A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy With Radiation Therapy for Patients With Borderline Unresectable Adenocarcinoma of the Pancreas
Phase: PHASE2
Conditions: Pancreatic Cancer
Sponsor: University of Arkansas

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation therapy 
for Patients with Unresectable or Borderline Resectable Adenocarcinoma of the Pancreas 
UAMS  
02/04/2015 
Page 1 of 34 
 
 
 
 
Title: 
A Phase II Study to Assess the Efficacy and Safety of 
Preoperative Chemotherapy with Radiation therapy for Patients 
with Unresectable or Borderline Resectable Adenocarcinoma of 
the Pancreas 
 
 
 
Sponsor:  
 
 
University of Arkansas for Medical Sciences (UAMS) 
 
 
 
 
4301 W. Markham Street 
 
 
 
 
Little Rock, AR 72205 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator:  
Issam Makhoul, MD 
 
 
 
 
University of Arkansas for Medical Sciences 
 
 
 
 
4301 West Markham, Slot 508 
 
 
 
 
Little Rock, AR 72205  
 
 
 
 
Sub-Investigators: 
 
 
 
 
 
 
 
 
 
 
Rangaswamy Govindarajan, MD 
 
Peter Emanuel, MD 
 
 
 
 
Jose Penagaricano, MD 
 
 
Donna Dunn, APN 
 
 
 
 
 
 
 
Liudmila Schafer, MD 
 
 
 
 
 
 
 
Matthew Hardee, MD 
Konstantinos Arnaoutakis, MD 
 
Pooja Motwani, MD 
Natasa Milojkovic, MD 
 
 
Fade Mahmoud, MD 
 
 
 
 
Ahmed Alwbari, MD 
 
Medical Monitor: 
 
Laura Hutchins, MD 
 
Statistician: 
 
 
Eric Siegel 
 
 
 
 
  
 
Protocol Version: 
 
3.0 
 
 
Version Date:  
 
 02/04/2015  
 
 
 
This protocol was prepared with the contribution of the GI Malignancy Study Group at UAMS. 
 

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation therapy 
for Patients with Unresectable or Borderline Resectable Adenocarcinoma of the Pancreas 
UAMS  
02/04/2015 
Page 2 of 34 
 
 
TABLE OF CONTENTS 
Title Page ................................................................................................................................... 1 
Table of Contents ...................................................................................................................... 2 
Abbreviations ............................................................................................................................ 4 
Protocol Summary .................................................................................................................... 6 
Background ............................................................................................................................... 6 
Rationale ................................................................................................................................. 8   
Objectives .................................................................................................................................. 9 
Primary Objectives .................................................................................................................. 9 
Secondary Objectives .............................................................................................................. 9 
Design and Methods ................................................................................................................. 9 
Study Calendar ...................................................................................................................... 10 
Eligibility Criteria .................................................................................................................... 12 
Procedures and Treatment Plan ............................................................................................ 13 
Radiation Therapy ................................................................................................................. 15 
Surgery .................................................................................................................................. 17 
Pathology .............................................................................................................................. 17 
Background Drug Information ................................................................................................ 17 
Pretreatment Evaluation ........................................................................................................ 21 
Preoperative Evaluation ......................................................................................................... 21 
Post-surgery Evaluation ......................................................................................................... 21 
Survival ................................................................................................................................. 22 
Criteria for Removal from Study ............................................................................................. 22 
Statistical Considerations ...................................................................................................... 22 
Data and Protocol Management ............................................................................................. 23 
Adverse Events Reporting Requirements ............................................................................. 24 
Adverse Events ..................................................................................................................... 24 
Recording of Adverse Events ................................................................................................ 25 
Method of detecting AE/SAE ................................................................................................. 25 
Audits and Inspections ........................................................................................................... 25 
Training of Staff ...................................................................................................................... 25 
Changes to the Protocol ......................................................................................................... 25 
Ethics ....................................................................................................................................... 26 

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation therapy 
for Patients with Unresectable or Borderline Resectable Adenocarcinoma of the Pancreas 
UAMS  
02/04/2015 
Page 3 of 34 
 
Ethics Review ........................................................................................................................ 26 
Ethical Conduct of the Study ................................................................................................. 26 
Written Informed Consent ...................................................................................................... 26 
Subject Data Protection ......................................................................................................... 26 
Emergency Procedures .......................................................................................................... 26 
Procedures in Case of Medical Emergency ........................................................................... 26 
Procedures in Case of Overdose ........................................................................................... 27 
Data Safety Monitoring Plan ................................................................................................... 27 
Investigational Products ......................................................................................................... 27 
Monitoring Report .................................................................................................................. 27 
Continuing Review ................................................................................................................. 28 
Data Quality Assurance and Documentation ........................................................................ 28 
Retention of Records .............................................................................................................. 28 
Tissue Banking ....................................................................................................................... 28 
References .............................................................................................................................. 29 
Appendix ................................................................................................................................. 33 
 
 
 

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation therapy 
for Patients with Unresectable or Borderline Resectable Adenocarcinoma of the Pancreas 
UAMS  
02/04/2015 
Page 4 of 34 
 
ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate aminotransferase 
BUN 
Blood Urea Nitrogen 
Cal9-9 
Carbohydrate Antigen 19-9 
CBC 
Complete Blood Count 
CCTO 
Cancer Clinical Trials Office 
Cis 
Cisplatin 
 
 
CRF 
Case Report Form 
CT 
Computed Tomography 
CXR 
Chest X-Ray 
DNA 
Deoxyribonucleic Acid 
EBRT 
External Beam Radiation Therapy 
FDG 
Fluorodeoxyglucose 
FU 
Fluorouracil 
GCP 
Good Clinical Practice 
Gem 
Gemzar 
GGT 
Gamma-glutamyl transferase 
GTV 
Gross Tumor Volume 
Gy 
Gray 
H & P 
History and Physical 
HUS 
Hemolytic-uremic Syndrome 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
Intravenous  
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Test 
MIP 
Maximum Intensity Projection 
N1 
Nodal Stage 1 
NCI 
National Cancer Institute  
NYHA 
New York Heart Association 

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation therapy 
for Patients with Unresectable or Borderline Resectable Adenocarcinoma of the Pancreas 
UAMS  
02/04/2015 
Page 5 of 34 
 
 
ABBREVIATIONS CONTINUED 
 
OAE 
Other Significant Adverse Event 
PET 
Positron Emission Tomography  
PTV 
Planning Target Volume 
RBC 
Red Blood Cells 
RNA 
Ribonucleic Acid 
R0R 
Margin-negative Resection 
R0RR 
Margin-negative Resection Rate 
RSC 
Research Support Center 
RT/XRT 
Radiation Therapy 
SAE 
Serious Adverse Event 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase  
SMV 
Superior Mesenteric Vein 
SOP 
Standard Operating Procedure 
STEAE 
Serious Treatment Emergent Adverse Event 
T3 
Tumor Stage 3 
UA 
Urine Analysis 
UAMS 
University of Arkansas for Medical Sciences 
ULN 
Upper Limits of Normal 
US 
Ultrasound 
WBC 
White Blood Count 
WHO 
World Health Organization 

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation therapy 
for Patients with Unresectable or Borderline Resectable Adenocarcinoma of the Pancreas 
UAMS  
02/04/2015 
Page 6 of 34 
 
PROTOCOL SUMMARY  
 
The purpose of this phase II clinical trial study is to assess the resection rate among subjects 
who have been initially diagnosed with unresectable or borderline resectable pancreatic 
adenocarcinoma. This will be done by providing preoperative treatment that will include 
alternating cycles of chemotherapy and radiotherapy treatment. In addition, this clinical trial will 
assess the safety of preoperative chemotherapy with radiation therapy for subjects with 
unresectable or borderline resectable adenocarcinoma of the pancreas, assess margin-negative 
resection rates, disease-free survival, assess overall survival rates, and determine patterns of 
local and distant recurrence.  
 
The study population in this clinical trial will consist of untreated subjects 18 years or older who 
have a histologically or cytologically confirmed diagnosis of unresectable or borderline 
resectable adenocarcinoma of the pancreas. The maximum feasible accrual is estimated to be 
20 subjects in a one-year period, and the target sample size is thus 20 subjects.  We expect to 
screen approximately 40 subjects in order to achieve our enrollment goal of 20 subjects at the 
University of Arkansas for Medical Sciences. Once the patient has undergone the necessary 
tests and the tumor has been staged, the principal investigator or co-investigators will determine 
if the patient is suitable to be inducted in this clinical trial. The course of preoperative treatment 
in this study will consist of an alternating combination of 6mg/M² of Gemzar for 24 hours and 7.0 
Gy of radiation therapy. The subject will undergo one of these therapies alternating daily for a 
total of 10 days then the subject will be allowed to rest for 4 weeks before undergoing restaging 
and surgery. After surgery, the subject will then undergo the conventional chemotherapy 
regimen consisting of 6 cycles (1 cycle = 28 days) of 1000mg/M² of Gemzar over a 30 minute 
infusion rate.  
 
