Phase II Study of Preoperative FOLFIRINOX Followed by Accelerated Short Course Radiation Therapy for Borderline-Resectable Pancreatic Cancer
Phase: PHASE2
Conditions: Pancreatic Cancer
Sponsor: Massachusetts General Hospital

PROTOCOL 11-328 
NCT01591733
Protocol Version Date:   5/19/16 
Phase II Study of Preoperative FOLFIRINOX Followed 
by Accelerated Short Course Radiation Therapy for 
Borderline-Resectable Pancreatic Cancer  

CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Protocol Version Date:   5/19/16 
Local Protocol #: 11-328  
Title: Phase II Study of Preoperative FOLFIRINOX followed by Accelerated Short Course 
Radiation Therapy for Borderline-Resectable Pancreatic Cancer 
 
Principal Investigator: Theodore S. Hong, MD (MGH)  
Coordinating Center: N/A
Co-Investigators: 
Janet E. Murphy, MD 
Alec Kimmelman, M.D. 
Harvey Mamon, MD, PhD (DFCI) 
Lawrence Blaszkowsky, MD  
Michael Blake, MD  
Thomas DeLaney, MD 
Jeffrey Clark, MD 
Eunice Kwak, MD, PhD 
David Ryan, MD 
Andrew Zhu, MD, PhD 
Jill Allen, MD 
Jeffrey Meyerhardt, MD 
Robert J Mayer, MD 
Charles Fuchs, MD 
Peter Enzinger, MD 
Matthew Kulke, MD 
Pankaj Bhargava, MD 
Dushyant Sahani, MD 
Jennifer Wo, MD  
Lorraine Drapek, RN, FNP-BC 
Ryan Nipp, MD 
Theresa McDonnell, DNP, ACNP-BC 
Ann Donnelly, NP 
Rhaea Photopoulos, MS, ANP-BC 
Caroline Kuhlman, MS, NP, AOCNP 
Patricia Tammaro, NP 
Emily Olson, NP 
 
Statistician: Beow Yeap, ScD, MGH
Study Coordinator/Data Manager: 
 
Responsible Research Nurse: TBN

Phase II Study of Neoadjuvant FOLFIRINOX + Proton RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong, MD  5/19/16 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized.
Agent(s): 5-Fluorouricil, Leucovorin calcium, Oxaliplatin, Irinotecan, Capecitabine, Proton or 
Photon Beam Irradiation, (no IND)
Funding Support: Federal Share of program income earned by Massachusetts General 
Hospital on C06 CA059267, Proton Therapy Research and Treatment Center

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
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TABLE OF CONTENTS 
 
1.1 
Study Design ........................................................................................................................8 
1.2 
Primary Objective ................................................................................................................8 
1.3 
Secondary Objectives ...........................................................................................................8 
2 
BACKGROUND ............................................................................................................... 9 
2.1 
Study Agents ........................................................................................................................9 
2.2 
Disease Background...........................................................................................................16 
3 
ELIGIBILITY CRITERIA ............................................................................................ 30 
3.1 
Inclusion Criteria: ..............................................................................................................30 
3.2 
Exclusion Criteria ............................................................................................................32 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ......................33 
4 
REGISTRATION PROCEDURES ............................................................................... 33 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...............................................33 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions ...........................................34 
5 
TREATMENT PLAN ..................................................................................................... 34 
5.1 
Pre-Treatment Criteria .......................................................................................................34 
5.2 
Agent Administration .........................................................................................................35 
5.3 
General Concomitant Medication and Supportive Care Guidelines: .................................41 
5.4 
Duration of Therapy ...........................................................................................................41 
5.5 
Duration of Follow Up .......................................................................................................41 
5.6 
Criteria for Removal from Study .......................................................................................42 
6 
EXPECTED TOXICITIES AND DOSING DELAYS/MODIFICATIONS .............. 42 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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6.1 
Anticipated Toxicities ........................................................................................................42 
6.2 
Toxicity Management ........................................................................................................44 
6.3 
Capecitabine and Proton Radiation .....................................................................................50 
7 
DRUG FORMULATION AND ADMINISTRATION ................................................ 50 
7.1 
5-Fluorouracil (5-FU; fluorouracil; Adrucil" ) ..................................................................50 
7.2 
Leucovorin Calcium (Folinic Acid). ..................................................................................51 
7.3 
Oxaliplatin [Eloxatin] ........................................................................................................52 
7.4 
Irinotecan (CPT-11, CAMPTOSAR®) .............................................................................54 
7.5 
Capecitabine .......................................................................................................................55 
8 
CORRELATIVE STUDIES ........................................................................................... 59 
8.1 
Correlative Studies: SNaPshot analysis .............................................................................59 
9 
STUDY CALENDAR ..................................................................................................... 61 
10 
MEASUREMENT OF EFFECT ................................................................................... 64 
10.1 
Evaluation Of Response .....................................................................................................64 
10.2 
Definitions..........................................................................................................................65 
10.3 
Disease Parameters ............................................................................................................66 
10.4 
Methods for Evaluation of Measurable Disease ................................................................66 
10.5 
Response Criteria ...............................................................................................................67 
10.6 
Response Review ...............................................................................................................68 
11 
ADVERSE EVENT REPORTING REQUIREMENTS.............................................. 68 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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11.1 
Definitions..........................................................................................................................68 
11.2 
Procedures for AE and SAE Recording and Reporting .....................................................71 
11.3 
Reporting Requirements ....................................................................................................71 
11.4 
Reporting to the Study Sponsor .........................................................................................72 
11.5 
Reporting to the Institutional Review Board (IRB) ...........................................................73 
11.6 
Reporting to Hospital Risk Management ...........................................................................74 
11.7 
Monitoring of Adverse Events and Period of Observation ................................................74 
12 
DATA AND SAFETY MONITORING ........................................................................ 74 
12.1 
Data Reporting ...................................................................................................................74 
12.2 
Safety Meetings .................................................................................................................76 
12.3 
Monitoring .........................................................................................................................76 
13 
REGULATORY CONSIDERATIONS ........................................................................ 77 
13.1 
Protocol Review and Amendments ....................................................................................77 
13.2 
Informed Consent...............................................................................................................77 
13.3 
Ethics and Good Clinical Practice (GCP) ..........................................................................78 
13.4 
Study Documentation.........................................................................................................79 
13.5 
Records Retention ..............................................................................................................79 
14 
STATISTICAL CONSIDERATIONS .......................................................................... 79 
14.1 
Study Design/Endpoints.....................................................................................................79 
14.2 
Sample Size/Accrual Rate ..................................................................................................80 
14.3 
Stratification Factors ..........................................................................................................80 
14.4 
Analysis of Secondary Endpoints ......................................................................................80 
14.5 Reporting and Exclusions ......................................................................................................82 
15 
PUBLICATION PLAN .................................................................................................. 82 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
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16
REFERENCES ..................................................................................................................83
 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
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1. OBJECTIVES
1.1
Study Design 
 
This is a single-arm Phase II study of the neoadjuvant administration of the FOLFIRINOX 
regimen and preoperative proton or photon RT followed by surgery in patients with borderline-
resectable adenocarcinoma of the pancreas.
1.2
Primary Objective 
1.2.1
To determine the rate of R0 resection of patients with borderline-resectable 
adenocarcinoma of the pancreas. 
1.3
Secondary Objectives 
1.3.1
To determine the progression-free survival of patients who receive preoperative 
FOLFIRINOX and preoperative short-course radiation therapy.
1.3.2
To determine overall survival in patients treated with preoperative FOLFIRINOX and 
short-course radiation therapy.
1.3.3
To determine the toxicity of FOLFIRINOX + short-course radiation therapy in patients 
with pancreatic cancer.  
1.3.4
To determine the surgical morbidity in patients undergoing pancreaticoduodenectomy 
or distal pancreatectomy who received preoperative FOLFIRINOX and preoperative 
short-course radiation therapy.
1.3.5
To determine 30-day post-operative mortality after pancreaticoduodenectomy or distal 
pancreatectomy in patients who receive preoperative FOLFIRINOX and short-course 
radiation therapy.
1.3.6
To determine pathologic downstaging of FOLFIRINOX + short course radiation 
therapy. 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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1.3.7
To determine local control rates with FOLFIRINOX + preoperative short-course 
radiation therapy.
1.3.8
To correlate mutational analysis biomarkers (SNaPSHOT assay) with response to 
treatment. 
1.3.9
To describe quality of life, symptom burden and mood in the study population 
1.3.10  To measure utilization of health services (emergency room, hospital and intensive care 
unit) in the study population 
2
BACKGROUND
2.1
Study Agents 
2.1.1
5-Fluorouracil 
 
5-Fluorouracil (5-FU) is a pyrimidine antagonist that interferes with nucleic acid biosynthesis.  
The deoxyribonucleotide of the drug inhibits thymidylate synthetase, thus inhibiting the 
formation of thymidylic acid from deoxyuridylic acid, thus interfering in the synthesis of DNA.  
It also interferes with RNA synthesis. It is systemically metabolized, with the enzyme 
dihydropyrimidine dehydrogenase (DPD) being rate-limiting.  It forms the backbone of treatment 
for most gastrointestinal malignancies, and is a crucial component of the FOLFIRINOX regimen, 
in which it is administered as a 400 mg/m2 bolus, followed by a 2400 mg/m2 46 hour infusion.  
Neutropenia and diarrhea are the dose limiting toxicities of 5-fluorouracil.  Nausea and vomiting 
with 5-fluorouracil tends to be mild but patients often become dehydrated due to diarrhea.  
Stomatitis is a common complication of 5-fluorouracil and typically occurs 5-8 days after 
initiating treatment.  Ileus may occur as a result of 5-fluorouracil enteritis. Anemia and 
thrombocytopenia are also associated complications. Dermatologic side effects are common, and 
include dryness of skin, palmar-plantar erythrodysesthesias (Hand-Foot syndrome), alopecia, 
loss of nails/brittle nails and a maculopapular rash.  Neurological complications are rare and 
consist of ataxia.  Cardiotoxicity is another very rare complication of 5-fluorouracil, manifested 
as ischemia and sometimes asymptomatic S-T changes.  Excessive lacrimation is common and 
less common is eye duct stenosis.  5-FU may also increase the INR in patients taking warfarin. 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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Initial dose of 5-FU may be reduced if necessary; then gradually increased to full dose if 
tolerated. All dose reductions are to be made at the discretion of the treating medical oncologist.  
2.1.2
Oxaliplatin  
 
Oxaliplatin is a platinum compound classified with the alkylating agents. Its mechanism of 
action is via intra-strand cross-linking, thereby inhibiting DNA replication and transcription. In 
the FOLFIRINOX regimen it is administered as an 85 mg/m2 infusion over 2 hours. 
Neurotoxicity is generally the dose-limiting toxicity of the drug, as it causes both immediate and 
delayed neuropathy manifesting as cold sensitivity (immediate) and parasthesias, numbness, and 
ataxia (incoordination, including abnormal gait) (delayed.) It is also associated with CNS 
complaints such as insomnia, mood alteration (depression, anxiety) neuropathy cranial (ptosis), 
vertigo, neuropathy sensory (including acute laryngeo-pharyngeal dysesthesias, L’Hermitte’s 
sign, paresthesia). Oxaliplatin is associated with allergic and hypersensitivity reactions including 
chills, flushing, or anaphylaxis. It is associated with mild ototoxicity. Bone marrow suppression 
(particularly thrombocytopenia), cardiac arrythmia, and hepatic toxicity, specifically increased 
alkaline phosphatase, increased bilirubin, increased GGT (gamma-glutamyl-transpeptidase), 
hepatic enlargement, increased AST (AST) (serum glutamic oxaloacetic transaminase), increased 
SGPT (ALT) (serum glutamic pyruvic transaminase) have been observed. It is associated with 
rare but serious pulmonary fibrosis. Initial dose of oxaliplatin may be reduced if necessary; then 
gradually increased to full dose if tolerated. All dose reductions are to be made at the discretion 
of the treating medical oncologist.   
2.1.3
Irinotecan 

Irinotecan is a camptothecin topoisomerase I inhibitor commonly used in gastrointestinal 
malignancies. In the FOLFIRINOX regimen it is delivered as a 180 mg/m2 infusion over 90 
minutes on Day 1 of treatment. Diarrhea and neutropenia are the major dose-limiting toxicities of 
irinotecan. Diarrhea can occur either acutely (within the first 24 hours) and delayed (after 2-4 
days.) Acute diarrhea is thought to be mediated by non-competitive inhibition of acetyl 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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cholinesterase activity by irinotecan, and is readily treatable with atropine, 0.25-1 mg, 
intravenously. Delayed diarrhea often manifests after the second or third weekly dose of 
irinotecan, and is thought to be secretory in nature, resulting from abnormal intestinal ion 
transport. Anti-diarrheal agents, such as loperamide, diphenoxylateatropine (Lomotil®), 
octreotide, scopolamine and bismuth are typically ineffective once grade IV diarrhea has 
occurred. The diarrhea usually lasts 5-7 days before resolving. Early recognition of diarrhea and 
prompt institution of an intensive and prolonged course of loperamide appears to be the most 
effective approach to this problem. Myelosuppression is manifested primarily as leukopenia and 
neutropenia. Other toxicities include nausea, vomiting, alopecia and cumulative fatigue or 
asthenia. Instances of possible drug related hepatic toxicity have occurred, but are rare. Initial 
dose of Irinotecan may be reduced if necessary; then gradually increased to full dose if tolerated. 
All dose reductions are to be made at the discretion of the treating medical oncologist. 
 
2.1.4
Leucovorin 
Leucovorin is a reduced folate which, when combined with 5FU, augments 5FU 
cytotoxicity by increasing the inhibition of TS by the 5FU active metabolite FdUMP. It is 
well-tolerated but can be associated with allergic reactions (rash, urticaria, anaphylaxis) and 
is contraindicated in patients with B12 deficiency and pernicious anemia. 
2.1.5
Capecitabine  
 
 
Capecitabine is a rationally designed oral fluoropyrimidine.1, 2 Given its lack of a need for an 
implantable access device or portable infusion pump and patient convenience, it has become an 
attractive agent to be combined with radiation therapy.  Capecitabine undergoes three steps of 
enzymatic activation before converting to the active drug.  It is readily absorbed from the 
gastrointestinal tract. In the liver, a 60 kDa carboxyesterase hydrolyzes much of the compound to 
5’-deoxy-5-fluorocytidine (5’-DFCR). Cytidine deaminase, an enzyme found in most tissues, 
including tumors, subsequently converts 5’-DFCR to 5’-deoxy-5-fluorouridine (5’-DFUR). The 
enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5’-DFUR to the active drug 5-
FU. Many tissues throughout the body express thymidine phosphorylase . Some human 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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carcinomas express this enzyme in higher concentrations than surrounding normal tissues.  
Capecitabine is rapidly and extensively absorbed with the peak plasma concentrations for the 
drug and its two main metabolites occurring shortly (0.5 - 1.5 hours) after administration.  Then 
concentrations decline exponentially with a half-life of 0.5 - 1 hour.  Plasma concentrations of 
the cytotoxic moiety 5-FU are very low.
Capecitabine is generally well tolerated.  Major side effects include diarrhea, nausea, 
hand-and-foot syndrome, vomiting, fatigue, and stomatitis.  The most frequent grade 3 or 4 
laboratory abnormality was elevated total bilirubin and alkaline phosphatase, or abnormal liver 
function tests.  Myelosuppression has been rarely reported (< 2%). 
Its role as a radiosensitizer has been most studied in rectal cancer.  Dunst et al reported 
the results of a phase I study using capecitabine in T3 and T4 rectal cancer.3 Thirty-six patients 
with rectal cancer received treatment in the adjuvant, neoadjuvant, or palliative setting with a 
total radiation dose of 50.4 Gy.  Capecitabine was administered at escalating doses from 250 to 
1,250 mg/m2 twice a day concurrently with radiation.  They were able to escalate the 
capecitabine dose to 825 mg/m2 twice a day.  Dose-limiting grade 3 hand-and-foot syndrome 
was observed in two of six patients treated at 1,000 mg/m2 bid.  Other toxicities were generally 
rare and/or mild.  One pathologic complete remission of a T3N1 tumor and nine partial 
remissions were observed in 10 patients treated in the neoadjuvant setting.  In another study, 
capecitabine was administered concurrently with radiotherapy in locally advanced rectal cancer.4  
The treatment consisted of 2 cycles of 14-day oral capecitabine (825 mg/m2 BID) and leucovorin 
(10 mg/m2 BID), each of which was followed by a 7-day rest period.  The overall downstaging 
rate, including both primary tumor and nodes, was 84%. A pathologic complete response was 
achieved in 31% of patients. Twenty-one patients had tumors located initially 5 cm or less from 
the anal verge; among the 18 treated with surgery, 72% received sphincter-preserving surgery.   
Grade 3 toxicities included hand-foot syndrome (7%), fatigue (4%), diarrhea (4%), and radiation 
dermatitis (2%).   NSABP is planning a prospective randomized trial to compare capecitabine 
with infusional 5-FU in patients undergoing preoperative radiation therapy.  Preliminary results 
from a trial combining capecitabine with radiation therapy in patients with locally advanced 
pancreatic cancer demonstrated the combination to be safe and tolerable at a dose of 825 mg/m2 
twice daily.5 
2.1.6
Proton Beam Radiation Therapy  

