI.  If this occurs, all subjects on 
study should be notified as soon as possible.  Additional procedures and/or follow up should occur 
in accordance with Section 11.7, which describes procedures and process for prematurely 
withdrawn patients. 
 
9 
RADIATION THERAPY 
9.1 
Type, Classification, Location, and Short Description 
Therapy is high dose image guided radiotherapy (HIGRT) delivered in 5 fractions.   
 
9.2 
Equipment 
       A linear accelerator with on board imaging is used for treatment delivery. 
 
9.3 
Dose Specifications 
5Gy will be delivered in 5 fractions to a total dose of 25Gy (ideally in consecutive days but 5 fraction 
treatment must be completed in a 10 day time period).  
 
9.4 
Localization, Simulation, and Immobilization 
Simulation: Patients will undergo CT and/or MRI simulation utilizing customized immobilization. If 
patient is able to tolerate, respiratory motion management will be implemented (breath-hold, 
abdominal compression, etc.). Administration of IV and oral contrast is preferred for target and 
normal tissue delineation but at the discretion of the treating physician. A pretreatment renal scan 
to assess kidney differential may be performed at the treating physician’s discretion prior to 
initiation of radiation treatment.  
 
9.5 
Imaging 
Prior to each fraction of treatment, image guidance will be utilized to confirm positioning. kVOBI and 
cone beam CT (CBCT) will be utilized.   
 


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9.6 
Treatment Planning/Target Volumes 
Gross Tumor Volume (GTV): tumor volume will be defined on the basis of CT, EUS, and MRI imaging.  
Clinical Target Volume (CTV):  
The CTV should include the primary tumor and involved nodal areas with margin for microscopic disease 
extension. Additionally the following nodal regions are suggested based on tumor location as follows:  
Pancreatic head: peri-pancreatic, para-aortic (celiac/SMA) 
Pancreatic body: peri-pancreatic, para-aortic (celiac/SMA)  
Pancreatic tail: peri-pancreatic, para-aortic (celiac/SMA) and splenic hilum 
Portal and pancreaticoduodenal lymph nodes will not routinely be included unless concern for gross 
disease in this region. For the para-aortic nodes the most proximal 1-1.5cm of the celiac axis and 
proximal 2.5-3cm of the SMA from the take-off of the aorta should be contoured. These contours should 
be expanded by 1-1.5cm for the CTV.   
Planning Target Volume (PTV): per treating physician discretion but typically CTV +0.5-1cm.  
 
9.7 Dose Limitations for Normal Tissue 
The following normal tissues will be contoured: 
Liver 
Stomach 
Duodenum  
Small bowel (peritoneal space, rather than bowel loops) 
Right kidney 
Left Kidney  
Spinal cord 
Normal Tissue Constraints: At the discretion of the treating physician, however, the following 
constraints/prioritizations are recommended:  
PTV
95% PTV covered by 95% Rx dose
Kidney
70% one kidney less than 15Gy
Liver
70%<24Gy
Spinal Cord
20Gy max
Small bowel
25Gy max
Duodenum
25Gy max
Stomach
25Gy max
9.8 Treatment Verification 
Imaging and treatment verification will be confirmed by a physicist and treating physician (or 
physician designee) prior to the delivery of each fraction.  
 
9.9 Quality Assurance of Dose Distribution 
Quality assurance will be performed of each treatment plan prior to delivery by a physicist.  
 
10.STUDY DRUG 
 There is no study drug involved. The chemotherapy Gemcitabine/nab-Paclitaxel is FDA-approved for 
patients with metastatic pancreatic cancer, but they will used off-label in this study as Standard of 
care. 
11.PATIENT ASSESSMENTS 
As per standard of care all patients will have staging chest, abdomen and pelvis imaging. Standard labs 
will include the following: CMP, CBC with differential, CEA, and CA 19-9. If applicable, pregnancy test will 
be obtained prior to chemotherapy and HIGRT initiation. Blood and urine biomarker specimens will be 


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obtained at baseline, prior to HIGRT, after HIGRT, and postoperatively. Prior to surgery, patients will be 
asked to consent to tumor banking in the Duke Biospecimen Repository and Processing Core (BRPC) for 
future studies 
 
