A Phase II, Open-label Pilot Study Evaluating the Safety and Activity of Liposomal Irinotecan in Combination With 5-FU and Oxaliplatin in Preoperative Treatment of Pancreatic Adenocarcinoma (NEO-Nal- IRI Study)
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma
Sponsor: University of Florida

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A Phase II, Open-label Pilot Study Evaluating the Safety and Activity of Nal-IRI in Combination 
with 5-FU and Oxaliplatin in Preoperative Treatment of Pancreatic Adenocarcinoma (NEO-Nal-
IRI Study) 
 
Protocol Number: 
UF-STO-PANC-004  
(SRMC identifier: UF-GI-008) 
 
UF IRB #: 
 
 
 
201800866 
 
 
 
 
 
 
Coordinating Center: 
 
University of Florida 
 
Principal Investigator:  
 
Thomas J. George, Jr., MD, FACP 
University of Florida 
1600 SW Archer Road 
Gainesville, FL 32608 
Telephone: (352) 273-8008 
Fax: (352) 265-0735 
Email: Thom.George@medicine.ufl.edu  
 
Junior Principal Investigator: 
Sherise Rogers, MD, MPH 
 
 
 
 
 
Email: Sherise.Rogers@medicine.ufl.edu 
 
Statistician:  
 
 
Ji-Hyun Lee, PhD 
 
 
 
 
 
Email: jihyun.lee@ufl.edu  
 
Protocol Management:                     UFHCC Project Management Office 
                                                            Email: PMO@cancer.ufl.edu  
 
Clinical Phase: 
Phase II 
 
IND Status: 
Exempt 
 
Investigational Agent(s): 
Nanoliposomal-Irinotecan (ONIVYDE®, Ipsen 
Biopharmaceuticals, Inc.) 
 
NCT# 
NCT03483038 
 
Date of Original Protocol:  
January 9, 2017 
 
Date of Current Protocol:  
March 14th, 2022  
 
Version of Current Protocol: 
6 
 
PROTOCOL REVISION RECORD 
Version 5.3, dated 30JUL2021 
Version 5.2, dated 21SEP2020 
Version 5.1, dated 09SEP2020 
Version 5.0, dated 03OCT2019 

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Version 4.0, dated 26JUN2019 
Version 3.0, dated 07FEB2019 
Version 2.0, dated 04SEP2018 
Version 1.0, dated 09JAN2017 
 
 
 
      
Keywords: 
Neoadjuvant, chemotherapy, pancreatic adenocarcinoma, 
ONIVYDE®, borderline resectable, resectable 
 
CONFIDENTIAL 
This protocol was designed and developed by the University of Florida Health Cancer Center.  The information contained in this document is regarded as confidential and, except to 
the extent necessary to obtain informed consent, may not be disclosed to another party unless law or regulations require such disclosure.  Persons to whom the information is disclosed 
must be informed that the information is confidential and may not be further disclosed by them. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY SCHEMA ............................................................................................................................................. 11 
PROTOCOL SYNOPSIS ............................................................................................................................... 12 
1.    BACKGROUND ........................................................................................................................................ 17 
1.1    PANCREATIC CANCER THERAPY ............................................................................ 17 
1.2   NANOLIPOSOMAL IRINOTECAN ............................................................................... 18 
1.3    OVERVIEW OF NON-CLINICAL STUDIES ............................................................... 20 
1.4    OVERVIEW OF CLINICAL STUDIES ......................................................................... 20 
1.4.1   Nal-IRI Pharmacokinetics in Humans..................................................................................... 24 
1.4.2   Nal-IRI Safety in Humans .......................................................................................................... 26 
1.5   RATIONALE FOR REGIMEN/DOSES/SCHEDULE .................................................... 28 
2.  OBJECTIVES ................................................................................................................................................. 29 
2.1    PRIMARY ....................................................................................................................... 29 
2.2     SECONDARY ................................................................................................................ 29 
2.3      EXPLORATORY .......................................................................................................... 29 
3.    STUDY DESIGN ............................................................................................................................................ 30 
3.1    STUDY OVERVIEW ...................................................................................................... 30 
4.   SELECTION OF SUBJECTS ............................................................................................................... 31 
4.1   NUMBER OF SUBJECTS ............................................................................................... 31 
4.2   INCLUSION CRITERIA.................................................................................................. 31 
4.3    EXCLUSION CRITERIA ............................................................................................... 32 
4.4    INCLUSION OF WOMEN AND MINORITIES............................................................ 33 
5.     REGISTRATION PROCEDURES .................................................................................................. 33 
6.    STUDY PROCEDURES ........................................................................................................................ 33 
6.1   SCREENING EVALUATIONS ....................................................................................... 34 
6.2   ON-TREATMENT EVALUATIONS (DAY 1 OF CYCLES 1 TO 8) +/- 3 DAYS ....... 34 
6.3   PRE-SURGICAL EVALUATION (WITHIN 4 WEEKS PRIOR TO SURGERY) ........ 34 
6.4   FOLLOW UP EVALUATIONS (4-6 WEEKS POST-OP) – END OF TREATMENT 
EVALUATION......................................................................................................................... 35 
6.5    SURVIVAL FOLLOW UP.............................................................................................. 35 
6.6    EFFICACY ASSESSMENTS ......................................................................................... 35 
6.6.1   Tumor Response ............................................................................................................................ 35 
6.6.2   Primary Efficacy Assessment .................................................................................................... 36 
6.6.3   Secondary Efficacy Assessments ............................................................................................. 36 
 
TABLE OF CONTENTS 
 
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7.   STUDY TREATMENT ............................................................................................................................ 36 
7.1    TREATMENT SCHEDULE/ADMINISTRATION ........................................................ 36 
7.2     SPECIFIC SUPPORTIVE CARE................................................................................... 37 
7.2.1   Dose Calculations .......................................................................................................................... 37 
7.2.2   Concomitant Therapy ................................................................................................................... 37 
7.2.3   Allowed Concomitant Therapy ................................................................................................. 37 
7.2.4   Radiotherapy ................................................................................................................................... 38 
7.2.5 Prohibited Concomitant Therapy ................................................................................................ 39 
7.3     DOSE MODIFICATIONS.............................................................................................. 40 
7.3.1   Dose Modification Table ............................................................................................................ 41 
7.3.2  Non- Hematologic Toxicity ......................................................................................................... 41 
7.3.3   Hematologic Toxicity .................................................................................................................. 42 
7.4   MANAGEMENT OF INFUSION REACTIONS ............................................................ 43 
7.4.1   Allergic Reaction ........................................................................................................................... 43 
7.4.2   Anaphylaxis .................................................................................................................................... 43 
7.4.3   Infusion Reaction Guidelines..................................................................................................... 43 
7.5      SUPPORTIVE CARE GUIDELINES ........................................................................... 44 
7.6     OTHER CONSIDERATIONS........................................................................................ 45 
8.     TREATMENT DISCONTINUATION ........................................................................................... 45 
8.1    REMOVAL OF SUBJECTS FROM STUDY ................................................................. 45 
8.2    CRITERIA FOR STUDY TREATMENT DISCONTINUATION ................................. 45 
8.3    REPLACEMENT OF SUBJECTS .................................................................................. 46 
9.    BIOLOGICAL SPECIMENS AND CORRELATIVES ............................................................ 46 
9.1   SOURCE OF SPECIMENS .............................................................................................. 46 
9.2   CORRELATIVE STUDIES ............................................................................................. 47 
9.3   PREPARATION, SHIPMENT AND STORAGE OF SPECIMENS ............................... 47 
10.   STUDY DRUG INFORMATION ..................................................................................................... 48 
10.1  STUDY DRUG NAME ................................................................................................... 48 
10.1.1  Identification ................................................................................................................................. 48 
10.1.2  Packaging and Labeling of Nal-IRI ........................................................................................ 48 
10.1.3  Drug Supply ................................................................................................................................... 48 
10.1.4  Storage, Handling and Dispensing....................................................................................... 48 
10.1.5    Administration of Nal-IRI ....................................................................................................... 49 
10.1.6    Drug Ordering and Accountability ....................................................................................... 49 

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10.1.7    Contraindications ....................................................................................................................... 50 
10.1.8     Adverse Event Profile ............................................................................................................. 50 
11.    ADVERSE EVENTS ............................................................................................................................. 53 
11.1   DEFINITIONS ................................................................................................................ 53 
11.1.1  Adverse Event ............................................................................................................................... 53 
11.1.2   Serious Adverse Event .............................................................................................................. 53 
11.1.3   Non-Serious Adverse Event..................................................................................................... 54 
11.2    PERIOD OF OBSERVATION ...................................................................................... 55 
11.3   DOCUMENTING / REPORTING OF ADVERSE EVENTS BY INVESTIGATOR .. 55 
11.3.1   Assessment of Causal Relationship of Study Drug .......................................................... 56 
11.3.2   Intensity of Adverse Events ..................................................................................................... 56 
11.3.3   Action Taken with Study Drug ............................................................................................... 57 
11.3.4    Definition of Outcome ............................................................................................................. 57 
11.4   IMMEDIATELY REPORTABLE EVENTS ................................................................. 57 
11.4.1  Serious Adverse Events .............................................................................................................. 57 
11.4.2   Other Events Requiring Immediate Reporting ................................................................... 58 
11.5   IND SAFETY REPORTS UNRELATED TO THIS TRIAL ......................................... 58 
12.    STATISTICAL METHODS ............................................................................................................... 59 
12.1    SAMPLE SIZE DETERMINATION ............................................................................ 59 
12.2    ANALYSIS OF PRIMARY ENDPOINT ..................................................................... 59 
12.3   ANALYSIS OF SECONDARY ENDPOINTS .............................................................. 59 
12.4   ANALYSIS OF EXPLORATORY ENDPOINTS ......................................................... 60 
12.5   ANALYSIS OF SAFETY DATA .................................................................................. 60 
12.6   ENHANCED AE SAFETY MONITORING ................................................................. 60 
13.  DATA AND SAFETY MONITORING ............................................................................................ 61 
13.1   DATA INTEGRITY AND SAFETY COMMITTEE .................................................... 61 
13.2    MONITORING .............................................................................................................. 61 
13.3   PRINCIPAL INVESTIGATOR RESPONSIBILITIES ................................................. 61 
14.    EMERGENCY PROCEDURES ....................................................................................................... 62 
14.1    EMERGENCY CONTACT ........................................................................................... 62 
14.2    EMERGENCY IDENTIFICATION OF INVESTIGATIONAL PRODUCTS ............ 62 
14.3    EMERGENCY TREATMENT ..................................................................................... 62 
15.  ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS ........... 62 
15.1   GOOD CLINICAL PRACTICE ..................................................................................... 62 

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15.2   INSTITUTIONAL REVIEW BOARD........................................................................... 63 
15.3   DELEGATION OF INVESTIGATOR RESPONSIBILITIES ...................................... 63 
15.4   SUBJECT INFORMATION AND INFORMED CONSENT ........................................ 63 
15.5   CONFIDENTIALITY..................................................................................................... 63 
15.6   PROTOCOL AMENDMENTS ...................................................................................... 64 
15.7    CASE REPORT FORMS .............................................................................................. 64 
15.8     RECORD RETENTION ............................................................................................... 64 
15.9     SUB-SITE MANAGEMENT AND COMMUNICATION PLAN .............................. 65 
16.      REFERENCES ...................................................................................................................................... 66 
17.     APPENDICES ......................................................................................................................................... 69 
APPENDIX A: SCHEDULE OF EVENTS ............................................................................. 70 
APPENDIX B: PERFORMANCE STATUS CRITERIA ........................................................ 72 
APPENDIX C: RECIST GUIDELINES (VERSION 1.1) ....................................................... 73 
APPENDIX D: FACT-G (VERSION 4): ................................................................................. 79 
APPENDIX E: SUMMARY OF CHANGES FROM PROTOCOL VERSION 4.0 TO 
VERSION 5.0 ........................................................................................................................... 81 
APPENDIX F: SUMMARY OF CHANGES FROM PROTOCOL VERSION 5.0 TO 
VERSION 5.1 ........................................................................................................................... 83 
APPENDIX G: SUMMARY OF CHANGES FROM PROTOCOL VERSION 5.1 TO 
VERSION 5.2 ........................................................................................................................... 86 
APPENDIX H: SUMMARY OF CHANGES FROM PROTOCOL VERSION 5.2 TO 
VERSION 5.3 ........................................................................................................................... 87 
APPENDIX I: SUMMARY OF CHANGES FROM PROTOCOL VERSION 5.3 TO 
VERSION 6 .............................................................................................................................. 88 
 

