The Effect of FOLFIRINOX and Stereotactic Body Radiation Therapy for Locally Advanced, Non-Resectable Pancreatic Cancer
Phase: PHASE2
Conditions: Pancreatic Cancer Non-resectable
Sponsor: University of Louisville

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

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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
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Sons, 1986.
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22
32. Ray HE and Rai SN. An evaluation of a Simon 2-stage phase II clinical trial design 
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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