Clinical trial NCT02128100
Conditions: Pancreatic Cancer Non-resectable
Keywords: Pancreatic Cancer
Sponsor: University of Louisville
Start date: 2014-09-19; Completion date: 2021-03-15
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study wants to find out how safe and effective the use of Folfirinox combined with Stereotactic Body Radiation Therapy )(SBRT) is for the treatment of pancreatic cancer.

Detailed description:
The study will be a prospective, non-randomized, single center, trial to assess the effects of FOLIRINOX chemotherapy with SBRT on locally advanced, non-resectable pancreatic cancer. Patients will either undergo a biopsy to confirm the diagnosis or have strong clinical suspicion of a new cancer or recurrence based on the recommendations of a multi-disciplinary GI oncology team. FOLFIRINOX with be delivered prior to SBRT for 4 cycles. Restaging imaging will occur prior to SBRT delivery. SBRT will be delivered using standard stereotactic techniques to a dose of 3200cGy at 650cGy per fraction delivered over 2 weeks. Additional adjuvant chemotherapy with be delivered at the physician's discretion. Patients will be reassessed both clinically and radiographically at 3 months, 6 months, 9 months and 12 months post-treatment. Quality of life analysis will occur at 3 month intervals after treatment. Blood will be drawn for exploratory biomarker analysis at strategic timepoints during treatment and followup. Following the initial imaging time points, standard surveillance will be employed with clinical assessment and imaging at 3 month intervals for the first 2 years post-treatment.

Arms: arm 1: Folfirinox

* Oxaliplatin 85 mg/m² for over 2 hours,
* Leucovorin 400n mg/m² for over 2 hours,
* Irinotecan 180 mg/m² for over 90 minutes, along with Leucovorin infusion
* Fluorouracil 400 mg/m² as a fast infusion over 15 minutes
* Fluorouracil 2400 mg/m² as a slow infusion over 46 hours

SBRT 5 treatments of stereotactic body radiation therapy (SBRT) over the course of two weeks with a minimum of 36 hours in between each treatment.
Interventions: intervention 1: Folfirinox intervention 2: Stereotactic Body Radiation Therapy
Intervention descriptions: intervention 1: * Oxaliplatin 85 mg/m² for over 2 hours,
* Leucovorin 400n mg/m² for over 2 hours,
* Irinotecan 180 mg/m² for over 90 minutes, along with Leucovorin infusion
* Fluorouracil 400 mg/m² as a fast infusion over 15 minutes
* Fluorouracil 2400 mg/m² as a slow infusion over 46 hours intervention 2: 5 treatments of stereotactic ablative radiotherapy (SABR) over the course of two weeks with a minimum of 36 hours in between each treatment.

Protocol documents:
Prot_SAP_000.pdf: 
The effect of chemotherapy and stereotactic body radiation therapy for locally 
advanced, non-resectable pancreatic cancer 
 
NCT02128100 
Protocol v.2 (10SEP2015) 
 


The effect of chemotherapy and stereotactic body radiation therapy for locally 
advanced, non-resectable pancreatic cancer 
JAMES GRAHAM BROWN CANCER CENTER
DEPARTMENT OF RADIATION ONCOLOGY
UNIVERSITY OF LOUISVILLE SCHOOL OF MEDICINE
529 S. Jackson Street
Louisville, KY 40202
TELEPHONE: 502-561-2700
FAX: 502-561-2709
CLINICAL TRIALS OFFICE
UNIVERSITY OF LOUISVILLE SCHOOL OF MEDICINE
Brown Cancer Center, Room 420
529 South Jackson Street, 4th Floor
Louisville, KY 40202
TELEPHONE: 502- 562-3429
FAX: 502- 562-3462
Version Date:  9/10/15
This protocol was designed and developed by the JGBCC, Department of Radiation Oncology. It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry. No other use or reproduction is 


1
authorized by the JGBCC, Department of Radiation Oncology nor does the JGBCC, Department of Radiation 
Oncology assume any responsibility for unauthorized use of this protocol.
Table of Contents
       STUDY SCHEMA
2
       SYNOPSIS 
3
1.0   BACKGROUND
4 
2.0   OBJECTIVES/STUDY DESIGN
6
3.0   PATIENT SELECTION
6 
3.1 Inclusion Criteria
3.2 Exclusion Criteria
4.0   TREATMENT PLAN
7 
4.1 SBRT
4.2 Chemotherapy
5.0   ADVERSE EVENTS
12
5.1 Expected SBRT Toxicities 
5.2 Expected Chemotherapy Toxicities 
6.0   FOLLOW-UP AND RESPONSE CRITERIA
13
7.0   STUDY CALENDAR
14
8.0  SUBJECT REGISTRATION AND DATA COLLECTION
16
9.0  DSMC REVIEW
16
10.  ETHICAL AND REGULATORY CONSIDERATIONS
16
11.  STATISTICAL CONSIDERATIONS
17
12.  REFERENCES
20
13. APPENDICES
23
Appendix A: Chemotherapy Dose Modifications
23


2
Study Schema
To combine chemotherapy with 5 fraction SBRT in patients with locally advanced, non-
resectable pancreatic cancer in order to determine treatment toxicity and efficacy.  


3
SYNOPSIS
Name of Sponsor:
James Graham Brown Cancer Center
Title of Study:
The effect of chemotherapy and stereotactic body radiation therapy for locally advanced, 
non-resectable pancreatic cancer 
Schema: Eligible primary locally advanced, unresectable pancreatic cancer.  Patients will 
be treated with chemotherapy and SBRT to 4000cGy delivered in 5 fractions over 14 days.
Primary objective:  To estimate toxicity and efficacy
Protocol No.:
BCC-RAD-13-chemotherapy and SBRT
Investigators:
Neal E Dunlap and Rebecca Redman
Study Center:
James Graham Brown Cancer Center
Study Duration:  Approximately 48 months


4
1.  Background
Pancreatic cancer remains the fourth leading cause of cancer deaths in the United States 
(1).  Despite efforts to improve chemotherapy and radiation treatment regimens, surgical 
ressection remains the only modality associated with long-term survival (2).  
Approximately 40-50% of pancreatic cancer patients present with localized yet 
unresectable disease with a reported median survival of 6 – 14 months.  These results vary based 
on the patient characteristics, intensity of treatment regimen and those with borderline resectable 
disease (3-7).  Although the Gastrointestinal study group established the standard of care as 
combined modality treatment with chemotherapy and radiation, the most appropriate method for 
integrating radiation into the treatment regimen remains unestablished especially with the 
introduction of newer, more intense chemotherapy regimems.  Data using combined modality 
therapy typically results in locoregional control rates of 40-50%, but the role of multi-modality 
therapy is not well defined.  Recent data from the Eastern Cooperative Oncology Group (ECOG) 
demonstated that radiation of 50.4Gy in combination with gemcitabine improves median survival 
compared to gemcitabine alone (8).  
Although many people ultimately fail distantly, locoregional control remains an 
important aspect of treatment due to the significant impact on morbidity and quality of life.  
Attempts have been made to increase radiaiton dose or hypofractionate radiation dose to improve 
outcome varying reults.  Recent advances in radiation therapy delivery using image-guidance 
and high dose delivery with stereotactic body radiation therapy have resulted in the potential of 
dose escalation to the primary tumor.  Schellenberg et al. (9)  demonstated that single fraction 
SBRT with gemcitabine showed local control rates of 82% with a median follow up of 22 
months.  Only 2 patients developed late grade 3 toxicity (12%) in the form of duodenal stricture 
requiring stent placement.  Similarly, Mahadevan et al (10) showed a 3-fraction SBRT regimen 
in combination with gemcitabine resulted in local control rates of 78% with 14% grade 3 
toxicity.
Despite improvements in locoregional control, the impact on overall survival has been 
limited as the vast majority of patients will ultimately die of metastatic disease.  Single-agent 
gemcitabine and gemcitabine-based doublets were the mainstay of treatment for metastatic 
pancreatic cancer until recently, although median survival rarely exceeded 8 months and 
objective response rates were generally less than 20% (11-14).  However, a randomized phase III 
study conducted by Conroy et al. (15) demonstrated that combination chemotherapy consisting 
of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) significantly improved 
median survival to 11.1 months as compared to 6.8 months in those treated with single-agent 
gemcitabine.  Treatment-related toxicity was also increased with FOLFIRINOX, primarily 
gastrointestinal (nausea, vomiting, and diarrhea), cytopenias, and neuropathy.  In addition, the 
objective response rate was 32% as compared to 9% with gemcitabine.  As a result of this study, 
FOLFIRINOX is now widely accepted as a standard first-line therapy for patients with locally 
advanced and unresectable or metastatic pancreatic adenocarcinoma who have a good 
performance status.  The influence of irinotecan on the efficacy of FOLFIRINOX is unknown as 
a similar response rate was reported in a single-arm study of 30 patients receiving infusional 5-
fluorouracil, leucovorin, and oxaliplatin (16).  Since the metabolism of irinotecan is primarily 
hepatic, FOLFOX is an acceptable alternative, particularly in patients with an abnormal 
bilirubin.   Gemcitabine and nab (nanoparticle albumin bound)-paclitaxel represents an 
alternative option for first-line treatment based upon results of a multicenter, randomized study 


5
of 861 patients with metastatic pancreatic cancer, which demonstrated superiority of this 
combination over gemcitabine alone (17).  Median overall survival in the gemcitabine and nab-
paclitaxel arm was 8.5 months with an objective response rate of 23%.  Although median 
survival was shorter than that reported with FOLFIRINOX, it remains an acceptable alternative 
for patients with  biliary obstruction or for those deemed not to be a candidate for 
FOLFIRINOX.
The objective of this phase II study is to combine chemotherapy with 5 fraction SBRT in 
patients with locally advanced, non-resectable pancreatic cancer in order to determine treatment 
toxicity and efficacy.  