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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There have been unprecedented efforts in radiation oncology to develop and use sophisticated,  
conformal photon techniques in order to improve the outcome for cancer patients. The aim of 
these new techniques is to concentrate the radiation dose distribution more completely on the 
disease target, thereby sparing critical normal tissues and increasing the target dose. Toward this 
end, many advances have been made and examples of new developments include tomotherapy 
and intensity modulated photon therapy. At the same time, heavy, charged-particle programs, 
particularly those for proton therapy, have been developed. Proton therapy dose distributions are 
superior to those of photon therapy and this provides the potential to further improve clinical 
outcomes. Several institutions have committed to build dedicated proton therapy centers such as 
the Francis H. Burr Proton Therapy Center (FHBPTC) at the Massachusetts General Hospital 
(MGH) and the Loma Linda University Medical Center proton therapy facility. Several more 
proton therapy centers are in the final planning stage. 
2.1.6.1
 The Advantages of Protons for Delivery of Conformal Therapy 
Characteristics of Proton Beams 
The basis for the advantages of 
proton beams lies in the physical laws 
that determine the absorption of energy 
in tissues exposed to photon or proton 
beams. In a specific tissue, photons are 
absorbed exponentially whereas protons 
have a finite range dependent upon the 
initial proton energy. Therefore, the 
depth dose characteristics of the two 
beams are qualitatively different (see Figure 1). Protons lose their energy in tissue mostly by 
coulombic interactions with electrons in the constituent atoms; however, a small fraction of 
energy is transferred through nuclear collisions. The energy loss per unit path length is relatively 
small and constant as the proton traverses the tissue until near the end of the proton range where 
the residual energy is lost over a short distance (approximately 0.7 cm in width at 80% of the 
maximum dose) and the proton comes to rest, resulting in a distinctive sharp rise in the tissue 
absorbed dose (energy absorbed per unit mass) - known as the Bragg peak (see the curve labeled 
"unmodulated proton beam" in Figure 1). In physical terms, the magnitude of the transfer of 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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X-RAYS
PROTONS
MEDULLOBLASTOMA
  
Figure 2. Posterior, single-beam treatment of the spinal 
axis.
energy to tissue per unit path length traversed by the protons is inversely proportional to the 
square of the proton velocity. The low dose region between the entrance and the Bragg peak is 
called the plateau of the dose distribution and the dose there is 30-40 percent of the maximum 
dose.  
The Bragg peak is too narrow in extent to irradiate any but the smallest of targets, 
ablation of the pituitary gland for example. For the irradiation of larger targets/tumors the beam 
energy is modulated - several beams of closely spaced energies (ranges) are superimposed to 
create a region of uniform dose over the depth of the target. These extended regions of uniform 
dose are called "spread-out Bragg peaks" (SOBP). This is shown in Figure 1 as the “modulated 
proton beam”.  
 For comparison, Figure 1 also shows the depth-dose curve for a 10 MV x-ray beam, an 
x-ray energy commonly used to treat deep 
seated tumors. Note that the x-ray beam 
dose rises to a maximum value at 
relatively shallow depths, then falls off 
exponentially to lower doses at the 
treatment depth.  A clinical comparison of 
single-beam proton and photon beams is 
shown in Figure 2 where a single posterior 
beam is used for the treatment of the 
spinal axis in the treatment of 
medulloblastoma. Note that, for the 
photon treatment, the heart, mediastinum, 
esophagus, lung and spinal cord are irradiated by the treatment beam whereas for the proton 
treatment, the beam stops abruptly distal to the target volume and there is no irradiation of the 
tissues and organs distal to the target volume.   
In the usual clinical situation, more than one radiation beam is used in both x-ray and 
proton treatments. However, the advantage shown for protons using single beams is present for 
each and every beam used. Therefore, one cannot overcome the physical disadvantage of x-rays 
by the use of multiple beams or complex beam arrangements. In modern proton therapy 
facilities, which have isocentric gantries and sophisticated beam delivery and control systems, 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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IMPT is a factor of two (on the average) less than for IMXT. Moreover, whatever improvement 
IMXT achieves over standard conformal x-ray therapy, a comparable improvement is achieved 
when IMPT is compared to standard conformal proton therapy. 
Figure 3 demonstrates the above points.  It is a comparison of two IMRT plans, one with 
x-rays and one with protons, designed to treat a paranasal sinus tumor (with three target volumes 
receiving 76, 66, and 56 Gy, respectively). The two plans were subject to identical dose 
constraints on normal tissues. The proton dose distribution (left) is clearly excellent; the photon 
distribution on the right is also very good.  However, the presentation of the dose in the top 
panels does not adequately reveal the significant differences between the two distributions.  The 
lower panels show the dose difference between the plans. X-rays deliver an additional “bath” of 
from 5 to 15 Gy throughout the brain and, in the region of the right eye (which is magnified in 
the lower left), up to 40 Gy more than the protons.  (The constraint on the right eye’s retina was 
50 Gy; had it been reduced, x-rays could certainly have reduced the dose in that region – but at 
the price of increased dose elsewhere and, perhaps, of greater non-uniformity of dose in the 
target volumes.) 
Pancreatic tumors also have a number of normal structures in close proximity that have 
limited radiation tolerance including kidneys, liver, spinal cord and stomach.  The lack of exit 
dose from proton beam radiation can allow for reduced dose to these and other normal tissues. 
 
2.2
Disease Background 
2.2.1
Defining the study cohort 
 
The optimal treatment sequence in 
the management of resectable pancreatic 
cancer is controversial, as is the role of 
chemotherapy versus chemoradiation in 
the pre- and postoperative setting. In 
borderline-resectable disease, the case 
for neoadjuvant treatment is more compelling but data for the definitive benefit is lacking, with 
case series rather than prospective clinical trials predominating the literature. The current trial 

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will enroll patients with borderline resectable disease,as defined by vascular criter (see inclusion 
criteria). Based on potential unresectability and/or micrometastatic spread at presentation, this 
group represents the opportune population to offer the combination of highly active systemic 
chemotherapy (the FOLFIRINOX regimen) with preoperative radiation therapy. 
2.2.1.1
Borderline-resectable disease based on NCCN criteria. 
 
The NCCN has adopted guidelines published by the Expert Consensus Report for Resectable 
and Borderline Resectable Pancreatic Cancer (2009) and now defines borderline-resectable 
pancreatic adenocarcinoma as: 
o No distant metastases 
o Venous involvement of the SMV/portal vein demonstrating tumor abutment with 
or without impingement and narrowing of the lumen, either tumor thrombus or 
enacasement but with suitable vessel proximal and distal to the area of vessel 
involvement, allowing for safe resection or reconstruction 
o Gastroduodenal artery encasement up to the hepatic artery with either short 
segment encasement or direct abutment of the hepatic artery, without extension to 
the celiac axis. 
o Tumor abutment of the SMA not to exceed greater than 180 degrees of the 
circumference of the vessel wall.6 
In addition to the above criteria dictated by the NCCN, the definition of “borderline-
resectable” can be expanded to include tumor invasion into retroperitoneal structures that can 
be surgically removed (ie. kidney).  
 
The clinical course and postoperative prognosis of patients with borderline resectable disease 
are difficult to delineate because patients are often considered alongside those with locally 
advanced, categorically unresectable, disease. Outcomes with neoadjuvant chemotherapy and 
chemoradiation in borderline-resectable disease will be discussed shortly. 
 
2.2.2
Neoadjuvant photon chemoradiation in resectable pancreatic adenocarcinoma 
In patients with resectable disease, prospective and retrospective data suggest that compared 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
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with surgery alone, the combination of pancreaticoduodenectomy with postoperative fluorouracil 
(5-FU) and external-beam radiation therapy (EBRT) improves survival duration and local-
regional control.8,9 However, the morbidity and often prolonged recovery time associated with 
pancreaticoduodenectomy prevent the timely delivery of postoperative chemotherapy and EBRT 
in at least 20% of eligible patients.10 The risk of delaying postoperative adjuvant chemoradiation 
has prompted investigators to assess the efficacy of chemotherapy and EBRT before 
pancreaticoduodenectomy in patients with potentially resectable adenocarcinoma of the 
pancreas.   
The concept of neoadjuvant therapy is based on several principles.11 First, it allows for 
management and potential sterilization of micrometastatic disease. Second, it delivers 
chemotherapy and radiation to an intact tumor with patent blood supply. Finally, it allows for 
biologic selection of patients with gross metastatic disease prior to highly morbid intervention 
such as laparotomy or pancreaticoduodenectomy. In practice, several additional considerations 
support the use of preoperative chemotherapy and EBRT.  Positive gross or microscopic margins 
of resection along the right lateral border of superior mesenteric artery (SMA) are common 
following pancreaticoduodenectomy, suggesting that surgery alone may be an inadequate 
strategy for local tumor control.12 Second, because chemoradiation is given before surgery, 
delayed postoperative recovery does not affect the delivery of multimodality therapy.  
Studies from the MD Anderson Hospital first used a standard-fractionation treatment schema 
of preoperative chemoradiation and pancreaticoduodenectomy.13-16 Radiation therapy was 
delivered 5 days/week over 5.5 weeks delivering a total dose of 50.4 Gy in 28 fractions.  5-FU 
was given concurrently by continuous infusion at a dosage of 300 mg/m2 per day, 5 days per 
week, through a central venous catheter.  Thirty-eight patients were evaluable for analysis of 
patterns of treatment failure; 1 perioperative death occurred.  Tumor recurrence was documented 
in 29 patients: 8 recurrences (21%) were local-regional (in the pancreatic bed and/or peritoneal 
cavity), and 30 (79%) were distant (in the lung, liver, and/or bone).  The liver was the most 
frequent site of tumor recurrence, and liver metastases were a component of failure in 53% of 
patients (69% of all patients who had recurrences).  Isolated local or peritoneal recurrences were 
documented in only 4 patients (11%).  In contrast, previous reports of pancreaticoduodenectomy 
alone for adenocarcinoma of the pancreas documented local recurrence in 50 to 85% of 
patients.17,18 The improvement in local-regional control with preoperative chemoradiation was 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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seen even though 14 of 38 evaluable patients had undergone laparotomy with tumor 
manipulation and biopsy prior to referral for chemoradiation and reoperation.  Excluding these 
14 patients, local or peritoneal recurrence was a component of treatment failure in only 2 patients 
(8%).  However, this 5.5-week chemoradiation program was associated with gastrointestinal 
toxicity (nausea, vomiting, and dehydration) that required hospital admission of one third of 
patients. Moreover, in an ECOG trial evaluating preoperative chemoradiation for pancreatic 
cancer patients, 51% of patients required hospital admission for toxicity of treatment during or 
within 4 weeks after completing chemoradiation.19 
These findings prompted a change in the delivery of preoperative chemoradiation at the MD 
Anderson in favor of short course EBRT.  In a series of prospective trials, investigators at MD 
Anderson treated 60 patients with either preoperative standard course RT at a total dose of 50.4 
Gy (1.8 Gy/Fraction, 28 fractions, 5 days/week), short course RT at a total dose of 30 Gy (3 
Gy/fraction, 10 fractions, 5 days/week), or postoperative standard course RT at a total dose of 
50.4 Gy.20   5-FU was given concurrently by continuous infusion 5-FU at a dosage of 300 mg/m2 
per day, 5 days/week.  This short course chemoradiation program was designed to avoid the 
gastrointestinal toxicity seen with standard-fractionation chemoradiation (5.5 weeks) while 
attempting to maintain the excellent local tumor control achieved with multimodality therapy.  
As with other neoadjuvant treatment schemas, restaging with chest radiography and abdominal 
CT was performed 4 weeks following completion of chemoradiation in preparation for 
pancreaticoduodenectomy.   The short course RT was associated with fewer grades 3 toxicity 
than standard course RT (7% vs 19%).  No difference in efficacy could be ascertained as no 
patient treated with preoperative chemoradiation who underwent R0 resection experienced a 
local recurrence. 
 More recently, data from 132 consecutive patients who received preoperative 
chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas also 
supported the use of rapid-fractionation chemoradiation.21 Forty-four patients received standard 
fractionation (45-50 Gy, 1.8 Gy/fraction/day) EBRT and 88 patients received short course EBRT 
(30 Gy, 3 Gy/fraction per day).  The median overall survival from the time of tissue diagnosis 
was 21 months.  Survival duration was not influenced by the dose of preoperative EBRT and 
chemotherapy used.  The data suggested that short course chemoradiation (30 Gy in 2 weeks) 

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20
combined with pancreaticoduodenectomy performed on accurately staged patients might be 
equivalent to standard-fractionation chemoradiation (45-50 Gy in 5-6 weeks). 
 
2.2.3
Neoadjuvant photon chemoradiation in borderline resectable pancreatic 
adenocarcinoma 
 
In addition to the rationale presented above for the potential benefit of neoadjuvant treatment 
in resectable pancreatic cancer, patients who present with borderline resectable disease have the 
added need for both upfront local control and timely systemic therapy. Local control aims to 
provide potential tumor downstaging to increase the chance of R0 resection. Systemic therapy 
aims to sterilize micrometastatic disease, as this population is at higher risk for micrometastatic 
extension at presentation (as high as 80%).11 
The largest case series of neoadjuvant therapy in borderline resectable disease comes from 
MD Anderson.22 One hundred sixty patients with borderline resectable disease (classified due to 
tumor abutment of the visceral arteries or short-segment occlusion of the SMV) were followed. 
Of these, 125 (78%) completed preoperative therapy and restaging. Preoperative therapy was 
generally administered off-protocol, but some patients were treated on protocols designed for 
patients with locally advanced disease. Chemoradiotherapy consisted of external beam radiation 
therapy (50.4Gy in 28 fractions or or 30 Gy in 10 fractions) with concomitant chemotherapy with 
5-fluorouracil, paclitaxel, gemcitabine, or capecitabine at radiosensitizing doses. Systemic 
chemotherapy consisted of gemcitabine alone or in combination; some patients received targeted 
agents. In total, 82 patients had induction chemotherapy and 117 had chemoradiotherapy. After 
neoadjuvant therapy, 66 (41%) subsequently underwent pancreatectomy. Vascular resection was 
required in 18 (27%) of 66 patients, and 62 (94%) underwent a margin-negative pancreatectomy. 
A partial pathologic response to induction therapy (< 50% viable tumor) was seen in 37 (56%) of 
66 patients. Median survival was 40 months for the 66 patients who completed all therapy and 13 
months for the 94 patients who did not undergo pancreatectomy (p < 0.001). 
A smaller, retrospective review of patients with borderline resectable pancreatic cancer 
treated with preoperative chemoradiation and chemotherapy at Fox Chase Cancer Center 
included 13 patients treated in the neoadjvuant setting with chemoradiation (radiosensitizer 
fluorouracil (5-FU) in 3 patients, gemcitabine in 9 patients, and capecitabine and bevacizumab in 

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1 patient administered with 50.4 Gy in 1.8-Gy fractions. 23 Patients received a median of 3 cycles 
of full-dose chemotherapy consisting of gemcitabine for 4 patients, gemcitabine 
and oxaliplatin for 3 patients, gemcitabine and erlotinib for 4 patients, gemcitabine and 
bevacizumab for 1 patient, and 5-FU and erlotinib for 1 patient. After neoadjuvant therapy, 12 of 
13 patients subsequently had surgery, resulting in 2 R1 and 11 R0 resections. Nine patients were 
alive with a median follow-up of 20 months. Five patients recurred at a median of 4 months.  
 
Finally, a recent series of 170 patients at University of Virginia included 40 patients with 
borderline resectable disease, and explored the benefit of shorter course radiation in the 
borderline setting. 24 Of the 40 borderline resectable patients enrolled, 34 (85%) completed 
neoadjuvant therapy consisting of 50 Gy of radiation in 28 fractions in 6 weeks (8 patients) or 
50 Gy in 20 fractions in 4 weeks plus chronomodulated capecitabine (8 patients.) After restaging, 
pancreatic resection was completed in 16 patients (46%). An R0 resection was achieved in 12 of 
the 16 patients (75%). Notably, 5 patients (63%) treated in 20 fractions had >90% pathologic 
response versus 1 (13%) treated in 28 fractions (P < .05). Borderline resectable patients 
completing surgery had similar survival to patients with resectable disease who underwent 
surgery. Patients receiving accelerated fractionation radiation had improved survival compared 
with patients treated with standard fractionation protocol. 
These case series demonstrate early promise for the neoadjuvant approach in pathologic 
downstaging to R0 resection. The Consensus statement for combined modality treatment of 
resectable and borderline resectable pancreas cancer states that at the present time, borderline 
resectable patients should ideally be enrolled in a clinical trial, and in its absence, “induction 
systemic chemotherapy followed by chemoradiation and CT assessment of resectability is the 
preferred approach.” 11 
 
2.2.4
The FOLFIRINOX regimen in advanced pancreatic cancer 
In advanced pancreatic cancer (M1 disease), the standard of care of gemcitabine monotherapy 
was challenged in 2010 with the presentation of the final results of the Prodige 4 – ACCORD 
11/04023 trial.  This large Phase III trial arose from promising interim results from a randomized 
phase II trial comparing FOLFIRINOX to gemcitabine in which a 31.8% response rate was 
detected in the FOLFIRINOX arm, compared to an 11.4% response rate in the gemcitabine arm. 25  

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22
In the Phase III trial, patients were randomized to FOLFIRINOX versus gemcitabine therapy, 
with CT assessment every two months and six months planned upfront therapy.26 The 
FOLFIRINOX regimen was delivered as a 14-day cycle consisting of oxaliplatin 85 mg/m2 
infused over two hours; 5FU 400 mg/m2 bolus with leucovorin 400 mg/m2, followed by infusional 
5FU with 2400 mg/m2 delivered over 46 hour infusion; and irinotecan 180 mg/m2 delivered over 
90 minutes.  Gemcitabine was delivered in the standard fashion of 1000 mg/m2 over 30 minutes 
given weekly on weeks 7/8 and then weekly 3/4. 27 
Patients were stratified by center, performance status (0 versus 1), and site of primary tumor 
(head of the pancreas versus body and tail.)  The study excluded patients with biliary obstruction, 
enrolling patients only with serum bilirubin values of 1.5x the upper limit of normal and lower. 
Notably, lesions in locations other than the head of the pancreas comprised the majority of the 
study population in both arms – 60.8% in the FOLFIRINOX arm and 63.2% in the gemcitabine 
arm. The primary endpoint of the study was overall survival, with the secondary endpoints of 
objective response rate (by RECIST), toxicity, progression-free survival, and quality of life 
measured on the EORTC QLQ-C30 v3.0 scale. One hundred seventy one patients were observed 
by intention-to-treat in each arm. 
The hematologic adverse event profile of the FOLFIRNOX regimen was significantly greater 
compared to gemcitabine. Rates of Grade 3/4 neutropenia (45.7% versus 21.0%), febrile 
neutropenia (5.4 versus 1.2%), and thrombocytopenia (9.1 versus 3.6%) were significantly higher. 
This resulted in 42.5% of patients in the FOLFIRINOX arm requiring G-CSF injection, versus 
5.3% in the gemcitabine arm (per 2010 ASCO presentation of the trial results). Nonhematologic 
Grade 3/4 toxicities were also more prevalent, with peripheral neuropathy, vomiting, fatigue, 
diarrhea, and alopecia all occurring in the FOLFIRINOX arm at a significantly greater rate.  