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ABBREVIATIONS  
AE 
adverse event 
ALT 
alanine transaminase (also SGPT) 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate transaminase (also SGOT) 
AUC 
area under curve 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
ChemoRT 
complete blood count 
Chemoradiotherapy 
CL 
clearance 
Cmax 
highest concentration determined in the measuring interval 
CPT-11 
unencapsulated irinotecan 
CR 
complete remission 
CrCl 
creatinine clearance 
CRF 
case report form 
CRO 
Clinical Research Office 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
clinical trials management system 
CTV 
clinical target volume 
DISC 
Data Integrity & Safety Committee 
DNA 
deoxyribonucleic acid 
DPD 
dihydrypyrimidine dehydrogenase 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of Treatment 
FDG 
fluorodeoxyglucose positron emission 
5-FU 
5-fluorouracil 
FSH 
follicle stimulating hormone 
fx 
fraction 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor 
GTV 
gross tumor volume 
Gy 
Gray 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IGRT 
Image-guided radiation therapy 

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IMRT 
Intensity-modulated radiation therapy 
IRB 
Institutional Review Board 
IV 
intravenous 
kg 
kilogram(s) 
LV 
leucovorin 
LLOQ 
lowest limit of quantification 
MCV 
mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
mITT 
modified Intention-to-Treat 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
Nal-IRI 
Nanoliposomal irinotecan 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NSAE 
non-serious adverse event 
OAR 
organs at risk 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PMO                 Project Management Office 
PET 
positron emission tomography 
PFS 
progression free survival 
PI 
principal investigator 
PK 
pharmacokinetics 
PR 
partial remission 
PS 
performance status 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
PTV 
planning target volume 
Q2W 
every two weeks 
Q3W 
every three weeks 
RECIST 
RT 
Response Evaluation Criteria In Solid Tumors 
Radiotherapy 
SAE 
serious adverse event 
SBRT 
stereotactic body radiation therapy 
SC 
subcutaneous 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase (also AST) 
SGPT 
serum glutamic pyruvate transaminase (also ALT) 

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SMA 
superior mesenteric artery 
UF 
University of Florida 
UFHCC 
University of Florida Health Cancer Center 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Signature Page 
 
A Phase II, Open-label Pilot Study Evaluating the Safety and Activity of Nal-IRI in 
Combination with 5-FU and Oxaliplatin in Preoperative Treatment of Pancreatic 
Adenocarcinoma (NEO-Nal-IRI Study) 
 
 
Study Principal 
Investigator: 
 
 
 
 
 
 
 
 
 
 
 
Local Principal 
Investigator: 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
Name of Facility 
 
 
 
 
 
 
 
Location of Facility (City/State) 
 
_____________________________ 
Signature of Investigator 
 
_____________________________ 
Printed Name of Investigator 
 
_____________________________ 
Name of Facility 
 
_____________________________ 
Location of Facility (City/State) 
 
 
 
 
 
 
__________________ 
Date 
 
By my signature, I agree to personally supervise the conduct of 
this study and to ensure its conduct in compliance with the 
protocol, informed consent, IRB procedures, the Declaration of 
Helsinki, ICH Good Clinical Practices guidelines, and the 
applicable parts of the United States Code of Federal Regulations 
or local regulations governing the conduct of clinical studies. 
 
 
 
 
 

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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
Progressive 
Disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NALIRIFOX Cycle Length = 2 weeks 
 
Accrual Goal= 28 subjects 
 
 
 
 
ONIVYDE® with 5-fluorouracil, 
leucovorin and oxaliplatin  
(NAPOLI-OX) every 2 weeks for a 
total of 8 cycles 
Surgical resection in the absence of 
documented progression within 4 to 8 
weeks following last dose of therapy 
 
Clinical Follow-up 30 days post-
operatively 
Response Assessment 
Pancreatic protocol CT 
abdomen/Pelvis with CT Chest 
Metastatic disease or surgically 
inoperable = Off protocol 
Still potentially resectable = Proceed 
with Chemo Radiotherapy 
Resectable or Borderline resectable 
pancreatic adenocarcinoma 

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PROTOCOL SYNOPSIS 
 
Title: 
A Phase II, Open-label Pilot Study Evaluating the Safety and 
Activity of Nal-IRI in Combination with 5-FU and Oxaliplatin in 
Preoperative Treatment of Pancreatic Adenocarcinoma (NEO-Nal-
IRI Study) 
Funding 
Organization: 
Ipsen Biopharmaceuticals, Inc. 
Investigational 
Agent Supplier: 
Ipsen Biopharmaceuticals, Inc. 
Rationale: 
Pancreatic cancer is the third leading cause of cancer deaths in US 
with modest survival even in early stage disease with the only chance 
for long-term survival is with complete resection of the cancer.  
Surgical resection is routinely followed by adjuvant chemotherapy, 
as it is widely believed that micro-metastatic disease is present even 
in early clinical stages of the disease.  This strategy is associated 
with a proven reduction in the risk of recurrence of the cancer with 
documentation that two drug therapy is superior to one.  Neoadjuvant 
(pre-operative) treatment offers many advantages in terms of earlier 
systemic treatment of micro-metastatic disease, limiting the toxicity 
of therapy to when patients are more likely to tolerate the side 
effects, and down staging of tumor to allow more patients to achieve 
complete surgical resection, which is thus far the best predictor of 
good long-term outcome.  Recognizing that multi-agent combination 
chemotherapy confers the best disease control in the metastatic and 
adjuvant settings, this rationale has been previously demonstrated to 
also be feasible in the neoadjuvant space, particularly for patients 
with high-risk disease including resectable or borderline resectable 
cancers.  
A major challenge in treating patients with aggressive combination 
of neoadjuvant therapy relates to toxicity, recognizing that patients 
need to be capable of receiving full doses and all cycles of therapy to 
ensure optimal down staging and micrometastatic sterilization, yet 
still be capable of safely undergoing a major surgical resection.  The 
most active therapy (inclusive of survival and response rates) in the 
metastatic setting is demonstrated by use of FOLFIRINOX therapy 
(5-fluorouracil, leucovorin, oxaliplatin and irinotecan), but it 
typically requires dose modifications, delays and growth factor 
support. Commonly, the irinotecan component of this polyagent 
therapy is reduced or dropped in clinical practice when toxicities 
develop, leading to several “modified” FOLFIRINOX regimens in 
use. The toxicity profile of irinotecan liposomal injection 
(ONIVYDE®) with 5-fluorouricil and leucovorin in the second line 
metastatic setting is very reasonable with the added benefit of 

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improved drug delivery to tumor.  In the neoadjuvant setting, where 
patient toxicity is paramount and tumor vasculature is undisrupted, 
the incorporation of ONIVYDE® could have an important anti-
neoplastic effect by improved biologic drug delivery and improved 
full treatment compliance.  Delivering a complete (4 month) course 
of systemic therapy with maintenance of patient health and 
minimization of post-op complications would represent a clinically 
significant step forward in the field of pancreatic cancer therapy.  
The current proposal aims to substitute irinotecan liposomal injection 
(ONIVYDE®) for traditional irinotecan in the standard FOLFIRINOX 
regimen and deliver the therapy in the neoadjuvant setting.  The 
primary goal of this strategy is to rapidly establish perioperative 
safety with regards to surgical outcomes.  Together, this study and 
the associated correlative studies will provide comprehensive, robust 
and efficient clinical and biologic data to support the further rational 
development of ONIVYDE®. 
Objectives: 
Primary: 
• To establish the safety and feasibility of ONIVYDE® in 
combination with 5-fluorouracil, leucovorin, and oxaliplatin 
(NALIRIFOX) in the neoadjuvant setting of resectable or 
borderline resectable pancreatic adenocarcinoma 
Secondary: 
• To determine the treatment completion rate of therapy 
defined by completion of all intended cycles 
• To determine the rate of complete surgical resection (R0) and 
other histopathologic downstaging 
• To determine radiographic objective response rate (ORR)of 
the primary tumor as measured by RECIST 1.1 criteria  
• To determine the biochemical response rate and pattern of 
response as measured by serial CA 19-9 levels 
• To determine the patient-reported quality of life during 
treatment as measured by the NCI validated FACT-G scale 
Exploratory:  
• To collect tissues and blood for post-hoc secondary 
exploratory biomarker, CTC, ctDNA, pharmacogenomic and 
tumor mutational profile assessments as well as potential 
PDX development. 
• Biospecimens will be collected and subsequently examined 
for microbiota content and any associations with patient and 
tumor characteristics, treatment outcomes and change over 
time. 
Study Design: 
This is a phase II, open label, single arm pilot trial. 

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Accrual Goal: 
A total of 28 evaluable subjects. 
Inclusion 
Criteria: 
Individuals eligible for study participation must meet the following 
criteria: 
A. Written informed consent obtained from the subject and the 
ability for the subject to comply with all the study-related 
procedures. 
B. Both males and females ≥ eighteen years of age.  
C. A new clinical diagnosis of resectable or borderline 
resectable, previously untreated pancreatic adenocarcinoma 
confirmed by pathologic specimen evaluation  
D. No clinical evidence of metastatic disease, confirmed by CT 
of chest/abdomen and pelvis with IV contrast (or MRI of 
abdomen and pelvis with non-contrast chest CT, if IV 
contrast is contraindicated). 
E. Potentially resectable local disease, confirmed by CT of 
abdomen with IV contrast (MRI abdomen if CT/contrast is 
contraindicated). Radiographic confirmation of resectable or 
borderline resectable pancreatic cancer is verified by 
documented consensus discussion of the GI Multidisciplinary 
Tumor Board.  The ultimate determination of whether a 
potential subject meets the criteria of “resectable or 
borderline resectable” lies in the consensus of the UF GI 
Multidisciplinary Tumor Board, or equivalent body (for 
external sites).    
F. Eastern Cooperative Oncology Group (ECOG) performance 
status score of 0 or 1. 
G. Treated biliary obstruction (if applicable). 
H. Subjects with known or suspected Gilbert’s disease must be 
formally tested for UGT1A1*28 with results available to 
study team prior to treatment initiation. 
I. Adequate organ function; as defined by: 
i. 
Hematologic-  
- 
ANC > 1,500 cells/µl without the use of 
hematopoietic growth factors; and 
- 
Platelet count > 100,000 cells/µl; and 
- 
Hemoglobin > 9 g/dL (blood transfusions are 
permitted for patients with hemoglobin levels below 9 
g/dL) 
ii. 
Hepatic- 

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- 
Serum total bilirubin within 1.5 ULN for the 
institution, with a trend downwards (biliary drainage 
is allowed for biliary obstruction), 
- 
AST and ALT less than or equal to 2.5 x ULN 
iii. 
Renal-  
- 
Serum creatinine of less than or equal to 1.5 x ULN 
iv. 
Cardiac- 
- 
Normal ECG or ECG without any clinically 
significant findings as defined by the treating 
physician 
J. Women of childbearing potential (WOCBP) must be using an 
adequate method of contraception to avoid pregnancy 
throughout the study and for at least 7 months after the last 
dose of study drug to minimize the risk of pregnancy.  Prior 
to study enrollment, women of childbearing potential must be 
advised of the importance of avoiding pregnancy during trial 
participation and the potential risk factors for an 
unintentional pregnancy.   
 
WOCBP include any woman who has experienced menarche 
and who has not undergone successful surgical sterilization 
(hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or who is not post-menopausal. Post-
menopause is defined as: 
• Amenorrhea that has lasted for ≥ 12 consecutive 
months without another cause, or 
• For women with irregular menstrual periods who are 
taking hormone replacement therapy (HRT), a 
documented serum follicle-stimulating hormone 
(FSH) level of greater than 35 mIU/mL. 
K. Males with female partners of child-bearing potential must 
agree to use physician-approved contraceptive methods (e.g., 
abstinence, condoms, vasectomy) throughout the study and 
should avoid conceiving children for 4 months following the 
last dose of study drug. 
Exclusion 
Criteria: 
Subjects with any of the following will not be eligible for study 
participation: 
A. A medical history of prior anti-cancer treatment for 
pancreatic cancer. 