6
2.  Objectives and Study Design
The objective of this prospective phase II protocol is to assess the toxicity and efficacy of 
chemotherapy with 5 fraction SBRT in patients with locally advanced, non-resectable pancreatic 
cancer in order to document treatment toxicity and estimate efficacy.  
2.1  Primary Objective:
2.1.1. To document treatment related toxicities
2.1.2. Establish the efficacy of treatment
2.2  Secondary Objectives:
2.2.1.   To estimate progression free survival
2.2.2.   To estimate local failure
2.2.3.   To estimate overall survival
2.2.4.   To estimate quality of life
2.2.5.   To explore effects of covariates (demographics, disease and treatment related) on 
toxicity, local failure, PFS and OS and QOL.
2.2.6. To explore the use of differential scanning calorimetry as a method for monitoring 
disease status
2.3  Study design:
The study will be a prospective, non-randomized, single center, trial to assess the effects of 
chemotherapy with SBRT on locally advanced, non-resectable pancreatic cancer.  Chemotherapy  
will be delivered prior to SBRT for 8 weeks.  Restaging imaging will occur prior to SBRT 
delivery.  Patients who develop unequivocal evidence of metastatic disease following 8 weeks of 
first-line chemotherapy will be followed off study for survival, but will not undergo SBRT or 
additional study-related procedures.  SBRT will be delivered using standard stereotactic 
techniques to a dose of 3200cGy at 650cGy per fraction delivered over 2 weeks.  Additional 
chemotherapy with be delivered at the physician’s discretion.  Patients will be reassessed both 
clinically and radiographically at 3 months, 6 months, 9 months and 12 months post-treatment.  
Quality of life analysis will occur at 3 month intervals after treatment.  Blood will be drawn for 
exploratory biomarker analysis at strategic timepoints during treatment and followup.  Following 
the initial imaging time points, standard surveillance will be employed with clinical assessment 
and imaging at 3 month intervals for the first 2 years post-treatment.
3. Patient Selection
     3.1  Eligibility Criteria


7
3.1.1
Age >/= 18 years
3.1.2
ECOG performance status 0-2
3.1.3
Pathologic diagnosis of pancreatic adenocarcinoma 
3.1.4
Imaging as follows:
-CT scan of the chest, abdomen and pelvis with IV and oral 
contrast within 8 weeks of registration
3.1.5
Evaluation by a surgical oncologist to determine non-resectability
3.1.6
Negative serum pregnancy test within 2 weeks prior to registration for 
women of childbearing potential.
3.1.7
CBC/differential obtained within 14 days prior to registration with 
adequate bone marrow function as follows:
3.1.7.1 ANC > 1,500 cell/mm3
3.1.7.2 Platelets > 100,000 cells/mm3
3.1.7.3 Hemoglobin > 8.0 g/dl (transfusion to obtain this value is 
permissible) 
3.1.8
Additional labs within 14 days prior to registration
3.1.8.1 CA 19-9
3.1.8.2 Creatinine <2mg/dl
3.1.8.3 Bilirubin <3mg/dl
3.1.8.4 AST and ALT < 3 x ULN
3.1.9
 Patients must provide study specific informed consent prior to study 
entry.
  
3.2 Exclusion Criteria
3.2.1. Metastatic disease as defined by the multi-disciplinary team
3.2.2. Prior anti-cancer therapy for a pancreatic tumor
3.2.3. Prior malignancy within the last 3 years
3.2.4. Pregnant women or lactating women
3.2.5. Acquired Immune Deficiency Syndrome (AIDS) based on CDC criteria.  
However HIV testing is not manditory for this protocol
4.
Treatment
 4.1 External Beam Radiation
4.1.1.  Localization, Positioning and Immobilization:
A volumetric planning CT study will be required to define the gross tumor 
volume (GTV) and planning target volume (PTV).  Each patient will be 


8
positioned in an immobilization device in the treatment position on a flat 
table.  Contiguous CT slices of 1-3 mm will be obtained to include the 
entire treatment volume.  The GTV, PTV and normal organs will be 
outlined on all appropriate CT slices.  
4.1.2.  4-D CT:  The use of 4-D CT radiation treatment planning is required on all     
patients.  Acceptable methods for acquiring tumor motion include:  design 
of the PTV to cover the excursion of the primary cancer and nodes during 
breathing such as an ITV approach, a maximum intensity projection (MIP) 
approach or a gating approach.
4.1.3   Treatment planning:  Treatment planning will be performed using 
either  conformal therapy or intensity modulated radiation therapy 
(IMRT).  Cyberknife treatment is allowed.  Any combination of coplanar 
or non-coplanar fields designed to cover the target volumes while limiting 
dose to critical structures is allowed.  Composite dosimetry plans of the 
prior treatment volume and the new treatment plan will be generated if 
prior dosimetry is available.  Standard SBRT treatment planning should be 
utilized.  Successful treatment planning should attempt to meet the 
following:
-Normalization:  The plan should be normalized such that 100% 
corresponds to the center of mass of the PTV
-Prescription Isodose Surface Coverage:  The prescription isodose 
surface will be chosen such that 95% of the PTV is conformally 
covered by the prescription isodose surface and 99% of the PTV 
receives a minimum of 90% of the dose.
4.1.4.  Critical structures and dose limits:  Standard dose constraints to critical
structures will be utilized for and SBRT as outlined by Quantitative  
Analyses of Normal Tissue Effects in the Clinic (QUANTEC)
4.1.5.  Treatments:  3200cGy delivered in 5 fractions at 650 cGy per faction to the 
PTV is required.  Radiation treatments must be completed within 14 days 
of initiation of therapy and have a minimum of 36 hours between 
fractions.  Daily image guidance is required with cone beam CT.  
Respiratory gating or abdominal compression may be utilized as deemed 
appropriate by the treating physician and physicist.
4.2 Chemotherapy
4.2.1
Patients will receive one of the following chemotherapy regimens at the 
discretion of the treating physician:
FOLFIRINOX administered intravenously on day 1 of each 14-day cycle 
for 4 cycles:  

Oxaliplatin 85 mg/m2 over 2 hours

Leucovorin 400 mg/m2 over 2 hours


9

Irinotecan 180 mg/m2 over 90 minutes, concurrent with leucovorin 
through a Y-connector, started 30 minutes into leucovorin infusion 
(Irinotecan may be omitted at the discretion of the treating 
physician.  Reason for omission should be noted.)

Fluorouracil 400 mg/m2 iv push

Fluorouracil 2400 mg/m2 over 46 hours
-OR-
Gemcitabine and nab-Paclitaxel administered intravenously on days 1, 
8, and 15 of each 28-day cycle:

Gemcitabine 1000 mg/m2 over 30 minutes

Nab-Paclitaxel 125 mg/m2 over 30 mnutes
See Appendix A for suggested chemotherapy dose modifications.
4.2.2
Chemotherapy dose rounding allowed per institution protocol as long as 
rounded dose is within 10% of calculated dose.
4.2.3
BSA should not be capped.  Actual weight should be used.  Recalculation 
of BSA and drug doses is required if patient has a 10% or greater change 
in weight from previously calculated doses.
4.2.4
Antiemetic regimen:  A standard, FDA-approved antiemetic regimen will 
be administered to patients prior to the start of chemotherapy at the 
discretion of the treating oncologist.  An example of such a regimen 
includes a 5HT3 receptor antagonist and dexamethasone.  
4.2.5
Growth factor support is recommended with FOLFIRINOX, but not 
required.  If not administered as primary prophylaxis and ANC < 1500 on 
day 1 of any cycle, the addition of growth factor support and/or dose 
reduction is strongly encouraged with subsequent cycles.
4.2.6
Supportive therapy will be administered at the discretion of the treating 
oncologist.  Examples include prevention/treatment of delayed nausea, 
diarrhea, and fever.  The prophylactic administration of atropine 0.5 mg 
IV is strongly encouraged to prevent or decrease symptoms of the 
cholinergic syndrome associated with irinotecan.
4.2.7
Pharmaceutical Data:
1.
Oxaliplatin
4.2.7.1.1
Mechnism of action: Oxaliplatin, a platinum derivative, 
is an alkylating agent. Following intracellular 
hydrolysis, the platinum compound binds to DNA 
forming cross-links which inhibit DNA replication and 