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23
Despite greater toxicity, the FOLFIRINOX regimen outperformed gemcitabine in all outcomes 
measures. The partial response rate was 31% [24.7-39.1, 95% CI] versus 9.4% [5.9 – 15.4%, 95% 
CI] in the gemcitabine arm. Stable disease rates were more comparable, with 38.6% SD rate in the 
FOLFIRINOX arm and 41.5% in the gemcitabine arm. Overall this led to superior disease control 
rates (CR+PR+SD) for FOLFIRINOX versus gemcitabine, 70.2% and 50.9%, respectively. With a 
median follow-up of 26.6 months [95% CI: 20.5 – 44.9], progression-free survival of patients in 
the FOLFIRINOX arm was 6.4 months, versus 3.3 months in the gemcitabine arm (HR 0.47, 95% 
CI [0.37-0.59].)  This translated to a median overall survival of 11.1 months in the FOLFIRINOX 
arm versus 6.8 months in the gemcitabine arm (HR 0.57, p<0.0001), with a 48.4% one-year 
survival rate (versus 20.6% one-year survival in the gemcitabine arm.)  
The compelling features of the Prodige-4/ACCORD results that mandate moving the regimen 
into the neoadjuvant setting are twofold: first, its demonstrated superiority in systemic disease 
control, and second, its superior objective response rates. In the setting of high-risk or borderline 
resectable disease, the goal of providing chemotherapy to potentially downstage to surgical 
respectability while controlling local spread is paramount. FOLFIRINOX has compelling study to 
suggest it is more active in the preoperative setting than the current standard of gemcitabine-based 
therapy. As the current study plans to enroll patients with lesions in the body and tail in greater 
numbers than are representative of the clinic volume, it will potentially mirror the study population 
of the Prodige-4 trial as well. 
2.2.5
Proton-based Short Course Radiation Therapy for pancreatic cancer: MGH Experience 
 
The safety and efficacy of a one-week course of preoperative proton beam therapy and 
capecitabine followed by early pancreaticoduodenectomy (PD) was explored in a prior study in 
our institution in a different study population.  Patients with radiographically resectable, biopsy-
proven pancreatic cancer of the head of the pancreas were enrolled from May 2007-March 2010 
on this IRB-approved, NCI-sponsored clinical trial. Eligibility included no CT involvement of 
the SMA or celiac arteries; adequate renal, hepatic and hematopoetic function; and ECOG 
Performance Status 0/1. Dose level 1 consisted of Proton Beam Therapy delivered 3 Gy x 10 
Monday to Friday. Pateints in subsequent dose levels received 5 Gy x 5 in progressively 
shortened schedules: level 2 (week 1 Monday, Wednesday, Friday, week 2 Tuesday, Thursday), 

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level 3 (week 1 Monday, Tuesday, Thursday, Friday, week 2 Monday), level 4 (week 1 Monday-
Friday). Proton beam therapy was targeted at pancreatic mass with elective nodal coverage. 
Patients received Capecitabine 825 mg/m2 BID weeks 1 and 2 Monday-Friday.  Surgery was 
performed 1-6 weeks after completion of chemotherapy.  Patients were recommended to receive 
6 months of gemcitabine after surgery.  31 patients were enrolled on study.  27 patients are 
eligible for this analysis. Three patients were treated at each of dose levels 1-3. Six patients were 
at dose level 4, which was selected as the MTD. No dose limiting toxicities were observed.  
There were no unexpected 30-day post-op complications noted in comparison to historical 
controls. Four of 21 resected patients had positive margins. 17/21 had positive nodes. Median 
follow up is 10 months. There have been 2 local failures/progression in ALL patients, both with 
synchronous metastatic disease (at 10 months and 17 months). Metastatic failure has occurred in 
15 out of 27 patients (56%). In summary, we found pre-operative Chemo Radiation Therapy with 
1 week of Proton Beam Therapy and capecitabine followed by early surgery feasible and 
associated with satisfactory local control.  
In summary, we hypothesize that preoperative FOLFIRINOX therapy will optimize the 
neoadjuvant treatment of patients with borderline pancreatic adenocarcinoma based on its 
superior response rate demonstrated in the Prodige-4/ACCORD trial. We anticipate that this 
benefit will be further potentiated by preoperative proton or photon radiation therapy. The 
combination allows for high-efficacy therapy to be delivered expeditiously and with manageable 
tolerable toxicity prior to pancreaticoduodenectomy or distal pancreatectomy. 
 
2.2.6
Equivalence of Proposed Radiation Schedules 
2.2.6.1 Clinical Efficacy 
 
The role of neoadjuvant and adjuvant radiation therapy for resectable pancreatic cancer it to 
improve locoregional control by sterilizing microscopic disease that may not be removed with 
surgery.  Hence, there may not be a clear benefit to higher doses of radiation therapy in this 
setting.  The table below shows the biological and normalized equivalence among a conventional 
radiation schedule and the two proposed dose arms in this study. 
Efficacy Comparison of Conventional and proposed radiation schedules: 

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Schedule 
Dose per 
fraction
#
Tx
Total
Dose 
*B.E.D (Gy) 
(no time 
correction) 
**N.T.D (Gy) 
(no  time
correction) 
*B.E.D. (Gy) 
(time
correction) 
**N.T.D. (Gy) 
(time
correction) 
Conventional 
1.8 Gy 
28 
50.4 
50.4 
59.5 
46.8 
39 
MDACC 
3 Gy 
10 
30 
39 
32.5 
39 
32.5 
MGH Proton 
5 Gy 
(RBE) 
5 
25 
37.5 
31.3 
37.5 
31.3 
 
*B.E.D. – Biologically equivalent dose 
**N.T.D. – Normalized Total Dose, or equivalent physical dose if delivered in 2 Gy fractions. 
RBE – Relative Biological Equivalent, assuming a Relative Biological Effectiveness of 1.1. 
 
No repopulation (no time correction): 
B.E.D = nd(1+d/DE) 
 
With repopulation (time correction): 
B.E.D = nd(1+d/DE) – (T-Tk)(ln2/(D˜ Tpot)) 
 
Where: 
n = number of fractions 
d = dose per fraction 
nd = total dose 
T = total time of treatment in days 
Tk  = time after start of treatment repopulation begins 
Tpot = potential doubling time 
 
Assuming: 
DE = 10  
D = 0.35 T = assuming treatment starts on a Monday with no breaks during treatment 
Tk  = 28 d  
Tpot = 5 days  
 
N.T.D. = B.E.D./ (1+2/DE
 
As demonstrated in the above Table, the reason for similar clinical outcomes between a 
conventional schedule and the MD Anderson 30 Gy short course may be due to both the larger 
fraction size and shorter treatment time.  Similarly, in looking at the 25 Gy schedule, one would 
expect very similar clinical efficacy. 
2.2.6.2 Clinical Toxicity 
 
With alteration of a radiation schedule, there is always concern that the toxicity of treatment may 
increase.  However, when investigators at MD Anderson moved from a conventional schedule to 
a short course, the clinical tolerability in fact improved.   Furthermore, with larger fraction sizes, 
there is also a concern for increased late effects.  Using linear-quadratic formulation, the risk for 
late effects appears to be lower for late effects than with a conventional schedule. 

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Late Effect Comparison of conventional, MD Anderson Short Course, and proposed schedule 
(DE = 3): 
 
Schedule 
Dose/fraction 
# Tx 
Total Dose 
B.E.D (Gy) 
**N.T.D. (Gy) 
Conventional 
1.8 Gy 
28 
50.4 
80.6 
48.4 
MDACC 
3 Gy 
10 
30 
60 
36 
MGH Proton 
5 CGE 
5 
25 
66.7 
40 
 
In a randomized trial for low-lying rectal cancers comparing conventional fraction with 5 Gy x 5, 
an analysis of perioperative complications was also performed28.  There were no differences in 
the rates of complications or in severe complications.  These results suggest that there should not 
be an increase in surgical complications with this either of the proposed radiation schedules in 
this study. 
 
Recommended dose limits for both acute and late effects can be adjusted for the accelerated 
schedule. However, the fewer number of fractions render the constraints significantly more 
stringent.  
2.2.7
Correlative Science Background 
2.2.7.1
Correlative Laboratory Studies 
Preclinical and clinical work in the Steele Lab and elsewhere has identified the stromal-derived 
factor 1 alpha (SDF1α) as an attractive candidate for biomarkers of resistance to various 
therapies, but its role after proton beam radiation therapy is unknown. Based on findings from 
preliminary studies, we propose here to evaluate the changes in blood circulating SDF1α and 
circulating myeloid cells to explore potential associations between the changes in these 
biomarkers and resistance to treatment. These biomarkers will be monitored from baseline 
throughout FOLFIRNOX therapy, before and after a one-week schedule of proton beam 
radiation therapy (or a two-week schedule of photon radiation), after pancreaticoduodenectomy, 
and at time of disease progression.  In exploratory studies, we will evaluate several other 
cytokines using multiplex protein array (Meso-Scale Discovery, Inc.). 
 
Circulating cell populations will be evaluated by fluorescence-based flow cytometry. Protein 
concentration in plasma will be measured using ELISA kits for SDF1˜ and MSD multiplex kits 
for cytokines (IL-1, IL-6, IL-8 and TNF-˜) vascular growth factors (VEGF, sVEGFR1, PlGF 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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27
and bFGF). These techniques have been used in the Steele Lab for over 8 years to evaluate 
patients’ samples. 
2.2.7.1
Patient Reported Outcomes (PRO) background 
 
There are few published studies measuring patient-reported symptoms and quality of life (QOL) 
outcomes in patients with pancreatic cancer. Most of the existing studies assessing QOL in 
patients with pancreatic cancer are focused on individuals with advanced disease.[6, 7] The few 
studies that have included patients with operable pancreatic cancer included small sample sizes 
in heterogeneous patients.[8, 9] Despite the fact that depression is a frequently reported symptom 
in patients with pancreatic cancer, the prevalence among different stages of disease has not been 
thoroughly investigated.[10] A more detailed and comprehensive understanding of the burdens 
faced by patients with locally advanced pancreatic cancer will identify areas for clinicians to 
enhance their supportive care efforts. 
 
Studying patients’ symptom burden and QOL while they are participating in a clinical trial 
provides an opportunity to better understand their disease- and treatment-related outcomes. 
Patients’ symptom burden and QOL are better indicators of their treatment tolerability than 
clinician-reported toxicity monitoring. Combining objective endpoints, such as response rate, 
with subjective patient-reported outcomes has become increasingly important in determining 
efficacy, toxicity, and safety and for allowing comparisons across treatment arms.[11] 
Additionally, evaluating patient-reported measures may help highlight patients’ difficulties with 
treatment adherence by demonstrating additional side effects and toxicities of therapy.[12] 
Increased attention to patients’ symptom burden and QOL while they are participating in a 
clinical trial provides an opportunity to improve their quality of care.[13, 14] Thus, we aim to 
describe QOL, symptom burden and mood in this study population to help us better identify the 
side effects and challenges faced by patients with borderline resectable pancreatic cancer. 
 
A randomized trial comparing the efficacy of gemcitabine and FOLFIRINOX in metastatic 
pancreatic cancer also assessed QOL, using the European Organization for the Research and 
Treatment of Cancer QOL Questionnaire C30 (EORTC QLQ-C30).[7]  The authors 
demonstrated that FOLFIRINOX not only prolonged survival, but also significantly reduced 
QOL impairment compared to gemcitabine for patients with metastatic cancer.  Thus, in addition 
to the utility of describing the symptom burden and QOL in patients with borderline resectable 
pancreatic cancer, it will also be useful to compare these outcomes in patients receiving different 
chemotherapy regimens. 
 
We will use the EORTC QLQ-C30, a validated instrument designed for prospective clinical trials 
that evaluates five functions (physical, role, cognitive, emotional, and social), and nine 
symptoms (fatigue, pain, nausea and vomiting, dyspnea, loss of appetite, insomnia, constipation, 
diarrhea, and financial difficulties) to measure QOL.[15] We will use the Edmonton Symptom 
Assessment System-revised (ESAS-r) to measure symptoms, which has been previously 
validated in patients with advanced cancer.[16] The ESAS-r consists of ten items assessing pain, 
fatigue, drowsiness, nausea, anorexia, dyspnea, depression, anxiety, well-being, and a free-
response item. We will include constipation as the free-response item. The ten items are scored 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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5/19/16 
 
28
on a scale of 0-10 (0 reflecting no reported presence of the symptom and 10 reflecting the worst 
possible severity of the symptom). We will instruct patients that items are to be rated based on 
the previous 24-hour period. We will use the Hospital Anxiety and Depression Scale (HADS) to 
assess symptoms of depression and anxiety.[17] The HADS is a 14-item questionnaire that 
contains two 7-item subscales assessing depression and anxiety symptoms during the past week. 
The questionnaire consists of a four-point item response format that quantifies the degree to 
which participants experience a particular emotion. Scores on each subscale range from 0 to 21, 
with a cutoff of 8 or greater denoting clinically significant depression or anxiety symptoms. 
2.2.7.2
Health Care Utilization background 
 
As oncologists strive to improve care quality and lower health care costs, their focus has turned 
to reducing avoidable admissions and decreasing hospital length of stay (LOS) for patients with 
cancer.[18, 19]  Patients with pancreatic cancer often experience symptoms related to the cancer 
itselt or the therapies used to treat it.[8] Symptom management for these patients may necessitate 
frequent clinic visits, surgical interventions, and ultimately admissions to the hospital. Avoiding 
unnecessary hospitalizations is an area needing improvement for patients with cancer, but a 
better understanding of health care utilization is necessary in order to develop future 
interventions.[20] Thus, we propose to collect data on study participants’ health care utilization 
including hospital admissions, intensive care unit stays and emergency room visits.  Similar to 
measuring patient-reported outcomes, assessing health care utilization will help us better 
understand study patients’ experience with their cancer treatment. 
 
2.2.7.3
SNaPshot analysis 
Tumor mutational analysis by SNaPshot technology.  In pancreas cancer, mutations of 
interest do not occur randomly, but rather a relatively small number of well-characterized 
mutations compromise the vast majority of activating mutations.  Other genes of interest already 
mentioned include APC, CTNNB1 (β-catenin), Braf, PTEN, and PIK3CA.  Our institution has 
recently begun using an adaptation of SNaPSHOT (Applied Biosystems) as our clinical method 
of determining KRAS mutational status in tumors, as described by Dias-Santagata et al. 28 This 
testing is routinely done on all newly diagnosed GI cancer patients. Table 1 below shows the list 
of mutations tested in our tumor SNaPSHOT platform. 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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Table 1: 
2.2
 
 
 
 
 
 
 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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30
3
ELIGIBILITY CRITERIA 
 
3.1
Inclusion Criteria: 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
3.1.1
Cytologic or histologic proof pancreatic ductal carcinoma is required prior to study 
entry. Diagnosis must be confirmed by the MGH pathology department. 
3.1.2
No evidence of metastatic disease as determined by chest CT scan, abdomen/pelvis CT 
scan (or MRI with gadolinium and/or manganese) within six weeks of study entry. All 
patients must be staged with a physical exam, chest CT, abdominal CT with 
intravenous contrast (or Abd MRI with gadolinium and/or manganese).  
3.1.3
Staging laparoscopy is not required at the outset of the trial, including in patients who 
might otherwise receive staging laparoscopy per NCCN guidelines (high-risk body and 
tail lesions), because patients will receive systemic chemotherapy at equivalent dose to 
patients who have documented Stage IV disease.  
3.1.4
Patients who are deemed ‘borderline resectable’ will be included. Borderline resectable 
is defined by the NCCN as tumors with venous involvement of the SMV/portal vein 
demonstrating tumor abutment with or without impingement and narrowing of the 
lumen, either tumor thrombus or enacasement but with suitable vessel proximal and 
distal to the area of vessel involvement, allowing for safe resection or reconstruction; 
gastroduodenal artery encasement up to the hepatic artery with either short segment 
encasement or direct abutment of the hepatic artery, without extension to the celiac 
axis; or tumor abutment of the SMA not to exceed greater than 180 degrees of the 
circumference of the vessel wall. Tumors involving retroperitoneal structures that can 
be surgically removed (ie. kidney), will also be included.  
3.1.5
Patients must be 18 years old or older. There will be no upper age restriction. 
3.1.6
Patients with ECOG-Performance Status of 0 or 1 are eligible. 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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31
3.1.7
Life expectancy of greater than 3 months. 
3.1.8
Lab Values within one week of study entry: 
 
 
 
ANC t 1000 cells/mm3 
 
 
 
Platelet count at least 100,000 cells/mm3. 
 