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B. Locally advanced unresectable disease (see the criteria for 
resectability from inclusion criteria) or evidence of metastatic 
disease.  
C. Any other invasive malignancy within the past three years. 
D. Presence of any known contraindications to or 
hypersensitivities to the investigational products. 
E. Use of strong CYP3A4 inhibitors or inducers, which cannot 
be discontinued prior to study entry. 
F. A non-surgical candidate. 
G. Subject is unable to understand, provide consent or comply 
with study requirements, treatments or instructions in the 
opinion of the treating physician. 
H. Uncontrolled diarrhea, active infection, known interstitial 
lung disease or other medical condition that precludes safe 
administration of this combination therapy consistent with 
manufacturer recommendations. 
I. Unwilling/unable to comply with birth control requirements 
while on study. 
J. Females or males of childbearing potential who are unwilling 
or unable to use an acceptable method to avoid pregnancy 
for the entire study period and for at least 7 months for 
females and 4 months for males after the last dose of study 
drug.  
K. Females who are pregnant or breastfeeding. 
L. History of any other disease, metabolic dysfunction, physical 
examination finding, or clinical laboratory finding giving 
reasonable suspicion of a disease or condition that 
contraindicates the use of protocol therapy or that might 
affect the interpretation of the results of the study or that puts 
the subject at high risk for treatment complications, in the 
opinion of the treating physician. 
M. Prisoners or subjects who are involuntarily incarcerated. 
N. Subjects who are compulsorily detained for treatment of 
either a psychiatric or physical illness. 
O. Subjects demonstrating an inability to comply with the study 
and/or follow-up procedures. 
P. Known dihydrypyrimidine (DPD) deficiency 
Efficacy 
Assessments: 
4 to 8 weeks after completion of neoadjuvant chemotherapy subjects 
will undergo surgical resection.  The primary endpoint is the 
complication rate for evaluable patients who complete surgery, and 

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1.    BACKGROUND 
1.1    Pancreatic Cancer Therapy 
 
Pancreatic cancer is the third leading cause of cancer deaths in US with modest survival even in 
early stage disease1.  It is poised to become the second leading cause of cancer deaths by 2030 2.  
The only chance for long-term survival is with complete resection of the cancer, but few are 
candidates for this approach with outcomes still being far from acceptable in this curative setting.  
Surgical resection is routinely followed by adjuvant chemotherapy, as it is widely believed that 
micro-metastatic disease is present even in early clinical stages of the disease.  This strategy is 
associated with a proven reduction in the risk of recurrence of the cancer with documentation 
that two drug therapy is superior to one3.  Neoadjuvant (pre-operative) treatment offers 
advantages in terms of earlier systemic treatment of micro-metastatic disease, limiting the 
 
this will be compared to expected complication rate.  Pre-operative 
imaging will be compared to the baseline studies to assess 
radiographic response and continued surgical resectability potential. 
RECIST Radiographic criteria and clinical evaluations will be used 
to determine radiographic response and resectability. Surgical 
resection rates will be calculated and pathologic downstaging will be 
determined. Biochemical response rates will be calculated by serial 
CA19-9 levels and characterized as those with normalization of 
CA19-9 during therapy, reduction without normalization or no 
reduction with assessment of the temporal nature of these changes 
and correlation to surgical resection rates.  Treatment completion 
rate will be calculated for all patients and is defined as the 
completion of all intended treatment cycles.  Statistical analyses will 
be conducted by the study biostatistician using SAS v9.1 (SAS 
institute, Cary, NC) 
Statistical 
Considerations: 
For this prospective phase II pilot study, the sample size justification 
is based on the primary endpoint, the complication rate for evaluable 
patients who complete surgery.  A sample size of 25 patients 
achieves ~80% to detect a reduction of 20% in the 30-day post-
operative complication rate (from 30% to 10%), using a one-sided 
exact test with a significance level of 0.05.  Assuming 10% drop-out 
rate, we will accrue a total of 28 patients for this study.  The study 
expects a 20-month accrual period with an additional follow-up of 7 
months after the last patient is enrolled. Subjects failing to proceed to 
surgery will be replaced, but all will support the secondary analyses.  
The sample size calculation is conducted by PASS 16.   
Estimated 
Enrollment 
Period: 
20 months                                                                               
Estimated Study 
Duration: 
27 months         
                                           

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toxicity of therapy to when patients are more likely to tolerate the side effects, and down staging 
of tumor to allow more patients to achieve complete surgical resection, which is thus far the best 
predictor of good long-term outcome4 .  Recognizing that multi-agent combination chemotherapy 
confers the best disease control in the metastatic and adjuvant settings, this rationale has been 
previously demonstrated to also be feasible in the neoadjuvant space, particularly for patients 
with high risk disease including borderline resectable cancers5. Our program has previously 
demonstrated success in investigator-initiated protocol development, enrollment and analysis 
associated with novel neoadjuvant pancreatic adenocarcinoma clinical trials6 .  In the setting of 
borderline resectable and LAPC, high-volume academic institutions and national professional 
guidelines support a neoadjuvant therapy approach with multi-agent chemotherapy.7 The 
development and favorable outcome with contemporary cytotoxic combination therapy in 
metastatic setting with FOLFIRINOX (5-Fluorouracil, Oxaliplatin, Irinotecan) with high 
response rates in metastatic setting had led to increased utilization of this particular regimen in 
the neoadjuvant setting.  The use of FOLFIRINOX chemotherapy in the neoadjuvant setting has 
been explored in several non-randomized studies with promising safety profile, surgical 
outcomes and long term results, but at the cost of significant toxicity.8,9 
A major challenge in treating patients with aggressive combination neoadjuvant therapy relates 
to toxicity, recognizing that patients need to be capable of receiving full doses and cycles of 
therapy to ensure optimal down staging and micrometastatic sterilization, yet still be capable of 
safely undergoing a major surgical resection.  The most active therapy (inclusive of survival and 
response rates) in the metastatic setting is demonstrated by use of FOLFIRINOX therapy (5-
fluorouracil, leucovorin, oxaliplatin and irinotecan), but it typically requires routine dose 
modifications, delays and growth factor support10.  Commonly, the irinotecan component of this 
polyagent therapy is reduced or dropped in clinical practice when toxicities develop, leading to 
several “modified” FOLFIRINOX regimens in use.  When used in the neoadjuvant setting, 
FOLFIRINOX regimens consistently require dose modifications (65%), but still demonstrate 
meaningful clinical down staging and surgically negative margins (70% R0 resection rate)11.  
However, toxicity limits the number of pre-operative cycles that can be delivered and post-
operative complications are not trivial.  Even at high to very high volume centers, 30-day post-
operative mortality secondary to pancreatic resection is in the range of 3.8-7.5%12. In addition to 
this, clinically significant complications including delayed gastric emptying (15-17%), bile leak 
(1-2%), and pancreatic fistula (2-22%) may require either prolonged hospitalization or 
readmission13-14. With the addition of FOLFORINOX, even at modified doses, this complication 
rate is as high as 27-35%15-18.  Such post-operative complications limit the ability to provide 
further adjuvant systemic therapy or radiotherapy. 
 
1.2   Nanoliposomal Irinotecan 
 
nal-IRI is irinotecan (also known as CPT-11) encapsulated in a liposome drug delivery system 
(liposomal irinotecan; nal-IRI). The active ingredient of the nal-IRI injection, irinotecan, is a 
member of the topoisomerase I inhibitor class of drugs and is a semi-synthetic and water soluble 
analog of the naturally-occurring alkaloid, camptothecin. Topoisomerase I inhibitors work to 
arrest uncontrolled cell growth by preventing the unwinding of DNA and therefore preventing 
replication. The pharmacology of irinotecan is complex, with extensive metabolic conversions 
involved in the activation, inactivation, and elimination of the drug19-21. Irinotecan is a prodrug 
that is converted by nonspecific carboxylesterases into a 100-1000 fold more active metabolite, 

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SN-3822 . SN-38 is cleared via glucuronidation, for which major pharmacogenetic differences 
have been shown, and biliary excretion. These drug properties contribute to the marked 
differences in efficacy and toxicity observed in clinical studies with irinotecan23, 24 . 
 
Drug carrier technologies represent a rational strategy to improve the PK and biodistribution of 
irinotecan while protecting it from premature metabolism. nal-IRI employs a novel 
intraliposomal drug stabilization technology for encapsulation of irinotecan into long-circulating 
liposome-based nanoparticles with high drug load and high in vivo stability. The stable 
nanoliposome formulation of irinotecan has several attributes that may provide an improved 
therapeutic index. The controlled and sustained release should improve activity of this schedule-
dependent drug by increasing duration of exposure of tumor tissue to drug, an attribute that 
allows it to be present in a higher proportion of cells during the more sensitive S-phase of the cell 
cycle. The improved PK, high intravascular drug retention in the liposomes, and EPR effect may 
potentially result in site-specific drug delivery to solid tumors. Stromal targeting results from the 
subsequent depot effect, where liposomes accumulating in tumor associated macrophages release 
the active drug and convert it locally to the substantially more cytotoxic SN-38. The 
preferentially local bioactivation should result in reduced exposure to potential sites of toxicity 
and increased exposure to neighboring cancer cells within the tumor.  
 
The toxicity profile of irinotecan liposomal injection (ONIVYDE®) with 5-fluorouricil and 
leucovorin in the second line metastatic setting is very reasonable with the added benefit of 
improved drug delivery to tumor25.  In the neoadjuvant setting, where patient toxicity is 
paramount and tumor vasculature is undisrupted, the incorporation of ONIVYDE® could have an 
important anti-neoplastic effect by improved biologic drug delivery and improved full treatment 
compliance.  Delivering a complete (4 month) course of systemic therapy with maintenance of 
patient health and minimization of post-op complications would represent a clinically significant 
step forward in the field of pancreatic cancer therapy.  
 
This protocol aims to substitute irinotecan liposomal injection (ONIVYDE®) for traditional 
irinotecan in the standard FOLFIRINOX regimen and deliver the therapy in the neoadjuvant 
setting.  The primary goal of this strategy is to rapidly establish perioperative safety with regards 
to surgical outcomes.  The doses and schedule will be those established by the safety run-in/Arm 
1 of the currently enrolling randomized phase II front-line study in metastatic pancreatic cancer 
(NCT02551991).  Recent safety data from that study supports the incorporation of ONIVYDE in 
this combination for previously untreated patients with metastatic pancreatic cancer36.  This 
study will also help establish a benchmark for radiographic response rate, pathologic down 
staging and treatment compliance.  Potential post-hoc correlative analyses include, but are not 
limited to, assessment of pancreatic cancer circulating tumor cells associated with treatment 
response, development of patient-derived cell lines and xenografts from refractory tumor 
removed at the time of surgical resection to determine pathways of resistance and 
microenvironmental immunosuppression, comprehensive mutational profiling of pancreatic 
adenocarcinoma tissue and pharmacologic precision medicine program assessments of novel 
pharmacogenomic profiles (e.g., additional haplotypes of UGT1A1, as well as UGT1A7, 
ABCG2/B1/C2, and SLCO1B1) associated with irinotecan-associated GI toxicity and 
myelosuppression26-28.  Taken together, this study will support continued development of this 
novel combination regimen in the adjuvant, perioperative or metastatic setting.   

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1.3    Overview of Non-Clinical Studies 
 
nal-IRI has been shown in preclinical settings to have a broad spectrum of activity in a wide 
range of solid tumors including colon, pancreatic, gastric, cervical, non-small cell lung, small 
cell lung, ovarian, thyroid, and breast cancers, as well as glioma, Ewing’s sarcoma, and 
neuroblastoma, often with a high degree of anti-tumor activity against resistant or difficult to 
treat cancer models29-31, . nal-IRI has also shown potent antitumor activity, including durable 
tumor regressions, and was markedly superior to the equivalent dose of free drug in a 
bioluminescent-based orthotopic xenograft pancreatic model32. 
 