10
transcription, resulting in cell death. Cytotoxicity is 
cell-cycle nonspecific.
4.2.7.1.2
Preparation/Administration: Do not freeze and protect 
from light the concentrated solution.  A final dilution 
must never be performed with a sodium chloride 
solution or other chloride-containing solutions.  The 
solution must be further diluted in an infusion solution 
of 250-500 mL of 5% Dextrose Injection, USP.  After 
final dilution, protection from light is not required.  
Oxaliplatin is incompatible in solution with alkaline 
medications or media (such as basic solutions of 5-
fluorouracil) and must not be mixed with these or 
administered simultaneously through the same infusion 
line. The infusion line should be flushed with 5% 
Dextrose Injection, USP prior to administration of any 
concomitant medication.
2.
Irinotecan
4.2.7.2.1
Mechanism of action: Irinotecan and its active 
metabolite (SN-38) bind reversibly to topoisomerase I-
DNA complex preventing religation of the cleaved 
DNA strand. This results in the accumulation of 
cleavable complexes and double-strand DNA breaks. 
As mammalian cells cannot efficiently repair these 
breaks, cell death consistent with S-phase cell cycle 
specificity occurs, leading to termination of cellular 
replication.
4.2.7.2.2
Preparation/Administration: Irinotecan should be 
diluted in 5% Dextrose Injection, USP, (preferred) or 
0.9% Sodium Chloride Injection, USP, to a final 
concentration range of 0.12 mg/mL to 2.8 mg/mL. 
Other drugs should not be added to the infusion 
solution.
3.
Fluorouracil
4.2.7.3.1
Mechanism of action: A pyrimidine analog 
antimetabolite that interferes with DNA and RNA 
synthesis; after activation, F-UMP (an active 
metabolite) is incorporated into RNA to replace uracil 
and inhibit cell growth; the active metabolite F-dUMP, 
inhibits thymidylate synthetase, depleting thymidine 
triphosphate (a necessary component of DNA 
synthesis).
4.2.7.3.2
Preparation/Administration: Fluorouracil Injection, 
USP is available for intravenouse use in 10 mL vials. 
Each mL contains 50 mg (available as 500 mg/10 mL) 


11
of fluorouracil in a colorless to faint yellow aqueous 
solution.  If a precipitate occurs due to exposure to low 
temperatures, resolubilize by heating to 140°F and 
shaking vigorously; allow to cool to body temperature 
before using.  Do not refrigerate or freeze. Protect from 
light.
4.
Leucovorin
4.2.7.4.1
Mechanism of action: Stabilizes the binding of 5-dUMP 
and thymidylate synthetase, enhancing the activity of 
fluorouracil.
4.2.7.4.2
Preparation/Administration: Reconstitute the 
lyophilized vial products with Bacteriostatic Water for 
Injection, USP (benzyl alcohol preserved), or Sterile 
Water for Injection, USP.  Because of the calcium 
content of the leucovorin solution, no more than 160 
mg of leucovorin should be injected intravenously per 
minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL 
solution per minute).  Leucovorin should not be mixed 
in the same infusion as 5-fluorouracil, since this may 
lead to the formation of a precipitate.
5.
Gemcitabine
4.2.7.5.1
Mechanism of action: A pyrimidine antimetabolite that 
inhibits DNA synthesis by inhibition of DNA 
polymerase and ribonucleotide reductase, cell cycle-
specific for the S-phase of the cycle (also blocks 
cellular progression at G1/S-phase). 
4.2.7.5.2
Preparation/Administration: Reconstitute in NS without 
preservatives to yield a concentration of 38 mg/mL; 
further dilute with NS prior to administration; final 
concentration may be as low as 0.1 mg/mL. Diluted 
solution stable at room temperature for 24 hours; do not 
refrigerate.
6.
Nab-Paclitaxel
4.2.7.6.1
Mechanism of action: Promotes microtubule assembly 
by enhancing the action of tubulin dimers, stabilizing 
existing microtubules, and inhibiting their disassembly, 
interfering with the late G2 mitotic phase, and inhibiting 
cell replication.
4.2.7.6.2
Preparation/Administration: Reconstitute in NS, swirl 
until complete dissolution occurs. Immediately use the 
reconstituted suspension in the vial or infusion bag, or 
refrigerate (2 to 8 degrees C) for a maximum of 24 


12
hours. Infuse IV over 30 minutes and use caution to 
avoid extravasation.
5. Adverse Events
 
5.1  Radiation Toxicities
5.1.1.  The CTEP Common Terminology Criteria for Adverse Events (CTCAE 
v4.0) will be used.  Standard radiation related toxicities are expected.   Toxicity 
will be defined as acute (<3 months from completion), subacute (3-12 months) 
and late (>12 months).  Reversible or permanent alopecia, bone marrow toxicity, 
skin pigmentation, nausea, and gastritis are expected side effects of radiation 
therapy.  
5.2 Chemotherapy Toxicities
5.2.1
Common Terminology Criteria for Adverse Events (CTCAE) v4.0 will be 
used to document and report adverse events.
5.2.2
The most common grade 3 or 4 adverse events occurring in more than 5% 
of patients receiving FOLFIRINOX in a multicenter phase II/III study (15) 
included neutropenia, febrile neutropenia, thrombocytopenia, anemia, 
fatigue, vomiting, diarrhea, peripheral neuropathy, transaminitis, and 
thromboembolism.  Alopecia, stomatitis, and hand/foot syndrome are also 
reported.  Irinotecan, in particular, causes both early and late diarrhea.  
The early form (during infusion or shortly thereafter) is often accompanied 
by abdominal cramping and other cholinergic symptoms (diaphoresis, 
flushing) and can be attenuated or prevented with the use of atropine, as 
suggested in this protocol.  In addition to acute and chronic sensory 
neuropathy, oxaliplatin may cause laryngopharyngeal dysesthesias.  All 
chemotherapeutic drugs carry the risk of an infusional reaction, including 
anaphylaxis.
5.2.3
The most common grade 3 or adverse events occurring in more than 5% of 
patients receiving gemcitabine and nab-paclitaxel included leukopenia, 
anemia, thrombocytopenia, fatigue, peripheral neuropathy, and diarrhea.  
Febrile neutropenia occurred in 3% of patients, with 26% of patients 
receiving growth factor support.
5.3  Adverse Event Reporting:  Adverse events (AE) and serious adverse events (SAE) 
will be reported in a timely manner through the appropriate channels.  The 
investigator will assess and determine whether the event is related to the study 
treatment and assign the following category (possible, probable, definite).  If 
possibly/probably related, investigator will specify whether AE/SAE is related to 
chemotherapy or SBRT.  Please see below for definitions of each.  Any and all 
AE/SAEs occuring during and up to 90 days after protocol-specified treatment (up to 
90 days post-SBRT) will be reported.
-AE:  Any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medical treatment or procedure regardless of whether 


13
it is considered related to the medical treatment or procedure.  (CTEP, NCI 
guidelines: Adverse event reporting requirements)
-SAE:  Any adverse experience occurring during any part of protocol treatment 
and 90 days after that results in the following: death, life-threatening adverse 
experience, inpatient hospitalization, a persistent or significant disability, or a 
cognitive anomaly.
- SAE  will include any event leading to the following:
· Death;
· A life-threatening adverse drug experience;
 
· Inpatient hospitalization or prolongation of existing hospitalization;
· A persistent or significant disability/incapacity;
 
· A congenital anomaly/birth defect.
Reporting of Adverse Events
All AEs, regardless of severity and whether or not they occurred during the study 
treatment or within 90 days following the last treatment, are to be documented by 
the Investigator appropriately, including date of onset, severity, action taken, 
outcome, and relationship to study drug.  Adverse events occurring between the 
time of signing informed consent to the time of the first dose will NOT be 
captured as AEs unless the AE is a direct result of a study-specific procedure or 
results in death from an event other than PD.
In the case of an SAE, the Investigator must notify the Institutional Review Board 
and the Co-Chairman of the Data Safety Monitoring Committee within 24 hours 
of becoming aware of the event.
6. Follow-up and Response Criteria
6. 1.    Follow Up
6.1.1. Follow-up:  Complete history and physical exam will be performed at 
each follow-up visit to assess for treatment related toxicity.  
6.1.2. Imaging:  Imaging will be obtained every 3 months for two years post-
treatment.  CT of the chest, abdomen and pelvis should be performed 
using IV and oral contrast.  Surveillance CT imaging of the chest will be 
obtained as recommended by the treating physician. 
6.2       Response Criteria
6.2.1. Response determination:  Response assessment will follow a modified 
version of the RECIST criteria guidelines as outlined below.  Response will be 
assessed from the planning CT scan by determining the longest tumor diameter.
Complete Response (CR):  Disappearance of all target lesions