The primary outcome of this clinical trial is the margin-negative resection rate. This will be 
determined by the tumor’s response to the pre/post-operative treatment so that the tumor can 
be removed surgically.. Once the subject has completed the treatment as described in the 
protocol, he/she will continued to be followed to assess survival and patterns of local and 
distance recurrence until recurrence and/or death up to five years. The purpose of this clinical 
trial will be an attempt to provide subjects with a more hopeful alternative to treatment for a 
disease that otherwise offers a grim prognosis.  
 
BACKGROUND  
 
Survival of patients with pancreatic cancer remains the most depressing among all cancer 
patients. The main hope for survival hinges on the possibility to resect the tumor but this is not 
really done to more than a minority of patients due to the pattern of presentation of this tumor. 
Patients with pancreatic cancer are staged into three groups: Resectable (~20% of total), locally 
advanced/unresectable (35%–40% of total), and Metastatic (40% of total).   
 
The rationale for pursuing preoperative therapy for patients with unresectable or borderline 
resectable pancreatic cancer includes: (a) potential for downstaging in order to maximize the 
chances for a margin-negative resection (R0R) (b) treating micrometastatic disease early, (c) 
giving “adjuvant” therapy in a “neoadjuvant” setting when it is better tolerated, and (d) using this 
approach to gauge the aggressiveness of the cancer and thereby select the best patients for 
surgery who have the greatest likelihood of a favorable postoperative outcome.1,2  Traditionally 

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation therapy 
for Patients with Unresectable or Borderline Resectable Adenocarcinoma of the Pancreas 
UAMS  
02/04/2015 
Page 7 of 34 
 
patients with pancreatic cancer were defined as either resectable or unresectable.  However, 
recent National Comprehensive Cancer Network guidelines include a definition of borderline 
resectability.  This definition includes patients with severe unilateral mesenteric/portal vein 
impingement, tumor abutment on the mesenteric artery, limited involvement of the vena cava, 
mesenteric vein occlusion with patent vein, and colon or mesocolon invasion.3  The Stanford 
criteria of marginally resectable pancreatic cancer are similar and highlights main vessel 
involvement.4  The M. D. Anderson Cancer Center criteria of borderline resectability include 
vessel involvement but also patients with concern for extrapancreatic disease and patients with 
marginal performance status due to reversible conditions (such as hyperbilirubinemia).5 
 
There have been several trials at M.D. Anderson Cancer Center of preoperative chemoradiation 
for resectable pancreatic cancer. The initial studies used a standard-fractionation treatment 
schema of preoperative chemoradiation and pancreaticoduodenectomy. In an early study, 
radiation therapy was delivered 5 days/week over 5.5 weeks with 18-MeV photons.6 Using a 
four-field technique, subjects received a total dose of 50.4 Gy prescribed to the 95% isodose at 
1.8 Gy/fraction (28 fractions). 5-FU was given concurrently by continuous infusion at a dosage 
of 300 mg/m2 per day, 5 days/week, through a central venous catheter. This treatment allowed 
improved locoregional control with preoperative chemoradiation.6  However, this 5.5-week 
chemoradiation program was associated with gastrointestinal toxicity (nausea, vomiting, and 
dehydration) that required hospital admission of one third of the subjects. These findings 
prompted a change in the delivery of preoperative chemoradiation at M.D. Anderson Cancer 
Center in favor of rapid-fractionation or short-course EBRT. In future trials at this institution, 
rapid-fractionation chemoradiation at a total dose of 30 Gy (3 Gy/fraction [10 fractions] 5 
days/week) was delivered over 2 weeks with concurrent chemotherapy. Rates of local tumor 
control and subject survival times achieved were equal to the results obtained with standard-
fractionation (5.5 weeks) chemoradiation. Subsequent trials also incorporated Gemzar as the 
systemic agent with concurrent rapid-fractionation RT.  
 
Gemzar is a potent radiation sensitizer of human pancreatic cancer cells, and laboratory studies 
suggest that gemzar lowers the threshold for radiation-induced tumor-cell apoptosis. Gemzar is 
also a systemic agent utilized for advanced pancreatic cancer. In another trial from M.D. 
Anderson, 
the 
Gem-XRT 
trial, 
subjects 
with 
biopsy-proven, 
potentially 
resectable 
adenocarcinoma of the pancreatic head or uncinate process received 7 weekly infusions of 
Gemzar (400 mg/m2) and 30 Gy of EBRT (3 Gy/Fx, M-F over 2 weeks beginning 3 days after 
the first dose of gem).7   Eighty six subjects were enrolled, all subjects completed the radiation 
component, and 85 of 86 subjects underwent restaging evaluation. Pancreaticoduodenectomy 
(PD) was successfully performed in 64 (74%) of 86 subjects. The median overall survival of all 
86 subjects was 22.7 months (95% CI 15.9, 29.5); the median progression-free survival was 
15.4 months (95% CI 7.8, 23.0). The 5-year survival for all 86 subjects was 27%.  Following 
surgical resection, local recurrences were rare (11%; isolated local recurrence in 3%) and the 
dominant site of failure was distant metastases, since pancreatic cancer is a systemic disease 
in most subjects. Therefore, the next trial, Gem-Cis-XRT was designed in response to this 
pattern of recurrence by delivering more systemic therapy using Gemzar-cisplatin followed by 
Gemzar-based chemoradiation, since at the time, a Gemzar-cisplatin doublet was showing 
promising activity in advanced disease. Results from this trial were not superior to those 
observed with Gem-XRT. The median survival for the 52 subjects who underwent PD after 
Gem-Cis-XRT was 31 months; less, although not statistically different, than the 34 month 
median survival observed for the 64 subjects who underwent PD following Gem-XRT (p=0.41). 

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation therapy 
for Patients with Unresectable or Borderline Resectable Adenocarcinoma of the Pancreas 
UAMS  
02/04/2015 
Page 8 of 34 
 
There was insufficient power to detect differences in survival based upon the sizes of the 2 
study populations, and it remains unclear if there were other confounding variables unique to 
such complicated treatment sequencing in subjects with pancreatic cancer. The higher 
incidence of local recurrence following surgery in this trial compared to Gem-XRT may be due to 
the greater proportion of subjects with T3 and/or N1 disease, the location of the primary tumor in 
relation to the SMA, and the unknown potential for chemotherapy given prior to chemoradiation 
to enhance radiation resistance. Therefore, to summarize, there have been multiple trials with 
encouraging results using neoadjuvant therapy for resectable pancreas cancer, but few trials 
addressing the new criteria of borderline resectability. 
 
A recent phase II study of chemoradiotherapy in the borderline and unresectable population has 
been performed at the New York University Cancer Institute.8  The treatment was well-tolerated 
with only 3 cases of grade-4 toxicity (fever and neutropenia).  Four out of 26 subjects in this 
study were converted from unresectable to resectable status and underwent potentially curative 
surgery.  The only other study to address this population included subjects with less advanced 
disease, employed a more liberal definition of borderline resectability, and excluded subjects 
with unresectable disease.5  In this retrospective study of 160 subjects from M. D. Anderson 
Cancer Center, 78% of the study subjects completed preoperative therapy and restaging, and 
41% underwent pancreatectomy. Vascular resection was required in 18 (27%) of 66 subjects, 
and 62 (94%) underwent pancreatectomy with a margin-negative resection. A partial pathologic 
response to induction therapy (< 50% viable tumor) was seen in 37 (56%) of 66 subjects. 
Median survival was 40 months for the 66 subjects who completed all therapy and 13 months 
for the 94 subjects who did not undergo pancreatectomy (p < 0.001).  It remains controversial, 
however, whether chemo-radiation therapy can convert a subject from borderline or 
unresectable status to resectable. 
 