AST and ALT d 2.5 x upper limit of normal, OR two consecutive downtrending values 
for patients who have undergone biliary stenting. 
 
Total Bilirubin d 1.5 x upper limit of normal, 
OR, for patients who have undergone biliary stenting, Total bilirubin <2.0 OR two 
downtrending values 
 
 
 
Serum Creatinine ≤ 1.5 mg/dl 
Creatinine Clearance t 30ml/min (as estimated by Cockroft Gault Equation):
 
 
 
 
 
 
 
Creatinine clearance for males = 
(140 - age [yrs]) (body wt [kg]) 
   
 
———————————— 
(72) (serum creatinine [mg/dL])
Creatinine clearance for females =  0.85 x male value  
3.1.9
The effects of radiation on the developing human fetus are known to be teratogenic.  
Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for 
the duration of study participation plus 30 days from the last date of study drug 
adminsitration. Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately. 
3.1.10 The mutational analysis (SNaPSHOT panel) requires a paraffin-embedded block or ten 
unstained slides from the untreated biopsy specimen obtained at the time of upper 
endoscopy or initial diagnostic biopsy. Patients without sufficient material for 
SNaPSHOT will NOT be excluded from the study as this constitutes a secondary, 
exploratory aim of the study. 
3.1.11 Ability to understand and the willingness to sign a written informed consent document. 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
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32
 
 
 
3.2
Exclusion Criteria 
Patients who fulfill any of the following criteria will be excluded: 
3.2.1
Serious concomitant systemic disorders incompatible with the study (at the discretion 
of the investigator), such as significant cardiac or pulmonary morbidity e.g. congestive 
heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well 
controlled with medication) or myocardial infarction within the last 12 months, ongoing 
infection as manifested by fever. 
3.2.2
Pregnant or lactating women. Women of childbearing potential with either a positive or 
no pregnancy test (serum or urine) at baseline.  (Postmenopausal woman must have 
been amenorrheic for at least 12 months to be considered of non-childbearing 
potential). 
3.2.3
Any prior chemotherapy, targeted/biologic therapy, or radiation for treatment of the 
patient’s pancreatic tumor.  
3.2.4
Treatment of other invasive carcinomas within the last five years with greater than 5% 
risk of recurrence at time of eligibility screening. Carcinoma in-situ and basal cell 
carcinoma/squamous cell carcinoma of the skin are allowed. 
 
3.2.5
Other serious uncontrolled medical conditions that the investigator feels might 
compromise study participation. 
3.2.6
Lack of physical integrity of the upper gastrointestinal tract or malabsorption 
syndrome. 
3.2.7
Known, existing uncontrolled coagulopathy.  

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
33
 
3.2.8
Prior systemic fluoropyrimidine therapy (unless given in an adjuvant setting and ted at 
least 6 months earlier). Prior topical flouropyrimidine use is allowed.  Prior 
unanticipated severe reaction to fluoropyrimidine therapy, or known hypersensitivity to 
5-fluorouracil or known DPD deficiency. 
3.2.9
Participation in any investigational drug study within 4 weeks preceding the start of 
study treatment. 
3.2.10 History of uncontrolled seizures, central nervous system disorders or psychiatric 
disability judged by the investigator to be clinically significant, precluding informed 
consent, or interfering with compliance or oral drug intake. 
 
3.2.11 Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment, 
without complete recovery. 
3.2.12 Patients should not be on cimetidine as it can decrease the clearance of 5-FU.  Another 
H2-blocker or proton pump inhibitor may be substituted before study entry. 
3.2.13 Participants may not be receiving any other study agents. 
3.2.14 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to 5-fluorouricil, irinotecan, or oxaliplatin. 
3.3
Inclusion of Women, Minorities and Other Under Represented Populations 
We do not expect the inclusion and exclusion criteria to either over or under represent women, 
minorities, or under represented populations. 
 
4
REGISTRATION PROCEDURES
 
4.1
General Guidelines for DF/HCC and DF/PCC Institutions 
 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
34
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4.2
Registration Process for DF/HCC and DF/PCC Institutions 
 
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Subject
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5
TREATMENT PLAN
 
Treatment will be administered on an outpatient basis and will include administration of the 
FOLFIRINOX regimen followed by Proton or Photon Radiation Therapy with capecitabine. 
Expected toxicities and potential risks as well as dose modifications for FOLFIRINOX and 
Radiation are described in Section 6 (Expected Toxicities and Dosing Delays/Dose 
Modification). No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the participant’s malignancy. 
 
5.1
Pre-Treatment Criteria 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
35
Prior to study enrollment patients must undergo the following evaluations: 
Within 42 days of enrollment:  Chest CT and Abdominal-pelvic CT (or MRI). If available, 
Paraffin-embedded block or ten unstained slides will be used from the untreated biopsy specimen 
obtained at the time of upper endoscopy or initial diagnostic biopsy for SNaPSHOT analysis. 
Within 7 days of enrollment: Physical exam, Lab studies (CBC with diff, Na, K, BUN, Cr, 
Glucose, Calcium, Albumin, AST, ALT, Total bilirubin, Alkaline phosphatase, CA19-9, 
CEA, and a urine or serum HCG for women of childbearing potential).  
 
If a patient has undergone biliary stent placement, the following eligibility guidelines will 
apply. If ALT and AST are elevated beyond 2.5 x the upper limit of normal at time of study 
enrollment, but demonstrate two consecutive down-trending values, the patient should begin 
treatment without Irinotecan, or with dose-reduced Irinotecan if clinically indicated. The 
agents 5-FU and Oxaliplatin may be given during Cycle 1 with Irinotecan incorporated as 
laboratory values permit. If total bilirubin is elevated above 2.0 mg/dl at time of enrollment, 
the patient may begin Cycle 1 with full dose 5-FU and Oxaliplatin, with Irinotecan 
incorporated as laboratory values permit. If total bilirubin is elevated between the upper limit 
of normal and 2.0 mg/dl at time of enrollment, the patient may receive full dose 5-FU and 
Oxaliplatin, with dose-reduced Irinotecan. Irinotecan may be increased to full dose in the first 
or second cycle if laboratory values permit. 
 
Evaluations obtained to confirm study eligibility may be used as pre-treatment evaluations 
provided they are done within the above timeframes. 
 
5.2
Agent Administration 
 
Study participants will receive up to 8 cycles of FOLFIRINOX as indicated in the study schema. 
All treatments shall be administered according to institutional standard of care.  
5.2.1
5-Fluorouricil: 5-FU will be administered at a dose of 400 mg/m2 push per 
institutional standard on day one, followed by a 1200 mg/M2/d by continuous 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
36
infusion via an ambulatory infusion pump for the subsequent two days. 5-Fluorouracil 
is not a vesicant or irritant. Initial dose of 5-FU may be reduced if necessary; then 
gradually increased to full dose if tolerated. All dose adjustments are to be made at the 
discretion of the treating medical oncologist. 
 
5.2.2
Oxaliplatin: Oxaliplatin will be administered as a dose of 85 mg/m2 by intravenous 
infusion over 120 minutes . Infusion time may be prolonged (up to 6 hours) in patients 
experiencing pharyngolaryngeal dysesthesia. Oxaliplatin is unstable in the presence of 
chloride or alkaline solutions. Do NOT mix or administer oxaliplatin with saline or 
other chloride-containing solutions. Do NOT administer other drugs or solutions in the 
same infusion line. Flush IV lines/catheters with Dextrose 5% in Water both before and 
after oxaliplatin administration. Initial dose of Oxaliplatin may be reduced if necessary; 
then gradually increased to full dose if tolerated. All dose adjustments are to be made at 
the discretion of the treating medical oncologist. 
 
5.2.3
Leucovorin: Leucovorin (400 mg/m2) will be diluted with 5% dextrose and 
administered concurrently (in separate containers using a Y-type administration set) by 
IV infusion over 2 hours.  
 
5.2.4
Irinotecan: In this study irinotecan will be administered as a dose of 180 mg/m2 by 
intravenous infusion over 90 minutes . Initial dose of Irinotecan may be reduced if 
necessary; then gradually increased to full dose if tolerated. All dose adjustments are to 
be made at the discretion of the treating medical oncologist. 
5.2.5
Capecitabine: The dose of capecitabine will be given orally 825 mg/m2 BID (total 
1650 mg/m2 per day) for a total of 10 days M-F during the week of, and the week after, 
proton beam radiation; or the two weeks of photon radiation.  The dose of capecitabine 
will be fixed unless there are dose level reductions. The daily dose will be administered 
in two divided doses approximately 12 hours apart.  The medication should be given 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
37
within 30 minutes after the end of a meal or snack and swallowed with about 8 oz. of 
water.  The dose of capecitabine will be calculated on the basis of milligrams of drug 
per square meter of body surface area (BSA).Doses will be rounded to the nearest 
multiple of whole tablets.  Capecitabine tablets are either 150 or 500 mg in size, so the 
dose given will be rounded to the nearest 150 mg tablet.  The BSA will be rounded to 
the nearest tenth and the investigator will prescribe capecitabine according to the 
following chart.  The dose of capecitabine will not exceed 2000mg po bid.  All dose 
adjustments will be at the discretion of the treating investigator. 
 
Table 1: Capecitabine Dosing 
BSA (m2) 
Dose BID 
(Total mg per dose) 
500 mg tabs 
150 mg tabs 
1.0 
800 
1 
2 
1.1 
1000 
2 
0 
1.2 
1000 
2 
0 
1.3 
1000 
2 
0 
1.4 
1150 
2 
1 
1.5 
1300 
2 
2 
1.6 
1300 
2 
2 
1.7 
1500 
3 
0 
1.8 
1500 
3 
0 
1.9 
1500 
3 
0 
2.0 
1650 
3 
1 
2.1 
1800 
3 
2 
2.2 
1800 
3 
2 
2.3 
2000 
4 
0 
2.4 
2000 
4 
0 
2.5 
2000 
4 
0 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
38
If vomiting occurs around the time of capecitabine ingestion or if doses of capecitabine 
are missed, additional (“make-up”) doses of capecitabine should not be administered.  A 
drug diary will be provided to document appropriate administration. 
5.2.6
Radiation Therapy 
5.2.6.1
Simulation and Planning 
Tumor volume will be defined on the basis of CT and MRI imaging findings and 
operative notes and findings. The primary tumor and any clinically enlarged lymph nodes will 
be treated with a margin of 2 cm to include peripancreatic nodes.  The porta hepatis, celiac 
axis, superior mesenteric artery (SMA) root, and the pancreaticoduodenal nodes will also be 
treated.  
Total dose will be prescribed to the 95 to 100% isodose line based on coverage and 
will be 25 CGE protons in 5 fractions (5 Gy/day) or 30 Gy photons in 10 fractions (3 Gy/day) 
with multifield techniques.   A dose painted boost to involved vasculature is permitted to a 
total dose of 30 Gy.  Radiation treatment assignment will be based on resource availability at 
the time of radiation planning. 
Patients will be simulated supine. Intravenous and oral contrast will be administered 
per standard department protocol.  4-D planning CT will be obtained for treatment planning to 
ascertain the extent of tumor motion.
The Gross Tumor Volume (GTV) is defined as the gross primary tumor and any lymph 
nodes enlarged over 1 cm during simulation using contrast given during CT or MRI.  The 
clinical target volume (CTV) will also include the following at-risk nodal basins: porta hepatis, 
celiac axis, superior mesenteric artery, and pancreaticoduodenal nodes as defined by the inner-
third of the duodenum.  Planning target volume (PTV): PTV will be customized based on 4D CT 
scan. Generally 0.5 cm expansion will be used, except for superiorly/inferiorly 0.7 cm will be 
used. 
Computerized dosimetry is required if more than two fields are used. All fields must be 
simulated using a machine that duplicates the geometry of the actual treatment machine.  Patient 
contours and isodose plots are required.  Isodose plots must account for the effect of all treated 
fields, including any blocking used.   
 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
39
5.2.6.2
Treatment 
All radiation treatment will be given with the patient at the Francis H. Burr Proton Therapy 
Center or the Clark Center for Radiation Oncology at MGH.  Film or digital images will be 
taken prior to each treatment in accordance with the Department of Radiation Oncology’s 
standard practice for all patients.  These images are used to verify the position of the patient 
and the aperture.  These digital images are permanently stored electronically for each patient. 
Radiation treatment must start on a Monday-Wednesday.    If the proton center is 
unexpectedly not functioning for 1-2 days, these fractions may be made up the following week. 
However, if the proton center is not functioning longer than 2 days, patients may receive photon 
radiation for the remaining fractions. If radiation therapy start is delayed beyond 4 weeks after 
completion of FOLFIRINOX due to toxicity, the patient will proceed to radiation therapy on 
study at the discretion of the treating investigator. 
5.2.6.3
Normal tissue volume and dose considerations 
Normal tissue guidelines are as outlined below.  
Table 2: Planning Goals - Normal tissue constraints 
Organ
Normalized 
Total Dose 
(2 Gy equivalents) 
Threshold Dose- 
5 fraction 
schedule
(CGE)
% Above 
threshold 
Liver 
23.0 Gy2 
17.5 
30% 
Kidney 
14.8 Gy3 
13 
30% 
Spinal Cord 
40.6 Gy2 
24 
0% 
Stomach 
38 Gy10 
7 
10% 
 
Assumed DE in subscripts 
x *  If possible -  Stomach dose threshold is to prevent nausea, an acute effect. No 
established guidelines exist. However, in the preliminary MGH IMRT experience, the 
above dose threshold is associated with ~ 10% rate of ANY anti-emetic use.  The daily 
NTD of the conventional schedule is 1.36 Gy.  This means that that the threshold dose 
(NTD) for a five fraction schedule is 6.8 Gy (2 Gy equivalents) and correlates with the 
listed dose threshold. 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
40
Treatment planning should be adjusted for decreased renal function based on an elevated 
serum creatinine, a history of unilateral or bilateral renal disease, and abnormalities in 
baseline laboratory or radiographic studies.  Additional studies to assess renal function will be 
performed as needed.  For protons, passively scattered protons and pencil beam protons are 
both permitted.  For photons, 3D photons and IMRT are both permitted. 
 
5.2.7
Other Modalities and Procedures 
5.2.7.1
Surgery: Surgery will be performed one to four weeks after completion of 
capecitabine therapy. If surgery is delayed beyond four weeks after completion of 
capecitabine, the patient will be taken off study.  At laparotomy, the liver and 
pancreas will be examined by palpation and inspection.  In the absence of 
metastases, tumor mobilization and surgical resection will be performed.  A 
pancreaticoduodenectomy (Whipple procedure) or distal pancreatectomy with 
standard lymphadenectomy will be done.  This involves dissection up to the 
superior mesenteric artery, with skeletonization of the right lateral and anterior 
aspects of the vessels.  Feeding jejunostomy and gastrostomy tubes may be placed 
at the discretion of the operating surgeon. 
5.2.7.2
Pathology: Processing the specimen and pathology will be reported according to 
the AJCC Cancer Staging Manual, 6th Edition.  Pancreatic transection margin, and 
the bile duct margin will be evaluated on frozen section.  Recorded on permanent 
section will be: tumor size, degree of differentiation (well, moderate, poor), lymph 
node status, and margin status.   
5.2.7.3
Chemotherapy: Patients may receive adjuvant chemotherapy afterat the discretion 
of the treating investigator.  If adjuvant chemotherapy is administered, at 
minimum, administration of FOLFIRINOX therapy will be contingent on patients 
meeting original inclusion criteria (lab parameters and performance status). 
Physicians may opt to provide FOLFOX or FOLFIRI in the postoperative setting, 
with the full FOLFIRINOX regimen administered only when the patient is able to 
tolerate this therapy. If there is evidence of progression, patients will be withdrawn 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
41
from the study and as per NCCN guidelines, proceed to second-line therapy (likely 
gemcitabine-based chemotherapy.) Appropriate dose reductions and modifications 
can be made at the discretion of the treating physician. 
5.3
General Concomitant Medication and Supportive Care Guidelines:  
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc. when appropriate.  The reason(s) for treatment, dosage, and the 
dates of treatment should be recorded on the flow sheets.  Erythropoietin is allowed.  As the 
Myeloid growth factors should not be used prophylactically but may be utilized to treat grade 3-4 
neutropenia rate experienced in the ACCORD trial was 79.9% (see Section 6.1), the study will 
mandate prophylactic administration of GM-CSF (Neulasta(ANC < 1000) with each cycle of 
therapy. This should be administered 24-48 hours after discontinuation of infusional 5-
fluorouracil.or without fever.  Patients may receive all concomitant therapy deemed necessary to 
provide adequate support.  No other cytotoxic therapy or radiotherapy may be used during 
therapy.  
 