Required 
studies 
Screen 
visit 
gemcitabin
e/nab-
paclitaxel 
HIGRT
Prior to 
surgery 
Post op
Initial 
F/U  
At 6-mos.
and 12-
mos. 
following 
therapy 
Years 2 through 5
Every 6 
mos. 
Every 
12 mos. 
History and 
Physical exam 
X
X 
(focused 
H&P) 
X 
(focuse
d H&P) 
X (focused 
H&P) 
x
x
x
Treatment visit
X (typically 
days 1,8,15 
during 
chemo) 
X 
(weekly)
Weight
X
X
X
X
X
X
X
X
X
CBC
X
X
X 4
X 4
X 4
X 4
Chemistries
X
X
X 4
X 4
X 4
X 4
Liver Function
X
X
X 4
X 4
X 4
X 4
Pregnancy test
(per institutional 
policy) 
X 
X
CEA/CA 19-9
X 1
       X
X
X 4
X 4
X 4
X 4
Chest imaging
X2
       X
X
at MD 
discretion) 
(at MD 
discretion) 
(at MD 
discretio
n) 
(at MD 
discretio
n) 
Abdominal/pelvi
c imaging 
X3
      X
X
at MD 
discretion) 
(at MD 
discretion) 
(at MD 
discretio
n) 
(at MD 
discretio
n) 
Toxicity 
assessment 
Continuous Toxicity Assessment
Serum 
collection 
X
X
X
X
Urine collection
X
X
X
X
11.1 
Pretreatment Evaluations/Management 
Not applicable 
                                                          
1 Completed within 30 days of initiating chemotherapy 
2 Completed within 30 days of initiating chemotherapy 
3 Completed within 30 days of initiating chemotherapy 
4 Completed at the discretion of the treating MD 


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11.2 
Screening Examination 
The screening examination will take place within 2 weeks of initiating chemotherapy.  An informed 
consent must be signed by the patient before any study screening procedure takes place. If 
however, standard of care evaluation procedures have been obtained and are within the screening 
evaluation time points, the SOC procedures do not need to be repeated and may be included in the 
screening examination.  Imaging and tumor markers (CEA/CA19-9), if completed within 30 days of 
initiating chemotherapy do not need to be repeated, unless at the discretion of the treating 
physician. 
 
11.3 
Treatment Period 
Treatment period will be from initiation of gemcitabine/nab-paclitaxel to 60 days post-surgery. 
Assessment will be performed by the respective medical oncologist during systemic therapy 
(typically day 1, 8, and 15 of each cycle) and weekly during by radiation oncologist during 
radiotherapy. Restaging imaging and labs will be performed after systemic therapy. If patient is 
found to have evidence of distant metastatic disease they will not proceed with HIGRT and will be 
treated at the discretion of the treating medical oncologist and/or radiation oncologist off study. Per 
standard of care patients will return for follow up (prior to surgery) 3-6 weeks post HIGRT with labs 
and restaging imaging. The decision to proceed with surgical resection after neoadjuvant therapy 
(chemotherapy and HIGRT) will be at the discretion of the treating physicians.  
 
11.4 
End of Treatment 
End of study treatment is defined as 60 days post-surgery (+/- 7 days). Toxicity will also be assessed 
at this visit and appropriate follow up arranged. 
  
11.5 
Follow-up Period 
Patients will remain on study for 2 years from diagnosis or until death.  Approximately 10-15% may 
survive greater than 2 years and we will continue to collect outcomes data from the electronic 
records at clinic visits q 6 months through year 2, then annually years 2 through 5. 
 
11.6 
End of Study 
Patients lost to follow up will be documented and censored at time of last follow up for statistical 
consideration purposes.  
 
11.7 
Early Withdrawal of Subject(s) 
 
11.7.1 Criteria for Early Withdrawal 
Subjects may voluntarily withdraw from the study at any time.  The PI may also withdraw a 
subject from the study at any time based on his/her discretion.  Reasons for PI-initiated 
withdrawal may include, but is not limited to the following: 
 
Adverse events 
 
Abnormal laboratory values 
 
Abnormal test procedure results 
 
Protocol deviation 
 
Administrative issues 
 
Disease progression 
 
Pregnancy 


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11.7.2 Follow-up Requirements for Early Withdrawal 
 
11.7.3 Replacement of Early Withdrawal(s) 
Subjects who prematurely withdraw will not be replaced unless neoadjuvant therapy has not 
been initiated.  
 