Rationale for the design of the current trial for Gemzar as a chemosensitizer in 
pancreatic cancer: 
In-vivo studies using colon and pancreatic cancer cell lines demonstrated that timing and 
duration of exposure are more important than the dose in determining the radiosensitizing effect 
of gemcitaibine.9 Cell kill was the greatest when the cells were incubated with Gemzar for the 
full 24 hours prior to irradiation. Furthermore, increasing the dose of Gemzar by 100 folds (from 
0.1 to 10 M) in a four-hour-exposure experiment did not increase radiosensitization. In in-vivo 
studies, the administration of Gemzar between 24 to 60 hours prior to radiation was associated 
with the longest growth delays of xenografts.10 Another study showed that the administration of 
small dose of Gemzar twice weekly during radiation resulted in significantly smaller tumors than 
one large dose of Gemzar in a xenograft animal model.11 A clinical study investigating twice a 
week Gemzar in addition to radiation therapy (50.4 Gy) showed that the maximum tolerated 
dose was 60 mg/m2, with gastrointestincal and hematologic toxicities being dose-limiting.12 The 
dose of 40 mg/m2 was chosen to move to phase II clinical trial in locally advanced, non-
metastatic pancreatic cancer subjects, and was used in combination with conventional radiation 
therapy (50.4 Gy in 180 cGy daily fractions over 5.5 wk). The main toxicities from this regimen 
were nausea and vomiting (44% and 49%) and neutropenia (40%).13 Median survival was 8.2 
months and local recurrence rate was 15% only. Side effects on these trials were attributed to a 
large radiated volume to encompass the regional nodal basins. Another trial evaluating 
gemcitabine and radiation in the adjuvant setting reported infrequent grade III/IV gastrointestinal 
or hematologic toxicities.14  These trials showed the feasibility of integrating Gemzar and 
radiation. The encouraging overall survival rates from neoadjuvant trials support the continued 

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation therapy 
for Patients with Unresectable or Borderline Resectable Adenocarcinoma of the Pancreas 
UAMS  
02/04/2015 
Page 9 of 34 
 
investigation of gemcitabine and radiation therapy.7  However, neither the optimal 
dose/schedule of Gemzar nor the appropriate dose/schedule of radiation are fully defined.15 The 
schedule dependency of single-agent Gemzar was explored in a phase I study that showed that 
the maximum tolerated dose in continuous infusion is 8 mg/m2/d (32 mg/m2/course over 96 
hours) when given every 3 wk, or 6 mg/m2/d (24 mg/m2/course over 96 hours) when given every 
2 wk.16 
   
Based on the pharmacokinetic of Gemzar, its schedule dependency and potential toxicity when 
combined with radiation therapy, we designed our study to take advantage of the present 
knowledge to optimize efficacy and minimize toxicity. We propose to administer Gemzar as a 
continuous infusion at the dose of 6 mg/m2 over 24 hours on Day One that will be followed by 
radiation therapy on Day Two. The same treatment will be given for five times over ten days 
alternating chemotherapy and radiation therapy. (See study calendar).  
 
OBJECTIVES 
 
Primary Objectives 
1. To assess the margin-negative resection rate (R0RR) in subjects with unresectable or 
borderline resectable adenocarcinoma of the pancreas treated with preoperative 
chemotherapy with external-beam radiation therapy followed by surgery.  
 
Secondary Objectives 
1. To assess the safety of preoperative chemotherapy with radiation therapy for subjects 
with unresectable or borderline resectable adenocarcinoma of the pancreas 
2. To assess disease-free survival 
3. To assess overall survival 
4. To determine patterns of local and distant recurrence 
 
DESIGN AND METHODS 
 
Subjects with unresectable or borderline resectable pancreatic cancer will be offered 
participation in the study. Subjects may be inpatient or outpatients.  Subjects should have a 
contrast CT scan within 28 days of enrollment. Unresectability or borderline resectability will be 
defined based on radiologic (CT scan) and operability will be defined based on clinical criteria 
(see eligibility criteria), and concurrent chemotherapy and radiation therapy will be administered 
as defined by the protocol. Chemotherapy will consist of 24-hour-continuous infusion of Gemzar 
on days 1, 3, 5, 7 and 9, while radiation therapy will consist of 7.0 Gy administered on days 2, 4, 
6, 8, and 10. At the completion of this treatment, the subjects will be given a 4-week break 
before they undergo restaging CT scan. Restaging will define two groups of subjects: those 
whose disease progressed locally or who developed distant metastatic disease, and those 
whose disease has responded or remained stable. Subjects whose disease progressed locally 
or who developed distant metastatic disease will be removed from the study. Subjects whose 
disease did not progress will proceed to surgery with exploratory laparotomy to assess 
resectability, and if their cancer is resectable, they undergo pancreatectomy. Within twelve 
weeks after surgery, subjects will start adjuvant chemotherapy with weekly Gemzar for six 
months as per standard of care. After completion of study–related treatment, subjects will be 
followed until recurrence and/or death up to five years. 

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation therapy for Patients with Unresectable 
Adenocarcinoma of the Pancreas 
UAMS 
02/04/2015 
 
 
Page 10 of 34 
 
 
 
 
 
*See the Study Calendar Footnotes on the following page.  
STUDY CALENDAR 
 
Pre-
Treatment 
Evaluation 
≤ 28 days 
Screening 
 
Day 
 
 
Pre-
Operative 
Evaluation 
Day 35 
(+/- 3d) 
Surgery 
Day 38 
(+/- 3d) 
Post 
Surgery 
Evaluation 
≤122 d  
Survival 
Follow-
up Q 6 
months 
 
 
 
T W 
R 
F S 
Sun 
M 
T 
W 
R 
F 
 
 
 
 
H&P & Concurrent Meds 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsa 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Kidney function b 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Blood Chemistriesc 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Liver Function (LFT’s)d 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
CBCe 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Xi 
 
Pregnancy Test (urine or serum) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ca19-9 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
CT chest, abdomen, and pelvisf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Xj 
X 
Adverse Events g 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Preop XRT 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
Preop chemo 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Tissue for correlative studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Post operative chemotherapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xh 
 

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation therapy for Patients with Unresectable 
Adenocarcinoma of the Pancreas 
UAMS 
02/04/2015 
 
 
Page 11 of 34 
 
 
Study Calendar Footnotes: 
 
a. Vital signs: blood pressure and pulse rate 
b. Kidney Function  includes BUN and Creatinine 
c. Blood Chemistries: Bilirubin, alkaline phosphatase, ALT, AST, , phosphorus, calcium, glucose, total protein, albumin, and electrolytes 
[sodium, potassium, CO2, chloride, and magnesium] 
d. Liver function includes: AST, ALT, GGT, alkaline phosphatase, LDH, and bilirubin.  
e. Complete Blood Count (CBC): Hemoglobin, hematocrit, red blood cells [RBC], white blood cells [WBC], platelets, and differential blood 
cell counts such as: neutrophils, lymphocytes, monocytes, eosinophils, basophils) 
f. Biphasic (arterial and venous CT of the abdomen with ≤ 3mm thick axial slices.  
g. All adverse events occurring during any part of the study will be reported appropriately to the IRB. 
h. Post operative chemotherapy treatment every weeks for 3 weeks and 4th week no treatment 
i. CBC will be drawn prior to start of each chemotherapy treatment 
j. CT of chest, abdomen, and pelvis prior to start of cycles 1, 3, 5. (1 cycle = 28 days) 
 

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation 
therapy for Patients with Unresectable Adenocarcinoma of the Pancreas 
UAMS 
02/04/2015 
 
 
Page 12 of 34 
 
 
Eligibility criteria 
 
Inclusion Criteria: 
 
1. Ages 18 years and above. There will be no upper age restriction. 
2. ECOG performance status ≤ 2. (See Appendix A –ECOG  Performance Status 
Scale).  
3. Cytologic or histologic proof of adenocarcinoma of the pancreas.  
4. Adequate renal, and bone marrow function: 
a. Leukocytes >= 3,000/uL  
b. Absolute neutrophil count >= 1,500/uL  
c. Platelets >= 100,000/Ul  
d. Serum creatinine <= 2.0 mg/dL 
5. Hepatic function (endoscopic or percutaneous drainage as needed) 
a. AST (SGOT)/ALT (SGPT) <= 5 X institutional ULN 
6. Borderline resectable pancreatic cancer: 
a. Short segment hepatic artery abutment (< 180° involvement) 
b. Tumor abutment (<180° ) of superior mesenteric artery 
c. Superior mesenteric/portal vein involvement beyond that of a simple 
resection and reconstruction 
d. Pancreatitis that obscures the determination of vessel involvement and 
may preclude an otherwise curative operation 
7. Unresectable pancreatic cancer: 
a. Tumors that encase (> 180° involvement) single or multiple arteries and 
veins (celiac axis, superior mesenteric artery, superior mesenteric/portal 
vein, hepatic artery) 
b. Occlusion of superior mesenteric/portal vein 
 
 
Exclusion Criteria: 
 
1. Infections such as cholangitis, pneumonia, or wound infections that would 
preclude protocol therapy. 
2. Women with a positive urine or serum pregnancy test are excluded from this 
study; women of childbearing potential (defined as those who have not 
undergone a hysterectomy or who have not been postmenopausal for at least 24 
consecutive months) must agree to refrain from breast feeding and practice 
adequate contraception as specified in the informed consent. Adequate 
contraception consists of oral contraceptive, implantable contraceptives, 
injectable contraceptives, a double barrier method, or abstinence.  
3. Subjects cannot have known heptic or peritoneal metastases detected by 
ultrasound (US), CT scan, or laparotomy/laparoscopy prior to treatment.  
4. Subjects with unstable angina or New York Heart Association (NYHA) Grade II or 
greater congestive heart failure will be excluded (see Appendix B). 
5. Known presence of central nervous system or brain metastases 
6. Subjects with prior radiotherapy to the upper abdomen or liver will be excluded. 
7. Subjects will be excluded if deemed unable to comply with study and/or follow-up 
procedures. 