5.4
Duration of Therapy 
Duration of therapy will depend on individual response, evidence of disease progression 
and tolerance. In the absence of treatment delays due to adverse events, treatment may 
continue until one of the following criteria applies: 
x 
Disease progression, 
x 
Intercurrent illness that prevents further administration of treatment, 
x 
Unacceptable adverse event(s), 
x 
Participant decides to withdraw from the study, or 
x 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
5.5
Duration of Follow Up 
Study participants  will be in active follow up after completion of neoadjuvant treatment and 
surgery per study guidelines, as outlined above, except in the case of documented progression, at 
which time they will be followed for survival only.  Participants removed from study for 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
42
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event. 
 
5.6
Criteria for Removal from Study 
Participants will be removed from study when any of the criteria listed in Section 5.4 
applies. The reason for study removal and the date the participant was removed must be 
documented in the study-specific case report form (CRF). Alternative care options will be 
discussed with the participant. 
 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator Theodore S. Hong, M.D. at 
 
 
6
EXPECTED TOXICITIES AND DOSING DELAYS/MODIFICATIONS 
 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Active Version of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible. 
6.1
Anticipated Toxicities 
 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
43
A list of the adverse events and potential risks associated with the agents administered in this 
study appear below and will determine whether dose delays and modifications will be made or 
whether the event requires expedited reporting in addition to routine reporting. 
 
6.1.1
FOLFIRINOX Therapy 
6.1.1.1
Anticipated Hematologic adverse events 
 
Below is the table of adverse events associated with the FOLFIRINOX regimen in the Prodige-
4/ACCORD trial in patients with advanced pancreatic adenocarcinoma. 
 
AE, % per patient 
Folfirinox 
N=171 (from NEJM 2011) 
All 
Grade 3/4 
Neutropenia 
79.9 
45.7 
Febrile Neutropenia 
  5.4 
  
Anemia 
90.4 
7.8 
Thrombocytopenia 
75.2 
9.1 
 
6.1.1.2
Anticipated Non-Hematologic adverse events 
Below is the table of adverse events associated with the FOLFIRINOX regimen in the Prodige-
4/ACCORD trial in patients with advanced pancreatic adenocarcinoma. 
 
AE, % per patient 
Folfirinox N=168 (from ASCO 2010) 
All 
Grade 3/4 
Infection without neutropenia 
6 
1.2 
Peripheral neuropathy 
70.5 
9 
Vomiting 
61.4 
14.5 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
44
Fatigue 
87.3 
23.2 
Diarrhea 
73.3 
12.7 
Alopecia (grade 2) 
32.5 
(11.4) 
ALT 
64.8 
7.3 
 
6.1.2
Radiation Therapy  
 
The most common toxicities of radiation therapy are fatigue, nausea, abdominal pain, diarrhea, 
indigestion, vomiting, weight loss and anorexia.   Other toxicities may include radiation fibrosis 
if surgery is delayed too long.  Much less common toxicities could include liver damage, kidney 
damage, delayed wound healing, and late second malignancies. 
 
6.1.3
Capecitabine 
The most common toxicities of capecitabine are diarrhea, indigestion, nausea, vomiting, weight 
loss, anorexia, and hand-foot syndrome (skin changes and tenderness of hands and feet, 
especially fingers and toes).   Other toxicities may include neutropenia, thrombocytopenia, 
anemia, cutaneous eruptions, alopecia, fever, and fatigue or general malaise.  Much less common 
toxicities could include allergic reactions and coronary vasospasm. 
6.2
 Toxicity Management 
6.2.1
FOLFIRINOX therapy 
 
“One cycle” will constitute one administration of FOLFIRINOX therapy, administered on Day 
1-3. Each cycle will be 14 days long, and will be repeated every 14 days, unless further dose 
delay is warranted by toxicities. Cycle adjustments of +3/-1 days may be made at the discretion 
of the treating physician. A break in therapy of up to one week for restaging is allowed. 
 The table below indicates potential dose levels for each of the agents for which dose 
modifications will be allowed. Dose adjustments of each agent may be made independently 
based on the specific types of toxicities observed. Only those agents specified in the sections 
below should be dose-reduced. 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
45
 
Patients who require multiple dose reductions during a cycle for grade 2 toxicity may, at the 
physician’s discretion, begin the following cycle at one dose level higher than 
the current dose reduction. If dose reduction beyond –3 for any agent is 
required, that agent should be discontinued.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leucovorin dose is always 400 mg/m2, IV given prior to the infusion of 5-FU. If any infusion of 
5-FU is to be skipped, leucovorin must also be skipped. Initial doses may be reduced, if 
necessary, at the physician’s discretion.  
 
If a patient has undergone biliary stent placement prior to enrollment, the following treatment 
guidelines will apply for Cycles 1 and 2. If ALT and AST are elevated beyond 2.5 x the upper 
limit of normal at time of study enrollment, but demonstrate two consecutive down-trending 
values, the patient should begin treatment without Irinotecan, or with dose-reduced Irinotecan 
if clinically indicated. The agents 5-FU and Oxaliplatin may be given during Cycle 1 with 
Irinotecan incorporated as laboratory values permit. If total bilirubin is elevated above 2.0 
mg/dl at time of enrollment, the patient may begin Cycle 1 with full dose 5-FU and 
Oxaliplatin, with Irinotecan incorporated as laboratory values permit. If total bilirubin is 
elevated between the upper limit of normal and 2.0 mg/dl at time of enrollment, the patient 
Agent*  
  
 
Oxaliplatin  
 
Irinotecan  
 
5-FU Bolus  
 
5-FU Infusion 
 
Initial  
Dose 
85 mg/m2  
 
180 mg/m2  
 
400 mg/m2  
 
2400 mg/m2 
per 46-48 hours 
Level –1 
65 mg/m2  
 
150 mg/m2  
 
320 mg/m2  
 
1920 mg/m2 
per 46-48 hrs 
 
Level –2  
 
50 mg/m2  
 
120 mg/m2  
 
270 mg/m2  
 
1600 mg/m2 
per 46-48 hrs 
 
Level –3 
40 mg/m2 
100 mg/m2 
230 mg/m2 
1360 mg/m2 
per 46-48 hrs 
 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
46
may receive full dose 5-FU and Oxaliplatin, with dose-reduced Irinotecan. Irinotecan may be 
increased to full dose in the first or second cycle if laboratory values permit. 
 
 
6.2.1.1
Hematologic toxicities 
 
The following dose modifications are based on toxicity demonstrated during a mid-cycle visit 
and/or at the time of laboratory assessment for planned administration of the next cycle of 
therapy (for example on the planned day of administration of Cycle 2 Day 1 after completing the 
14-day period constituting Cycle 1.) As the Grade 2-4 neutropenia rate in the PRODIGE-
ACCORD trial was 79.9%, in this trial prophylactic GM-CSF (Neulasta) will be administered 
24-48 hours after discontinuation of continuous infusion 5-FU. 
 
 
Dose Reduction Table for Hematologic Toxicity 
                                  (Note: DR = Dose Reduction) 
 
Hematologic 
Toxicity on the 
Day of Treatment 
(D1)
Action
Oxaliplatin
Irinotecan
5-FU Bolus 
(Leucovorin
follows 
protocol for 
5FU bolus)
5-FU
Continuous
Infusion
Neutropenia G2  
(ANC 1500-1000) 
– all patients 
should have 
Neulasta support 
per institutional 
guidelines
HOLD ALL 
THERAPY
Hold until 
ANC 
>=1500, 
resume 
without dose 
reduction 
Hold until 
ANC 
>=1500, 
resume 
without dose 
reduction
Hold until 
ANC 
>=1500, 
resume 
without dose 
reduction
Hold until 
ANC 
>=1500, 
resume 
without dose 
reduction
Neutropenia G3-4, 
Febrile 
neutropenia 
(ANC 1000-500, 
<500)
HOLD ALL 
THERAPY, 
Supportive 
care and 
antibiotics 
per 
institutional 
guidelines
Hold until 
ANC 
>=1500, 
resume @ 
permanent 
DL-1 level 
once 
resolved
Hold until 
ANC 
>=1500, 
resume @ 
permanent 
DL-1 level 
once 
resolved
Hold until 
ANC 
>=1500, 
resume @ 
permanent 
DL-1 level 
once 
resolved
Hold until 
ANC 
>=1500, 
resume @ 
permanent 
DL-1 level 
once 
resolved
Thrombocytopenia 
G1 
(LLN – 75K)
Treat with 
DR 
Oxaliplatin
Treat at 
permanent 
DL -1
No reduction
No reduction
No reduction

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
47
Thrombocytopenia 
G2 
(75K – 50K)
HOLD ALL 
THERAPY
Hold until 
resolved to 
>100K, 
resume at 
permanent 
DL-1
Hold until 
resolved to 
>100K, no 
reduction
Hold until 
resolved to 
>100K, No 
reduction
Hold until 
resolved to 
>100K, No 
reduction
Thrombocytopenia 
G3-4 
(50K – 25K, 
<25K)
HOLD ALL 
THERAPY
Hold until 
resolved to 
>100K.  
Resume @ 
permanent 
DL-1 if 
resolved in 1 
wk, 
permanent 
DL -2 if >1 
wk to 
resolve
Hold until 
resolved to 
>100K.  
Resume @ 
permanent 
DL-1.
Hold until 
resolved to 
>100K
Hold until 
resolved to 
>100K
 
6.2.1.2
Gastrointestinal toxicities: 
Lacrimation, rhinorrhea, miosis, diaphoresis, hot flashes, flushing, abdominal cramping, 
diarrhea, or other symptoms of early cholinergic syndrome may occur during or shortly after 
receiving irinotecan. Atropine, 0.25-1.0 mg IV or SC may be used to treat these symptoms. In 
patients with troublesome or recurrent symptoms, prophylactic administration of atropine shortly 
before irinotecan therapy may be considered. Additional antidiarrheal measures may be used at 
the discretion of the treating physician. Anticholinergics should be used with caution in patients 
with potential contraindications (e.g., obstructive uropathy, glaucoma, tachycardia, etc.) 
 
Late diarrhea (e.g., developing more than 24 hours after irinotecan) should be managed with 
loperamide. The following dose modifications are based on toxicity experienced during a cycle 
(i.e., after Day 1 of any cycle): 
 
The following dose modifications are based the grade of mucositis seen on the day of treatment 
for any day after Day 1 in any cycle.  
 
 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
48
Dose Reduction Table for Non-Hematologic Toxicity (Except Neuropathy) 
(Note: DR = Dose Reduction) 
 
Non-hematologic
Toxicity on the 
Day of 
Treatment (D1)
Action
Oxaliplatin
Irinotecan
5-FU Bolus 
(Leucovorin
DR follows 
protocol for 
5FU bolus 
DR)
5-FU
Continuous
Infusion
Diarrhea G2
DR 
Irinotecan 
Bolus 5FU, 
and CI 
5FU 
No reduction
Treat at 
permanent 
DL -1
Treat at 
permanent 
DL -1
Treat at 
permanent DL 
-1
Diarrhea G 3-4
DR 
Irinotecan 
and CI 
5FU and 
eliminate 
Bolus 5FU
No reduction
Treat at 
permanent 
DL -1
Permanently 
eliminate 
bolus
Treat at 
permanent DL 
-1
Mucositis G2
DR Bolus 
and CI 
5FU
No reduction
No reduction
Treat at 
permanent 
DL -1
Treat at 
permanent DL 
-1
Mucositis G3-4
DR 
Irinotecan 
and CI 
5FU, 
eliminate 
Bolus 5FU
No reduction
Treat at 
permanent 
DL -1
Permanently 
eliminate 
bolus
Treat at 
permanent DL 
-1
Nausea/Vomiting 
G3-4
HOLD 
ALL 
THERAPY
Maximal 
antiemetic 
therapy.  
Hold until 
resolved to 
G2 or less, 
resume @ 
permanent 
DL-1
Maximal 
antiemetic 
therapy.  
Hold until 
resolved to 
G2 or less, 
resume @ 
permanent 
DL-1
Maximal 
antiemetic 
therapy.  
Hold until 
resolved to 
G2 or less, 
resume @ 
permanent 
DL-1
Maximal 
antiemetic 
therapy.  Hold 
until resolved 
to G2 or less, 
resume @ 
permanent 
DL-1

 
 
6.2.1.3
Neurotoxicity
 
Toxicity Scale for the Sensory Neuropathies Associated with Oxaliplatin Symptoms:  

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
49
 
Grade 1  
 Paresthesias/dysesthesias* of short duration that resolve and 
do not interfere with function. 
 
Grade 2  
 Paresthesias/dysesthesias* interfering with function, but not 
in activities of daily living (ADL) 
 
Grade 3  
 Paresthesias/dysesthesias* with pain or with functional 
impairment that also interfere with ADL. 
 
Grade 4  
 Persistent paresthesias/dysesthesias* that are disabling or life 
threatening. 
 
* May be cold induced 
 
For grade 2 neurotoxicity persisting between treatments: Reduce oxaliplatin by one dose level 
for the next cycle and for all subsequent cycles. 
 
For grade 3 neurotoxicity resolving to grade 2 between treatments: Reduce oxaliplatin by one 
dose level for the next cycle and for all subsequent cycles. 
 
For recurrent grade 3 neurotoxicity resolving to grade 2 between treatments: Reduce 
oxaliplatin by one additional dose level for the next cycle and for subsequent cycles. Oxaliplatin 
will not be reduced beyond level –3. If further dose reduction is required for neurotoxicity, 
oxaliplatin will be discontinued. Patients should continue to receive other protocol therapy. 
 
For grade 3 neurotoxicity persisting between treatments: Discontinue oxaliplatin. Patients 
should continue to receive other protocol therapy. 
For grade 4 neurotoxicity: Discontinue oxaliplatin. Patients should continue to receive other 
protocol therapy. 
For pharyngo-laryngeal dysesthesia: Increase the duration of oxaliplatin infusion to 6 hours for 
all subsequent treatments.  
 
6.2.1.4
Extravasation

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
50
Extravasation of oxaliplatin has been associated with necrosis; if extravasation is suspected, the 
infusion should be stopped and the drug administered at another site. Extravasation may be 
treated according to institutional guidelines. 
6.3
Capecitabine and Radiation
 
Hematologic and Non-Hematologic Toxicity 
Capecitabine will be held for any Grade 3 or 4 toxicity. After toxicity resolves to < grade 1, 
capecitabine will be resumed at 600 mg/m2 BID to complete the 10 weekdays of therapy. 
Capecitabine can be held a maximum of 7 days. If further grade 3 or 4 toxicity is noted at the 
reduced dose level, after toxicity resolves to < grade 1, capecitabine will be resumed at 500 
mg/m2 BID to complete two weeks of therapy. If the second dose reduction is not tolerated, 
capecitabine will be stopped. Patients will keep a capecitabine diary and will record the number 
of capecitabine tablets and the time that they take the tablets.  
Grade 3 or 4 toxicities that are due to biliary ductal dilatation and resolved with placement of a 
biliary stent or with biliary stent change will not require a dose reduction of capecitabine or 
radiation therapy after stent placement.  Therapy may be withheld for procedures like ERCP and 
biliary stenting, and restarted at the treating physician's discretion. 
 
Radiation therapy will be held for Grade 3 or 4 nausea that is not well controlled with anti-
emetic support, until nausea resolves to Grade 2 or less.  It will then be resumed at same dose. 
7
DRUG FORMULATION AND ADMINISTRATION 
 
7.1
5-Fluorouracil (5-FU; fluorouracil; “Adrucil” ) 
 
Please refer to the package insert for complete product information. 
Availability 
5-FU is commercially available as a 50 mg/mL solution for injection in 10 mL, 20 mL, 50 mL 
and 100 mL vials. 
Preparation

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
51
Inspect for precipitate; if found, agitate or gently heat in water bath. Bolus injections 
are prepared using undiluted drug. 46-48 hour infusion of 5-FU should be prepared for 
administration via ambulatory infusion pump according to the individual institution’s standards. 
These solutions may be prepared in D5W or 0.9% NaCl. 5-FU should not be mixed in the same 
solution with most parenteral antiemetics. 
Storage and Stability 
Intact vials should be stored at room temperature and protected from light. Slight yellow discolor 
does not usually indicate decomposition. Stability in ambulatory pumps varies according to the 
pump, manufacturer of drug, concentration and diluent. Please refer to appropriate reference 
sources for additional information.  
Administration
In this study, 5-FU is administered as a 400 mg/m2 IV bolus followed by 2400 mg/m2 by IV 
infusion over 46 to 48 hours. 
Toxicity
Nausea, diarrhea, vomiting (mild); stomatitis: 5–8 days after treatment initiation; 
myelosuppression: granulocytopenia (9–14 days); thrombocytopenia (7–14 days); Alopecia; loss 
of nails; hyperpigmentation; photosensitivity; Maculopapular rash; palmar–plantar 
erythrodysethesias: (42–82% receiving continuous infusion); CNS effects: cerebral ataxia (rare); 
Cardiotoxicity: MI, angina; asymptomatic S–T changes 68%; ocular effects: excessive 
lacrimation and less commonly, tear duct stenosis. 
Drug Interactions 
Leucovorin enhances the cytotoxicity of 5-FU by forming a more stable tertiary complex with 
thymidylate synthase. Concommitant adminstration of 5-FU with warfarin has been reported to 
result in increased INR/prolonged prothrombin time. Patients receiving both drugs should be 
followed with weekly INRs.  
7.2
Leucovorin Calcium (Folinic Acid) Leucovorin Calcium (calcium folinate; 
citrovorumfactor; N 5-formyltetrahydrofolate; 5-formyl-FH4; folinic acid). 
 