14
Partial Response (PR):  At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference the baseline sum of LD
Progressive Disease (PD):  At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded since the treatment 
started or the appearance of one or more new lesions
Stable Disease (SD):  Does not qualify for a PR or PD
6.3 
Quality of life assessment
Quality of life is one of the measures we plan on examining.  SBRT offers a 
compressed treatment regimen and relative few side effects when compared to 
convential treatment methods in the retreatment setting.  
6.4.1  Function Assessment of Cancer Therapy – Pancreas (FACT-Hep):  The  
FACT-Hep quality of life assessement form (see Appendix B) will be utilized.  
This is an established tool for measuring patient quality of life both before and 
after intervention.  The form will consist of 41 questions and be administered at 
the following time points:  within 6 weeks of treatment and at 3 month intervals 
post-treatment.  The questionnaire should take approximately 8 minutes to 
complete.
6.4
Exploratory biomarker analysis
Differential scanning calorimetry (DSC) examines changes in the thermodynamic 
properties of high abundance plasma proteins. This is highly relevant since it is 
recognized that proteins and fragments shed from cancer tissue 
microenvironments enter the circulatory system.  Study of the high abundance 
proteome by DSC might therefore provide new information about pancreatic 
cancer biology and for monitoring of disease status.  Blood will be drawn at 
strategic timepoints during treatment and follow-up for this exploratory biomarker 
analysis.
7. Study Calendar
Assessment
Pretreatment 
During 
Chemotherapy 
Prior to 
Radiation
During 
Radiation 
6 weeks 
post-
treatment
3 months 
post-
treatment
6 months 
post-
treatment
Follow-
up (Q3 
months 
up to & 
including 
24 
months 
post-
treatment
History and 
physical
Within 4 
weeks
Q4wk
x
x
x
x
x


15
Performance 
status and 
weight
Within 4 
weeks
Q4wk
x
x
x
x
x
Diagnostic 
CT
Within 8 
weeks
x
x
x
x
4-D CT scan
1 week 
prior to 
radiation 
treatment 
during 
simulation
Tumor 
Response 
Evaluation
x
x
x
x
Adverse 
Event 
Evaluation
x
x
x
x
Quality of 
Life 
assessment
x
x
x
x
x (at 9 
and 12 
months 
post-
treatment 
only)
Biomarker 
evaluation 
(drawn with 
SOC lab)
x
Q2wk
x
x
x
x
x


16
8.   Subject Registration and Data Collection
8.1.1
Subject registration:  The informed consent process must be completed prior to 
initiation of any study required activities.  Registration into the study will occur when 
the following criteria are met:
-Patient meets all inclusion and no exclusion eligibility criteria
-Patient provides written informed consent
8.1.2
Patient study identification numbers will be assigned in ascending order.  
This patient identifier will be recorded in the Subject Enrollment Log and placed on 
the header of all case report forms and study related materials to identify the subject.  
Subject data will be recorded in a secure location and database in the Clinical Trials 
Office of the Brown Cancer Center. 
8.2.1
Data Collection:  Data will be collected according to the protocol requirements for 
all patients registered to the trial, including early termination and patients deemed 
ineligible.
8.3.1
The study chair and project team will collect monthly reports of the study project 
and accrual.
9.  DSMC Review
An independent committee, called the Data Safety and Monitoring Committee (DSMC) will 
review the progress of the study and monitor subjects’ accrual, serious adverse events and 
unexpected events.  Through this process the DSMC is also assessing the continuing validity 
and scientific merit of the trial.  The DSMC members are from the Study Chair’s Institution, 
the Brown Cancer Center, University of Louisville.  Members on the committee view 
themselves as representing the interests of the study patients and not that of the institution.  
The DSMC makes written reports summarizing their findings at each review.  The DSMC 
meets quarterly, or more frequently if requested by the Principal Investigator. The study 
statistician will provide the DSMC interim analysis reports determined by statistical methods 
noted in this protocol.
10.  Ethical and Regulatory Considerations
The following must be observed to comply with Food and Drug Administration regulations 
for the conduct and monitoring of clinical investigations; they also represent sound research 
practice.

Informed Consent

The principles of informed consent are described by Federal regulatory Guidelines 
(Federal Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office of 
protection from Research Risks Reports; protection of Human Subjects (Code of 


17
Federal regulations 45 CFR 46). They must be followed to comply with FDA 
regulations for the conduct and monitoring of clinical investigations.

Institutional Review; This study must be approved by an appropriate institutional 
review committee as defined by Federal regulatory Guidelines ( Ref. Federal Register 
Vol. 46, No 17, January 27, 1981, part 56) and the Office for protection from Research 
Risks Reports; Protection of Human Subjects (Code of Federal regulations 45, CFR 
46).
11. Statistical Considerations
11.1
Study Design:
The study will be a single-arm, single center, uncontrolled phase II trial to estimate the 
safety of the combined treatment and then estimate the efficacy in terms of the ORR, overall 
response (CR + PR +SD) rate in patients with advanced, non-resectable pancreatic cancer. 
11.2
End-Point Definitions:
We will use two main end-points. The primary end-point of interest is the clinical 
response. The progression-free survival, PFS, is directly related to the sustained response rate 
and thus the time to the first event will also be monitored. The second end-point will be 
tolerability/toxicity to treatment.  Secondary end-points to be considered are the overall survival, 
OS, which is the time to first event or death due to any reason, quality of life. 
11.3
Sample Size:
There is no data available at the institution to support the sample size justification based 
on efficacy of this treatment. In the published literature, Conroy et al. (2011) report overall 
response rate to be around 25%.  We expect that the overall response rate should be between 7-
30%. Therefore an ORR rate less than 10% should indicate the treatment is not sufficiently 
promising (P0 = 0.10). We expect the therapy to increase the overall response rate to 
approximately 25% (P1 = 0.25). Using Simon’s two-stage minimax design for phase II trials 
(Simon, 1989) we plan to enroll a maximum of 28 patients using alpha=5% and power=70%. In 
first stage, 13 patients will be enrolled. Table S1 gives the details of the justification of this 
sample size. 
Table S1. Sample size justification P0 =0.10, P1=0.25, alpha=5% and power =70%
MiniMax Two Stage Design
MiniMax Design
First Stage Sample Size (n1)
13
Upper Limit For 1st Stage Rejection of Drug (# of ORR)
1
Maximum Sample Size (n)
28
Upper Limit for 2nd Stage Rejection of Drug (# of ORR)
5
Expected Sample Size If Po = 0.10
19


18
Probability of Early Termination at Po=0.50
0.62
11.4
Accrual and Follow-up:
Based on our experience we plan to enroll 15 patients per year. It will take approximately 
2.0 years to complete the enrollment of 28 patients. Depending on the combination treatment’s 
performance we may not need to enroll all 28 participants. The live patients will be followed two 
additional years after the completion of the treatment.
11.5
Statistical Analysis:
Patients receiving treatment will be presented.  Patients receiving treatment who are 
found not to have fully met the eligibility criteria will also be presented.  On-study protocol 
violations will also be presented.  Patients who do not complete the required observations will be 
listed and evaluated separately as necessary.  Reasons for study discontinuation and date of 
withdrawal from study will be presented.
Descriptive statistics related to the participant characteristics, treatment, and prognostic 
factors will be reported.  Clinical response rates (complete, partial, and sustained) along with 
95% confidence intervals will be estimated (Yuan and Rai 2011). The progression-free survival 
and overall survival will be estimated by Kaplan-Meier method (Kaplan and Meier 1958). 
Differences in survival will be evaluated through the estimated hazard rates using the un-
weighted log-rank tests. The PFS time will be determined as the time from enrollment until the 
first adverse event (i.e., disease progression or death due to any cause).  The OS time will be 
determined as the time from enrollment until death or last follow-up evaluation. In order to 
examine the significant prognostic factors, we will use the Cox proportional hazards regression 
models in both univariable and multivariable settings (Cox 1972; Cantor 2003; Kalbfleisch and 
Prentice 2002). Descriptive statistics associated with the toxic events will be reported. Logistic 
regression model will be used to find association with the presence of higher grade toxicity and 
clinical and demographic factors (Fleiss 1986, Fleiss et al 2003; Dmitrienko et al. 2005). For 
longitudinal measures such as quality of life (QOL) mixed model approach will be used (Diggle 
et al. 2002; Littell 2006). The differential scanning calorimetry (DSC) will be used to predict the 
response outcome using the method of Rai and others (2013). The factors to be analyzed are 
ethnicity, gender, age, pathological subtype, etc. The various factors will be placed into 
categorical variables. All calculations will be performed with SAS statistical software (SAS, 
2003). 
11.6
Monitoring Rule:
Safety monitoring of the accumulated outcomes data is designed to ensure the continuing 
safety of the currently enrolled participants and participants not yet enrolled.  This is achieved by 
stopping the trial early to reduce the number of participants exposed to a harmful or ineffective 
treatment. 
11.7
Non-efficacious Treatment (Futility):