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation 
therapy for Patients with Unresectable Adenocarcinoma of the Pancreas 
UAMS 
02/04/2015 
 
 
Page 13 of 34 
 
 
8. Subjects with a known hypersensitivity to Gemzar are excluded. 
9. Multiple positive lymph nodes, which will make the radiotherapy treatment 
volume too large. Peripancreatic involved nodes can be included in the 
radiotherapy treatment volume if the field of involved nodes is less than 7.5cm. 
 
 
Informed Consent will be obtained. 
 
 
Type of Study: Prospective phase II, single institution clinical trial.  
 
Procedures and Treatment Plan 
1. Preoperative Therapy:  
a. Gemzar: 6 mg/M2/24 hours on day 1, 3, 6, 8 and 10. External beam 
radiation therapy will be delivered at 7.0 Gy each on days 2, 4, 7, 9 and 
11. Subjects may miss up to 2 doses of chemotherapy and/or 2 
treatments of radiation.  Subjects missing more than 2 chemotherapy or 
radiation treatments will be removed from the protocol.  If any days of 
chemotherapy and radiation are missed, these days will be made up prior 
to day 122.  Chemotherapy and radiation therapy will be given in the 
same sequence as pre-operative treatment. 
 
2. Postoperative Therapy: 
a. All subjects will get baseline restaging scans after surgery prior to starting 
postoperative adjuvant therapy) within 4 weeks prior to beginning 
adjuvant therapy. Gemzar - 1000 mg/M2 IV over 30 min; Days 1, 8, 15 q 
28 days +/- 3 days for 6 cycles beginning within 12 weeks of surgery 
(repeat restaging scans after every 2 cycles of therapy.  Subjects not able 
to start chemotherapy within 12 weeks of surgery will be removed from 
the protocol. 
 
Dose Adjustments for Preoperative Gemzar: 
 
(1) Gemzar Dose Adjustment/Modifications for days 5 and 8 of preoperative Gemzar 
 
Table 1: Hematologic Toxicities - Dose Adjustment of Gemzar during a cycle 
ANC (x103/mcl) 
Platelets (x103/mcl) 
Percent dose of Gemzar1 
> or = 1.5 
And > or = 100 
100 
1-1.49 
Or 75-99 
50 
<1 
Or <75 
0 
1. Percent dosage refers to the dose of drugs on the first day of the cycle. 
 
 
 
 
 
 
 

A Phase II Study to Assess the Efficacy and Safety of Preoperative Chemotherapy with Radiation 
therapy for Patients with Unresectable Adenocarcinoma of the Pancreas 
UAMS 
02/04/2015 
 
 
Page 14 of 34 
 
 
Table 2: Non-Hematological Toxicity due to Gemzar 
(Excluding alopecia, inadequately treated nausea and vomiting) 
Worst toxicity during previous cycle 
Percent of Gemzar dose  
from the previous cycle1 
Grade 0/1 
100 
Grade 2 
75 
Grade 3-4 
50 
1. Percent dosage refers to the dose of drugs on the first day of the cycle. 
  
 
(2) Gemzar Intracycle Dose Adjustment/Modifications (days 8 and 15 of each 
postoperative cycle) 
 
Table 3: Hematologic Toxicities - Dose Adjustment of Gemzar during a cycle 
ANC (x103/mcl) 
Platelet (x103/mcl) 
Percent dose of Gemzar1 
> 1.0 
And >75 
100 
0.51-0.99 
Or 51-74 
50 
<0.5 
Or <50 
0 
1. Percent dosage refers to the dose of drugs on the first day of the cycle. 
  
(3) Intra-cycle Dose Adjustments for Non-Hematological Toxicity due to Gemzar 
(excluding alopecia, nausea, vomiting, and diarrhea, ocular visual and dermatological), 
based on the NCI- Common Toxicity Criteria v.3, as follows: 
 
Table 4: Non-Hematologic Toxicities - Dose Adjustment of Gemzar during a cycle 
Worst toxicity during cycle 
Percent dose of Gemzar1 
0/1 
100 
2 
75 
3-4 
0 
1. Percent dosage refers to the dose of drugs on the first day of the cycle 
 
 (3) Dose Adjustments of Gemzar on Subsequent Treatment Cycles (Based on the worst 
toxicity due to Gemzar on any day of the previous cycle). 
 
Table 5: Hematological Toxicity due to Gemzar 
Worst toxicity in previous cycle 
Percent in Gemzar dose from the 
previous cycle1 
ANC 
Platelets 
<0.5 
or <50 
75 
0.5-0.99 
or 51- 74 
75 
>1.0 
and >75 
100 
1. Percent dosage refers to the dose of drugs on the first day of the previous 
cycle. 
 
Note: The physician should keep reducing doses in subsequent cycles if still faced with 
significant hematological toxicity. Subject may have a maximum of 2 dose reductions on 
the protocol. If greater than 2 dose reductions are necessary, the subject will be 
removed from the protocol. 

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Table6: Non-Hematological Toxicity due to Gemzar (Excluding alopecia, 
inadequately treated nausea and vomiting) 
 
Worst toxicity during previous 
cycle 
Percent of Gemzar dose from the 
previous cycle1 
Grade 0/1 
100 
Grade 2 
75 
Grade 3-4 
75 
1. Percent dosage refers to the dose of drugs on the first day of the cycle. 
 
Note: The physician should keep reducing the doses in subsequent cycles if still faced 
with significant hematological toxicity. Subjects may have a maximum of 2 dose 
reductions on the protocol. If greater than 2 dose reductions are necessary, the subject 
will be removed from the protocol.  
 
Radiation Therapy 
1. Pre-CT Simulation imaging studies: 
a. Biphasic (arterial and venous) CT of the chest, abdomen, and pelvis with 
≤ 3mm thick axial slices. 
 
2. CT-Simulation:  
Subjects are placed in the supine position using an alpha-cradle as an 
immobilization device. A respiratory gated (4D) CT scan of 2mm slice thickness 
with oral contrast is obtained for radiotherapy planning. 
 
3. Tumor motion evaluation: 
The 4D CT is reconstructed into the 0, 25, 50 and 75% phases of the respiratory 
cycle for superior-inferior tumor motion evaluation in the coronal plane. For 
tumors with motion of ≤ 5mm in the superior to inferior plane no respiratory 
gating is needed to account for tumor motion. In this case a 0 to 90% respiratory 
phase maximum intensity projection (MIP) axial scan is to be used for target 
segmentation and the 25% respiratory phase axial scan is to be used for actual 
treatment planning. For tumor motion larger than 5mm the 35 to 65% respiratory 
phase MIP axial scan is used for target segmentation and the 50% respiratory 
phase axial scan is used for planning. Tumor and normal organ segmentation is 
done in the radiotherapy planning station with capabilities of image fusion. 
 
4. Gross Tumor Volume (GTV) Segmentation: 
To account for all respiratory-associated movement, as well as potential 
deformation of the tumor during the respiratory cycle, the GTV is contoured on 
the MIP axial scans. An additional 3 to 5mm circumferential expansion is to be 
used to create the planning target volume (PTV). 
 
5. Segmentation of nodal regions: 
No prophylactic radiotherapy is to be given to the regional lymph nodes.17-19 
 
6. Segmentation of normal structures: 

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The following normal structures need to be contoured: 
a. Stomach 
b. Duodenum 
c. Bowel 
d. Liver 
e. Kidney 
f. Spinal cord 
 
7. Stereotactic Treatment Planning: 
Intensity modulated stereotactic planning with co- or non-coplanar beams 
arrangements will be custom designed for each case to deliver highly conformal 
prescription distributions. Non-opposing, non-coplanar beams are preferable. 
Typically, ≥ 10 beams of radiation will be used. Generally, more beams are used 
for larger lesion sizes. In order to obtain acceptable coverage, field aperture and 
shape should correspond nearly identically (2mm) to the projection of the PTV 
along a beam’s eye view.  Prescription lines covering the PTV will typically be the 
60-90% (from a maximum dose of 100%). Higher isodoses must be manipulated 
to occur within the PTV and not in adjacent normal tissue.  
 