Please refer to the package insert for complete product information. 
Availability 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
52
Leucovorin calcium is commercially available in: 50 mg, 100 mg, 350 mg vials for 
reconstitution. 
Storage and Stability 
Intact vials should be stored at room temperature and protected from light. Solutions 
reconstituted with BWI are stable for at least 7 days at room temperature. 
 
Preparation
Leucovorin may be reconstituted with Bacteriostatic Water for Injection (BWI) or with Sterile 
Water For Injection. Solutions should be further diluted in D5W, 0.9% NaCl or Rungers solution 
for infusion over two hours. 
Administration
Leucovorin will be administered as a 400 mg/m2 IV infusion over 2 hours (+/- 10 minutes) after 
oxaliplatin/irinotecan administration. Leucovorin may also be administered concurrently with 
oxaliplatin/irinotecan as a separate IV infusion. 
Toxicity
The only adverse reactions associated with leucovorin are allergic reactions. These are extremely 
uncommon.  

7.3
Oxaliplatin [Eloxatin] 
 
Availability 
Oxaliplatin is commercially available as an aqueous solution in vials containing 50 mg and 100 
mg at a concentration of 5 mg/mL. The vials do not contain any preservative and they are 
intended for single use. Oxaliplatin is commercially available.  
Storage and Stability 
Intact vials should be stored at room temperature. Solutions diluted in D5W are stable for 6 
hours at room temperature or 24 hours under refrigeration. 
Preparation
The calculated dose of oxaliplatin should be diluted for infusion with 250 mL to 500 mL D5W. 
Oxaliplatin should not be diluted with a sodium chloride solution. Needles, syringes, catheters or 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
53
IV administration sets containing aluminum should not be used with oxaliplatin. As with other 
platinum compounds, contact with aluminum may result in a black precipitate. 
Administration
Oxaliplatin will be administered by intravenous infusion over 120 minutes (+/- 10 minutes). 
Infusion time may be prolonged (up to 6 hours) in patients experiencing pharyngolaryngeal 
dysesthesia. Oxaliplatin is unstable in the presence of chloride or alkaline solutions. Do NOT 
mix or administer oxaliplatin with saline or other chloride-containing solutions. Do NOT 
administer other drugs or solutions in the same infusion line. Flush IV lines/catheters with 
Dextrose 5% in Water both before and after oxaliplatin administration. 
Toxicity
The most commonly observed oxaliplatin toxicities include neurotoxicity, GI toxicity, and 
myelosuppression. Three neurotoxicity syndromes have been seen: acute sensory neuropathy 
develops within hours to 2 days after oxaliplatin administration.   Symptoms include, 
paresthesias, dysesthesias, and hypothesia of the hands, feet and perioral region. Jaw spasm, 
abnormal tongue sensation, dyarthria, eye pain and a sensation of chest pressure have also been 
noted. Acute sensory neuropathy symptoms may be exacerbated by exposure to cold temperature 
or cold objects. Symptoms are reversible, usually resolving within 14 days and commonly 
recurring with further dosing. This syndrome has been observed in about 56% of patients 
receiving oxaliplatin with 5-FU and leucovorin. Acute pharyngolaryngeal dysesthesia is reported 
to occur in 1-2% of patients. This syndrome is characterized by a subjective sensation of 
difficulty breathing or swallowing without laryngospasm or bronchospasm or objective evidence 
of hypoxia. Avoidance of cold drinks, food and air is suggested in order to minimize 
pharyngolaryngeal dysesthesia. Antianxiety agents (e.g.lorazepam) may be used to 
treat pharyngolaryngeal dysesthesias once oxygen saturation has been documented 
to be normal. Peripheral neuropathy persisting > 14 days is characterized by paresthesias, 
dysesthesias, and hypothesia. Abnormalities in momioception may also be seen. Symptoms of 
persistent neuropathy may improve upon discontinuation of oxaliplatin. Various agents have 
been used in an attempt to minimize neurotoxicity of oxaliplatin (e.g. carbamazepine, Mg+, 
Ca++). Calcium and magnesium infusions appear to be beneficial in preventing neurotoxicity. 
Gastrointestinal toxicities include nausea, vomiting (oxaliplatin is considered to be moderately 
emetogenic) and diarrhea. Neutropenia is reported in 73% of patients receiving oxaliplatin with 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
54
5-FU and leucovorin (44% grade 3 or 4). Grade 3 or 4 thrombocytopenia is reported to occur in 
4% of patients receiving the combination. Allergic reactions, similar to those seen with other 
platinum compounds, have also been observed in patients treated with oxaliplatin. Reactions  
range from rash to anaphylaxis. Rarely, oxaliplatin has been associated with pulmonary fibrosis, 
which may be fatal.  Oxaliplatin should be discontinued in the presence of unexplained 
pulmonary symptoms (e.g. nonproductive cough, dysphagia) or pulmonary infiltrates until 
interstitial lung disease or pulmonary fibrosis have been ruled out. Recent reports of oxaliplatin 
extravasation suggest that tissue necrosis may result and that oxaliplatin should be considered a 
vesicant. No standard treatment exists for oxaliplatin extravasation although heat and sodium 
thiosulfate have both been suggested. Veno-occlusive disease (VOD) of the liver is a rare 
complication associated with oxaliplatin and 5-FU. Clinical manifestations of VOD include 
hepato-megaly, ascites, and jaundice. Histologically, VOD is characterized by diffuse damage in 
the centrilobular zone of the liver. Sequelae of VOD include hepatomegaly, splenomegaly, portal 
hypertension, and esophageal varices. A recent analysis of resected liver metastases in 153 
patients indicated histological findings consistent with VOD in 6/27 patients who received 5-FU 
alone, 4/17 patients who received 5-FU and irinotecan, 20/27 patients who received 5-FU and 
oxaliplatin, and 14/16 who received 5-FU, oxaliplatin and irinotecan. The remaining 66 patients 
had not received chemotherapy prior to resection. There were no such findings in these patients. 
For more information on toxicities associated with oxaliplatin, please see the package insert. 
 
7.4
Irinotecan (CPT-11, CAMPTOSAR®) 
 
Availability 
Irinotecan is commercially available as a 20 mg/mL solution for injection in 2 mL and 5 mL 
vials. 
Storage and Stability 
Intact vials should be stored at controlled room temperature 59° to 86° F (15° to 30° C) and 
when protected from light. Solutions diluted in D5W are reported to be stable for 48 hours under 
refrigeration and protected from light. Irinotecan solutions should not be frozen as the drug may 
precipitate. 
Preparation

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
55
Irinotecan is diluted in 5% dextrose (D5W) 500 mL to a final concentration of 0.12 – 1.1 mg/mL. 
Administration
In this study irinotecan will be administered as an IV infusion over 90 minutes (+/- 10 minutes). 
Toxicities 
Virtually all phase I and II studies of irinotecan have reported neutropenia and/or late diarrhea 
(diarrhea occurring more than 24 hours after irinotecan administration) as the dose-limiting 
toxicities (depending upon the schedule). Other commonly observed adverse events include 
nausea and vomiting, anorexia, abdominal cramping, alopecia, asthenia, lymphocytopenia, and 
anemia. Dehydration has occurred as a consequence of diarrhea, particularly when associated 
with severe vomiting. Patients may have an acute syndrome of lacrimation, diaphoresis, 
abdominal cramping, and diarrhea (early diarrhea) during or shortly after irinotecan 
administration; this syndrome is thought to be cholinergically mediated and may be treated and 
subsequently prevented with atropine. Sporadic cases of pulmonary toxicity, manifested as 
shortness of breath, nonproductive cough, and transient infiltrates on chest X-ray have been 
reported. Infrequent occurrences of mucositis or colitis (sometimes with gastrointestinal 
bleeding) have been observed. Occasionally, abnormalities of serum creatinine, hepatic enzymes, 
or thrombocytopenia have been observed. Further information regarding irinotecan may be 
obtained from the package insert. 
7.5
Leucovorin  
Storage
For stability of leucovorin, please refer to the leucovorin (e.g., WELLCOVORIN) Package Insert 
or Summary of Product Characteristics. 
 
 
 
 
7.6
Capecitabine

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
56
Description: Capecitabine (Xeloda) is a fluoropyrimidine carbamate with antineoplastic activity.  
It is an orally administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) that is 
converted to 5-fluorouracil. 
Form: Capecitabine is supplied as a biconvex, oblong film-coat tablets for oral administration.  
Each light-peach colored tablet contains 150 mg capecitabine, and each peach colored tablet 
contains 500 mg capecitabine.   
Storage and Stability: Store at 25o C (77o F); excursions permitted to 15o to 30o C (59o to 86o F), 
keep bottles or storage devices tightly closed. 
Compatability: Capecitabine and some of its metabolites are converted principally by liver 
enzymes (carboxylesterase and cytidine deaminase and TP in tumor tissues). At present, it is 
unknown whether this metabolism is likely to be influenced by other treatments or alcohol, 
which either induce or inhibit certain liver enzymes. 
Allopurinol:  Oxypurinol, a metabolite of allopurinol, can potentially interfere with 5-FU 
anabolism via orotate phosphoribosyltransferase.  Although this was originally used as a strategy 
to protect normal tissues from 5-FU-associated toxicity, further laboratory studies suggested 
possible antagonism of the anticancer activity of 5-FU in some tumor models.  If a patient is 
receiving allopurinol, the need for taking this medicine should be ascertained.  If possible, 
allopurinol should be discontinued prior to starting on this regimen, and another agent substituted 
for it. 
Sorivudine and Brivudine: A metabolite of the above two investigational antiviral agents, 
5-bromovinyluracil, is a potent inhibitor of dihydropyrimidine dehydrogenase, the enzyme that 
catabolizes 5-FU.  Patients should not receive concurrent therapy with either of these antiviral 
agents while receiving capecitabine.  If  a patient has received prior sorivudine or brivudine, then 
at least four weeks must elapse before the patient receives capecitabine therapy 
Anticoagulants: See Warnings and Precautions Section 6.9 In a drug interaction study 
with single dose warfarin administration, there was a significant increase in the mean AUC of S-
warfarin. The maximum observed INR value increased by 91%. This interaction is probably due 
to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites.   

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
57
Phenytoin: Increased phenytoin plasma concentrations have been reported during 
concomitant use of Xeloda with phenytoin, suggesting a potential interaction. Patients taking 
phenytoin concomitantly with Xeloda should be regularly monitored for increased phenytoin 
plasma concentrations and associated clinical symptoms. 
Laxatives:  The use of drugs with laxative properties should be avoided. 
Warnings and Precautions: 
Renal Insufficiency: Patients with moderate renal impairment as measured by serum 
creatinine (> 1.3) at baseline require dose reduction. Patients with mild and moderate renal 
impairment at baseline should be carefully monitored for adverse events. Prompt interruption of 
therapy with subsequent dose adjustments will be made if a patient develops a grade 2 to 4 
adverse event.  Capecitabine is contraindicated in patients with a calculated creatinine clearance 
of < 30 ml/min.  Creatinine level will be checked and creatinine clearance calculated on Study 
Day 8 for all subjects to ensure safety of continued administration of capecitabine. 
Pregnancy/Nursing: Capecitabine may cause fetal harm when given to a pregnant 
woman. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving 
this drug, the patient should be apprised of the potential hazard to the fetus. Women of 
childbearing potential should be advised to avoid becoming pregnant while receiving treatment 
with capecitabine. Because of the potential for serious adverse reactions in nursing infants from 
capecitabine, the patient will be instructed that nursing must be discontinued when receiving 
capecitabine therapy. 
Coagulopathy: Patients receiving concomitant capecitabine and oral coumarin-derivative 
anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) 
monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically 
important Capecitabine-Warfarin drug interaction was demonstrated in a clinical pharmacology 
trial. Altered coagulation parameters and/or bleeding, including death, have been reported in 
patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as 
warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases 
in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time 
capecitabine was introduced. These events occurred within several days and up to several months 
after initiating capecitabine therapy and, in a few cases, within one month after stopping 
capecitabine. These events occurred in patients with and without liver metastases. Age greater 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
58
than 60 and a diagnosis of cancer independently predispose patients to an increased risk of 
coagulopathy. 
Cardiotoxicity: The cardiotoxicity observed with capecitabine includes myocardial 
infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, 
electrocardiographic changes, and cardiomyopathy.  These adverse events may be more common 
in patients with a prior history of coronary artery disease. 
This treatment is foreseen as a self-administered out-patient treatment, and in certain 
circumstances adverse events that could occur, such as diarrhea, or hand-foot syndrome can 
rapidly become serious. In the case where a patient experiences any toxicity between scheduled 
visits, the patient will be instructed to contact the clinic as soon as possible, for further 
directions, discontinuation of study medication, and/or treatment. 
 
Handling: Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe disposal 
of capecitabine in a self-contained and protective environment. 
 
Availability: Capecitabine is commercially available and will not be provided free of charge by 
the study.  It is expected that the study participants or their insurers will be responsible for the 
cost of Capecitabine.   
 
Preparation 
N/A- Capecitabine comes in tablet formulation 
  
Administration 
Tablets should be swallowed with water 30 minutes after the end of a meal (breakfast and dinner).  
If necessary, tablets may be crushed. 
 
Ordering 
Capecitabine will be prescribed by the treating medical oncologist; prescriptions will be filled by 
the study participants at their pharmacy of choice. 
 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
59
Accountability  
N/A drug is not study supplied. 
 
Destruction and Return 
N/A drug is not study supplied. 
 
8
CORRELATIVE STUDIES 
8.1
Correlative Studies: Circulating Biomarkers 
 
Based on findings from preliminary studies, we propose here to evaluate the changes in blood circulating SDF1α 
and circulating myeloid cells throughout the treatment course to explore potential associations between the changes 
in these biomarkers and resistance to treatment. In exploratory studies, we will evaluate several other cytokines 
using multiplex protein array (Meso-Scale Discovery, Inc.). 
 
8.1 Experimental Design 
Blood will be drawn by venipuncture, and the first 7-10 ml blood will be excluded or used for other analysis. The 
following 8 ml will be collected in an EDTA tube. The EDTA tube with the blood sample will be shipped in wet ice 
within 2 hours of drawing for further processing at Steele Laboratory at MGH.  We will analyze the correlation 
between plasma SDF1α and circulating myeloid cells with multiple measures of outcome (ORR, TTP, OS) in 
patients with borderline resectable pancreatic cancer before, during, and after treatment. 
8.2 Collection 
To this end we will measure circulating biomarkers at the following stages:  
(i) 
Pretreatment 
(ii) 
At beginning and end of  FOLFIRINOX therapy 
(iii) After radiation therapy  
(iv) One month post-operatively  
(v) 
At the time of disease progression 
 
Samples will be collected at the following timepoints: 
a. 
Prior to the start of therapy 
b.  
Day 8 of Cycle 1 of  FOLFIRINOX  
c.              After Cycle 4 (and Cycle 8 if received) of FOLFIRINOX 
d.              After chemoradiation OR pre-operatively 
e.. 
1 month after completion of therapy. 
f.              1  month after pancreaticoduodenectomy (Whipple procedure)  

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
60
g.  
Within 2 weeks after radiologic progression   
 
8.3 Shipping Instructions 
 
The tube containing the blood should be shipped with the following information 
1. 
Study Number at the DF/HCC 
2. 
Patient number on the study 
3. 
Patient’s initials 
4. 
Treating physician’s name 
5. 
Date of collection 
6. 
Date of shipping 
 
The tube of blood should be placed in a sealable container and placed in a box with the necessary information. The 
box should be marked Biohazard.  
The blood will be shipped to:  
 
 
 
 
 
 
 
8.2
Patient Reported Outcomes 
QOL (EORTC QLQ-C30, version 3.0), symptoms (ESAS-r), and mood (HADS) will be 
assessed at time of informed consent prior to neoadjuvant therapy; at weeks 3, 7, 11, and 15 of 
neoadjuvant chemotherapy; at week 2 of capecitabine chemoradiotherapy; and during active 
follow up. All PRO administrations have a window of +/- 2 weeks from the assigned assessment 
timepoint.  
 
Pretreatment
FOLFIRINOX
ChemoRT 
Post-op
At time of 
informed consent
Day 1 of cycles 
2,4,6,8
[Week 3, 7, 11, 
15]
Week 2, 
day1
At 3 month follow up, then  every 6months for 
the first 2 years of follow up, then yearly until 
completion of year 5
EORTC QLQ-C30 
EORTC QLQ-
C30 
EORTC 
QLQ-C30
EORTC QLQ-C30 
ESAS-r 
ESAS-r 
ESAS-r 
ESAS-r 
HADS 
HADS 
HADS 
HADS 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
61
 
8.3
Correlative Studies: SNaPshot analysis 
 
Mutational analysis will be performed by tumor SNaPSHOT for the mutations listed in 
section 2.2.6.1. Paraffin-embedded block or ten unstained slides will be used from the 
untreated biopsy specimen obtained at the time of upper endoscopy or initial diagnostic 
biopsy.  Analysis will be performed as described by Dias-Santagata (47) at the Translational 
Research Laboratory at MGH. 
 