11.8 
Study Assessments 
11.8.1 Medical History 
History will include a 10-point ROS by medical oncology and radiation oncology.  
Weekly treatment checks during radiation therapy will be focused histories.  
 
11.8.2 Physical Exam 
Physical examination of a least 7 systems (including Abdomen) will be included.  
Weekly treatment checks during radiation therapy and follow up will be a focused examination. 
  
11.8.3 Correlative Assessment 
Blood and urine will be collected at aforementioned time points. Specimens will be stored in a -
80° freezer in locked facilities in the Department of Radiation Oncology for future study and 
analysis. The specimens may be used specifically for this study and potentially for unspecified 
research.  The reason, biomarkers and assays are changing rapidly. This study is expected 
to enroll over 3 years, during that time it is possible a new biomarker or assay could be 
developed that is relevant to the study of pancreatic cancer. A study amendment would be 
submitted in the event of this occurring. 
 
12  SAFETY MONITORING AND REPORTING 
The PI is responsible for the identification and documentation of adverse events and serious adverse 
events, as defined below.  At each study visit, the PI or designee must assess, through non-suggestive 
inquiries of the subject or evaluation of study assessments, whether an AE or SAE has occurred. 
 
12.1 
Adverse Events 
The original protocol was written to include neoadjuvant chemotherapy toxicity data capture for 25 
enrolled patients. The trial has now been amended to increase sample enrollment to 40 patients. It is 
not felt to be clinically meaningful to continue to capture toxicity data for the neoadjuvant 
chemotherapy regimen of gemcitabine/nab-paclitaxel given the published data on this regimen in over 
800 patients with metastatic disease.20, 21 CTCAE v 4 non-hematologic acute toxicity Grade 2 or higher 
will be collected during the study period from time of HIGRT through postoperative period for the 
additional 15 enrolled patients.   
An adverse event (AE) is any untoward medical occurrence in a subject receiving study therapy and 
which does not necessarily have a causal relationship with this treatment.  For this protocol, the 
definition of AE also includes worsening of any pre-existing medical condition 
An AE can therefore be any unfavorable and unintended or worsening sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of  HIGRT, whether or not 
related to  HIGRT.  Abnormal laboratory findings without clinical significance (based on the PI’s 


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judgment) should not be recorded as AEs.  But laboratory value changes that require therapy or 
adjustment in prior therapy are considered adverse events. 
 
From the time the subject signs the informed consent form through the End of Study visit (as 
defined in Section 11.4), all AEs must be recorded in the subject medical record and adverse events 
case report form. 
 
AEs will be assessed according to the CTCAE version 4.0.  If CTCAE grading does not exist for an AE, 
the severity of the AE will be graded as mild (1), moderate (2), severe (3), life-threatening (4), or 
fatal (5). 
 
Attribution of AEs will be indicated as follows: 
 
Definite:  The AE is clearly related to the study therapy 
 
Probably:  The AE is likely related to the study therapy 
 
Possible:  The AE may be related to the study therapy 
 
Unlikely:  The AE is doubtfully related to the study therapy 
 
Unrelated:  The AE is clearly NOT related to the study therapy 
 
See section 8.1.4 for additional safety considerations.  
 
12.1.1 AEs of Special Interest 
No special AEs of particular concern or emphasis. 
12.1.2 Reporting of AEs 
No specific reporting requirements for AEs. 
 
12.2 
Serious Adverse Events 
An AE is considered “serious” if in the opinion of the investigator it is one of the following outcomes: 
 
Fatal 
 
Life-threatening 
 
Constitutes a congenital anomaly or birth defect 
 
A medically significant condition (defined as an event that compromises subject safety or 
may require medical or surgical intervention to prevent one of the three outcomes above). 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant incapacity or substantial disruption to conduct normal life 
functions. 
 
12.2.1 Reporting of SAEs 
SAEs will be reported to the IRB as per institutional policy.  
 
12.3 
Other Reportable Information 
The study team will adhere to the institutional policy on subjects and pregnancy stringently.  
 