19
In the first stage we will enroll 13 participants and if we observe at most 1 ORR we will 
not enroll any new participants.  If we observe 2 or more ORR in the first stage, then we plan to 
enroll an additional 15 patients. In order for the treatment to be declared effective there has to be 
ORR in at least 6 patients. If the ORR is only 7%, we will have 62% chance of stopping the 
study early and, at most, 19 patients will be treated on the potentially ineffective therapy. 
11.8
Toxic Treatment (Safety):
The cumulative number of grade 3 or 4 toxic events will be monitored after each person 
is enrolled (Ray and Rai, 2011). If the cumulative number of toxic events produces enough 
evidence to conclude that the true toxicity rate is greater than or equal to 33% (Pt0 = 0.33) then 
the trial will be stopped early for safety reasons.  The cumulative number of toxic events after 
each is person is treated will be compared to the boundary values in Table S2. If the cumulative 
number of toxic events after person i is treated is greater than or equal to the associated boundary 
value bi then the combination treatment is rejected for safety considerations. With this rule, there 
is only a 5% chance of stopping the trial early for lack of safety if the true toxicity rate is less 
than 33%. Continual assessment of the toxic events ensures we do not expose an undue number 
of patients to a harmful treatment.    
Table S2. Toxicity Boundaries, N = 42, Pt0 = 0.33, and alpha=0.05
Minimum Number 
of Subjects
Maximum Number 
of Subjects
Number of 
Toxicities
4
4
4
5
6
5
7
7
6
8
9
7
10
11
8
12
14
9
15
16
10
17
18
11
19
19
12
20
22
13
23
23
14
24
27
15
28
28
16
The combined procedure has similar operating characteristics to the Simon 2-Stage 
design (Ray and Rai, 2011).  The probability of stopping early under the null hypothesis of low 
response or high toxicity is 67.8% with an expected sample size of 27.9 patients. 


20
12. References
1.
Jemal A, Siegel R, Ward E, et al. Cancer statistics (2006). CA Cancer J Clin 56: 106.
2.
S.F. Sener, A. Fremgen, H.R. Menck et al. Pancreatic cancer: A report of treatment and 
survival trends for 100,313 patients diagnosed from 1985–1995, using the National 
Cancer Database J Am Coll Surg, 189 (1999), pp. 1–7
3.
E. Ben-Josef, A.F. Shields, U. Vaishampayan et al. Intensity-modulated radiotherapy 
(IMRT) and concurrent capecitabine for pancreatic cancer Int J Radiat Oncol Biol Phys, 
59 (2004), pp. 454–459
4.
A. Brade, J. Brierley, A. Oza et al. Concurrent gemcitabine and radiotherapy with and 
without neoadjuvant gemcitabine for locally advanced unresectable or resected pancreatic 
cancer: A phase I-II study Int J Radiat Oncol Biol Phys, 67 (2007), pp. 1027–1036
5.
J.D. Earle, J.F. Foley, H.S. Wieand et al. Evaluation of external-beam radiation therapy 
plus 5-fluorouracil (5-FU) versus external-beam radiation therapy plus hycanthone 
(HYC) in confined, unresectable pancreatic cancer. (1994). Int J Radiat Oncol Biol Phys, 
28: 207.
6.
M. Hoyer, H. Roed, L. Sengelov et al. Phase-II study on stereotactic radiotherapy of 
locally advanced pancreatic carcinoma Radiother Oncol, 76 (2005), pp. 48–53.
7.
P. Li, Y. Chao, K.H. Chi et al. Concurrent chemoradiotherapy treatment of locally 
advanced pancreatic cancer: Gemcitabine versus 5-fluorouracil, a randomized controlled 
study Int J Radiat Oncol Biol Phys, 57 (2003), pp. 98–104.
8.
Loehrer, P. J., Feng, Y., Cardenes, H., Wagner, L., Brell, J. M., Cella, D., ... & Benson, 
A. B. (2011). Gemcitabine alone versus gemcitabine plus radiotherapy in patients with 
locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. 
Journal of Clinical Oncology, 29(31), 4105-4112.
9.
Schellenberg, D., Goodman, K. A., Lee, F., Chang, S., Kuo, T., Ford, J. M., ... & Koong, 
A. C. (2008). Gemcitabine chemotherapy and single-fraction stereotactic body 
radiotherapy for locally advanced pancreatic cancer. International Journal of Radiation 
Oncology* Biology* Physics, 72(3), 678-686.
10. Mahadevan, A., Jain, S., Goldstein, M., Miksad, R., Pleskow, D., Sawhney, M., ... & 
Vollmer, C. (2010). Stereotactic body radiotherapy and gemcitabine for locally advanced 
pancreatic cancer. International Journal of Radiation Oncology* Biology* Physics, 
78(3), 735-742.
11. Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, …& Neoptolemos 
JP. (2009). Phase III randomized comparison of gemcitabine versus gemcitabine plus 
capecitabine in patients with advanced pancreatic cancer. Journal of Clinical Oncology, 
27(33):5513.
12. Colucci G, Labianca R, Di Costanzo F, Gebbia V, Carteni G, Massidda B, … & Perrone 
F. (2010). Randomized phase III trial of gemcitabine plus cisplatin compared with single-
agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the 
GIP-1 study. Journal of Clinical Oncology, 28(10):1645.
13. Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, … & Benson AB 
III. (2009). Phase III, randomized study of gemcitabine and oxaliplatin versus 
gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) 
in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology 


21
Group. Journal of Clinical Oncology, 27(23):3778.
14. Stathopoulos GP, Syrigos K, Aravantinos G, Polyzos A, Papakotoulas P, Fountzilas G, 
… & Georgoulias V. (2006). A multicenter phase III trial comparing irinotecan-
gemcitabine with gemcitabine monotherapy as first-line treatment in patients with locally 
advanced or metastatic pancreatic cancer. British Journal of Cancer, 95(5):587.
15. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, … & Ducreux 
M. (2011). FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. New 
England Journal of Medicine, 364(19):181.
16. Ghosn M, et al. FOLFOX-6 combination as the first-line treatment of locally advanced 
and/or metastatic pancreatic cancer.  Am J Clin Oncol 2007; 30(1): 15.
17. Von Hoff DD, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus 
gemcitabine.  NEJM 2013; 369(18): 1691.
18. Garbet NC, Miller JJ, Jenson AB, Chaires JB. Calorimetry outside the box: a new 
window into the plasma proteome. Biophys J 2008; 94: 1377-83.
19. GarbetNC, Mekmaysy CS, Helm CW, Jenson AB, Chaires JB. Differential scanning 
calorimetry of blood plasma for clinical diagnosis and monitoring. Exp Mol Pathol 2009; 
86: 186-91.
20. Garbett NC, Merchant ML, Helm CW, Jenson AB, Klein JB, Chaires JB. Detection of 
Cervical Cancer Biomarker Patterns in Blood Plasma and Urine by Differential Scanning 
Calorimetry and Mass Spectrometry. PLOS ONE 2014; 9(1):e84710.
Statistical References:
21. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical Trials, 
10:1-10, 1989.
22. Yuan, X and Rai, SN. Confidence Intervals for Survival Probabilities: A Comparison 
Study. Communications in Statistics – Simulation and Computation, 40(7): 978-991, 
2011.
23. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Journal of 
American Statistical Association, 53:457-481, 1958.
24. Cox DR. Regression and life-tables. J R Stat Soc B. 34:187-220, 1972.
25. Kalbfleisch JD and Prentice RL. The Statistical Analysis of Failure Time Data, 2nd ed. 
New York: Wiley & Sons, 2002.
26. Dmitrienko A, Molenberghs G, Chuang-Stein, C and Offen W. Analysis of Clinical 
Trials Using SAS®: A practical Guide. Cary, NC, USA: SAS Institute Inc., 2005.
27. Fleiss, JL. Design and Analysis of Clinical Experiments. New York: John Wiley and 
Sons, 1986.
28. Fleiss JL, Levin, B and Paik MC. Statistical Methods for Rates and Proportions, 3rd 
Edition. New York: John Wiley and Sons, 2003.
29. Diggle PJ, Heagerty PJ, Liang KY and Zeger SL. Analysis of Longitudinal Data. 2nd 
Edition. New York: Oxford University Press, 2002.
30. Littell RC, Milliken GA, Stroup WW, Wolfinger R and Schabenberger O. SAS® for 
Mixed Models 2nd Edition, Cary, NC: SAS Institute Inc., 2006.
31. The SAS System V9, Cary, NC: SAS Institute Inc., 2003.


22
32. Ray HE and Rai SN. An evaluation of a Simon 2-stage phase II clinical trial design 
incorporating toxicity monitoring. Contemporary Clinical Trials, 32:428-436, 2011.
33. Rai SN, Pan J, Cambon A, Chaires JB and Garbett NC. Group Classification in High-
Dimensional Data: Application to Differential Scanning Calorimetry Plasma 
Thermogram Analysis of Cervical Cancer and Control Samples. Open Access Medical 
Statistics, 3:1-9, 2013.