8. Prescription dose constraint: 
a. Prescription: 35Gy in five equal fractions, one fraction every other day. 
b. Maximum dose: 100% corresponds to the maximum dose and must exist 
within the PTV. 
c. Prescription isodose: will be chosen such that 95% of the PTV is 
conformally covered by the prescription isodose surface and 99% of the 
PTV recceivs at least 90% of the prescription dose. 
d. Conformality: Conformality of the PTV coverage will be judged such that 
the ratio of the volume of the prescription isodose to the volume of the 
PTV is ideally < 1.2. 
 
9. Critical organ dose-volume limits: 
The following table lists recommended maximum dose limits to a point or volume 
within several critical organs:   
 
ORGAN 
DOSE LIMIT 
Liver 
Average dose: 10Gy (2Gy/fraction) 
Kidney 
Average dose: 10Gy (2Gy/fraction) 
Spinal Cord 
Maximum dose: 20Gy (4Gy/fraction) 
Stomach 
Maximum dose: 28.75Gy (5.75Gy/fraction); 50% of 
volume 25Gy (5Gy/fraction) 
Duodenum 
Maximum dose: 28.75Gy (5.75Gy/fraction); 50% of 
volume 25Gy (5Gy/fraction) 
Other Bowel 
Maximum dose: 28.75Gy (5.75Gy/fraction); 50% of 
volume 25Gy (5Gy/fraction) 
 
 
 

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10. Toxicity 
Adverse events with Gemzar Radiation Therapy: 
 
 
Surgery 
Surgery will be planned 28 days (+/- 3 days) after the last dose of chemotherapy.  The 
liver and pancreas will be examined by palpation and inspection.  In the absence of 
metastases, tumor mobilization and surgical resection will be performed with standard 
surgical technique.   
 
Pathology 
Pancreatic transection margin and the bile duct margin (if transected) will be evaluated 
on frozen section. Recorded on permanent section will be: tumor size, degree of 
differentiation (well, moderate, poor), margin status, lymph node status, and degree of 
treatment effect. 
 
Background drug Information 
1. Gemzar: 
A chemotherapeutic drug used to treat pancreatic cancer, Non-small cell lung 
cancer, Bladder cancer, Soft-tissue sarcoma, and Metastatic breast cancer.20   
Gemzar is classified as an antimetabolite. During a certain stage in mitosis 
pyrimidine is needed to complete the process of cellular division. Gemzar works 
by interfering with the metabolism of pyrimidine which inhibits cell division and 
growth.  
 
2. Chemistry: 
Gemzar HCl is 2`-deoxy-2`, 2`-difluorocytidine monohydrochloride (β-isomer). 
 
3. Clinical Pharmacology:  
Gemzar pharmacokinetics is linear, and is described by a 2-compartment model.  
Population pharmacokinetic analyses of combined single-and multiple-dose 
studies showed that the volume of distribution of Gemzar was significantly 
influenced by duration of infusion and gender. Clearance was affected by age 
and gender. Differences in either clearance volume or distribution based on 
Likely 
Less Likely 
Rare but Serious 
Nausea and vomiting 
Fever 
Liver dysfunction 
Abdominal pain 
Muscle aches 
Renal dysfunction 
Gastrointestinal discomfort 
Rash 
Bowel obstruction 
Diarrhea 
Headaches 
Gastric ulceration 
Fatigue 
Muscle weakness 
Duodenal ulceration 
Transient skin erythema 
Confusion 
Small bowel ulceration 
Dry skin over treatment 
area 
Constipation 
Gastrointestinal bleeding 
Low blood counts 
 
 
Loss of appetite 
 
 
Weight loss 
 
 
Loss of hair 
 
 

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subject characteristics or the duration of infusion results in changes in half-life 
and plasma concentrations.  The half-life of Gemzar for short infusions ranged 
from 32-94 minutes, and the value for long infusions varied from 245-638 
minutes, depending on age and gender, reflecting a greatly increased volume of 
distribution with longer infusions. The lower clearance in women and the elderly 
result in higher concentrations of Gemzar for any given dose.  The volume of 
distribution was increased with infusion duration. Volume of distribution of 
Gemzar was 50 L/m2 following infusions lasting <70 minutes, indicating that 
Gemzar, after short infusions, is not extensively distributed into tissues. For 
longer infusions, the volume of distribution rose to 370 L/m2, reflecting slow 
equilibration of Gemzar within the tissue compartments. The maximum plasma 
concentrations of dFdU (inactive metabolite) were achieved up to 30 minutes 
after discontinuation of infusions, and the metabolite was excreted in urine 
without undergoing further biotransformation. The metabolite did not accumulate 
with weekly dosing, but its elimination is dependent on renal excretion, and could 
accumulate with decreased renal function. The effects of significant renal or 
hepatic insufficiency on the disposition of Gemzar have not been systematically 
assessed. 
 
4. Human Toxicity: 
a. Hematologic: In studies in pancreatic cancer, myelosuppression is the 
dose-limiting toxicity with Gemzar, but < 1% of subjects discontinued 
therapy for either anemia, leucopenia, or thrombocytopenia. Red blood 
cell transfusions were required by 19% of subjects. The incidence of 
sepsis was less than 1%.  Petechiae or mild blood loss (hemorrhage), 
from any cause, was reported in 16% of subjects; less than 1% of 
subjects required platelet transfusions. Subjects should be monitored for 
myelosuppression during Gemzar therapy and dosage modified or 
suspended according to the degree of hematologic toxicity. 
b. Gastrointestinal: Nausea and vomiting were commonly reported (69%) 
but were usually mild to moderate severity. Severe nausea and vomiting 
(WHO grade 3/4) occurred in <15% of subjects. Diarrhea was reported by 
19% of subjects, and stomatitis by 11% of subjects. 
c. Hepatic: In clinical trials, Gemzar was associated with transient 
elevations of one or both serum transaminases in approximately 70% of 
subjects, but there was no evidence of increasing hepatic toxicity with 
either longer duration of exposure to Gemzar or with greater total 
cumulative dose.  Serious hepatotoxicity, including liver failure and death, 
has been reported very rarely in subjects receiving Gemzar alone or in 
combination with other potentially hepatotoxic drugs. 
d. Renal:  In clinical trials, mild proteinuria and hematuria were commonly 
reported. Clinical findings consistent with the 
Hemolytic-Uremic 
Syndrome (HUS) were reported in 6 of 2429 subjects (0.25%) receiving 
Gemzar in clinical trials. Four subjects developed HUS on Gemzar 
therapy, two immediately post-therapy. Diagnosis of HUS should be 
considered 
if 
the 
subject 
develops 
anemia 
with 
evidence 
of 
microangiopathic hemolysis, elevation of bilirubin or LDH, retculocytosis, 
severe thrombocytopenia, and/or evidence of renal failure (elevation of 

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serum creatinine or BUN).  Gemzar therapy should be discontinued 
immediately.  Renal failure may not be reversible, even with 
discontinuation of therapy, and dialysis may be required. HUS and/or 
renal failure have been reported following one or more dose of Gemzar 
since Gemzar has been on the market. Renal failure leading to death or 
requiring dialysis, despite continuation of therapy, has been rarely 
reported. The majority of cases of renal failure leading to death were due 
to HUS. 
e. Fever: The overall incidence of fever was 41%. This is in contrast to the 
incidence of infection (16%) and indicates that Gemzar may cause fever 
in the absence of clinical infection. Fever was frequently associated with 
other flu-like symptoms and was usually mild and clinically manageable. 
f. Rash: Rash was reported in 30% of subjects. The rash was typically a 
macular or finely granular maculopapular pruritic eruption of mild-to-
moderate severity, involving the trunk and extremities. Pruritus was 
reported in 13% of subjects. 
g. Pulmonary: In clinical trials, unrelated to underlying disease, has been 
reported in associated with Gemzar therapy. Dyspnea was occasionally 
accompanied by bronchospasm. Pulmonary toxicity has been reported 
with the use of Gemzar.  The etiology of these effects is unknown. If such 
effects develop, Gemzar should be discontinued. Early use of supportive 
care measures may help ameliorate these conditions. Parenchymal 
toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary 
adema, and adult respiratory distress syndrome (ARDS), has been 
reported rarely following one or more doses of Gemzar administered to 
patients with various malignancies. Some subjects experienced the onset 
of pulmonary symptoms up to 2 weeks after the last Gemzar dose. 
Respiratory failure and death occurred very rarely in some patients 
despite discontinuation of therapy.  
h. Edema: Edema (13%), peripheral edema (20%), and generalized edema 
(<1%) were reported. Less than 1% of subjects discontinued due to 
edema. 
i. 
Flu-like Symptoms: "Flu syndrome" was reported for 19% of subjects. 
Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, 
and myalgia, were commonly reported. Fever and asthenia were also 
reported frequently as isolated symptoms. Insomnia, rhinitis, sweating, 
and malaise were reported infrequently. Less than 1% of subjects 
discontinued due to flu-like symptoms. 
j. 
Infection: Infections were reported for 16% of subjects. Sepsis was rarely 
reported (<1%). 
k. Alopecia: Hair loss, usually minimal, was reported by 15% of subjects. 
l. 
Neurotoxicity: There was a 10% incidence of mild parasthesias and a 
<1% rate of severe parasthesias. 
m. Extravasation: Injection-site-related events were reported for 4% of 
subjects. There were no reports of injection-site necrosis. Gemzar is not a 
vesicant. 