12.4 
Special Warnings and Precautions 
Not applicable.  
 


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12.5 
Safety Oversight Committee (SOC) 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS 
sponsor-investigator phase I and II, therapeutic interventional studies that do not have an 
independent Data Safety Monitoring Board (DSMB). The primary focus of the SOC is review of safety 
data, toxicities and new information that may affect subject safety or efficacy. Annual safety reviews 
includes but may not be limited to review of safety data, enrollment status, stopping rules if 
applicable, accrual, toxicities, reference literature, and interim analyses as provided by the sponsor-
investigator.  The SOC in concert with the DCI Monitoring Team (see Section 13.1 for Monitoring 
Team description) oversees the conduct of DUHS cancer-related, sponsor-investigator greater-than-
minimal-risk intervention studies that do not have an external monitoring plan, ensuring subject 
safety and that the protocol is conducted, recorded and reported in accordance with the protocol, 
standing operating procedures (SOPs), Good Clinical Practice (GCP), and applicable regulatory 
requirements. The DCI Safety Oversight Committee (SOC) will perform annual reviews on findings 
from the DCI Monitoring Team visit and additional safety and toxicity data submitted by the 
Principal Investigator. 
 
12.6 
External Data and Safety Monitoring Board (DSMB) 
Not applicable.  
 
13. QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Monitoring 
The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits to ensure subject 
safety and to ensure that the protocol is conducted, recorded, and reported in accordance with the 
protocol, standard operating procedures, good clinical practice, and applicable regulatory 
requirements.  As specified in the DCI Data and Safety Monitoring Plan, the DCI Monitoring Team 
will conduct routine monitoring after the third subject is enrolled, followed by annual monitoring of 
1 – 3 subjects until the study is closed to enrollment and subjects are no longer receiving study 
interventions that are more than minimal risk.   
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency 
of serious and/or unexpected toxicities, or other concerns and may be initiated upon request of 
DUHS and DCI leadership, the DCI Cancer Protocol Committee, the Safety Oversight Committee 
(SOC), the sponsor, the Principal Investigator, or the IRB.  All study documents must be made 
available upon request to the DCI Monitoring Team and other authorized regulatory authorities, 
including but not limited to the National Institute of Health, National Cancer Institute, and the FDA.  
Every reasonable effort will be made to maintain confidentiality during study monitoring. 
 
13.2 
Audits 
The Duke School of Medicine Office of Audit, Risk and Compliance (OARC) office may conduct 
confidential audits to evaluate compliance with the protocol and the principles of GCP. The PI agrees 
to allow the OARC auditor(s) direct access to all relevant documents and to allocate his/her time and 
the time of the study team to the OARC auditor(s) in order to discuss findings and any relevant 
issues. 
 
 OARC audits are designed to protect the rights and well-being of human research subjects. OARC 
audits may be routine or directed (for cause). Routine audits are selected based upon risk metrics 
generally geared towards high subject enrollment, studies with limited oversight or monitoring, 
Investigator initiated Investigational Drugs or Devices, federally-funded studies, high degree of risk 


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(based upon adverse events, type of study, or vulnerable populations), Phase I studies, or studies 
that involve Medicare populations. Directed audits occur at the directive of the IRB or an authorized 
Institutional Official. 
 
OARC audits examine research studies/clinical trials methodology, processes and systems to assess 
whether the research is conducted according to the protocol approved by the DUHS IRB. The 
primary purpose of the audit/review is to verify that the standards for safety of human subjects in 
clinical trials and the quality of data produced by the clinical trial research are met. The audit/review 
will serve as a quality assurance measure, internal to the institution. Additional goals of such audits 
are to detect both random and systemic errors occurring during the conduct of clinical research and 
to emphasize “best practices” in the research/clinical trials environment. 
 
13.3 
Data Management and Processing 
13.3.1 Study Documentation 
Study documentation includes but is not limited to source documents, case report forms, 
monitoring logs, appointment schedules, study team correspondence with sponsors or 
regulatory bodies/committees, and regulatory documents that can be found in the DCI-
mandated “Regulatory Binder”, which includes but is not limited to signed protocol and 
amendments, approved and signed informed consent forms, FDA Form 1572, CAP and CLIA 
laboratory certifications, and clinical supplies receipts and distribution records. 
 