23
13.Appendices
Appendix A
FOLFIRINOX Suggested Dose Modifications*
Hematologic Toxicity
Absolute neutrophil count 
<1500/mm3
Occurrence
Fluorouracil
Irinotecan
Oxaliplatin
Hold treatment until ≥ 
1500/mm3, then resume 
treatment with dose 
modifications
1st
Delete bolus;
maintain 
continuous infusion 
at 100%
150 mg/m2
85 mg/m2
Add growth factor if not used 
with previous cycle(s)
2nd
Same as above
150 mg/m2
60 mg/m2
3rd
Discontinue
Discontinue
Discontinue
Platelet count < 
75,000/mm3
Occurrence
Fluorouracil
Irinotecan
Oxaliplatin
Hold treatment until ≥ 
75,000/mm3, then resume 
treatment with dose 
modifications
1st
Bolus 300 mg/m2; 
continuous infusion 
1800 mg/m2 over 46 
hours
180 mg/m2
60 mg/m2
2nd
Same as above
150 mg/m2
60 mg/m2
3rd
Discontinue
Discontinue
Discontinue
Gastrointestinal Toxicity
Diarrhea grade 3-4
Occurrence
Fluorouracil
Irinotecan
Oxaliplatin
Hold treatment until 
recovered to ≤ grade 2, then 
resume with dose 
modifications
1st
Delete bolus; 
maintain continuous 
infusion at 100%
150 mg/m2
85 mg/m2
Verify patients are using 
loperamide
2nd
Continuous infusion 
1800 mg/m2 over 46 
hours
150 mg/m2
60 mg/m2
3rd
Discontinue
Discontinue
Discontinue
Other Toxicity
Grade 3-4 toxicities justify a dose reduction of the responsible chemotherapy drug at the 
discretion of the treating oncologist.


24
Gemcitabine/nab-Paclitaxel Suggested Dose Modifications*
Dose Level
Gemcitabine
Nab-Paclitaxel
Full dose
1000 mg/m2
125 mg/m2
-1
750 mg/m2
100 mg/m2
-2
500 mg/m2
75 mg/m2
Chemotherapy should be discontinued in subjects requiring more than 2 dose reductions.
Hematologic Toxicity
Day
ANC
(cells/mm3)
Platelet count
(X1000 
cells/mm3)
Gemcitabine 
dose
Nab-
Paclitaxel 
dose
1
<1000
or
<75
Hold until 
ANC>1000 and 
plt >75
Hold until 
ANC>1000 
and plt >75
8
500-999
or
50-74
-1
-1
<500
or
<50
Hold
Hold
15
>1000
and
>75
Previous dose 
or -1 if day 8 
held
Previous dose 
or -1 if day 8 
held
500-999
or
50-74
-1
-1
<500
or
<50
Hold
Hold
Other Toxicity
Grade 3-4 toxicities:  Withhold chemotherapy until ≤ grade 1, then resume at next lower dose 
level. 
Renal Impairment (All drugs)
No dose adjustments are required for creatinine clearance (CrCl ) >30mL/min as calculated by 
Cockcroft-Gault:
CrCl = (140 - age) x IBW / (Scr x 72)        (x 0.85 for females)


25
Hepatic Impairment (All drugs)
Consider delaying treatment to exclude biliary obstruction.  
Bilirubin 1.5-3 mg/dL
Bilirubin >3 mg/dL
Irinotecan
75% of dose
Use not recommended
Nab-Paclitaxel
Reduce dose to 80 mg/m2
Use not recommended
Gemcitabine
Initial dose of 800 mg/m2; 
may increase as tolerated
Initial dose of 800 mg/m2; 
may increase as tolerated
Oxaliplatin
No dosage adjustment necessary
Fluorouracil
No dosage adjustment necessary for bilirubin <5 mg/dL
*Dose adjustments are ultimately made at the discretion of the treating oncologist.


26
APPENDIX B:  FACT-HEP QUESTIONNAIRE


27


28

ICF_001.pdf: 
The effect of chemotherapy and stereotactic body radiation therapy for locally 
advanced, non-resectable pancreatic cancer 
 
NCT02128100 
ICF 16APR2018 


Consent version date:  April 16, 2018
Page 1 of 12
INFORMED CONSENT AND RESEARCH AUTHORIZATION 
The Effect of chemotherapy and Stereotactic Body Radiation Therapy for Locally Advanced, 
Non-Resectable Pancreatic Cancer
IRB assigned number:  
14.0413 
NCT #:
NCT02128100
Investigator(s) name & address:
Neal Dunlap, MD
James Graham Brown Cancer Center
University of Louisville
529 South Jackson Street
Louisville, KY 40202
Site(s) where study is to be conducted:
James Graham Brown Cancer Center
University of Louisville Hospital
Phone number for subjects to call for questions: 502-562-4360 or 1-888-802-8149 (toll free)
This is a clinical trial, a type of research. Your study doctor will explain the trial to you. Clinical trials 
include only people who choose to take part. Before you decide whether to take part in this study or 
not, it is important for you to understand why this clinical trial, or research study, is being done, what it 
will involve, and how it will affect your daily life. Please take time to read the following information 
carefully. You may discuss your decision with your friends and family. You can also discuss it with 
your study doctor. If you have any questions, you can ask your study doctor for more explanation.
Introduction and Background Information
You are invited to participate in this research study because you have pancreatic cancer and will be 
receiving treatment for it. The study is being conducted at the James Graham Brown Cancer Center 
and University Hospital under the direction of Neal Dunlap, MD. Approximately 28 local subjects will 
be invited to participate. 
Purpose
The purpose of this study is to find out if chemotherapy combined with Stereotactic Body Radiation 
Therapy (SBRT) is a safe and effective therapy for the treatment of pancreatic cancer.
SBRT is a radiation therapy that delivers high dose radiation to a target within the body.
Procedures
Your participation in this study will last for approximately 48 months.  If you consent to participate, you 
will have the following procedures while you are in this study.   
Screening Period: 
UofL Institutional Review Boards
IRB NUMBER: 14.0413
IRB APPROVAL DATE: 05/15/2018


The Effect of chemotherapy and Stereotactic Body Radiation Therapy for Locally Advanced, 
Non-Resectable Pancreatic Cancer
Consent version date: April 16, 2018
                        Page 2 of 12
Before your treatments begin, certain tests, exams and procedures need to be done to find out if you 
can be in this clinical research study. If you recently had any of these procedures, they may not have 
to be repeated. Some of these tests are normally part of regular care and may be done even if you 
are not part of the study.  After all screening procedures are completed, your study doctor will review 
the results and tell you whether or not you can be included in the study. 

Complete medical history (questions about your health including cancer diagnosis, prior 
treatments, current medications that you are taking, and allergies you may have). 

Physical examination including body weight, height, and vital signs. (Vital signs will include 
blood pressure, temperature, breathing rate and heart rate).

A blood sample (approximately 1 teaspoon [5 mL]) will be collected at screening for biomarker 
assessments.  

You will be asked to complete a Quality of Life form that will take approximately 8 minutes to 
finish.  You may decline to answer any question that may make you feel uncomfortable.
Treatment planning:

You will need to have a CT scan with IV contrast. The IV contrast is a liquid dye you will ingest 
to enhance the scan images.  A CT scan, or Computerized tomography, uses several x-rays 
from different angles to create a 3-

dimensional (3D) picture of your tumor.

You will have a 4-dimensional CT scan in order to plan your radiation treatment. This scan is 
similar to the CT scan with IV contrast but also captures tumor and organ movement. This 
usually takes about an hour.

Treatment planning will be performed using either 3D conformal radiotherapy or intensity 
modulated radiation therapy (IMRT) based on the discretion of the treating physician.  IMRT is 
a type of radiation that allows more accurate targeting of the tumor tissue while avoiding 
healthy tissue.  Standard SBRT treatment will be discussed.  Cyberknife treatment may also 
be used.  
Treatment
You and your doctor will decide which type of chemotherapy is recommended for treatment of your 
cancer.  You will receive a total of 8 weeks of chemotherapy prior to any possible radiation therapy.  
Possible chemotherapy regimens include:

FOLFIRINOX (a combination of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) 
administered over a total of approximately 6 hours every 2 weeks
UofL Institutional Review Boards
IRB NUMBER: 14.0413
IRB APPROVAL DATE: 05/15/2018


The Effect of chemotherapy and Stereotactic Body Radiation Therapy for Locally Advanced, 
Non-Resectable Pancreatic Cancer
Consent version date: April 16, 2018
                        Page 3 of 12

FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) administered over a total of approximately 
4 hrs every 2 weeks

Gemcitabine and nab-Paclitaxel administered over approximately 2 hours weekly for 3 weeks, 
followed by one rest week.
Following 8 weeks of chemotherapy, you will undergo a CT scan to determine if your cancer has 
responded to the chemotherapy.  If your cancer has progressed or spread at that time, you will not 
receive radiation as part of this clinical trial, and your doctor will talk to you about other treatment 
recommendations.  If your cancer is stable or has decreased in size, you will then move on to 
radiation treatments. 

You will have 5 treatments of stereotactic body radiation therapy (SBRT) over the course of 
two weeks with a minimum of 36 hours in between each treatment.

A blood sample (approximately 1 teaspoon [5mL]) may be collected for biomarker 
assessments every two weeks during chemotherapy, again before radiation and then every 6 
weeks, 3 months and 6 months after treatment. This blood sample will be collected when you 
have routine laboratory assessments.   