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n. Allergic: Bronchospasm was reported for less than 2% of subjects. 
Anaphylactoid reaction has been reported rarely. Gemzar should not be 
administered to subjects with a known hypersensitivity to this drug. 
o. Cardiovascular: During clinical trials, two percent of subjects 
discontinued therapy with Gemzar due to cardiovascular events such as 
myocardial 
infarction, 
cerebrovascular 
accident, 
arrhythmia, 
and 
hypertension. Many of these subjects had a prior history of cardiovascular 
disease. Congestive heart failure and myocardial infarction have been 
reported very rarely with the use of Gemzar. Arrhythmias, predominantly 
supraventricular in nature, have been reported very rarely. 
p. Vascular Disorders: Clinical signs of peripheral vasculitis and gangrene 
have been reported very rarely.  
q. Skin: Cellulitis and non-serious injection site reactions in the absence of 
extravasation have been rarely reported. Sever skin reactions, including 
desquamation and bullous skin eruptions, have been reported very rarely. 
r. Hepatic: Increased liver function tests including elevations in aspartate 
aminotransferase (AST), alaine aminotransferase (ALT), gamma-glutamyl 
transferase (GGT), alkaline phosphatase, Lactate dehydrogenase (LDH), 
and bilirubin levels have been reported rarely. Serious hepatotoxicity 
including liver failure and death has been reported very rarely in patients 
receiving Gemzar alone or in combination with other potentially 
hepatotoxic drugs.  
s. Injury, Poisoning, and Procedural Complications: Radiation recall 
reactions have been reported.  
 
5. Pharmaceutical Data:  
Gemzar is supplied as a lyophilized powder in sterile vials containing 200 mg or 1 
g of Gemzar as the hydrochloride salt (expressed as the free base), mannitol, 
and sodium acetate. Drug vials will be reconstituted with normal saline added to 
the vial to make a solution ideally containing 10 mg/mL or less. The 
concentration for 200 mg and 1 g vials should be nor greater than 40 mg/mL. An 
appropriate amount of drug will be prepared with normal saline and administered 
as a continuous infusion at 6 mg/m2/24 hours x 5 (on day 1, 3, 5, 7 and 9; total 
dose 30 mg/m2/ten days). Once the drug has been reconstituted, it should be 
stored at room temperature and used within 24 hours. 
 
6. Storage and Stability: 
Store at controlled room temperature (20-250C), should be handled and disposed 
of in a manner consistent with other anti-cancer drugs. 
 
7. Route of Administration: 
Intravenous continuous infusion at fixed dose rate of 6mg/m2/24h. 
 
8. Supplier:  
Gemzar is commercially available from Eli Lilly and Company, Indianapolis, 
Indiana. 
 
 

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Pretreatment Evaluation 
Within 28 Days Prior to Study Enrollment: Subjects must have appropriate lab and 
radiographic studies (CT chest, abdomen and pelvis); CBC; blood chemistries; liver 
function tests; kidney function test; and pregnancy test) conducted prior to study 
enrollment to meet eligibility criteria. A history and physical, concurrent medications, and 
vitals will also be collected during the pre-treatment evaluation.  These studies are 
considered standard of care in the evaluation and treatment of patients with pancreatic 
cancer.   
 
Preoperative Evaluation: 
1. During therapy, a study investigator or oncology nurse must see each subject 
before Tuesday and Sunday of pre-operative chemotherapy, +/- 3 days 
respectively and at the pre-operative evaluation visit. 
2. The subject will be assessed as follows: 
a. Complete blood count (CBC: hemoglobin, hematocrit, red blood cells 
[RBC], white blood cells [WBC], platelets, and differential blood cell 
counts (neutrophils, lymphocytes, monocytes, eosinophils, basophils) 
before day 1 and 5 of Gemzar.(+/- 2 days) 
b. Blood 
chemistries 
(bilirubin, 
alkaline 
phosphatase, 
ALT, 
AST, 
phosphorus, calcium, glucose, total protein, albumin, and electrolytes 
[sodium, potassium, CO2, chloride, and magnesium] on day 1. 
c. Kidney Function: includes BUN and creatinine 
d. Liver function: AST, ALT, GGT, alkaline phosphatase, LDH, and bilirubin. 
e. History and physical and concurrent medications will be collected. 
f. Vital signs (blood pressure and pulse rate)will be collected. 
g. Subjects must have a WBC count greater than or equal to 3000 cells/uL 
and platelet count greater than or equal to 100,000 cells/IU to meet 
eligibility criteria. 
3. After completion of treatment, subjects will have approximately a 4 week rest 
period followed by a restaging chest, abdomen, and pelvis CT scan, Ca19-9 and 
then surgery. 
 
Post-surgery Evaluation: 
Within 12 weeks  after surgery, the subject will have: 
1. Complete blood count: hemoglobin, hematocrit, RBC, WBC, platelets), and 
differential blood cell counts (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) before each dose of Gemzar.  
2. Blood chemistries (bilirubin, alkaline phosphatase, ALT, AST, BUN, creatinine, 
phosphorus, calcium, glucose, total protein, albumin, and electrolytes [sodium, 
potassium, CO2, chloride, and magnesium]) every 4 weeks ± 2 days.   
3. Vital signs (blood pressure and pulse rate) on days of infusion prior to treatment. 
4. Within 12 weeks (13 to 17 weeks +/- 2 days after enrollment) of completion of 
surgery, subjects with an adequate performance status will be considered for 
adjuvant therapy with Gemzar.  A restaging scan will be required prior to starting 
adjuvant therapy and will be repeated prior to cycles 1, 3, and 5 of postoperative 
therapy. 
 
 

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Survival: 
1. The primary endpoint in this study is resection rate. Survival will be followed as a 
secondary endpoint, as measured from the time of histologic or cytologic 
diagnosis of pancreatic adenocarcinoma. Patterns of tumor recurrence and 
survival will be assessed by reviewing routine surveillance CT scans. 
2. After completion of Gemzar adjuvant chemotherapy. All subjects will be followed 
with a CT scan of the chest, and abdomen with/without pelvis approximately 
every 6 months following surgery for five years. 
 
Criteria for Removal from Study: 
1. Inability of subject to comply with study requirements 
2. Determination by the investigator that it is no longer safe for the subject to 
continue therapy 
3. Local progression or metastatic disease after chemoradiation. 
 
Statistical Considerations: 
1. This is a single-arm phase II study of preoperative chemotherapy (Gemzar) with 
radiation therapy in subjects with borderline resectable or unresectable 
pancreatic adenocarcinoma. The primary objective is to assess margin-negative 
resection rate (R0RR) after preoperative chemotherapy with radiation therapy for 
subjects with unresectable or borderline resectable adenocarcinoma of the 
pancreas. R0RR is defined as percentage of subjects with R0R compared to the 
total number of subjects who entered the trial. 
2. Secondary endpoints include an assessment of safety of preoperative 
chemotherapy and radiation therapy in this population.  Other secondary 
endpoints include disease-free survival, overall survival, and the patterns of 
recurrence (local, regional, or distant). 
3. A total of 20 subjects will be accrued at a rate of 1-2 subjects per month. 
Approximately 24% of subjects will likely not undergo surgery (from the MD 
Anderson experience; due to distant metastases on restaging), which results in 
an estimated total ±margin of error of approximately 15±4 subjects. 
4. The UAMS CCTO will collect the data.  
5. Statistical Methods: Subjects with pancreatic cancer will undergo an initial 
“baseline” assessment via CT scan.  On the basis of their baseline CT scan, 
subjects with pancreatic cancer are staged into three groups: Resectable (~20% 
of total), locally advanced/unresectable (35%–40% of total), and Metastatic (40% 
of total).  The protocol proposes to recruit subjects in the Locally Advanced 
group, treat them with a combination of Gemzar and radiation, administer 
another CT scan at Day 37 (±2 days) after treatment commences, and determine 
from the CT scan the proportion of subjects who have progressed locally or 
developed metastatic disease. Subjects who have evidence of progression (local 
progression or metastatic spread) will not be taken to surgery. All the other 
subjects will be offered exploratory laparotomy for resection.  The maximum 
feasible accrual is estimated to be 20 subjects in a one-year period, and the 
target sample size is thus 20 subjects.  We expect to screen approximately 
40 subjects in order to achieve our enrollment goal of 20 subjects at the 
University of Arkansas for Medical Sciences.  A 30% R0 resection rate 