Source documents are original records that contain source data, which is all information in 
original records of clinical findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial.  Source documents include but are not limited 
to hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at 
the pharmacy, at the laboratories and at medico-technical departments involved in the clinical 
trial.  When possible, the original record should be retained as the source document.  However, 
a photocopy is acceptable provided that it is a clear, legible, and an exact duplication of the 
original document. 
 
13.3.2 Case Report Forms (CRFs) 
REDCAP database will be the primary data collection document for the study.  The CRFs will be 
updated in a timely manner following acquisition of new source data.  Only the PI and persons 
listed as key personnel are permitted to make entries, changes, or corrections in the CRF. 
 
An audit trail will be maintained automatically by the electronic CRF management system, 
REDCAP. All users of this system will complete user training, as required or appropriate per 
regulations. 
 
13.3.3 Data Management Procedures and Data Verification 
Clinical research nurses will have access to REDCAP based on their specific roles in the protocol.  
. The designated data manager will be managing the REDCAP database.  
 
Completeness of entered data will be checked automatically by the eCRF system, and users will 
be alerted to the presence of data inconsistencies.  Additionally, the data manager, and clinical 


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research nurses will cross-reference the data to verify accuracy.  Missing or implausible data will 
be highlighted for the PI requiring appropriate responses (i.e. confirmation of data, correction of 
data, completion or confirmation that data is not available, etc.). 
 
The database will be reviewed and discussed prior to database closure, and will be closed only 
after resolution of all remaining queries.  An audit trail will be kept of all subsequent changes to 
the data. 
 
13.3.4 Coding 
All medical terms will be coded with MedDRA (Medical Dictionary for Regulatory Activities).  
  
13.3.5 Study Closure 
Following completion of the studies, the PI will be responsible for ensuring the following  
activities: 
 
 
Data clarification and/or resolution 
 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
 
Review of site study records for completeness 
 
Shipment of all remaining laboratory samples to the designated laboratories 
 
14 .STATISTICAL METHODS AND DATA ANALYSIS 
Primary Objective: To determine if neoadjuvant gemcitabine/nab-paclitaxel and HIGRT is feasible in 
patients with potentially resectable pancreatic cancer.  
The neoadjuvant regimen will be considered feasible if (a) the trial can accrue 25 patients in no more 
than 3 years, (b) if at least 17 of the 25 patients adhere to the neoadjuvant regimen, and the acute 
grade 3+ non-hematologic acute toxicity is less than 50% (excluding fatigue and alopecia).  
Secondary Objectives:  
1. To evaluate grade ≥2 acute toxicity  
 
CTCAE version 4 will be used for all toxicity assessments. The acute toxicity rate, defined as any non-
hematologic grade 2+ toxicity occurring during treatment through 60 days post-surgery, will be 
estimated with its exact 80% confidence interval (CI). Likewise, we will determine the rate of grade 2+ 
hematologic toxicity occurring during HIGRT treatment through 60 days post treatment and the 
proportion of patients requiring treatment breaks longer than 7 days.   
 
The 15 additional patients will allow us to estimate the various toxicity rates of interest with more 
accuracy.  For example, the table below shows the decrease in the width of the 80% CI when using a 
sample of 40 patients as compared to 25 patients. These calculations are given for two different 
estimated rates.   
Sample size 
Estimated rate 
80% CI 
Width of CI 
25 
0.50 
0.37 – 0.63 
0.26 
40 
0.50 
0.40 – 0.60 
0.20 
25 
0.20 
0.10 – 0.30 
0.20 
40 
0.20 
0.12 – 0.28 
0.16 
 
 
2. To assess number of patients who undergo surgical resection.  
3. To assess the R0 resection rate 


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The rates for secondary objectives 2-3 will be calculated with their exact 80% confidence intervals.   
Exploratory Objectives:  
1. To assess perioperative surgical complication (i.e wound complications/infections, delayed 
gastric emptying, pancreatic leak, estimated blood loss, operative time) within 60 days post-
surgery 
 
The rates for will be calculated with their exact 80% confidence intervals.   
2. To assess late toxicity with this neoadjuvant regimen  
 
Late toxicity will be defined as any Grade 3+ non-hematologic toxicity or Grade 3+ hematologic toxicity 
occurring after the completion of the neoadjuvant regimen up to 6 months post HIGRT. The proportion 
of patients experiencing any type of late toxicity will be estimated with it 80% CI.   
3. To evaluate local control and rate of distant metastasis with this neoadjuvant regimen  
 