The PK properties of nal-IRI were evaluated in an HT-29 colon cancer subcutaneous xenograft 
model29. Both irinotecan and SN-38 were cleared very rapidly (within 8 hours) from the plasma 
following non-liposomal irinotecan administration; however, nal-IRI clearance was 
demonstrated to be considerably slower and remained in circulation for over 50 hours. SN-38 
plasma exposure was also greater though C-max levels were reduced following nal-IRI 
administration, suggesting the advantage of the irinotecan liposomal formulation in prolonging 
exposure and half-life via the ability of the lipid bilayer to protect the conversion of prodrug 
CPT-11 to SN-38. Further, both irinotecan and SN-38 accumulated in tissues for extended time 
(at least 1 week after nal-IRI administration), yet there were relatively higher levels of prolonged 
accumulation in the tumor compared to normal tissue, where the metabolites are at very low 
levels after 48 hours (Figure B). Activation of irinotecan to SN-38 by the liver is the primary 
path for SN-38 tumoral accumulation when non-liposomal irinotecan is administered. In 
contrast, these data suggest that accumulation of nal-IRI in the tumor and subsequent liposome 
breakdown and local conversion of irinotecan to SN-38 is responsible for the enhanced tumor 
exposure of SN-38 when nal-IRI is administered. These preclinical data demonstrating longer 
retention time in tumor lesions with nal-IRI administration compared to non-liposomal irinotecan 
administration formed the basis for clinical development. 
 
 
1.4    Overview of Clinical Studies 
 

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nal-IRI has been studied in patients with solid tumors, including cervical cancer, gastric cancer, 
pancreatic cancer, and colorectal cancer (see Table A). An overview of disease areas currently 
being studied is presented in Table B; additional study details can be found at ClinicalTrials.gov.  
 
Table A. Summary of Published Clinical Studies with nal-IRI 
Study 
PEP0201 
PEP0202 
PEP020332 
PEP020633 
PEP020831 
NAPOLI-125 
Colorectal34 
Tumor Type 
Solid 
tumors 
Cervical 
Solid 
Tumors 
Gastric 
Pancreas 
Pancreas 
Colorectal 
Phase 
1 
1 
1 
1 
2 
3 
2 
Study 
Design 
Open label, 
dose 
escalation 
Open 
label, dose 
escalation 
Open 
label, dose 
escalation 
Open 
label, 3-
arm study 
comparing 
nal-IRI, 
docetaxel, 
and 
irinotecan 
(44 
pts/arm) 
Open 
label, 
single arm 
Randomized 
comparison 
of nal-IRI 
and nal-
IRI+5-FU/LV 
vs common 
control (5-
FU/LV) 
Comparison of 
nal-IRI + 5-
FU/LV + 
bevacizumab 
versus FOLFIRI 
+ bevacizumab 
Dosing 
Frequency 
Q3W 
Q3W 
Q3W 
Q3W 
Q3W 
Q3W (mono 
arm) 
Q2W (combo 
arm) 
Q2W 
Dose Level, 
mg/m2* 
60 (n=1) 
120 (n=6) 
180 (n=4) 
60 (n = 3) 
80 (n = 3 
60 (n=3) 
80 (n=6) 
100 (n=5) 
120 (n=2) 
120 
120 
120 (mono 
arm) 
80 (combo 
arm) 
80 
Combination 
and Dose 
No 
Cisplatin 
60 mg 
5-FU/LV 
2000/500 
mg/m2 
No 
No 
5-FU/LV 
2000/200 
mg/m2 
5-FU/LV 
2400/400 mg/m2 
+ bevacizumab 
5 mg/kg 
Key Result 
MTD 
identified 
as 120 
mg/m2 
Study 
terminated 
MTD 
identified 
as 80 
mg/m2 
Similar 
safety 
profile 
across 
irinotecan 
and nal-
IRI arms; 6 
responses 
in nal-IRI 
arm met 
primary 
endpoint 
Median 
surival = 
5.2 months 
Combination 
arm achieved 
median OS 
6.1 months, 
1.9-month 
improvement 
over control 
arm 
(HR=0.57; 
P=0.0009) 
 
*The doses of nal-IRI in publications written before October 2015 were expressed as the irinotecan hydrochloride 
trihydrate. nal-IRI dosing according to the prescribing information is expressed as the irinotecan free base. 
Therefore, the published expression of the 80 mg/m2 dose based on irinotecan hydrochloride trihydrate is equivalent 
to a 69.3 mg/m2 dose based on irinotecan free base. This was rounded to 70 mg/m2 to minimize any potential dosing 
errors. Similarly, the nal-IRI monotherapy arm (120 mg/m2 irinotecan hydrochloride trihydrate) is equivalent to 100 
mg/m2 of irinotecan free base.  
 
 

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Table B. Other Clinical Studies with nal-IRI 
Study 
Tumor 
Type 
Phase 
Study Design 
Dosing 
Frequency 
Dose Level, mg/m2 
Combination 
Status 
NCT02551991 
Pancreas 
 
Open label 
comparison of 
nal-IRI + 5-
FU/LV + 
oxaliplatin or nal-
IRI + 5-FU/LV vs 
nab-paclitaxel + 
gemcitabine 
Q2W 
70 
Oxaliplatin 
Enrolling 
N/A 
Glioma 
1 
Open label, dose 
escalation 
Q3W 
Heterozygous* 
60 (n=3)  
90 (n=6)  
120 (n=3)  
150 (n=6) 
Wild 
Type* 
120 (n=6)  
180 (n=7)  
240 (n=3) 
None 
Enrollment completed; 
MTD identified for 
heterozygous=150 mg/m2 
and MTD identified for 
wild-type=120 mg/m2 
NCT02640365 
Colorectal 
1b 
Open label, dose 
escalation of nal-
IRI + irinotecan 
(Group A; 
noncolorectal) or 
nal-IRI + 5-
FU/LV + 
irinotecan + 
bevacizumab 
(Group B; 
colorectal) 
Q2W 
60 or 80 mg*  
 
Irinotecan, 
bevacizumab 
Enrolling 
NCT01770353 
Solid 
tumors 
1 
Open label, 
ferumoxytol prior 
to first dose 
Q2W 
80* 
None 
 
NCT02022644 
Pancreas 
2 
Open label, dose 
escalation using 
convection-
enhanced 
delivery for direct 
tumoral injection 
Single dose 
Dose* 
 
20  
40 
60 
80 
Tumor 
Volume 
1-4 cm3 
1-4 cm3 
2-5 cm3 
2-6 cm3 
None 
 
NCT02013336 
Pediatric 
solid 
tumor 
1 
Open label, dose 
escalation 
Q3W 
60 (n=3)*  
90 (n=3)*  
120 (n=3)*  
150*  
Cyclophosphamide 
 

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180* 
210* 
NCT02631733 
Solid 
tumors 
1 
Open label, dose 
escalation of 
velaparib 
Q2W 
70 
Velaparib  
 
NCT02231723 
Pancreas 
1 
Open label, dose-
escalation study 
of BBI608 + 
Gemcitabine and 
nab-Paclitaxel or 
mFOLFIRINOX 
or, FOLFIRI or 
nal-IRI+5-FU/LV 
Q2W 
70 
BBI-608 
(Napabucasin) 
 
*The doses of nal-IRI in publications and protocols written before October 2015 were expressed as the irinotecan hydrochloride trihydrate. nal-IRI dosing 
according to the prescribing information is expressed as the irinotecan free base. Therefore, the published expression of the 80 mg/m2 dose based on irinotecan 
hydrochloride trihydrate is equivalent to a 69.3 mg/m2 dose based on irinotecan free base. This was rounded to 70 mg/m2 to minimize any potential dosing errors.  
 

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1.4.1   Nal-IRI Pharmacokinetics in Humans 
 
The PK profile of single agent nal-IRI has been investigated in several studies, in which plasma 
levels of total irinotecan, SN-38 and encapsulated irinotecan were measured. In a single phase II 
clinical study, direct comparison of the PK of irinotecan and SN-38 in patients administered nal-
IRI or conventional (i.e., free) irinotecan was evaluated33, 35. Compared to the administration of 
conventional irinotecan 300 mg/m2 Q3W, administration of nal-IRI 120 mg/m2 Q3W resulted in 
higher exposure of total irinotecan (Cmax: 13.4-fold, AUC0-∞: 46.2-fold, t1/2: 2.0-fold), and higher 
SN-38 t1/2 (3-fold) and marginally higher AUC0-∞ (1.4-fold), however, SN-38 Cmax was reduced 
by 5.3-fold (Figure C). In other PK studies of single agent nal-IRI, similar findings were 
observed when compared to standard doses of conventional irinotecan. Based on population PK 
analysis, no significant association was observed between the PK parameters of total irinotecan 
and SN-38 following nal-IRI monotherapy and when co-administered with 5-FU/LV. This result 
is consistent with the lack of drug interaction noted between irinotecan and 5-FU33. A summary 
table of PK parameters from 95 patients who received 60-180 mg/m2 nal-IRI is found below (see 
Table C).  
 
 
 
 
 
 
 
 
 

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Table C. Summary Statistics of nal-IRI PK Parameters across Multiple PK Studies 
PK Parameters 
Dose, 
mg/m2 
Analytes 
Total Irinotecan 
SN-38 
N 
Median 
%IQR 
N 
Median 
%IQR 
Cmax, μg/mL or 
ng/mL 
60 
4 
28.8 
86 
4 
3.8 
226 
80 
25 
38.0 
36 
25 
4.7 
89 
90 
6 
53.6 
37 
6 
7.5 
89 
100 
11 
41.9 
41 
11 
6.2 
79 
120 
45 
59.4 
32 
45 
7.2 
57 
180 
4 
102.4 
87 
4 
11.8 
89 
T1/2 
60 
4 
22.0 
87 
3† 
145.1 
233 
80 
23† 
26.85 
110 
13† 
49.3 
103 
90 
6 
14.8 
97 
6 
35.7 
53 
100 
11 
21.6 
192 
10† 
62.3 
37 
120 
45 
15.6 
198 
40† 
57.4 
67 
180 
4 
22.8 
86 
4 
50.2 
122 
AUC0-∞, h·μg/mL 
or h·ng/mL 
60 
4 
352 
489 
3† 
813 
249 
80 
23† 
1030 
169 
13† 
587 
69 
90 
6 
1481 
1123 
6 
506 
102 
100 
11 
919 
256 
10† 
453 
99 
120 
45 
1258 
192 
40† 
574 
64 
180 
4 
2076 
90 
4 
1069 
183 
Vd, L/m2 
60 
4 
3.0 
87 
NA 
80 
23† 
2.2 
55 
90 
6 
1.5 
40 
100 
11 
2.2 
24 
120 
45 
1.9 
52 
180 
4 
2.1 
30 
†T1/2 and AUC0-∞ were not calculated for a subset of patients due to insufficient number of samples in the terminal 
phase. NA= not available. Cmax are in μg/ml for total irinotecan and ng/ml for SN-38; AUC are in h μg/ml for total 
irinotecan and h ng/ml for SN-38. [Data on File, Merrimack Pharmaceuticals, Inc.] 
 
The above PK results obtained from patients treated with either nal-IRI or non-liposomal 
irinotecan confirmed the preclinical observation that nal-IRI extended plasma PK of both CPT-
11 and SN-38 compared to treatment with non-liposomal irinotecan. Further, a Phase I clinical 
study of nal-IRI monotherapy (NCT01770353) investigated tumor levels of both CPT-11 and 
SN-38 following treatment with nal-IRI using post-treatment biopsies. Based on model 
predictions, SN-38 levels in tumor were expected to be higher than in plasma, suggesting local 
conversion of CPT-11 to SN-38 in the tumor microenvironment with nal-IRI (Figure D – Item 
A). Predictions were confirmed by measuring levels of CPT-11 and SN-38 in tumor biopsy 
samples collected from patients 72 hours post-dose, demonstrating 5-fold higher levels of SN-38 
in the tumor than the plasma (Figure D – Item B and C). Collectively the evidence suggests that 
the prolonged systemic exposure to CPT-11 and SN-38 leads to prolonged levels of SN-38 in 
tumor tissue, which in turn leads to prolonged DNA damage to tumor cells, suggesting an 
advantage of nal-IRI compared to conventional irinotecan. 
 