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(R0RR) would be considered evidence of treatment efficacy, whereas a 10% 
R0RR would not.  
6. Statistical Analysis: This is a phase II study designed to obtain preliminary 
estimate of the R0RR associated with the proposed treatment, for purposes of 
determining the feasibility of a future larger randomized clinical trial.  In this pilot 
study, the two most important pieces of information will be (1) the “point estimate” 
or observed proportion of subjects who underwent R0 resection after their 
treatment, and (2) the “interval estimate” or exact binomial 2-sided 90% 
confidence interval on the observed proportion R0RR.  Twenty subjects with 
locally advanced pancreatic cancer will be enrolled, treated, and assessed via 
CT scan then explored for whether their disease has become resectable 
following treatment.  The table below shows the observed proportions, and the 
upper and lower 90% confidence limits on each observed proportion that we 
would obtain if from four to seven subjects (out of 20 enrolled) underwent 
resection with successful R0 outcome following treatment. 
 
Number 
R0RR  
Observed 
Proportion 
90% Lower  
Conf Limit 
90% Upper 
Conf Limit 
4 
0.20 
0.0714 
0.4010 
5 
0.25 
0.1041 
0.4556 
6 
0.30 
0.1396 
0.5078 
7 
0.35 
0.1773 
0.5580 
 
It should be noted that the 90% lower confidence limit will be above 0.10 if the 
number of R0 resections is 5 or more.  Inasmuch as a R0RR of 0.10 represents 
lack of treatment efficacy, this result indicates that 20 subjects will confer enough 
precision on the observed proportion R0RR to meet the information-collection 
goals of this pilot study. 
 
For secondary analyses, overall survival is defined as the time from enrollment to 
death or last follow-up. Disease-free survival is defined as the time from surgery 
to progression or death or last follow-up, whichever occurs first. Kaplan-Meier 
method will be used to estimate the overall survival.  Disease-free survival will 
also be estimated using the Kaplan-Meier method. The Kaplan-Meier method 
also will be used to generate the curves of the time to local or distant failure.  
 
DATA AND PROTOCOL MANAGEMENT 
 
Study management will be handled by the Cancer Clinical Trials Office (CCTO) in the 
Winthrop P. Rockefeller Cancer Institute, 4301 West Markham, Slot #724, Little Rock, 
AR 72205. 
 
After informed consent is obtained, subjects will be registered on the trial by CCTO.  
 
 
 

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ADVERSE EVENTS REPORTING REQUIREMENTS 
 
Investigators are required to report to the UAMS IRB ALL serious treatment emergent 
adverse event (STEAE) as soon as possible. The methods for collecting safety data are 
described below.  
 
Adverse Events 
1. Definitions 
The definitions of adverse events (AEs), serious adverse events (SAEs) and 
other significant adverse events (OAEs) are given below.  It is of the utmost 
importance that all staff involved in the study is familiar with the content of this 
section.  The principal investigator is responsible for ensuring this. 
 
2. Adverse Event (AE) 
An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the 
product.  An undesirable medical condition can be symptoms (e.g., nausea, 
chest pain), or signs (e.g., tachycardia, enlarged liver).  In clinical studies, an AE 
can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered.   
 
3. Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, 
treatment, washout, follow-up), and at any dose of the investigational product, 
comparator or placebo, that fulfills one or more of the following criteria: 
a. Results in death 
b. Is immediately life-threatening 
c. Requires 
in-subject 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization 
d. Results in persistent or significant disability or incapacity 
e. Is a congenital abnormality or birth defect in the offspring of the subject 
f. Is an important medical even that may jeopardize the subject or may 
require medical intervention to prevent one of the outcomes listed above.  
 
Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening, or result in death or 
hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above. These should 
also usually be considered serious. 
 
The causality of SAEs (i.e., their relationship to study treatment) will be assessed 
by the investigator(s), who in completing the relevant case report form must 
answer “yes” or “no” to the question “Do you consider that there is a reasonable 
possibility that the event may have been caused by the drug?”   
 
4. Other Significant Adverse Event (OAE) 

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OAEs will be identified by the Drug Safety Physician and if applicable also by the 
Clinical Study Team Physician during the evaluation of safety data for the Clinical 
Study Report.  Significant adverse events of particular clinical importance, other 
than SAEs and those AEs leading to discontinuation of the subject from study 
treatment, will be classified as OAEs.  Examples of these are marked 
hematological and other laboratory abnormalities, and certain events that lead to 
intervention (other than those already classified as serious), dose reduction or 
significant additional treatment.  For each OAE, a narrative may be written and 
included in the Clinical Study Report. 
 
Recording of Adverse Events: 
Any detrimental change in a subject’s condition, subsequent to the subject entering the 
study should be considered an AE.   
 
Method of detecting AE/SAE: 
At each visit the method of detecting AE and SAEs in this study will be by: 
1. Information volunteered by the subject, or caregiver 
2. Open-ended and non-leading verbal questioning of the subject at every visit such 
as the following: How are you feeling? Have you had any (other) medical 
problems since your last visit 
3. Observation by the investigational team, other care providers or relatives 
 
AUDITS AND INSPECTIONS 
 
Regulatory authorities or the Institutional Review Board (IRB) may perform audits or 
inspections, including source data verification.  The purpose of such an audit or 
inspection is to systematically and independently examine all study related activities and 
documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonization (ICH), and 
any applicable regulatory requirements.   
 
TRAINING OF STAFF 
 
The principal investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).  Dr. Makhoul will ensure that appropriate training 
relevant to the study is given to all study staff, and that any new information of relevance 
to the performance of this study is forwarded to the staff involved. 
 
 
A Site Initiation Visit will be conducted at the University of Arkansas for Medical 
Sciences for UAMS staff. 
 
CHANGES TO THE PROTOCOL 
 
Study procedures will not be changed without approval from the IRB. If it is necessary 
for the study protocol to be amended, the amendment or a new version of the study 
protocol (Amended Protocol) must be approved by the UAMS IRB, and if applicable, by 

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the local regulatory authority, before implementation.  Local and federal (Food and Drug 
Administration [FDA]) requirements must be followed. 
 
If a protocol amendment requires a change to the Written Informed Consent Form, the 
IRB must be notified.  Approval of the revised Written Informed Consent Form by the 
IRB and study sponsor is required before the revised form is used.  
 
The principal investigator is responsible for the distribution of these documents to the 
sub-investigators and staff involved with the study.  
 
ETHICS 
 
Ethics Review: 
The final study protocol, including the final version of the Written Informed Consent 
Form, must be approved in writing by the UAMS IRB.  The principal investigator is 
responsible for informing the IRB of any amendment to the protocol in accordance with 
local requirements.  In addition, the IRB must approve all advertising used to recruit 
subjects for the study.  The protocol must be re-approved by the IRB annually. 
 
Ethical Conduct of the Study: 
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and 
applicable regulatory requirements. 
 
Written Informed Consent: 
The principal investigator will ensure the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study. 
Subjects must also be notified that they are free to discontinue from the study at any 
time. The subject should be given the opportunity to ask questions and allowed time to 
consider the information provided. The subject’s signed and dated informed consent 
must be obtained before conducting any procedure specifically for the study. 
 
The principal investigator must store the original, signed Written Informed Consent Form 
in the subject’s medical record as well as his/her study subject file.  A copy of the signed 
Written Informed Consent Form must be given to the subject. The consent process will 
be documented in the subject’s medical records.  
 
Subject Data Protection: 
The Written Informed Consent Form will explain that for data verification purposes, a 
regulatory authority, and the IRB may require direct access to parts of the hospital or 
practice records relevant to the study, including subjects’ medical history. 
 
EMERGENCY PROCEDURES 
 
Procedures in Case of Medical Emergency: 
The principal investigator(s) is responsible for ensuring that procedures and expertise 
are available to handle medical emergencies during the study. 
 