Time-to-local-failure will be defined as the length of time from date of diagnosis to local failure; distant 
failures will be ignored and deaths will be censored. The distribution of time-to-failure will be estimated 
with the Kaplan-Meier method. Distant metastases will be defined as the length of time from enrollment 
to distant failure. The distribution of distant metastasis will be estimated with the Kaplan-Meier 
method.  
4. To evaluate median progression free survival (PFS) 
 
PFS will be defined as the length of time from date of diagnosis to local or distant failure or death, 
whichever comes first. The distribution of PFS will be estimated with the Kaplan-Meier method. 
5. To evaluate median overall survival with this neoadjuvant regimen 
 
Overall survival (OS) will be defined as the length of time from date of diagnosis to death due to any 
cause. The distribution of OS will be estimated with the Kaplan-Meier method. 
6. To evaluate pathologic complete response (pCR), percentage of viable tumor, percent fibrosis 
and histological grading of treatment response in surgical specimen with this neoadjuvant 
regimen compared to historical control rates with chemoradiation (CRT) alone and neoadjuvant 
SBRT.  
 
Pathologic complete response is defined as absence of viable cells in the surgical specimen (i.e., 
ypT0N0M0) as determined at the time of pathological review. The pCR rate will be estimated with its 
exact 80% confidence interval in all patients who go on to surgical resection and in only those patients 
who completed the neoadjuvant regimen.  Histological grading of treatment response will be 
determined. The distribution of the percentage of viable tumor and percentage of fibrosis in the surgical 
specimen will be estimated with a boxplot. 
7. To evaluate radiographic response after receipt of neoadjuvant gemcitabine/nab-paclitaxel and 
hypofractionated radiotherapy (RT) in the neoadjuvant setting 
 
The distribution of tumor response on radiologic imaging after neoadjuvant gemcitabine/nab-paclitaxel 
and after HIGRT on restaging will be tabulated based on tumor measurements.  
8. To explore the effects of this neoadjuvant regimen on markers of tumor perfusion and hypoxia 
 
Blood and urine will be obtained at baseline, prior to HIGRT, after HIGRT, and postoperatively. Urine will 
be collected in order to measure isoprostanes. Each of the markers will be statistically analyzed as 


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follows. Side-by-side boxplots will be used to describe the distribution of the biomarker across time. The 
mean of the biomarker (with 80% CI) will be plotted against time. We hypothesize that this neoadjuvant 
regimen will modulate plasma, serum and urine markers of angiogenesis and oxidative stress in patients 
 
ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
15.1 
Regulatory and Ethical Compliance 
This protocol was designed and will be conducted and reported in accordance with the International 
Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the 
Declaration of Helsinki, and applicable federal, state, and local regulations. 
 
15.2 
DUHS Institutional Review Board and DCI Cancer Protocol Committee 
The protocol, informed consent form, advertising material, and additional protocol-related 
documents must be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol 
Committee (CPC) for review.  The study may be initiated only after the Principal Investigator has 
received written and dated approval from the CPC and IRB. 
 
The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent form.  The CPC should be informed about any 
protocol amendments that potentially affect research design or data analysis (i.e. amendments 
affecting subject population, inclusion/exclusion criteria, agent administration, statistical analysis, 
etc.).  
 
The Principal Investigator must obtain protocol re-approval from the IRB within 1 year of the most 
recent IRB approval.  The Principal Investigator must also obtain protocol re-approval from the CPC 
within 1 year of the most recent IRB approval, for as long as the protocol remains open to subject 
enrollment. 
 
15.3 
Informed Consent 
The informed consent form must be written in a manner that is understandable to the subject 
population.  Prior to its use, the informed consent form must be approved by the IRB. 
 
The Principal Investigator or authorized key personnel will discuss with the potential subject the 
purpose of the research, methods, potential risks and benefits, subject concerns, and other study-
related matters.  This discussion will occur in a location that ensures subject privacy and in a manner 
that minimizes the possibility of coercion.  Potential subjects will have the opportunity to contact 
the Principal investigator or authorized key personnel with questions, and will be given as much 
time as needed to make an informed decision about participation in the study. 
 