At screening, 6 weeks post treatment, and at months 3, 6, 9, and 12 post treatment, you will be 
asked to complete the Quality of Life questionnaire that will take approximately 8 minutes to 
finish.  You may decline to answer any question that may make you feel uncomfortable.
Follow-Up:

You will have study doctor visits and a CT scan every 3 months during treatment and at 24 
months after treatment completion.

A blood sample (approximately 1 teaspoon [5 mL]) may be collected for biomarker 
assessments every 3 months, up to and including, 24 months after treatment completion. This 
blood sample will be collected when you have routine laboratory assessments.   

You will again be asked to fill out the Quality of Life questionnaires at 9 months and 12 months 
after treatment completion. You do not have to answer any questions that make you feel 
uncomfortable.
Potential Risks
Chemotherapy Side Effects
The following table details the known side effects related to FOLFIRINOX:
Most Common - More than 5% of Subjects Experienced:

Neutropenia (decrease in the main part of the white blood cells) 
UofL Institutional Review Boards
IRB NUMBER: 14.0413
IRB APPROVAL DATE: 05/15/2018


The Effect of chemotherapy and Stereotactic Body Radiation Therapy for Locally Advanced, 
Non-Resectable Pancreatic Cancer
Consent version date: April 16, 2018
                        Page 4 of 12

Febrile neutropenia (development of fever, often with other signs of infection)

Thrombocytopenia (low platelets in the blood)

Anemia (low red blood cell count)

Fatigue (feeling tired)

Vomiting

Diarrhea

Peripheral neuropathy (weakness, numbness and pain, usually in your hands and feet)

Transaminitis (liver enzymes in the blood stream)

Thromboembolism (formation of a clot in the blood stream)

Alopecia (hair loss)

Stomatitis (mouth sores)

Hand/foot Syndrome (redness, swelling, and pain on the palms of the hands and/or the soles 
of the feet. Sometimes blisters appear)

Abdominal cramping

Heavy sweating, flushing

Nerve damage  (weakness, numbness and pain, usually in your hands and feet)

Difficulty swallowing or breathing
The following table details the known side effects related to Gemcitabine and nab-Paclitaxel:
Most Common - More than 5% of Subjects Experienced:

Leukopenia (reduction of white blood cells in the blood)

Anemia (low red blood cell count)

Thrombocytopenia (low platelets in the blood)

Fatigue (feeling tired)

Peripheral Neuropathy (weakness, numbness and pain, usually in your hands and feet)

Diarrhea
Common - 3% of Subjects Experienced:

Febrile neutropenia (is the development of fever, often with other signs of infection, in a 
patient with neutropenia, an abnormally low number of neutrophil granulocytes (a type of 
white blood cell) in the blood)
Radiation Side Effects
Most Common - More than 5% of Subjects Experienced:

Reversible or permanent hair loss

Bone marrow toxicity

Skin pigmentation

Nausea

Gastritis (inflammation of the lining of the stomach)
UofL Institutional Review Boards
IRB NUMBER: 14.0413
IRB APPROVAL DATE: 05/15/2018


The Effect of chemotherapy and Stereotactic Body Radiation Therapy for Locally Advanced, 
Non-Resectable Pancreatic Cancer
Consent version date: April 16, 2018
                        Page 5 of 12
Risks and side effects related to Infusion
The insertion of an intravenous (IV) drip to infuse chemotherapy may cause pain, swelling, bruising, 
bleeding or (rarely) infection at the place where the needle is inserted.  You may also feel dizziness 
and faint when chemotherapy is being infused.
Risks and side effects related to Radiological Tests
Some of the tests that will be performed (CT scans) will expose you to controlled amounts of 
radiation. You may feel claustrophobic inside the scanner. The CT scans will involve dyes being 
injected into one of your veins. There is a risk of allergic reaction to dye. This reaction may be mild 
(such as a skin rash or hives) to severe (such as breathing difficulties, shock and renal failure). There 
also is a risk that the injection of dyes or collection of blood samples may cause pain, swelling, 
bruising, irritation or redness at the site, infection at the site of the needle puncture, or feeling faint. 
Your study doctor will take steps to prevent this from happening, and may recommend medications 
that may help with these particular side effects.
Risks of Blood Sample Collection
The collection of blood samples may cause pain, swelling, bruising, irritation or redness at the site, 
infection at the site of the needle puncture, or feeling faint. Your study doctor will take steps to 
prevent this from happening and may recommend medications that may help with these particular 
side effects.
It is very important that you report any side effects to your study doctor as soon as possible; you 
should not wait until your next scheduled visit.
In addition, you may suffer harms that we have not seen before. 
Possible Pregnancy Risks 
You should discuss pregnancy risks with your doctor before signing this consent form. Women who 
are pregnant or breast feeding may not participate in this research study.  If you are pregnant or 
become pregnant, your unborn child may suffer harms that we have not seen before. If you (or your 
partner) become pregnant while in this study, the sponsor may ask to follow the outcome of the 
pregnancy.  If you agree to allow the study doctor to follow your pregnancy, you will be asked to read 
and sign a separate consent form for permission to follow the outcome of your pregnancy.  
If you are a man taking part in the study and your partner becomes pregnant, the study doctor may 
ask you to ask your partner for permission to follow her pregnancy.  If she agrees, she will be asked 
to sign a separate consent form mentioned above.
UofL Institutional Review Boards
IRB NUMBER: 14.0413
IRB APPROVAL DATE: 05/15/2018


The Effect of chemotherapy and Stereotactic Body Radiation Therapy for Locally Advanced, 
Non-Resectable Pancreatic Cancer
Consent version date: April 16, 2018
                        Page 6 of 12
Before starting this research study, females able to have children will have a pregnancy test.  Talk to 
your doctor about the best method of birth control to use while you are in this study.  It is important 
that you call your study doctor at 502-562-4360 right away if you become pregnant or father a child 
during the course of this study.  If you or your partner becomes pregnant, a decision may have to be 
made whether or not to end the pregnancy.  
We do not know the effects of chemotherapy on an unborn baby.  There is a risk that your unborn 
baby could be harmed if you become pregnant during your participation in the study.  (If you ask, your 
study doctor will discuss the possible risks to your unborn child and your options should you become 
pregnant while in this study.)  
Benefits
You may not benefit by participating in this study. The information collected may not benefit you 
directly; however, the information may be helpful to others.
Alternatives
Your other choices may include:
• Getting treatment or care for your cancer without being in a study
• Taking part in another study
• Getting no treatment
Talk to your study doctor about your choices before you decide if you will take part in this study.
  
Research Related Injury 
If you are injured by being in this research study, the study doctor will arrange for you to get medical 
treatment. The study site, or your study doctor has not set aside money to pay for treatment of any 
injury. You and your insurance will be billed for the treatment of these injuries. Before you agree to 
take part in this research study you should find out whether your insurance will cover an injury in this 
kind of research. You should talk to the study doctor or staff about this. If you are injured, there is no 
money set aside for lost wages, discomfort, disability, etc. You do not give up your legal rights by 
signing this form. If you think you have a research related injury, please call your study doctor, Dr. 
Dunlap at 502-562-4360.
Compensation
You will not be compensated for your time, inconvenience, or expenses while you are in this study.
Costs
If you are injured by this research, there may be additional costs for participating in this research 
study. There may be additional costs to you for participating in this research study over the usual 
costs of your routine care outside of this research study. You and/or your insurance company will be 
billed for all office visits, tests, medications and procedures involved in this research study and as part 
UofL Institutional Review Boards
IRB NUMBER: 14.0413
IRB APPROVAL DATE: 05/15/2018


The Effect of chemotherapy and Stereotactic Body Radiation Therapy for Locally Advanced, 
Non-Resectable Pancreatic Cancer
Consent version date: April 16, 2018
                        Page 7 of 12
of your routine medical care outside of this research study. Examples include doctor’s office visits, 
blood tests, x-rays, CT scans, EKGs, medications, and hospital stays. You will be responsible for 
paying your co-pay that is associated with any office visit, test, medication or procedure. None of the 
charges from the doctor’s office, pharmacy or hospital during your participation in this study will be 
paid for by the study. Some insurance companies will not pay for medical bills for people who 
participate in a research study. It is your responsibility to find out what costs, if any, your insurance 
company will cover before taking part in the study. If your insurance company does not pay for your 
bills associated with this study, you will be responsible for paying them. “According to Kentucky State 
Law (KRS Chapter 304.17A-136, Coverage for Cancer Clinical Trials) insurance plans may not deny 
coverage for routine treatment costs incurred during your participation in a cancer study if your 
insurance plan would have covered those costs had you not been in the study. This law is for your 
protection. For more information about this law, ask your study doctor.
HIPAA Research Authorization 
The Health Insurance Portability and Accountability Act of 1996 (HIPAA) provides federal safeguards 
for your protected health information (PHI).   Examples of PHI are your name, address, and birth date 
together with your health information.  PHI may also include your medical history, results of health 
exams and lab tests, drugs taken and results of this research study.  Your PHI may not be used or 
shared without your agreement, unless it meets one of the HIPAA exceptions. 
State and federal privacy laws protect your health information.  In most cases, health information that 
identifies you can be used or shared by the research team only if you give your permission by signing 
this form.   
If you sign this form your health information will be used and shared to answer the research questions 
described above and to make sure that the research was done correctly. The time period when 
information can be used or shared ends when all activities related to this study are completed.  
Your access to your health information will not be limited during this study.  
You do not have to sign this form. However, if you do not sign this form, you will not be able to take 
part in this research. This will not change the health care or health care benefits you would otherwise 
receive.
Site(s) where health information about you will be used or shared for this research:
In our research, the research team will look at and may share information about you and your health.  
Federal law requires that health care providers and researchers protect the privacy and security of 
health information that identifies you.  We may ask for your health information from the following:
Affiliated Sites:
University of Louisville 
University of Louisville Hospital/J. Graham Brown Cancer Center
UofL Institutional Review Boards
IRB NUMBER: 14.0413
IRB APPROVAL DATE: 05/15/2018