 
9
STUDY CALENDAR 
Baseline laboratory evaluations are to be conducted within seven days prior to study 
entry. Non-laboratory evaluations (imaging, etc) must be done <42 days (6 weeks) prior 
to the start of therapy.  
All pre-study assessments must be performed prior to administration of any study 
medication, unless otherwise noted. All study assessments and medications should 
be administered within + 3 days of the protocol-specified date, unless otherwise 
noted. All follow up assessments may be performed +/- 21 days of the protocol-
specified date. 
 
Required Data Table 
Tests and Observation 
Prior to Study 
Day 1 of each 
cycle of  
FOLFIRINOX 
and at Restaging 
During 
ChemoRT 
Post-op 
F/U(2) 
Signed informed consent 
and registration 
X 
 
 
 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
62
History 
X 
 
 
 
Physical Examination 
X 
X 
X weekly 
X 
Vital Signs and 
performance status 
X 
 
X weekly 
X 
Height/Weight/Surface 
Area 
X 
 
X at start of 
ChemoRT 
 
Toxicity Assessment 
 
X 
X weekly 
X 
Laboratory (1):  
 
 
 
 
CBC/plts/diff 
X 
X 
X Days 1, 8 
and 15  
X 
Serum chemistries (Na, 
K, BUN, Cr, Glucose, 
Calcium, Albumin, AST, 
ALT, Total bilirubin, 
Alkaline phosphatase) 
X 
X 
X Days 1, 8 
and 15  
X 
Creatinine clearance 
calculation (Cockroft 
Gault) 
X 
X (day 1  of 
cycles 1, 3, 5, 
and 7 only) 
X Days 1, 8 
and 15 
 
CA19-9 
X 
X (at restaging 
visits only) 
X, Days 1 and 
15 
X 
CEA 
X 
X (at restaging 
visits only) 
X Days 1 and 
15 
X 
Pregnancy test* 
X 
 
 
 
Staging: 
 
 
 
 

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Chest CT Abd-pelvic CT 
(or MRI) 
X 
X after first 
week of cycle 4 
and first week of 
last cycle of 
FOLFIRINOX 
 
X  
Tumor SNaPshot (3) 
X 
 
 
X 
Nutritional Assessment 
X(4) 
X(4) 
X(4) 
 
Correlative Studies 
X(5) 
X(5) 
X(5) 
X(5) 
PROs (EORTC QLQ, 
ESAS-r, HADS) (details 
in section 8.2) 
X 
X 
X 
X 

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Notes 
(1) Pre-study Laboratory values need to be obtained within 7 days of study entry. 
(2) Post-op follow up schedule is as follows. For years 1 and 2 follow up will be visit and labs at 
least every three months, scans at least every 6 months, For year 3, visit and labs will be at least 
every 3 months and scans will be at least every 12 months. For years 4 and 5 visit and labs will 
be at least every 6 months and scans will be at least every 12 months.  For patients with R0, R1 
and R2 resections, the first post-op CT scan, visit and labs are 3-8 weeks postoperatively. All 
follow up assessments may be performed +/-21 days of the protocol-specified date. 
(3) Tumor SHaPshot will be done once for each participant, either on the pre-treatment biopsy 
specimen (if available) or on the resected tumor specimen. 
(4) Nutritional assessment will include meeting with an oncology nutritionist for evaluation and 
education at the beginning of treatment. The patient will then track dietary protein intake 
throughout treatment until time of surgery. The patient’s logged protein intake will be reviewed 
in post-op follow up by the treatment team. Both the nutritionist evaluation and protein tracking 
are optional resources available to patients and are not required by the protocol. 
(5) Peripheral blood for correlative studies will be obtained with clinical labs at pretreatment, 
day 8 of Cycle 1 FOLFIRINOX, at restaging visits, after proton beam radiation therapy/pre-
operatively, 1 month after completion of therapy, 1 month post-operatively, and within two 
weeks of radiographic progression (these blood draws are optional). 
10
MEASUREMENT OF EFFECT
10.1 Evaluation Of Response 
 
10.1.1 Imaging Response
Response to therapy and/or progression after induction chemotherapy with FOLFIRINOX will 
be evaluated in this study using the international criteria proposed by the RECIST (Response 
Evaluation Criteria in Solid Tumors) committee.  Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST criteria. In the event 
that CT staging cannot be utilized, restaging MRI will be the substitute modality. 

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10.1.2 Pathological Response
All patients will undergo a full pathological review of their pancreaticoduodenectomy specimen 
according to the AJCC Staging Classification, 6th.  Initial gross evaluation and identification of 
resection margins will be performed jointly by the surgeon and the pathologist.  Pathological 
complete response will be defined as the absence of any viable tumor cells within the pathologic 
specimen. 
10.1.3 Progression-free survival
 
Progression-free survival will be defined as the time from date of protocol entry to first 
objective documentation of progressive disease (distant or local) or death.  Patients who die 
without a reported prior progression will be considered to have progressed on the day of their 
death.  
10.1.4 Time to death
Time to death will be calculated as the time from date of protocol entry to date of death 
 
10.1.5 Time to local recurrence 
 
 
A local recurrence will be defined as any evidence of tumor recurrence within the radiation 
field.  The time to local recurrence will be calculated from the date of protocol entry to the first 
objective documentation of a local recurrence. 
10.2 Definitions
10.2.1 Evaluable for toxicity. All participants who receive at least one dose of study 
treatment will be evaluable for toxicity from the time of their first treatment. 
10.2.2 Evaluable for objective response. Only those participants who have measurable 
disease present at baseline, have completed at least 4 cycles of induction 
chemotherapy, and have had their disease re-evaluated will be considered 

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evaluable for response. These participants will have their response classified 
according to the definitions stated below. (Note: Participants who exhibit 
objective disease progression or die prior to the end of induction chemotherapy 
will also be considered evaluable.) 
10.3 Disease Parameters 
10.3.1 Measurable disease. Measurable disease is the presence of at least one (1) 
lesion that can be accurately measured in at least one dimension with longest 
diameter  >20 millimeters (mm) using conventional techniques (CT, MRI, x-ray) or  
>10 mm with spiral CT scan. Measurable lesions must be at least 2 times the slice 
thickness in mm. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
10.3.2 Target lesions: The primary tumor is the target lesion.  
10.4 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or digital 
measurement tool. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
anti-tumor effect of a treatment. 
10.4.1 Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes). For the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size of 
the lesion, is recommended. 
10.4.2 Conventional CT and MRI. These techniques should be performed with cuts of 10 
mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 
mm contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen, 

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and pelvis. Head and neck tumors and those of extremities usually require specific 
protocols. 
10.4.3 Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only 
be available in some centers. Therefore, the utilization of such techniques for 
objective tumor response should be restricted to validation purposes in reference 
centers. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained. 
10.4.4 Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met criteria 
for response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive disease. 
10.5 Response Criteria  
10.5.1  Evaluation of Target Lesions 
10.5.1.1 Complete Response (CR): Disappearance of all target lesion. 
10.5.1.2
Partial Response (PR):  At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesion, taking as reference the baseline sum LD. 
10.5.1.3
Progressive Disease (PD):  At least a 20% increase in the sum of the longest 
diameter (LD) of target lesion, taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or more new lesions  (new lesions 
must be > slice thickness).  

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10.5.1.4
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD since the 
treatment started. 
10.5.1.5
Unknown (UN): Assessment of target lesions cannot be made due to insufficient 
or unevaluable data. In this case, a concise explanation must be given. 
Note: If tumor response data is missing for target lesions, the overall assessment must be UN 
unless there is new disease that would result in an overall assessment of PD. However, if there 
is missing or unevaluable data for non-target lesions, but data is available for all target lesions, 
the overall response for that time point will be assigned based on the sum LD of all target 
lesions. Additionally, the assessment of CR cannot be made if there is missing or unevaluable 
data for non-target lesions. In this case, the overall assessment would be PR. 
10.6 Response Review 
Central radiology review is not planned, as most patients will proceed to chemoradiation and 
surgery after restaging.
11 ADVERSE EVENT REPORTING REQUIREMENTS
11.1 Definitions
11.1.1 Adverse Event (AE)
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.  
11.1.2 Serious adverse event (SAE)

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A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  
x Results in death 
x Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more sever form. 
x Requires or prolongs inpatient hospitalization (i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
x Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
x Is a congenital anomaly or birth defect; or 
x Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
x routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 

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x elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
x emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
x respite care 
x grade 4 lipase and lymphocytes 
 
11.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
11.1.3.1 Expected adverse event 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected adverse events associated with the study `
 
agent(s). 
11.1.3.2 Unexpected adverse event 
 
For the purposes of this study, an adverse event is considered unexpected when it 
varies in nature, intensity or frequency from information provided in the current adverse 
event list, the Investigator’s Brochure, the package insert or when it is not included in the 
informed consent document as a potential risk.   
11.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event and the 
study treatment. Attribution will be assigned as follows: 
 
x Definite – The AE is clearly related to the study treatment. 
x Probable – The AE is likely related to the study treatment. 

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x Possible – The AE may be related to the study treatment.  
x Unlikely - The AE is doubtfully related to the study treatment. 
x Unrelated - The AE is clearly NOT related to the study treatment. 
11.2 Procedures for AE and SAE Recording and Reporting 
 
Reporting Participating investigators will assess the occurrence of AEs and SAEs at all 
participant evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-
specific case report forms.  
 
The descriptions and grading scales found in the CTEP Active Version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE 
reporting. The CTEP Active Version of the CTCAE is identified and located on the 
CTEP website at: 
 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
All appropriate treatment areas should have access to a copy of the CTEP Active 
Version of CTCAE. 
11.3 Reporting Requirements 
 
For multi-site trials where a DF/HCC investigator is serving as the principal 
investigator, each participating investigator is required to abide by the reporting 
requirements set by the DF/HCC. The study must be conducted in compliance with 
FDA regulations, local safety reporting requirements, and reporting requirements of the 
principal investigator.  
 

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Each investigative site will be responsible to report SAEs that occur at that institution 
to their respective IRB. It is the responsibility of each participating investigator to 
report serious adverse events to the study sponsor and/or others as described below.  
11.4 Reporting to the Study Sponsor 
11.4.1 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, during 
treatment, or within 30 days of the last dose of treatment must be reported to the DF/HCC 
Overall Principal Investigator on the local institutional SAE form. This includes events 
meeting the criteria outlined in Section 11.1.2, as well as the following: 
 
x Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at 
least possibly related/associated with the intervention. 
 
x All Grade 4 (life-threatening or disabling) events that are unexpected 
AND not specifically listed in the protocol as not requiring reporting. 
 
x All Grade 5 (fatal) events while the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the time 
of continuing review.  
 
Participating investigators must report each serious adverse event to the DF/HCC Overall 
Principal Investigator within 24 hours of learning of the occurrence. In the event that the 
participating investigator does not become aware of the serious adverse event 
immediately (e.g., participant sought treatment elsewhere), the participating investigator 
is to report the event within 24 hours after learning of it and document the time of his or 

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73
her first awareness of the adverse event. Report serious adverse events by telephone, 
email or facsimile to: 
 
  
 
Theodore S. Hong, M.D. 
 
 
 
Within the following 48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether 
the event has resolved or continues, if and how the event was treated, and whether the 
participant will continue or discontinue study participation. 
11.4.2 Non-Serious Adverse Event Reporting 
 
Non-serious adverse events will be reported to the DF/HCC Overall Principal Investigator 
on the toxicity Case Report Forms.   
11.5 Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events directly to the DFCI 
Office for Human Research Studies (OHRS). 
 
Other investigative sites should report serious adverse events to their respective IRB 
according to the local IRB’s policies and procedures in reporting adverse events. A copy of 
the submitted institutional SAE form should be forwarded to: 
 
 
 
Theodore S. Hong, M.D. 
 
 
 
 
 
The DF/HCC Principal Investigator will submit SAE reports from outside institutions to the 
DFCI Office for Human Research Studies (OHRS) according to DFCI IRB policies and 
procedures in reporting adverse events.  

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11.6 Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject safety 
reports or sentinel events that require reporting according to institutional policy. 
11.7 Monitoring of Adverse Events and Period of Observation 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last study 
intervention should be followed to their resolution, or until the participating investigator 
assesses them as stable, or the participating investigator determines the event to be 
irreversible, or the participant is lost to follow-up. The presence and resolution of AEs and 
SAEs (with dates) should be documented on the appropriate case report form and recorded in 
the participant’s medical record to facilitate source data verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall Principal Investigator and their respective IRB of any 
unanticipated death or adverse event occurring after a participant has discontinued or 
terminated study participation that may reasonably be related to the study.  
12 DATA AND SAFETY MONITORING 
12.1 Data Reporting 
12.1.1 Method  
The ODQ will collect, manage, and monitor data for this study. 

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12.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or electronic) 
to the ODQ is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Lab Form 
Within 14 days of registration; and within 14 
days of protocol defined laboratory 
assessment 
Tumor Measurement/Staging 
Form 
Within 14 days of registration; and within 14 
days of protocol defined restaging assessment 
Chemotherapy Treatment 
Form 
Within 10 days of the last day of the cycle of 
neoadjuvant FOLFIRINOX; within 10 days of 
the last cycle of adjuvant chemotherapy, if any 
Chemoradiation Treatment 
Form 
Within 10 days of completion of neoadjuvant 
combined capecitabine and proton radiation 
Toxicity/Adverse Event 
Report Form 
Every two weeks during neoadjuvant 
FOLFIRINOX; weekly during 
chemoradiation; and within 14 days of 
protocol defined follow up visit 
PRO’s 
Within 14 days of completion 
Surgery/Pathology Form 
Within 14 days of surgery 
Off Treatment/Off Study Form
Within 14 days of completing treatment or 
being taken off study for any reason 

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Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date 
12.2 Safety Meetings 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the 
study. Information that raises any questions about participant safety will be addressed 
with the Principal Investigator and study team. 
 
The DSMC will meet as required to review toxicity and accrual data.  Information to be 
provided to the committee may include:  up-to-date participant accrual; current dose 
level information; DLT information; all grade 2 or higher unexpected adverse events 
that have been reported; summary of all deaths occurring within 30 days for Phase I or 
II protocols; for gene transfer protocols, summary of all deaths while being treated and 
during active follow-up; any response information; audit results, and a summary 
provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
 
12.3 Monitoring
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by representatives 
designated by the DF/HCC Overall Principal Investigator (or Protocol Chair) or 
DF/HCC. The purpose of these audits or inspections is to examine study-related 
activities and documents to determine whether these activities were conducted and 
data were recorded, analyzed, and accurately reported in accordance with the protocol, 

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institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements.  
All data will be monitored for timeliness of submission, completeness, and adherence 
to protocol requirements. Monitoring will begin at the time of participant registration 
and will continue during protocol performance and completion.  
13
REGULATORY CONSIDERATIONS 
13.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) and 
any other necessary documents must be submitted, reviewed and approved by a 
properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) 
will disseminate protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
 
13.2 Informed Consent 
 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 

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dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file.  
13.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
x 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
x 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr54 02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr312 02.html  
x 
State laws 
x 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  

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It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
13.4 Study Documentation 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
13.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
14 STATISTICAL CONSIDERATIONS  
14.1 Study Design/Endpoints 
 
This is a single-arm, phase II study to investigate the preoperative administration of 
FOLFIRINOX chemotherapy and accelerated short-course radiation therapy in patients 
with borderline-resectable adenocaricoma of the pancreas. 
 
The primary endpoint of this study is R0 resection rate determined by final pathology of 
the surgical specimen. The previously studied approach involved four months of induction 
gemcitabine followed by six weeks of neoadjuvant 5-FU-based chemoradiation (50.4 Gy). 
Our internal data support a historical R0 resection rate of 20% for patients with resectable 

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disease who received induction chemoradiation (CRT) (8 of 40) or induction 
chemotherapy followed by chemoradiation (C-CRT) (6 of 30). In a retrospective surgical 
series at MGH, median tumor size was 29 mm for the CRT group and 35 mm for C-CRT 
group. Among patients considered 'borderline resectable' upfront (n = 24), 5 of 24 = 21% 
had eventual margin-negative resection (or 7 of 24 = 29%, if < 1 mm is considered as a 
negative margin / R0 resection).   
14.2 Sample Size/Accrual Rate 
 
The accrual goal of 50 patients is projected to be enrolled over a total period of 4 years based on 
the observed rate of accrual during the first two years since the protocol was open to patient 
entry. 
 The preoperative protocol regimen will have demonstrated an improvement in efficacy if 
an R0 resection were achieved in at least 16 of 50 patients. The decision rule is associated 
with 90% power if preoperative FOLFIRINOX and short-course radiation were able to 
improve the R0 resection rate to 40%. In contrast, the probability of type 1 error is only 3% 
if the underlying rate of R0 resection were truly the same as the historical data of 20%. All 
protocol patients who begin the preoperative regimen will be included in the denominator 
for analysis of the R0 resection rate, including those who do not undergo surgery due to 
progression or other reasons.
14.3 Stratification Factors 
 
Not applicable.  
14.4 Analysis of Secondary Endpoints 
 
Progression-free survival: All patients who start the protocol therapy will be analyzed 
based on the definition in Section 10.1.3. The Kaplan-Meier method will be used to 
estimate progression-free survival with 90% confidence intervals constructed by 
Greenwood’s formula.
Overall survival: Overall survival will be defined as the duration between the dates of 
protocol enrollment and death. The survival time of patients who are not known to have 
died will be censored at the date they were last known to be alive. 