Before conducting any study-specific procedures, the Principal Investigator or designee must obtain 
written informed consent from the subject or a legally acceptable representative.  The original 
informed consent form will be stored with the subject’s study records, and a copy of the informed 
consent form will be provided to the subject.  
 
15.4 
Study Documentation 
Study documentation includes but is not limited to source documents, case report forms (CRFs), 
monitoring logs, appointment schedules, study team correspondence with sponsors or regulatory 
bodies/committees, and regulatory documents that can be found in the DCI-mandated “Regulatory 
Binder”, which includes but is not limited to signed protocol and amendments, approved and signed 


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informed consent forms, FDA Form 1572, CAP and CLIA laboratory certifications, and clinical 
supplies receipts and distribution records. 
 
Source documents are original records that contain source data, which is all information in original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents include but are not limited to hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments involved in the clinical trial.  When possible, 
the original record should be retained as the source document.  However, a photocopy is acceptable 
provided that it is a clear, legible, and an exact duplication of the original document. 
 
A case report form (CRF) (RECAP database) will be the primary data collection document for the 
study. Only the Principal Investigator and clinical research nurses are permitted to make entries, 
changes, or corrections in the CRF.  For paper CRFs, errors will be crossed out with a single line, and 
this line will not obscure the original entry.  Changes or corrections will be dated, initialed, and 
explained (if necessary).  The Principal Investigator or authorized key personnel will maintain a 
record of the changes and corrections.  For electronic CRFs, an audit trail will be maintained by the 
electronic CRF management system. 
 
15.5 
Privacy, Confidentiality, and Data Storage 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data 
will be maintained.  Research Data Security Plans (RDSPs) will be approved by the appropriate 
institutional Site Based Research group. 
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during 
the course of the study.  Prospective participants will be consented in an exam room where it is just 
the research staff, the patient and his family, if desired. For all future visits, interactions with 
research staff (study doctor and study coordinators) regarding research activities will take place in a 
private exam room. All research related interactions with the participant will be conducted by 
qualified research staff who are directly involved in the conduct of the research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock 
and key accessible only by the research staff. Subjects will be identified only by a unique study 
number and subject initials.  Electronic records of subject data will be maintained using a dedicated 
database (Redcap), which is housed in an encrypted and password-protected DCI file server.  Access 
to electronic databases will be limited to the research study team in the department of radiation 
oncology. The security and viability of the IT infrastructure will be managed by the DCI and/or Duke 
Medicine.   
 
Upon completion of the study, research records will be archived and handled per DUHS HRPP policy.     
 
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or 
publications in scientific journals. 
 


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15.6 
Data and Safety Monitoring 
Data and Safety Monitoring will be performed in accordance with the DCI Data and Safety 
Monitoring Plan.  For a more detailed description of the DSMP for this protocol, refer to Section 12 
(Sections 12.5 and 12.6 in particular) along with section 13. 
 
15.7 
Protocol Amendments 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB 
prior to implementation.  IRB approval is not required for protocol changes that occur to protect the 
safety of a subject from an immediate hazard.  However, the Principal Investigator must inform the 
IRB and all other applicable regulatory agencies of such action immediately. 
 
15.8 
Records Retention 
The Principal Investigator will maintain study-related records for the longer of a period of: 
 
at least two years after the date on which a New Drug Application is approved by the FDA  
 
at least two years after formal withdrawal of the IND associated with this protocol  
 
at least six years after study completion  
 
 
15.9 
Conflict of Interest 
The Principal Investigator and Sub-Investigators must comply with applicable federal, state, and 
local regulations regarding reporting and disclosure of conflict of interest.  Conflicts of interest may 
arise from situations in which financial or other personal considerations have the potential to 
compromise or bias professional judgment and objectivity.  Conflicts of interest include but are not 
limited to royalty or consulting fees, speaking honoraria, advisory board appointments, publicly-
traded or privately-held equities, stock options, intellectual property, and gifts. 
 
The Duke University School of Medicine’s Research Integrity Office (RIO) reviews and manages 
research-related conflicts of interest.  The Principal Investigator and Sub-Investigators must report 
conflicts of interest annually and within 10 days of a change in status, and when applicable, must 
have a documented management plan that is developed in conjunction with the Duke RIO and 
approved by the IRB/IEC. 
 
15.10 Registration Procedure 
Not applicable for this study 
 
 
 


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