The Effect of chemotherapy and Stereotactic Body Radiation Therapy for Locally Advanced, 
Non-Resectable Pancreatic Cancer
Consent version date: April 16, 2018
                        Page 8 of 12
Protected health information (PHI) that will be used or shared for research 
Consultation reports
Diaries and questionnaires
Discharge summaries
Specimens
Healthcare provider orders
History and physical exams
Laboratory, x-ray, and other tests
Records of your operation(s)
Medical progress notes
Records about the study drug and other drugs you may be taking
Revocation of Research Authorization
You may cancel the permission you have given to use and share your protected health information at 
any time.  This means you can tell us to stop using and sharing your protected health information.  If 
you cancel your permission:

We will stop collecting information about you.

You may not withdraw information that we had before you told us to stop.
o
We may already have used it or shared it.
o
We may need it to complete the research.

Staff may ask your permission to follow-up with you if there is a medical reason to do so.
To cancel your permission, you must complete a written “Revocation of Research Authorization” form 
located at the end of this document.  You may also obtain a copy from your study doctor, designated 
personnel or from the Human Subjects Protections Program Office website 
(http://louisville.edu/research/humansubjects/subject-information). 
Information Available on ClinicalTrials.gov
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.
Confidentiality
Total privacy cannot be guaranteed.  We will protect your privacy to the extent permitted by law.  If 
the results from this study are published, your name will not be made public. Once your information 
leaves our institution, we cannot promise that others will keep it private.  
Your information may be shared with the following:
UofL Institutional Review Boards
IRB NUMBER: 14.0413
IRB APPROVAL DATE: 05/15/2018


The Effect of chemotherapy and Stereotactic Body Radiation Therapy for Locally Advanced, 
Non-Resectable Pancreatic Cancer
Consent version date: April 16, 2018
                        Page 9 of 12

The University of Louisville Institutional Review Board, Human Subjects Protection Program 
Office, Privacy Office and others involved in research administration at the University

The local research team

People who are responsible for research and HIPAA oversight at the institutions where the 
research is conducted

People responsible for billing, sending and receiving payments related to your participation in 
the study 

Government agencies, such as: 
o
Office for Human Research Protections 
o
Office of Civil Rights
o
Food and Drug Administration 

Data Safety Monitoring Board(s) related to the study 
Security 
Your information will be kept private by password-protected computers and limited access areas for 
storage of information at University of Louisville premises.
 
Voluntary Participation
Taking part in this study is completely voluntary. You may choose not to take part at all.  If you decide 
not to be in this study, you won’t be penalized or lose any benefits for which you qualify. If you decide 
to be in this study, you may change your mind and stop taking part at any time. If you decide to stop 
taking part, you won’t be penalized or lose any benefits for which you qualify.  You will be told about 
any new information learned during the study that could affect your decision to continue in the study.
Termination
Your study doctor or the study sponsor has the right to stop this study at any point. Your study doctor 
may take you out of this study with or without your okay.  Reasons why this may occur include: 
If you stop taking part in this study, it could harm you.  You may be asked to follow these steps for 
your own safety: 
• if your study doctor believes it is in your best interest;
• if you do not follow the study rules; or
• if the study is stopped.
Participation in Other Research Studies
You may take part in this study if you are currently in another non therapeutic research study.  It is 
important to let your doctor know if you are in another research study.
UofL Institutional Review Boards
IRB NUMBER: 14.0413
IRB APPROVAL DATE: 05/15/2018


The Effect of chemotherapy and Stereotactic Body Radiation Therapy for Locally Advanced, 
Non-Resectable Pancreatic Cancer
Consent version date: April 16, 2018
                        Page 10 of 12
Contact Persons
If you have any questions, concerns, or complaints about the research study, please contact Dr. Neal 
Dunlap at 502-562-4360.
Research Subject’s Rights
If you have any questions about your rights as a research subject, you may call the Human Subjects 
Protection Program Office at (502) 852-5188.  You may discuss any questions about your rights as a 
research subject, in private, with a member of the Institutional Review Board (IRB).  You may also call 
this number if you have other questions about the research, and you cannot reach the study doctor, 
or want to talk to someone else. The IRB is an independent committee made up of people from the 
University community, staff of the institutions, as well as people from the community not connected 
with these institutions.  The IRB has approved the participation of human subjects in this research 
study. 
Concerns and Complaints
If you have concerns or complaints about the research or research staff and you do not wish to give 
your name, you may call the toll free number 1-877-852-1167.  This is a 24 hour hot line answered by 
people who do not work at the University of Louisville.  
UofL Institutional Review Boards
IRB NUMBER: 14.0413
IRB APPROVAL DATE: 05/15/2018


The Effect of chemotherapy and Stereotactic Body Radiation Therapy for Locally Advanced, 
Non-Resectable Pancreatic Cancer
Consent version date: April 16, 2018
                        Page 11 of 12
Acknowledgment and Signatures
This informed consent document is not a contract.  This document tells you what will happen during 
the study if you choose to take part.  Your signature indicates that this study has been explained to 
you, that your questions have been answered, and that you agree to take part in the study.  You are 
not giving up any legal rights to which you are entitled by signing this informed consent document.  
You will be given a copy of this consent form to keep for your records. 
_______________________________________
__________________________________________
Subject Name (Please Print)
Signature of Subject
   Date Signed
___________________________________________
______________________________________________
Printed Name of Legal Representative (if applicable)
Signature of Legal Representative   
    Date Signed
    
___________________________________________      
Relationship of Legal Representative to Subject
_________________________________________
______________________________________________
Printed Name of PersonExplaining Consent Form
Signature of Person Explaining 
Date Signed
Consent Form (if other than the Investigator)
 
___________________________________________
______________________________________________
Printed Name of Investigator
Signature of Investigator
Date Signed
______________________________________________________________________________________________
Principal Investigator:
Phone Numbers:
Neal Dunlap, MD
502-562-4360
UofL Institutional Review Boards
IRB NUMBER: 14.0413
IRB APPROVAL DATE: 05/15/2018


The Effect of chemotherapy and Stereotactic Body Radiation Therapy for Locally Advanced, 
Non-Resectable Pancreatic Cancer
Consent version date: April 16, 2018
                        Page 12 of 12
REVOCATION OF AUTHORIZATION FOR USE AND DISCLOSURE OF YOUR HEALTH 
INFORMATION FOR RESEARCH
Return To:
To Whom It May Concern:
I would like to discontinue my participation in the research study noted above. I understand that health 
information already collected will continue to be used as discussed in the Authorization I signed when joining 
the study.
Your options are (choose one):
□Withdraw from Study & Discontinue Authorization:
Discontinue my authorization for the future use and disclosure of protected health information. In some instances, the 
research team may need to use your information even after you discontinue your authorization, for example, to notify 
you or government agencies of any health or safety concerns that were identified as part of your study participation. 
□Withdraw from Study, but Continue Authorization:
Allow the research team to continue collecting information from my personal health information. This would be done 
only as needed to support the goals of the study and would not be used for purposes other than those already 
described in the research authorization.
____________________
___
_____
________
Printed Name and Signature of Subject
Date Signed
____________________
___
_____
________
Signature of Subject’s Legal Representative (if subject is unable to sign)
Date Signed
___________________
___
_____
________
Printed Name of Subject’s Legal Representative 
Birthdate of Subject
_________________________________________________
Relationship of Legal Representative to Subject
____________________
___
_____
________
Subject’s Address
Subject’s Phone Number
Optional:
I am ending my participation in this study because: 
___________________
___
_____
PI Address:
529 South Jackson Street
      
Louisville, KY 40202
PI Phone:          (502) 562-4360
Institutional Review Board
MedCenter One, Suite 200
501 E. Broadway
Louisville, KY 40202
OR
Do not sign this letter unless you are withdrawing from this research.   You will be 
sent confirmation that this notice was received.
UofL Institutional Review Boards
IRB NUMBER: 14.0413
IRB APPROVAL DATE: 05/15/2018