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Procedures in Case of Overdose: 
There is currently no known antidote for Gemzar.  The treatment of AEs associated with 
overdose should be supportive for the underlying adverse symptoms. 
Doses of study treatment in excess of that specified in the clinical study protocol are 
considered to be an overdose. Overdose, with or without associated symptoms should 
be handled in the same way as a deviation and sent to IRB.  Signs or symptoms of an 
overdose that meet the criteria of serious should be reported as a SAE in the appropriate 
timeframes and be documented as clinical sequelae to an overdose. 
 
DATA SAFETY MONITORING PLAN 
 
The principal investigator and all research staff associated with this trial have received 
training and certification in human subject protections research and are ultimately 
responsible for monitoring the safety of this trial. 
 
The PI will continuously monitor this trial and more frequently safety related data. This 
trial will also be reviewed periodically by physicians and research staff at the 
Gastrointestinal Malignancy Group meeting.  
 
Monitoring will be provided by the Research Support Center (RSC) for this clinical trial.  
The monitor will assure that the rights and well – being of human subjects are protected 
and the data are accurate, complete and verifiable from source documents and the trial 
is conducted in compliance with currently approved protocol/amendments, with good 
clinical practice (GCP) and the applicable regulatory requirements. 
 
The monitor will be familiar with the protocol, the informed consent form, any other 
information provided to the subjects, the standard operating procedures (SOP), GCP 
and applicable regulatory requirements. 
 
Monitors will have access to subject medical records and other study-related records. 
The principal investigator agrees to cooperate with the monitor (s) to ensure that any 
problems detected in the course of these monitoring visits are resolved.  Personal 
contact between the monitor and the investigator will be maintained throughout the 
clinical trial to assure that the investigator is fulfilling his obligations and the facilities 
used in the clinical trial remain acceptable. 
 
Investigational Products: 
Gemzar is the current standard of care for the treatment of pancreatic cancer. The doses 
used in this protocol are much smaller than usual for this drug. Radiation therapy for 
unresectable pancreatic cancer is also considered standard of care. The total dose used 
here is below usual too. The only difference with standard of care in the use of these 
therapeutic methods is the shortened schedule of chemoradiotherapy administration.  In 
addition, we are attempting to perform margin negative surgery on subjects initially felt to 
be borderline or unresectable.  
 
Monitoring Report: 
After each monitoring visit a separate monitoring report will be generated and submitted 
to the principal investigator and project manager. This report will include significant 

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findings related to deficiencies and deviations from the protocol, SOPs, GCP, and the 
applicable regulatory requirements and actions taken to prevent recurrence of the 
detected deviations. The report will make recommendations for actions to be taken to 
secure compliance.   
 
Continuing Review: 
An annual report will be compiled and sent to the IRB to report on number of subjects 
enrolled in the study and safety events and accrual schedule.  
 
DATA QUALITY ASSURANCE AND DOCUMENTATION 
 
CRF’s should be filled by qualified personnel, reviewed, dated and signed by the 
investigator.  The forms have to be completed in a neat and legible manner with black or 
blue ballpoint pen.  No entries should be erased or over written or correction fluid or 
white out be used. Corrections can only be crossed out with a single line and should 
have the date and initials of the person making the change. 
 
Source Documents are defined as original documents with original observations and 
information about the clinical investigation.  All electronic source documents should be 
21 CFR 11 compliant.  Source documents will include progress notes, computer print 
outs, laboratory data and all recorded data from automated instruments.  Monitor will 
review CRF’s against source documentation for accuracy of the information. Subject 
Confidentiality will be maintained. CRFs will not include any personal identification 
information such as name etc.  Subjects will be identified with Initials and subject study 
number only. 
 
RETENTION OF RECORDS 
 
All documentation related to this trial will be retained for 2 years after the investigator is 
complete.  
 
TISSUE BANKING 
 
All tissue samples will be collected according to UAMS Tissue bank SOPs. The subject 
will be asked to give permission for the storage of their pancreatic tumor tissue for future 
correlative studies that will include DNA, RNA or protein studies. 
 
 
 
 

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REFERENCES 
References 
 
 
1.  Raut CP, Evans DB, Crane CH et al. Neoadjuvant therapy for resectable 
pancreatic cancer. Surg Oncol Clin N Am 2004; 13:639-61, ix. 
 
2.  Crane CH, Varadhachary G, Settle SH et al. The integration of chemoradiation in 
the care of patient with localized pancreatic cancer. Cancer Radiother 2009; 
13:123-143. 
 
3.   Borderline resectable criteria. NCCN clinical guidelines Pancreatic 
adenocarcinoma, http://www nccn org 2009. 
 
4.  Mehta VK, Fisher G, Ford JA et al. Preoperative chemoradiation for marginally 
resectable adenocarcinoma of the pancreas. J Gastrointest Surg 2001; 5:27-35. 
 
5.  Katz MH, Pisters PW, Evans DB et al. Borderline resectable pancreatic cancer: 
the importance of this emerging stage of disease. J Am Coll Surg 2008; 206:833-
846. 
 
6.  Evans DB, Rich TA, Byrd DR et al. Preoperative chemoradiation and 
pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg 1992; 
127:1335-1339. 
 
7.  Evans DB, Varadhachary GR, Crane CH et al. Preoperative gemcitabine-based 
chemoradiation for patients with resectable adenocarcinoma of the pancreatic 
head. J Clin Oncol 2008; 26:3496-3502. 

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8.  Marti JL, Hochster HS, Hiotis SP et al. Phase I/II trial of induction chemotherapy 
followed by concurrent chemoradiotherapy and surgery for locoregionally 
advanced pancreatic cancer. Ann Surg Oncol 2008; 15:3521-3531. 
 
9.  McGinn CJ, Lawrence TS, Zalupski MM. On the development of gemcitabine-
based chemoradiotherapy regimens in pancreatic cancer. Cancer 2002; 95:933-
940. 
 10.  Mason KA, Milas L, Hunter NR et al. Maximizing therapeutic gain with 
gemcitabine and fractionated radiation. Int J Radiat Oncol Biol Phys 1999; 
44:1125-1135. 
 11.  Fields MT, Eisbruch A, Normolle D et al. Radiosensitization produced in vivo by 
once- vs. twice-weekly 2'2'-difluoro-2'-deoxycytidine (gemcitabine). Int J Radiat 
Oncol Biol Phys 2000; 47:785-791. 
 12.  Poplin EA, Corbett T, Flaherty L et al. Difluorodeoxycytidine (dFdC)--
gemcitabine: a phase I study. Invest New Drugs 1992; 10:165-170. 
 13.  Blackstock AW, Tepper JE, Niedwiecki D et al. Cancer and leukemia group B 
(CALGB) 89805: phase II chemoradiation trial using gemcitabine in patients with 
locoregional adenocarcinoma of the pancreas. Int J Gastrointest Cancer 2003; 
34:107-116. 

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 14.  Blackstock AW, Mornex F, Partensky C et al. Adjuvant gemcitabine and 
concurrent radiation for patients with resected pancreatic cancer: a phase II study. 
Br J Cancer 2006; 95:260-265. 
 15.  Huguet F, Girard N, Guerche CS et al. Chemoradiotherapy in the management of 
locally advanced pancreatic carcinoma: a qualitative systematic review. J Clin 
Oncol 2009; 27:2269-2277. 
 16.  Rajdev L, Goldberg G, Hopkins U et al. A phase I trial of gemcitabine 
administered as a 96-h continuous intravenous infusion in patients with advanced 
carcinoma and lymphoma. Med Oncol 2006; 23:369-376. 
 17.  McGinn CJ, Zalupski MM, Shureiqi I et al. Phase I trial of radiation dose 
escalation with concurrent weekly full-dose gemcitabine in patients with 
advanced pancreatic cancer. J Clin Oncol 2001; 19:4202-4208. 
 18.  Murphy JD, Adusumilli S, Griffith KA et al. Full-dose gemcitabine and 
concurrent radiotherapy for unresectable pancreatic cancer. Int J Radiat Oncol 
Biol Phys 2007; 68:801-808. 
 19.  Schellenberg D, Goodman KA, Lee F et al. Gemcitabine chemotherapy and 
single-fraction stereotactic body radiotherapy for locally advanced pancreatic 
cancer. Int J Radiat Oncol Biol Phys 2008; 72:678-686. 

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 20.  Gemcitabine prescribing information. http://pi.lilly.com/us/gemzar.pdf.  2007. 3-
22-2010.  
Ref Type: Internet Communication 
 
 

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Appendix  
A: ECOG Performance Scale 
ECOG 
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about more than 50% of waking 
hours 
3 
Capable of only limited selfcare, confined to bed or chair more 
than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally 
confined to bed or chair. 
5 
Dead 
 
 
 
 

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B: New York Heart Association Class Scale 
 
NYHA 
Class 
Symptoms 
I 
No symptoms and no limitation in ordinary physical activity, e.g. 
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.