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1.4.2   Nal-IRI Safety in Humans 
 
It has been shown in animal and human PK studies that once irinotecan is released from the nal-
IRI liposomes, the conversion of irinotecan to SN-38 is similar to that of the unencapsulated 
irinotecan.  The safety of nal-IRI, therefore, may be indirectly compared with the safety of 
irinotecan, primarily based on a qualitative comparison of adverse reactions, as reported in the 
Camptosar US label for irinotecan32.  The comparison is qualitative, as both irinotecan and nal-
IRI have been used in different doses and schedules as monotherapy and combination therapy 
with other chemotherapeutic agents; therefore, quantitative comparisons are difficult.  The most 
common adverse reactions of irinotecan and nal-IRI are similar and are mainly gastrointestinal 
events and myelosuppression.  The common adverse reactions (>30%) observed in clinical 
studies with irinotecan in combination with other agents are: nausea, vomiting, abdominal pain, 
diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including 
lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal 
bilirubin, and alopecia.  The common adverse reactions (>30%) observed in single agent 
irinotecan therapy in clinical studies are: nausea, vomiting, abdominal pain, diarrhea, 
constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, 
fever, body weight decreasing, and alopecia32.  With respect to liposomal irinotecan, nal-IRI, 
when used in combination with 5-FU and leucovorin, the most common adverse reactions 
(≥20%) observed in clinical trials considered to be related are: diarrhea, nausea, vomiting, 
decreased appetite, neutropenia, fatigue, anemia, stomatitis and pyrexia.  The overall safety 
profile of nal-IRI is presented in detail in the related Investigator Brochure.  Additionally, Table 
D summarizes the most common ≥Grade 3 adverse events with ≥2% incidence compared with 
the control arm from the NAPOLI-1 trial comparing nal-IRI + 5-FU/LV (at a dose of 70 mg/m2 
given on an every-2-week schedule), or nal-IRI monotherapy (at a dose of 100 mg/m2 given on 

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an every-3-week schedule), with 5-FU/LV alone (given weekly for 4 weeks followed by 2 weeks 
of rest) in the same population of patients who had received prior gemcitabine therapy. 
 
In the phase II NALIRIFOX study (NCT02551991)38, the MTD (liposomal irinotecan 50 
mg/m2 [free-base equivalent], oxaliplatin 60 mg/m2, 5-fluorouracil 2400 mg/m2, leucovorin 400 
mg/m2 every 2 weeks) was based on dose-limiting toxicities and cumulative safety data in four 
dose-exploration cohorts. The MTD was received by 32 of 56 patients, seven during dose 
exploration and 25 during dose expansion (median age 58.0 years [range, 39-76], 28 [87.5%] 
with metastatic disease at diagnosis [29 at study entry], and one receiving study treatment at data 
cutoff [26 February 2020]). Of these patients, 22 of 32 had grade ≥3 treatment-related TEAEs, 
most commonly neutropenia (31.3%), febrile neutropenia (12.5%) and hypokalaemia (12.5%); 
ten had serious treatment-related TEAEs; and three died from TEAEs considered unrelated to 
treatment. Median PFS and OS were 9.2 (95% CI: 7.69-11.96) and 12.6 (8.74-18.69) months, 
respectively. 
 
NOTE: nal-IRI dosing according to the prescribing information is expressed as the irinotecan 
free base. The doses of nal-IRI in publications written before October 2015 were expressed as 
the irinotecan hydrochloride trihydrate. Converting a dose based on irinotecan hydrochloride 
trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular 
Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of 
irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. Therefore, 
the published expression of the 80 mg/m2 dose based on irinotecan hydrochloride trihydrate is 
equivalent to a 69.3 mg/m2 dose based on irinotecan free base. This was rounded to 70 mg/m2 to 
minimize any potential dosing errors. Similarly, the ONIVYDE® monotherapy arm (120 mg/m2 
irinotecan hydrochloride trihydrate) is equivalent to 100 mg/m2 of irinotecan free base. 
Information published prior to October 2015 included the background sections of this protocol 
uses the trihydrate doses (80 mg/m2 and 120 mg/m2).  
 
Table D: Most Common Grade ≥3 Adverse Events Observed in Nal-IRI Containing Arms 
Occurring at ≥5% Overall with ≥2% Incidence Versus 5-FU/LV  
Adverse Event, % 
Nal-IRI+5-FU/LV 
(n=117) 
Nal-IRI 
(n=147) 
5-FU/LV 
(n=134) 
Any Grade  
 
Grades 3/4 
 
Any Grade  
 
Grades 3/4 
 
Any Grade 
 
Grades 3/4  
 
Diarrhea 
59.0 
12.8 
70.1 
21.1 
26.1 
4.5 
Vomiting 
52.1 
11.1 
54.4 
13.6 
26.1 
3.0 
Nausea 
51.3 
7.7 
60.5 
5.4 
34.3 
3.0 
Decreased 
appetite 
44.4 
4.3 
49.0 
18.8 
32.1 
2.2 
Fatigue 
40.2 
13.7 
36.7 
6.1 
27.6 
3.7 
Neutropenia* 
39.3 
27.4 
25.2 
15.0 
5.2 
1.5 
Anemia 
37.6 
9.4 
32.7 
10.9 
23.1 
6.7 
Hypokalemia 
2.0 
3.4 
21.8 
11.6 
9.0 
2.2 
*Includes agranulocytosis, febrile neutropenia, granulocytopenia, neutropenia, neutropenic sepsis, decreased 
neutrophil count, and pancytopenia25.  
5-FU/LV=5-fluorouracil/leucovorin.  
 
 

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1.5   Rationale for Regimen/Doses/Schedule 
 
Pancreatic cancer is the third leading cause of cancer deaths in US with modest survival even in 
early stage disease1.  It is poised to become the second leading cause of cancer deaths by 20302.  
Long term survival for patients with this disease are still <10%.  The only chance for long-term 
survival is with complete resection of the cancer, but few are candidates for this approach with 
outcomes still being far from acceptable even in this curative setting.  Surgical resection is 
routinely followed by adjuvant chemotherapy, as it is widely believed that micro-metastatic 
disease is present even in early clinical stages of the disease.  This strategy is associated with a 
proven reduction in the risk of recurrence of the cancer with documentation that two drug 
therapy is superior to one3.  Neoadjuvant (pre-operative) treatment offers advantages in terms of 
earlier systemic treatment of micro-metastatic disease, limiting the toxicity of therapy to when 
patients are more likely to tolerate the side effects, and down staging of tumor to allow more 
patients to achieve complete surgical resection, which is thus far the best predictor of good long-
term outcome4. Recognizing that multi-agent combination chemotherapy confers the best disease 
control in the metastatic and adjuvant settings, this rationale has been previously demonstrated to 
also be feasible in the neoadjuvant space, particularly for patients with high-risk disease 
including borderline resectable cancers5.  Our program has previously demonstrated success in 
investigator-initiated protocol development, enrollment and analysis associated with novel 
neoadjuvant pancreatic adenocarcinoma clinical trials6. 
 
A major challenge in treating patients with aggressive combination like FOLFIRINOX in 
neoadjvuant setting is toxicity which commonly leads to dose modification of irinotecan 
component. The toxicity profile of irinotecan liposomal injection (ONIVYDE®) with 5 
fluorouracil and leucovorin in second line metastatic setting is very reasonable25.  In the current 
study, nal-IRI will be evaluated instead of conventional irinotecan to improve the safety, 
tolerability, and ultimately efficacy of the FOLFIRINOX regimen. By adding oxaliplatin to the 
NAPOLI-1 regimen that has proven efficacy in post-gemcitabine pancreatic cancer, the potential 
to increase DNA damage and potentiate efficacy exists. Further, due to the nal-IRI prolonged PK 
properties and sustained tumor exposure, it is thought that using nal-IRI instead of conventional 
irinotecan would improve upon the efficacy of FOLFIRINOX. The standard dose regimen of 
FOLFIRINOX which demonstrated efficacy is 85 mg/m2 oxaliplatin, 180 mg/m2 irinotecan, and 
fluorouracil at a dose of 400 mg/m2 administered by IV bolus followed by a continuous infusion 
of 2400 mg/m2. Yet due to toxicity, modified FOLFIRINOX regimens are often used (e.g. 
elimination of the 5-FU bolus and irinotecan dose reduction) with unknown effects on the 
efficacy and safety of modified schedules. . The combination of ONIVYDE® with 5-flurouracil 
and oxaliplatin is currently being studied in the phase 2 study in previously untreated metastatic 
pancreatic cancer36. In the current study, a modified triplet regimen is proposed, whereby no 
bolus of 5-FU will be administered based on currently ongoing phase 2 study of NALIRIFOX in 
previously untreated metastatic pancreatic adenocarcinoma. The dose of oxaliplatin (60 mg/m2) 
in this combination regimen with the standard continuous infusion dose of 5-FU (excluding the 
bolus), and the every 2 week dose of nal-IRI was previously shown to be tolerable and 
efficacious in combination with 5-FU.  Note that with nal-IRI dosing, the Cmax of SN-38 is 
predicted to be lower than would be expected for standard dosing with non-liposomal irinotecan. 
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may have less toxicity than FOLFIRI34. Based on this data, toxicity of the nal-IRI-containing 
triplet regimen is not expected to be greater than that seen with FOLFIRINOX in metastatic 
setting and proposed study would help us determine safety and toxicity of this regimen in 
neoadjuvant setting. 
2.  OBJECTIVES 
2.1    Primary 
• To establish the safety and feasibility of ONIVYDE® in combination with 5-fluorouracil, 
leucovorin, and oxaliplatin (FOLNal-IRINOX) in the neoadjuvant setting of resectable or 
borderline resectable pancreatic adenocarcinoma 
• Primary endpoint: 30-day post-op complication rate as measured by hospital readmission, 
death, second surgery or interventional procedure or major complications extending 
hospital stay.   
2.2     Secondary 
• To determine the treatment completion rate of therapy defined by completion of all 
intended cycles 
• To determine the rate of complete surgical resection (R0) and other histopathologic 
downstaging 
• To determine radiographic objective response rate (ORR) of the primary tumor as 
measured by RECIST 1.1 criteria  
• To determine the biochemical response rate and pattern of response as measured by serial 
CA 19-9 levels 
• To determine the patient-reported quality of life during treatment as measured by the NCI 
validated FACT-G scale 
 
2.3      Exploratory 
• To collect tissues and blood for post-hoc secondary exploratory biomarker, CTC, ctDNA, 
pharmacogenomic and tumor mutational profile assessments as well as potential PDX 
development.  
• Biospecimens will be collected and subsequently examined for microbiota content and 
any associations with patient and tumor characteristics, treatment outcomes and change 
over time. 
 
 
 
 
 
 
 
 
 

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3.    STUDY DESIGN 
 
3.1    Study Overview 
 
This is an open-label, single arm pilot trial of ONIVYDE® with 5-fluorouracil, leucovorin and 
oxaliplatin (NALIRIFOX) in the neoadjuvant setting of resectable or borderline resectable 
pancreatic adenocarcinoma.  A total of 28 subjects are planned.  Each subject will be 
administered the outlined study drug regimen every two weeks as outlined in Table 3.1.  Each 
subject will receive a total of eight treatments.  Evaluations will be taken Day 1 of each cycle, 
within four weeks prior to planned surgery, and four to six weeks post-operatively. 
 
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all inclusion 
criteria and none of the exclusion criteria will be entered into the study.  
 
The following treatment regimens will be used: 
 
Table 3.1: Study Treatment Regimen (FOLFNal-IRINOX) 
Agent 
Dose 
Route/Duration 
Schedule 
 
ONIVYDE® 
 
50 mg/m2 [starting 
dose is 36 mg/m2 
(Dose Level -1) for 
subjects who are 
homozygous for 
UGT1A1*28] 
 
IV over 90 minutes 
 
1 every 14 days 
 
Oxaliplatin 
60 mg/m2 
 
IV over 120 minutes 
 
1 every 14 days 
 
Leucovorin 
 
400 mg/m2 
 
IV over 120 minutes 
 
1 every 14 days 
 
5-fluorouracil infusion 
 
2400 mg/m2 
IV continuous 
infusion for 46 hours 
 
1 every 14 days 
Administer sequentially as written, except oxaliplatin and leucovorin, which may be 
administered concurrently in separate bag using a Y-line.  In the event that oxaliplatin is 
discontinued, leucovorin can be administered alone and the administration duration may be 
shorted to fifteen minutes. 
 
Total duration of active subject participation will be approximately 7-8 months.  After the post-
surgical visit, subjects will be followed for survival approximately every 6 months for 5 years. 
 