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Toxicity: All patients who begin protocol treatment will be included in the toxicity profile. 
Toxicity summaries will include the frequency and proportion of patients experiencing 
each type of toxicity, as well as summaries by toxicity category and grade.  
Surgical morbidity: Analysis will be based on the patients who undergo
pancreaticoduodenectomy or distal pancreatectomy. The surgical morbidity rate will be 
calculated as the proportion of patients who experience peri- and post-operative 
complications within 30 days of surgery. A 90% confidence interval will be obtained using 
the exact binomial distribution. 
30-day post-operative mortality rate: Analysis will be based on the patients who undergo
pancreaticoduodenectomy or distal pancreatectomy. The 30-day post-operative mortality 
rate will be calculated as the number of patients who die within 30 days of surgery. A 90% 
confidence interval will be obtained using the exact binomial distribution.  
Pathologic downstaging: Analysis will be based on the patients who undergo
pancreaticoduodenectomy or distal pancreatectomy. The pathologic downstaging rate will 
be calculated as the proportion of patients with the primary tumor and nodes downstaged 
based on final pathology of the surgical specimen. 
Local control rate: Local control will be defined as the time from protocol enrollment to 
the first objective documentation of local failure. Patients who have not experienced a local 
failure will be censored at the last date they were known to have local control. Kaplan-
Meier methodology will be used to estimate the local control rate.  
Mutational analysis: The frequency of genetic mutations characterized by the SNaPshot 
platform (sections 2.6.1 and 8.1) will be summarized. A sample size of 50 patients will 
provide 90% confidence intervals of maximal width +12%, but the interval widths will be 
narrower in practice as the mutation rates are typically quite low. We shall analyze PFS 
differences by mutational status if 5 failure events have been observed within each 
mutational subgroup.  However, the analysis will be purely exploratory due to the limited 
numbers expected per mutation subgroup. 
Circulating biomarkers: The association between plasma SDF1α and circulating myeloid 
cells with outcome measures will be examined by logistic regression for ORR or by Cox 
regression for TTP and OS. Pretreatment levels as well as the changes during and after 
treatment from baseline will be analyzed. Biomarker levels are typically log-transformed 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
82
for analysis, but we shall also consider other approaches such as categorizing based on the 
observed distribution or dichotomizing at the median. 
Patient-reported outcomes: We will use descriptive statistics to describe QOL (EORTC 
QLQ-C30), symptom burden (ESAS-r) and mood (HADS) for the entire study cohort. 
Mean values and standard deviations will be used to describe QOL and symptom burden 
(T-test or Wilcoxon as appropriate). We will score the HADS subscales for depressive and 
anxiety symptoms categorically, using a cut-off of >7 to describe the proportion of patients 
with these symptoms. We will use Chi-square or Fisher’s Exact Test, as appropriate, to 
analyze the categorical variables.  
Health care utilization: We will use descriptive statistics to describe hospitalizations, ICU 
stays, ED visits and palliative care use for the entire study cohort. Mean values and 
standard deviations will be used to describe continuous variables (T-test and Wilcoxon 
rank sum, as appropriate).  We will use Chi-square or Fisher’s Exact Test, as appropriate, 
to analyze the categorical variables. 
 
14.5 Reporting and Exclusions 
All patients who begin protocol treatment will be included in the analysis of all the 
primary and secondary endpoints, except for the surgical outcomes as noted in 14.4. 
15 PUBLICATION PLAN 

The results will be made public within 24 months of the end of data collection. A report may 
be published in a peer reviewed journal, or an abstract that meets the requirements of the 
International Committee of Medical Journal Editors. A full report of the outcomes will be 
made public no later than three (3) years after the end of data collection.

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
83
REFERENCES 
 
1. Ninomiya I, Terada I, Yoshizumi T, et al. Anti-metastatic effect of capecitabine on human 
colon cancer xenografts in nude mouse rectum. Int J Cancer 2004;112(1):135-42. 
2. Miwa M, Ura M, Nishida M, et al. Design of a novel oral fluoropyrimidine carbamate, 
capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes 
concentrated in human liver and cancer tissue. Eur J Cancer 1998;34(8):1274-81.  
3. Dunst J, Reese T, Sutter T, et al. Phase I trial evaluating the concurrent combination of 
radiotherapy and capecitabine in rectal cancer. J Clin Oncol 2002;20(19):3983-91. 
4. Kim JS, Kim JS, Cho MJ, Song KS, Yoon WH. Preoperative chemoradiation using oral 
capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 
2002;54(2):403-8. 
5. Ben-Josef E, Shields AF, Vaishampayan U, et al. Intensity-modulated radiotherapy 
(IMRT) and concurrent capecitabine for pancreatic cancer. Int J Radiat Oncol Biol Phys 
2004;59(2):454-9. 
6. NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. V.2.2010 
(www.nccn.org) 
7. Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, Sauter PK, Coleman 
J, Hruban RH, Lillemoe KD. Resected adenocarcinoma of the pancreas – 616 patients: 
results, outcomes, and prognostic indicators. J. Gastrointest Surg. 2000; 4(6) 567-79. 
8. Kalser MH, Ellenberg SS. Pancreatic Cancer. Adjuvant Combined Radiation and 
Chemotherapy Following Curative Resection [Published Erratum Appears in Arch Surg 
1986 Sep;121(9):1045]. Arch Surg 1985;120(8):899-903. 
9. Lim JE, Chien MW, Earle CC. Prognostic factors following curative resection for 
pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients. 
Ann Surg 2003;237(1):74-85. 
10. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after 
curative resection of cancer of the pancreas and periampullary region: phase III trial of 
the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 1999;230(6):776-
82; discussion 82-4. 
11. Abrams RA, Lowy AM, O’Reilly EM, Wolff RA, Picozzi VJ, MMM, Pisters PWT. 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
84
Combined Modality Treatment of Resectable and Borderline Resectable Pancrease 
Cancer: Expert Consensus Statement. Ann Surg Oncol 2009 16: 1751-56. 
12. Willett CG, Lewandrowski K, Warshaw AL, Efird J, Compton CC. Resection margins in 
carcinoma of the head of the pancreas. Implications for radiation therapy. Ann Surg 
1993;217(2):144-8. 
13. Rich TA, Evans DB, Curley SA, Ajani JA. Adjuvant radiotherapy and chemotherapy for 
biliary and pancreatic cancer. Ann Oncol 1994;5(Suppl 3):75-80. 
14. Staley CA, Lee JE, Cleary KR, et al. Preoperative chemoradiation, 
pancreaticoduodenectomy, and intraoperative radiation therapy for adenocarcinoma of 
the pancreatic head. Am J Surg 1996;171(1):118-24; discussion 24-5. 
15. Evans D, Abbruzzese J, Lee J, Cleary K, Rich T. Preoperative chemoradiation and 
pancreaticoduodenectomy for adenocarcinoma of the pancreas (Meeting abstract). Proc 
Annu Meet Am Soc Clin Oncol 1994;13:A692. 
16. Evans DB, Pisters PW. Preoperative chemoradiation therapy for pancreatic cancer. Surg 
Clin North Am 2001;81(3):709-13. 
17. Tepper JE. Adjuvant Irradiation of Gastrointestinal Malignancies: Impact On Local 
Control and Tumor Cure. Int J Radiat Oncol Biol Phys 1986;12(4):667-71. 
18. Whittington R, Bryer MP, Haller DG, Solin LJ, Rosato EF. Adjuvant Therapy of 
Resected Adenocarcinoma of the Pancreas. Int J Radiat Oncol Biol Phys 
1991;21(5):1137-43. 
19. Hoffman JP, Lipsitz S, Pisansky T, Weese JL, Solin L, Benson AB, 3rd. Phase II trial of 
preoperative radiation therapy and chemotherapy for patients with localized, resectable 
adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group Study. J Clin 
Oncol 1998;16(1):317-23. 
20. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation 
strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the 
pancreas. J Clin Oncol 1997;15(3):928-37. 
21. Breslin TM, Hess KR, Harbison DB, et al. Neoadjuvant chemoradiotherapy for 
adenocarcinoma of the pancreas: treatment variables and survival duration. Ann Surg 
Oncol 2001;8(2):123-32. 
22. Katz MH, Pisters PW, Evans DB, Sun CC, Lee JE, Fleming JB, Vauthey JN, Abdalla 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
85
EK, Crane CH, Wolff RA, Varadhachary GR, Hwang RF. Borderline Resectable 
Pancreatic Cancer: The Importance of This Emerging Stage of Disease. Ann Surg Oncol 
2009; 16:1727–1733 
23. Brown KM, Siripurapu V, Davidson M, Cohen SJ, Konski A, Watson JC, Li T, Ciocca 
V, Cooper H, Hoffman JP. Chemoradiation followed by chemotherapy before resection 
for borderline pancreatic adenocarcinoma.  The American Journal of Surgery 2008;195: 
318–321 
24. Stokes JB, Nolan NJ, Stelow EB, Walters DM, Weiss GR, de Lange EE, Rich TA, 
Adams RB, Bauer TW. Preoperative Capecitabine and Concurrent Radiation for 
Borderline Resectable Pancreatic Cancer. Ann Surg Oncol. 2011 Jan 7. [Epub ahead of 
print] 
25. Conroy T et al. J Clin Oncol 2005;23:1228-36 or Ychou M et al. J Clin Oncol 
007;25:18S:201s  
26. Conroy T, Desseigne F, Ychou M, Bouché O, et al. FOLFIRINOX versus Gemcitabine 
for Metastatic Pancreatic Cancer. N Engl J Med 2011; 364:1817-1825 
27. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, 
Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, 
Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-
line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 
1997;15(6):2403-13. 
28. Dias-Santagata D, Ahkavanfard S, David SS, et al.  Rapid targeted mutational analysis of 
human tumours: a clinical platform to guide personalized cancer medicine.  EMBO Mol 
Med 2010;2:1-13. 

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Theodore S. Hong 
5/19/16 
 
86
APPENDICES  
Appendix A: Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
40 
Disabled, requires special care 
and assistance. 

Phase II Study of Neoadjuvant FOLFIRINOX with Short Course RT for Borderline Resectable Pancreatic Cancer 
Theodore S. Hong 
5/19/16 
 
87
to bed or chair more than 50% of 
waking hours. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
 

ENGLISH 
 
EORTC QLQ-C30 (version 3)
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the 
number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential. 
Please fill in your initials:
bbbb
Your birthdate (Day, Month, Year):
cececdde
Today's date (Day, Month, Year):  
31 cececdde
__________________________________________________________________________________________ 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4  
5. 
Do you need help with eating, dressing, washing  
 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
 
Please go on to the next page

ENGLISH 
 
During the past week:
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
For the following questions please circle the number between 1 and 7 that  
best applies to you 
29. How would you rate your overall health during the past week? 
 
 1 
2 
3 
4 
5 
6 
7 
 Very poor 
 
 
 
 
 
Excellent 
30. How would you rate your overall quality of life during the past week? 
 
 1 
2 
3 
4 
5 
6 
7 
 Very poor 
 
 
 
 
 
Excellent 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 

Edmonton Symptom Assessment System:
(revised version) (ESAS-R)
Please circle the number that best describes how you feel NOW:
 
No Pain
0¬
1¬
2¬
3¬
4¬
5¬
6¬
7¬
8¬
9¬
10¬
Worst Possible
Pain
 
 
No Tiredness
(Tiredness = lack of energy) 
0¬
1¬
2¬
3¬
4¬
5¬
6¬
7¬
8¬
9¬
10¬
Worst Possible
Tiredness
No Drowsiness
(Drowsiness = feeling sleepy)
 
0¬
1¬
2¬
3¬
4¬
5¬
6¬
7¬
8¬
9¬
10¬
Worst Possible
Drowsiness
No Nausea
 
0¬
1¬
2¬
3¬
4¬
5¬
6¬
7¬
8¬
9¬
10¬
Worst Possible
Nausea
No Lack of
Appetite
 
Worst Possible
Lack of Appetite
No Shortness
of Breath
 
0¬
1¬
2¬
3¬
4¬
5¬
6¬
7¬
8¬
9¬
10¬
Worst Possible
Shortness of Breath
No Depression
(Depression = feeling sad)
 
0¬
1¬
2¬
3¬
4¬
5¬
6¬
7¬
8¬
9¬
10¬
Worst Possible
Depression
No Anxiety
(Anxiety = feeling nervous)
 
 
 
0¬
1¬
2¬
3¬
4¬
5¬
6¬
7¬
8¬
9¬
10¬
Worst Possible
Anxiety
Best Wellbeing
(Wellbeing = how you feel overall) 
 
 
0¬
1¬
2¬
3¬
4¬
5¬
6¬
7¬
8¬
9¬
10¬
Worst Possible
Wellbeing
No __________
Other Problem (for example constipation)
 
0¬
1¬
2¬
3¬
4¬
5¬
6¬
7¬
8¬
9¬
10¬
Patient’s Name __________________________________________ 
Date _____________________ 
Time ______________________ 
Completed by (check one):
 
Patient
 
Family caregiver
 
Health care professional caregiver
 
Caregiver-assisted
BODY DIAGRAM ON REVERSE SIDE
ESAS-r
Worst Possible
_______________
 
0¬
1¬
2¬
3¬
4¬
5¬
6¬
7¬
8¬
9¬
10¬
 
 
Revised: November 2010

Please mark on these pictures where it is that you hurt:  

Appendix D: HADS  
f:\institut\cultadap\project\4480\study4480\questionnaire\original\forproject\hadsukoriq03_mapi.doc_18/01/08_aja 
Hospital Anxiety and 
Depression Scale (HADS)
FOLD HERE 
Name: ______________________________________________________  Date: _______________  
Clinicians are aware that emotions play an important part in most illnesses. If your clinician knows about 
these feelings he or she will be able to help you more. 
This questionnaire is designed to help your clinician to know how you feel. Read each item below and 
underline the reply which comes closest to how you have been feeling in the past week. Ignore the 
numbers printed at the edge of the questionnaire. 
Don’t take too long over your replies, your immediate reaction to each item will probably be more 
accurate than a long, thought-out response. 
FOLD HERE 
 
Now check that you have answered all the questions 
 
 
 
 
A 
D 
TOTAL
 
 
 
 
HADS copyright © R.P. Snaith and A.S. Zigmond, 1983, 1992, 1994.  
Record form items originally published in Acta Psychiatrica Scandinavica, 67, 361–70,  
copyright © Munksgaard International Publishers Ltd, Copenhagen, 1983. 
This edition first published in 1994 by nferNelson Publishing Company Ltd,  
9th Floor, 389 Chiswick High Road, London W4 4AL 
GL Assessment is part of the GL Education Group 
This form may not be reproduced by any means without first obtaining permission from the publisher.  
Email: permissions@gl-assessment.co.uk 
A 
D 
I feel tense or ‘wound up’ 
3
 
Most of the time 
2
 
A lot of the time 
1
 
From time to time, occasionally 
0
 
Not at all 
I still enjoy the things I used to enjoy 
 
 
0 
 
Definitely as much 
 
 
1 
 
Not quite so much 
 
2 
 
Only a little 
 
 
3 
 
Hardly at all 
I get a sort of frightened feeling as if 
something awful is about to happen 
3
 
Very definitely and quite badly 
 
2 
 
 
Yes, but not too badly 
 
1 
 
 
A little, but it doesn’t worry me 
 
0 
 
 
Not at all 
I can laugh and see the funny side of things 
 
 
0 
 
As much as I always could 
 
 
1 
 
Not quite so much now 
 
 
2 
 
Definitely not so much now 
 
 
3 
 
Not at all 
Worrying thoughts go through my mind 
 
3 
 
 
A great deal of the time 
 
2 
 
 
A lot of the time 
 
1 
 
 
Not too often 
 
0 
 
 
Very little 
I feel cheerful 
 
3 
 
Never 
 
 
2 
 
Not often 
 
 
1 
 
Sometimes 
 
 
0 
 
Most of the time 
I can sit at ease and feel relaxed 
0
 
Definitely 
1
 
Usually 
2
 
Not often 
3
 
Not at all 
A
D
I feel as if I am slowed down 
Nearly all the time 
 
 
3 
Very often 
 
 
2 
 
Sometimes 
 
 
1 
 
Not at all 
 
 
0 
 
I get a sort of frightened feeling like 
‘butterflies’ in the stomach 
Not at all 
 
0 
 
 
Occasionally 
 
1 
 
 
Quite often 
 
2 
 
 
Very often 
 
3 
 
 
I have lost interest in my appearance 
Definitely 
 
3 
I don’t take as much care as I should 
 
2 
I may not take quite as much care 
 
1 
I take just as much care as ever 
 
0 
I feel restless as if I have to be on the move 
Very much indeed 
 
3
Quite a lot 
 
2 
 
 
Not very much 
 
1 
 
 
Not at all 
 
0 
 
 
I look forward with enjoyment to things 
As much as I ever did 
 
 
0 
Rather less than I used to
1
Definitely less than I used to 
 
 
2 
 
Hardly at all 
 
 
3 
 
I get sudden feelings of panic
Very often indeed 
 
3 
 
 
Quite often 
 
2 
 
 
Not very often 
 
1 
 
 
Not at all 
 
0 
 
 
I can enjoy a good book or radio or 
television programme
Often 
 
 
0 
Sometimes 
 
 
1 
 
Not often
2
Very seldom 
 
 
3