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4.   SELECTION OF SUBJECTS 
 
Subjects with a diagnosis of pancreatic adenocarcinoma who meet the following inclusion and 
exclusion criteria will be eligible for participation in this study.   
4.1   Number of Subjects 
 
A total of 28 evaluable subjects are to be enrolled. 
4.2   Inclusion Criteria  
Subjects must meet all of the following criteria to be eligible for study participation: 
A. Written informed consent obtained from the subject and the ability for the subject to 
comply with all the study-related procedures.                               
B. Both males and females ≥ eighteen years of age. 
C. A new clinical diagnosis of borderline resectable, or resectable, previously untreated 
pancreatic adenocarcinoma confirmed by pathologic specimen. 
D. No clinical evidence of metastatic disease, confirmed by CT of chest/abdomen and pelvis 
with IV contrast (or MRI of pancreas with non-contrast chest CT, if IV contrast is 
contraindicated).  
E. Potentially resectable local disease, confirmed by CT of the abdomen with IV contrast 
(MRI abdomen if CT/contrast is contraindicated) which radiographically confirmation of  
resectable or borderline resectable pancreatic cancer verified by documented consensus 
discussion of the GI Multidisciplinary Tumor Board and guided by the published expert 
consensus criteria for resectable or borderline resectable.  The ultimate determination of 
whether a potential subject meets the criteria of “resectable or borderline resectable” lies 
in the consensus of the UF GI Multidisciplinary Tumor Board, or equivalent body (for 
external sites). 
F. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. 
G. Treated biliary obstruction (if applicable) 
H. Subjects with known or suspected Gilbert’s disease must be formally tested for 
UGT1A1*28 with results available to study team prior to treatment initiation 
I. Adequate organ function; as defined by: 
i. 
Hematologic-  
- 
ANC > 1,500 cells/µl without the use of hematopoietic growth factors; and 
- 
Platelet count > 100,000 cells/µl; and 
- 
Hemoglobin > 9 g/dL (blood transfusions are permitted for patients with 
hemoglobin levels below 9 g/dL)  
ii. 
Hepatic- 
- 
Serum total bilirubin within 1.5 ULN for the institution, with a trend downwards 
(biliary drainage is allowed for biliary obstruction), 
- 
AST and ALT less than or equal to 2.5 x ULN  

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iii. 
Renal- 
- 
Serum creatinine less than or equal to 1.5 x ULN 
iv. 
Cardiac- 
- 
Normal ECG or ECG without any clinically significant findings as defined by the 
treating physician   
J. Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception to avoid pregnancy throughout the study and for at least 7 months after the 
last dose of study drug to minimize the risk of pregnancy.  Prior to study enrollment, 
women of childbearing potential must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.   
 
WOCBP include any woman who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or who is not post-menopausal. Post-menopause is defined as: 
• Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or 
• For women with irregular menstrual periods who are taking hormone replacement 
therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of 
greater than 35 mIU/mL. 
K. Males with female partners of child-bearing potential must agree to use physician-
approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the 
study and should avoid conceiving children for 4 months following the last dose of study 
drug. 
4.3    Exclusion Criteria 
Subjects with any of the following will not be eligible for study participation:  
A. A medical history of prior anti-cancer treatment for pancreatic cancer. 
B. Locally advanced unresectable disease (see the criteria for resectability from inclusion 
criteria) or evidence of metastatic disease. 
C. Any other invasive malignancy within the past three years.           
D. Presence of any known contraindications to or hypersensitivities to the investigational 
products. 
E. Use of strong CYP3A4 inhibitors or inducers which cannot be discontinued prior to study 
entry. 
F. A non-surgical candidate. 
G. Subject is unable to understand, provide consent or comply with study requirements, 
treatments or instructions in the opinion of the treating physician. 

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H. Uncontrolled diarrhea, active infection, known interstitial lung disease or other medical 
condition that precludes safe administration of this combination therapy consistent with 
manufacturer recommendations. 
I. Unwilling/unable to comply with birth control requirements while on study.  
J. Females or males of childbearing potential who are unwilling or unable to use an 
acceptable method to avoid pregnancy for the entire study period and for at least 7 
months for females and 4 months for males after the last dose of study drug.  
K. Females who are pregnant or breastfeeding. 
L. History of any other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of protocol therapy or that might affect the interpretation of the 
results of the study or that puts the subject at high risk for treatment complications, in the 
opinion of the treating physician. 
M. Prisoners or subjects who are involuntarily incarcerated. 
N. Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
illness. 
O. Subjects demonstrating an inability to comply with the study and/or follow-up 
procedures. 
P. Known dihydrypyrimidine (DPD) deficiency 
4.4    Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
5.     REGISTRATION PROCEDURES 
 
All study participants must be registered with the UF Clinical Trial Management System 
(OnCore) prior to participation in this trial.  This is not registration into the trial. The 
participating site must fax or email the completed study specific eligibility checklist and 
registration forms, supporting documents and signed informed consent to the Coordinating 
Center. Unsigned or incomplete forms will be returned to the site. Once documents are received, 
the designated Research Coordinator will review them to confirm eligibility and to complete the 
registration process. If eligibility cannot be confirmed, the research coordinator will query the 
site for clarification or additional documents as needed. Subjects failing to meet all study 
eligibility requirements will not be registered and will be unable to participate in the trial. 
6.    STUDY PROCEDURES 
 
Please see the Schedule of Events located in Appendix A. 

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6.1   Screening Evaluations   
Written informed consent must be obtained prior to performing any study-specific evaluations or 
tests. Tests or evaluations performed as standard of care within the specified screening period, 
but prior to informed consent, may be accepted for this study and need not be repeated. 
The following pre-treatment measurements will be obtained within 28 days prior to the initiation 
of therapy: 
 
a. A medical history and physical exam, including vital signs, will be obtained from each 
subject. 
b. Vital Signs – Temperature, resting pulse, blood pressure and respiratory rate 
c. Height, weight and ECOG performance will be obtained from each subject. 
d. Blood and urine samples will be obtained for the following laboratory studies: 
 
- CBC with differential count 
- Comprehensive metabolic panel 
- CA 19-9 
- Urinalysis 
- Urine pregnancy test (females of potential child-bearing status only).  This test must be 
done within 7 days of treatment. 
e. ECG (document any abnormalities)  
f. CT of chest/abdomen and pelvis with IV contrast (or MRI of abdomen/pelvis with non-
contrast chest CT, if IV contrast is contraindicated). 
g. Submission of diagnostic tumor specimen  
6.2   On-Treatment Evaluations (Day 1 of Cycles 1 to 8) +/- 3 days 
 
On-Treatment evaluations must be obtained prior to treatment provision. 
 
a. Height, weight and ECOG performance status will be obtained from each subject. 
b. An interim medical history and physical exam, including vital signs, symptoms 
evaluation for toxicity and adverse effect assessment will be obtained from each subject. 
c. Blood samples for a CBC with differential count, comprehensive metabolic panel, and 
CA 19-9 will be obtained.   
d. Research blood samples 
e. A urine or serum pregnancy test will be obtained for all females of childbearing potential 
at the start of each cycle during study treatment, 
f. ECG (only on Day 1 of Cycles 1-8) (as medically indicated) 
g. FACT-G, quality of life assessment (only on Day 1 of Cycles 1, 5, and 8). 
h. Microbiota sample collection (only at Day 1 of Cycles 1 and 5).  Stool collection may be 
performed at home and mailed or brought to clinic, or obtained in clinic.  Urine and oral 
samples will be collected in clinic.       
6.3   Pre-surgical Evaluation (within 4 weeks prior to surgery) 
 
Pre-surgical evaluations should be within four to eight weeks following the last dose of 
chemotherapy. 

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a. Height, weight and ECOG performance status will be obtained from each subject. 
b. An interim medical history and physical exam, including vital signs, will be obtained 
from each subject. 
c. Blood samples for a CBC with differential count, comprehensive metabolic panel, and 
CA 19-9 will be obtained. 
d. Research blood samples 
e. CT of chest/abdomen and pelvis with IV contrast (or MRI of abdomen/pelvis with non-
contrast chest CT, if IV contrast is contraindicated) should be performed following, but 
no more than 4 weeks after the administration of the last cycle of neoadjuvant 
chemotherapy.  
f. Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 will be utilized to 
assess tumor response 
g. ECG (as medically indicated) 
h. FACT-G, quality of life assessment. 
i. Microbiota sample collection (after completion of chemotherapy and after completion of 
radiotherapy if performed).  Stool collection may be performed at home and mailed or 
brought to clinic, or obtained in clinic.  Urine and oral samples will be collected in clinic. 
 
6.4   Follow up Evaluations (4-6 weeks post-op) – End of Treatment Evaluation 
   
a. Height, weight and ECOG performance status will be obtained from each subject. 
b. An interim medical history and physical exam, including vital signs, will be obtained 
from each subject. 
c. Blood samples for a CBC with differential count, comprehensive metabolic panel, and 
CA 19-9 will be obtained. 
d. Documentation of the pathology report findings with submission of surgical specimen 
samples will be obtained. 
e. Research blood samples 
f. Submission of surgical pathologic tumor specimen 
g. FACT-G, quality of life assessment. 
h. Microbiota sample collection (at post-surgical/EOT visit).  Stool collection may be 
performed at home and mailed or brought to clinic, or obtained in clinic.  Urine and oral 
samples will be collected in clinic. 
6.5    Survival Follow up  
 
Survival follow-up every 6 months for 5 years and documentation of any recurrence. 
6.6    Efficacy Assessments 
 
6.6.1   Tumor Response 
Tumor response will be assessed using RECIST (version 1.1) criteria.  Reference Appendix 
C for guidelines. 
 

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6.6.2   Primary Efficacy Assessment 
Determine the activity of ONIVYDE® plus leucovorin, and oxaliplatin (NALIRIFOX) in 
subjects with pancreatic adenocarcinoma. 
 
6.6.3   Secondary Efficacy Assessments 
Determine radiographic response rate by RECIST (Version 1.1) criteria, the rate of surgical 
resection, the biochemical response rate and pattern measured by CA 19.9 serum levels, and 
quality of life of subject receiving protocol therapy.  All radiographic images and responses 
will be reviewed and confirmed by a third party investigator-independent radiographic 
review. 
 
Quality of life measurements will be collected and recorded by subjects with subsequent 
analysis performed on all subjects.  Specifically, the FACT-G (Functional Assessment of 
Cancer Therapy – General, Version 4.0) will be employed as a previously validated subject 
self-reporting tool in oncology patients.  Reference Appendix D for FACT-G questionnaire. 
 
Additional exploratory tissue and serum correlative analyses in protocol participants is 
further detailed in Section 9.2. 
 
7.   STUDY TREATMENT 
All subjects entering the screening phase will receive a unique subject number. This number will 
be used to identify the subject throughout the study. Subjects withdrawn from the study will 
retain their subject number.  
7.1    Treatment Schedule/Administration 
 
Refer to Table 3.1 for the protocol treatment regimen. 
 
Overall treatment plan 
• 
ONIVYDE® with 5-fluorouracil, leucovorin and oxaliplatin (NALIRIFOX) at the 
recommended for phase II doses determined from NCT02551991-IV dosing every 2 
weeks x 8 total treatments (4 months) 
• 
Surgical resection in the absence of documented progression within 4-8 weeks following 
last dose of therapy.  Clinical response assessment following last cycle of  
NALIRIFOX. 
• 
Optional chemoradiotherapy with evidence of local disease progression or as otherwise 
defined in Section 7.2.4 
• 
Optimal supportive care and growth factor support per recommendations from 
NCT02551991 
• 
Clinical follow-up 4-6 weeks post-operatively (EOT visit) 
• 
Survival follow-up every 6 months for 5 years and documentation of any  recurrence. 

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7.2     Specific Supportive Care 
 
7.2.1   Dose Calculations 
 
Mosteller/Dubois formula would be used for body surface area calculator according to the 
institution guidelines. Actual body weight would be used for the BSA calculation which would 
be obtained within 72 hours prior to Day 1 of each cycle. Formula used for BSA calculation 
should be consistent throughout the treatment.  
 
CrCl would be calculated using MDRD equation: 
 
GFR (ml/min/1.73 m2) = 175 x (SCr)-1.154 x (Age)-0.203 x (0.742, if female) x (1.212, if African American) 
   
7.2.2   Concomitant Therapy 
 
Relevant medical history should be obtained at screening and include prior medications and 
treatment history.  All medications taken within 4 weeks prior to screening, regardless of 
indication, should be recorded. However, routine pre-treatment supportive care medications do 
not need to captured. 
 
Any therapy or medication (except study drugs), administered from screening until the post-op 
visit (or pre-op visit if the subject does not proceed with surgery), is considered a concomitant 
therapy or medication. However, if a course of a new anti-cancer therapy is initiated prior to that 
follow-up period visit, a record of concomitant medications will no longer be performed. 
Medications administered as a routine part of the resection surgery and associated hospitalization 
will not be recorded.  If the use of any concomitant treatments (medications or procedures) 
becomes necessary, the treatment must be recorded, including the name of the drug or treatment, 
dose, route, date, indication for use, expected duration, and frequency of treatment. Assessment 
and documentation of concomitant medications will be done at each visit. (See section 7.2.4 for 
prohibited concomitant medication.) Guidelines for treating certain medical conditions with 
concomitant medication is discussed in section 7.2.3.  
 
7.2.3   Allowed Concomitant Therapy 
 
See protocol-specific supportive care information in Section 7.2.  All other supportive measures 
consistent with optimal patient care will be given throughout the study.   
 
Nausea:  Dexamethasone and 5HT3 blocker will be prescribed as premedication and 
anti-emetics will be prescribed and changed as clinically warranted during study period.   
 
Diarrhea:  Acute diarrhea and abdominal cramps, developing during or within 24 hours 
after nal-IRI administration, may occur as part of a cholinergic syndrome. The syndrome 
can be treated with atropine. Prophylactic or therapeutic administration of atropine, 
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cholinergic symptoms during the study. Diarrhea can be debilitating and on rare 
occasions is potentially life-threatening. Diarrhea should be managed according to 
institutional guidelines or according to ASCO guidelines37. In general, for grade 3 or 4 
diarrhea, nal-IRI should be withheld. Loperamide should be initiated for late-onset 
diarrhea of any severity. Intravenous or subcutaneous atropine 0.25 to 1 mg should be 
administered (unless clinically contraindicated) for early-onset diarrhea of any severity.  
 
Neutropenia:   Use of G-CSF or Peg-G-CSF is permitted to treated neutropenia and 
neutropenic fever, however prophylactic use of G-CSF is permitted for high risk patients 
as per treating physician’s discretion and if subject has already experienced neutropenic 
fever or an episode of grade 3 or 4 neutropenia.  Please refer to Section 7.3.3 for 
neutropenia adverse event guidelines. If needed, either G-CSF 5mcg/kg/dose 
subcutaneous on Days 4-10 of each cycle or PegG-GCF 6 mg subcutaneous on Day 4 of 
each cycle are acceptable as per treating physician discretion.  
 
Infusional Hypersensitivity: Platinum hypersensitivity can cause dyspnea, 
bronchospasm, itching, and hypoxia. Appropriate treatment includes supplemental 
oxygen, steroids, antihistaminic, bronchodilators or vasopressors as per treating 
physician’s discretion.  
 
Pharyngo-laryngeal Dysesthesias: Oxaliplatin induced pharyngo-laryngeal dysesthesia, 
which can be triggered by cold, is generally treated with anxiolytics. If pharyngo-
laryngeal dysesthesia occurs during infusion, treat based on severity:  
Grade 1 – prolong infusion to 6 hours  
Grades 2 or 3- Stop infusion, administer benzodiazepines, reassure subject, 
and restart infusion at the discretion of treating physician. 
   
7.2.4   Radiotherapy 
 
External beam radiotherapy is only allowable following completion of neoadjuvant 
chemotherapy and study drug treatment based upon repeat imaging and clinical assessments at 
the pre-operative time point with either of the following scenarios: 
1) Evidence of local disease progression that is resulting in uncontrolled pain, 
obstruction or other clinically relevant complication suggestive of conversion to a 
locally advanced clinical stage. 
2) Radiographic evidence at the time of surgical planning of local disease persistence 
that, in the opinion of the treating surgeon and with consensus of the multidisciplinary 
tumor board, jeopardizes the ability to attain a margin negative surgical outcome. 
 
The schedule of radiotherapy in this protocol should conform to the following parameters:  
 
Radiation planning and dosing:  
- 
Supine with arms up in VacLoc immobilization.   

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Segmentation, Contours and Dose Specifications:  
- 
CTV1 Includes: Primary Tumor (GTV), primary lymphatics and region at risk. 
This includes the SMA origin with 7 – 15 mm margin, SMA and SMV vessels 
adjacent to the pancreatic head, regional lymphatics (including the porta hepatic, 
gastro-hepatic, celiac and superior mesenteric nodes).   
- 
CTV2 Includes:  Primary Tumor (GTV) plus enlarged lymph nodes with 7 – 15 
mm margin. PTV Expansions are 10 mm depending on motion and physics 
dosimetry protocol. 
- 
Organs at Risk segmentation (OAR): Small bowel, large bowel, duodenum, 
stomach, liver, kidneys, and spinal cord. 
 
IMRT / IGRT Radiotherapy Prescription:  
CTV1: 45 - 50.4 Gy at 1.8 Gy/Fx to >95% PTV  
CTV2: (GTV Boost) Final Dose of 50.4 – 54 Gy at 1.8 Gy/Fx to >95% PTV 
 
Concomitant infusional 5-FU or daily capecitabine, per NCCN guidelines and institutional 
practice, is strongly recommended.   
 
Alternative radiotherapy dosing with short course or SBRT, or proton therapy, may be 
considered upon review of the case, at the discretion of the PI and with consultation of 
radiotherapy sub-investigators. 
 
In any situation requiring radiotherapy, surgery should still be planned 4-8 weeks after the last 
dose of chemoradiotherapy or radiotherapy. Please note additional consideration for pre-surgical 
imaging assessments in the Scheduled of Events (Appendix A), as an additional assessment may 
be required after completion of radiotherapy. 
Otherwise, radiotherapy use is prohibited during study treatment.  Patients may undergo post-
operative radiotherapy after completing the EOT assessment if surgical resection resulted in a 
positive margin or other feature that justifies this modality.  If a patient has radiographic 
progression of disease that renders them inoperable or they develop metastatic disease during the 
course of study treatment, these patients will be removed from study and can be treated per 
institutional practice.   
7.2.5 Prohibited Concomitant Therapy 
 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial:  
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol  
• Chemotherapy not specified in this protocol  

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• Investigational agents other than the study drug in this trial  
• Radiation therapy  
• The following drugs are noted in the irinotecan prescribing information as interacting 
with irinotecan: St. John’s Wart, CYP3A4 inducing anticonvulsants (phenytoin, 
phenobarbital, and carbamazepine), ketoconazole, itraconazole, troleandomycin, 
erythromycin, diltiazem and verapamil. Treatment with these agents and any others that 
interact with irinotecan, 5-FU, or oxaliplatin, or should be avoided. 
 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in 
the trial. Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed. However, 
intranasal influenza vaccines (e.g. Flu - Mist®) are live attenuated vaccines, and are not allowed. 
7.3     Dose Modifications 
The National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events Version 4 
(CTCAE) will be used to grade toxicity (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). All 
dose reductions for all arms should be based on the worst preceding toxicity. If a subject’s dose 
is reduced during the study due to toxicity, it should remain reduced for the duration of the study; 
dose re-escalation to an earlier dose is not permitted.   
Treatment should be delayed to allow sufficient time for recovery to levels, and upon recovery, 
treatment should be administered according to the guidelines in the tables below. 
If the subject had febrile neutropenia, the ANC must have resolved to ≥ 1500/mm3 and the 
subject must have recovered from infection. For Grade 3 or 4 non-hematological toxicities, 
treatment should be delayed until they resolve to Grade 1 or baseline. Guidelines for dose 
adjustments of each individual treatment within the regimen are found in the tables below for 
hematologic toxicities (section 7.3.3), and for non-hematological toxicities (section 7.3.2), In 
case a patient experiences an infusion reaction, either institutional guidelines or the guidelines 
provided for infusion reaction management (see Section 6.4) should be followed. 
Oxaliplatin may be discontinued if allergic reaction occurs or other toxicity that precludes safe 
continuation of oxaliplatin, even at lower doses. Subjects may continue to receive irinotecan 
liposome injection + 5-FU/LV at the discretion of the investigator and continue in the study.  
In general, treatment holds may not exceed beyond 14 days without patient removal from this 
trial unless the situation is discussed and approved by the PI due to circumstances that do not 
jeopardize the integrity of the trial data or patient safety. 
 
 

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7.3.1   Dose Modification Table 
 
 
Agent 
Dose level 0  
(starting dose) 
Dose Level -1 
Dose level -2 
Oxaliplatin 
60 mg/m2 
50 mg/ m2 
40 mg/ m2 
ONIVYDE® 
50 mg/m2 
42 mg/m2 
36 mg/m2 
ONIVYDE® in 
UGT1A1*28 
homozygous  
 
36 mg/m2 
29 mg/m2 
5-Fluorouracil 
infusion 
2400 mg/m2 
1920 mg/m2 
1600 mg/m2 
7.3.2  Non- Hematologic Toxicity 
 
Toxicity – NCI Grade (v.4) Suggested Dose Modification 
Gastrointestinal  
Diarrhea 
Grade 1/2 
No Dose modification  
Initiate/optimize supportive care 
Grade 3/4 
Optimize supportive care and hold treatment until ≤ Grade 1 
• 1st occurrence - Reduce ONIVYDE® to Dose Level -1 
• 2nd occurrence - Reduce infusion 5-FU to Dose Level -1 and 
test for UGT1A1*28 
• 3rd occurrence - Reduce ONIVYDE® to Dose Level -2 
• 4th occurrence - Reduce infusion 5-FU to Dose Level -2 
• 5th occurrence - Discontinue ONIVYDE®  
Hepatic  
Total bilirubin, AST, 
or Alk Phos  
Grade 3  
 
Hold treatment until ≤ Grade 2 – provide/replace biliary stent if 
needed or other workup 
• 1st occurrence – Resume at previous dose  
• 2nd occurrence - Reduce Oxaliplatin to Dose Level -1  
• 3rd occurrence - Reduce ONIVYDE® to Dose Level -1 
• 4th occurrence – Discontinue ONIVYDE®  
 
Grade 4 
Discontinue protocol therapy unless resolution of non-study 
associated etiology (i.e., biliary stent migration) 
• 1st occurrence – Resume at previous dose  
• 2nd occurrence - Discontinue offending agent 
Interstitial Lung Disease 
or Pulmonary Fibrosis 
 
Any Grade 
 
Hypersensitivity reaction can be secondary to Oxaliplatin or 
ONIVYDE® and it will be treated based on severity and as per 
treating physician’s discretion.  
Hypersensitivity reaction 
Any Grade 
Hypersensitivity reaction can be secondary to Oxaliplatin or 
ONIVYDE® and it will be treated based on severity and as per 
treating physician’s discretion.  

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Toxicity – NCI Grade (v.4) Suggested Dose Modification 
Guidelines provided in section 7.4.1. 
Other Clinically Significant Non-Hematologic Toxicities* 
Grade 3 
Hold treatment until AE resolves to ≤ Grade 1.  
• 1st occurrence – Reduce the suspected offending agent to 
Dose Level -1 
• 2nd occurrence – Reduce the suspected offending agent 
to Dose Level -2 
• 3rd occurrence – Discontinue the suspected offending 
agent  
Grade 4 
Hold treatment until AE resolves to ≤ Grade 1.  
• Reduce the suspected offending agent to Dose Level -1 
• 2nd occurrence – Discontinue the suspected offending 
agent 
* Determination of “clinically significant” Aes and “offending drug” is at the discretion of the 
treating physician.  In all situations where toxicity justifies discontinuation of an agent, only 
the individual offending agent should be eliminated from the regimen and continuation of 
treatment otherwise per protocol is recommended. 
 
7.3.3   Hematologic Toxicity 
 
Toxicity – NCI Grade (v.4) 
Suggested Dose Modification 
Hematologic Neutrophils/ 
granulocytes Grade 3,4 or 
Severe Neutropenia 
Hold treatment and check weekly until ANC ≥ 1500/mm3.  
• 1st Occurrence – Reduce ONIVYDE® to Dose Level -1 
• 2nd occurrence – Reduce 5-FU infusion to Dose Level -1 
• 3rd occurrence - Reduce Oxaliplatin to Dose Level -1   
• 4th occurrence - Reduce ONIVYDE® to Dose Level -2  
• 5th occurrence - Discontinue ONIVYDE  
Either GCSF or Peg-GCSF is permitted when appropriate 
Thrombocytopenia Grade 2 
(1st Event) 
Hold treatment and check weekly until platelets are ≥ 
75,000/mm3. Resume treatment at same dose level. 
Grade 2 (2nd Event) or 
Grade 3, 4 
Hold treatment and check weekly until platelets are ≥ 
75,000/mm3.  
• Upon recovery - Reduce Oxaliplatin to Dose Level -1  
• 2nd occurrence – Reduce ONIVYDE® to Dose Level -1  
• 3rd occurrence - Reduce Oxaliplatin to dose level -2 
• 4th occurrence – Reduce 5-FU to dose level -1  
• 5th occurrence -  Discontinue Oxaliplatin 
• 6th occurrence - Discontinue ONIVYDE®  

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Other hematologic toxicities do not require dose modification.  However, red blood cell 
transfusion should be considered for hemoglobin < 8 g/dL or significant symptoms of anemia.  
In all situations where toxicity justifies discontinuation of an agent, only the individual 
offending agent should be eliminated from the regimen and continuation of treatment 
otherwise per protocol is recommended after discussion with the PI. 
7.4   Management of Infusion Reactions 
 
The guidelines described in this section can be followed in case of infusion reactions to any 
study treatment given per protocol (e.g. nal-IRI, oxaliplatin etc.). Infusion reactions will be 
defined according to the National Cancer Institute CTCAE (Version 4.03) definitions of an 
allergic reaction or anaphylaxis as defined below. 
 
7.4.1   Allergic Reaction 
 
Allergic reaction (i.e., a disorder characterized by an adverse local or general response from 
exposure to an allergen): 
 
Grade 1:  
Transient flushing or rash, drug fever <38° C (<100.4°F); intervention not 
indicated. 
Grade 2:  
Intervention or infusion interruption indicated; responds promptly to symptomatic 
treatment (e.g., antihistamines, NSAIDS, narcotics); prophylactic medications 
indicated for ≤ 24 hours. 
Grade 3: 
Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms following initial improvement; 
hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary 
infiltrates). 
Grade 4:  
Life-threatening consequences; urgent intervention indicated. 
 
7.4.2   Anaphylaxis 
 
Anaphylaxis (i.e., a disorder characterized by an acute inflammatory reaction resulting from the 
release of histamine and histamine-like substances from mast cells, causing hypersensitivity 
immune response), presents with breathing difficulty, dizziness, hypotension, cyanosis and loss 
of consciousness and may lead to death: 
 
Grade 1:  
Not applicable. 
Grade 2:  
Not applicable. 
Grade 3:  
Symptomatic bronchospasm, with or without urticaria; parenteral intervention 
indicated; allergy-related edema/angioedema; hypotension. 
Grade 4:  
Life-threatening consequences; urgent intervention indicated. 
 
7.4.3   Infusion Reaction Guidelines 
 

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Institutional policies or the following treatment guidelines shall be used for the management of 
infusion reactions. 
 
Grade 1: 
• Slow infusion rate of offending agent by 50%. 
• Monitor patient every 15 minutes for worsening of condition. 
• Future infusions may be administered at a reduced rate (e.g. over 120 minutes for nal- 
IRI), at the discretion of the Investigator. 
 
Grade 2: 
• Stop infusion of offending agent. 
• Administer diphenhydramine hydrochloride 50 mg IV, acetaminophen 650 mg orally, 
and oxygen. 
• Resume infusion at 50% of the prior rate once infusion reaction has resolved. 
• Monitor subject every 15 minutes for worsening of condition. 
• For all subsequent infusions, pre-medicate with diphenhydramine hydrochloride 50 mg 
IV, dexamethasone 10 mg IV, and acetaminophen 650 mg orally. 
• Future infusions may be administered at a reduced rate (e.g. over 120 minutes for nal- 
IRI), at the discretion of the Investigator. 
 
Grade 3: 
• Stop infusion and disconnect infusion tubing from patient. 
• Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 10 mg IV, 
bronchodilators for bronchospasm, and other medications or oxygen as medically 
necessary. 
• No further treatment will be permitted during this visit. 
 
Grade 4: 
• Stop the infusion and disconnect infusion tubing from subject. 
• Administer epinephrine, bronchodilators or oxygen as indicated for bronchospasm. 
• Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 10 mg IV and 
other medications as medically necessary. 
• Consider hospital admission for observation. 
• No further treatment will be permitted during this visit. 
 
For subjects who experience a > grade 1 infusion reaction, pre-medication with a combination of 
diphenhydramine hydrochloride 50 mg IV, dexamethasone 10 mg IV, and acetaminophen 650 
mg orally or per institutional guidelines may be provided as part of subsequent treatments. 
7.5      Supportive Care Guidelines 
 
Subjects should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, antidiarrheals, analgesics, etc., when appropriate. Supportive care, 
especially pain control, will be optimized in all subjects. Guidance is provided for management of 
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are strongly urged to discuss with Medical Monitor and/or the Principal Investigator prior to 
discontinuing study treatment for reasons other than radiographic PD.  
7.6     Other Considerations 
 
Other toxicities requiring special attention include: 
 
QTc prolongation that occurs in the setting of diarrhea induced electrolyte imbalance should be 
treated with appropriate electrolyte repletion. Once the underlying abnormality is corrected and 
the ECG abnormalities have reversed, treatment may continue under careful monitoring and with 
appropriate dose modification for diarrhea as described above.                                                     
 
8.     TREATMENT DISCONTINUATION 
8.1    Removal of Subjects From Study 
Subjects who discontinue participation in the clinical study on their own or subjects who are 
withdrawn by the investigator, for reasons other than completion of treatment, disease 
progression or toxicity, will be defined as premature withdrawals. Subjects who are not initiated 
on study drug, but sign informed consent and undergo at least some of the screening procedures 
will be considered screening failures. A record of these patients will be maintained by the study 
site. Subjects who are treated with at least one full course of NALIRIFOX will contribute to the 
intention-to-treat analyses. Any subjects that do not complete surgery will be replaced, but all 
patients will contribute to the intention-to-treat design of the study and relevant endpoints.   
8.2    Criteria For Study Treatment Discontinuation 
 
A subject will be discontinued from protocol therapy under the following circumstances: 
• Any anti-cancer therapy or medication (except study drugs), administered from screening 
until the completion of the EOT visit. 
• Any adverse event which, in the Investigator’s opinion, requires termination of the study 
medication. 
• Disease progression, unless at the discretion of the principal investigator (in collaboration 
with any co-sponsors or collaborators) continued treatment with study drug is appropriate. 
• Substantial non-compliance (>25% of missed doses accounting for delays and dose 
modifications per protocol or instructions from research team staff for Aes), with the 
requirements of the study. 
• The patient presents with a beta-HCG test consistent with pregnancy.  Pregnancy will be 
reported along the same timelines as a serious adverse event. 
• The patient uses illicit drugs or other substances that may, in the opinion of the Investigator, 
have a reasonable chance of contributing to toxicity or otherwise interfering with results. 

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• The development of a second malignancy that requires treatment, which would interfere with 
this study. 
• The patient is lost to follow-up. 
• Interruption in study drugs administration for greater than 14 days (see Dose Modification 
section). 
• Development of an intercurrent illness or situation which would, in the judgment of the 
investigator, affect assessments of clinical status and study endpoints to a significant degree. 
 
The Investigator will make every reasonable effort to keep each patient in the study unless it is in 
the patient’s best interests to discontinue participation.  If a patient is removed from the study or 
declines further participation, all EOT evaluations should be performed if the patient is willing 
and able to be assessed.  The EOT visit should occur on the date of the visit that the patient was 
removed from study or within the next 30 days.  A description of the reason(s) for withdrawal 
from the study must be recorded on the case report form (CRF).  The Investigator should also 
ensure that all patients are followed up for survival status after the Final Study Visit. 
 
Relevant visit data should be entered on the CRF and any unused study medication will be 
accounted for and returned for all patients participating in the study, even for a brief period of 
time.  Patients who discontinue following entry will have relevant information completed and 
recorded on the CRF.  All patients who discontinue because of adverse events or clinically 
significant laboratory abnormalities should be followed up until they recover or stabilize, and the 
subsequent outcome will be recorded.  If any patient should die during the trial or within 30 days 
of stopping study treatment, the Investigator will inform the UF Health Data Integrity and Safety 
Committee.   
 
8.3    Replacement of Subjects 
 
Subjects will be replaced if they have not received any doses of study drug prior to their 
discontinuing participation in the protocol for any reason.  Subjects will also be replaced if they 
do not complete surgery as listed in section 8.1.  Subjects will be replaced if they initiate a 
different, new course of anti-cancer therapy (aside from radiotherapy as described in the 
protocol, section 7.2) in the interval between the last dose of Onivyde and surgery. 
 
9.    BIOLOGICAL SPECIMENS AND CORRELATIVES 
9.1   Source of Specimens 
Blood, serum, and plasma will be collected at different time points for study evaluations. All 
specimens collected as part of this study will be labeled with a study-specific ID number distinct 
from their personal information. A master code key that links specimen ID with patient identifiers 
will be maintained in a restricted section of OnCore available only to the PI or approved study 
team delegates. A new biopsy is obtained for diagnostic reasons, the biopsy must be performed 
from a tumor site that is not the only site of measurable disease. For subjects with only one site of 
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still shows measurable disease and/or the biopsy is not expected to impact the measurability of the 
lesion. 
9.2   Correlative Studies 
Tissues and blood samples will be collected as exploratory analyses which may include but are 
not limited to biomarker, pharmacogenomic, CTC enumeration, cell-free DNA, and tumor 
mutational profile assessments in an attempt to characterize individual treatment responses and 
correlate with pathologic/radiographic response. It is also planned to utilize specimens for 
potential PDX implantation with supplemental correlative analyses to determine mechanism of 
response or resistance.  Subject tissue and blood samples collected during this study may also be 
used for additional analyses proposed and conducted by the PI and study team that cannot 
currently be anticipated. De-identified subject blood and tissue samples will be sent to Tempus to 
the following research location for testing: 600 W Chicago Ave. Ste 510, Chicago, IL 60654. 
 
Collection of biospecimens will allow these and/or other analyses to take place in a preplanned, 
but post-hoc manner. Only genetic tests that are obtained by the treating physician as part of 
routine clinical care will be disclosed to the patient by the treating physician. No genetic test 
results from the correlative analyses in this study will be disclosed. Any molecular tests 
performed as part of routine clinical care in a CLIA-approved laboratory should be made 
available through the ordering physician and are not the responsibility of the study, even if that 
information is subsequently collected and analyzed as part of the study.   
Each subject will be asked to provide stool, oral and urine microbiome samples at a minimum of 
4 time points (unless they receive radiotherapy per protocol, in which case, 5 time points), as 
noted in sections 6.2 and 6.3. Processing, storage and analyses will be conducted through the 
UFHCC Microbiome Biorepository. Biospecimens will be collected and subsequently examined 
for microbiota content and any associations with patient and tumor characteristics, treatment 
outcomes and change over time. 
9.3   Preparation, Shipment and Storage of Specimens 
 
All blood and tissue samples will be labeled with the subject’s unique study number and 
physically stored at the Clinical and Translational Science Institute (CTSI) Biorepository at the 
University of Florida. Processing, storage and analyses of microbiota specimens (stool, oral, and 
urine) will be conducted through the UFHCC Microbiome Biorepository.   During the life of the 
study, these biospecimens remain available only to the study team and only those exploratory 
analyses listed in Section 9.2 will be considered, unless added through a protocol amendment. 
For analyses that require research collaborations outside of UF, only de-identified specimens will 
be shared. Samples will be stored for the life of the study and will then be destroyed or 
transferred to a UFHCC Biospecimen bank (UFHCC Biobank; IRB201901513) for general 
research use if subjects agree to enroll in the separate banking study. 
 

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At study enrollment, all subjects will be given the option to provide permission for their blood, 
tumor tissue, and microbiota samples to be collected and stored for long-term use (i.e., beyond 
the life of this study). Thus, future research on remaining biospecimens after the study-specific 
analyses have been completed can only be considered by subjects providing their additional 
consent on an IRB-approved consent form for optional biobanking.  Future specific use of those 
biomaterials will require secondary IRB approval. At the closure of this treatment trial, any 
biospecimens remaining from subjects who have provided consent for long-term storage/use will 
be destroyed or transferred to the UFHCC Biobank. For subjects who consent to the treatment 
study, but decline secondary long-term storage, their biomaterials will be destroyed at the 
completion of the treatment trial and will not be transferred.  
 
10.   STUDY DRUG INFORMATION 
10.1  Study Drug Name 
 
Irinotecan liposomal [MM-398] (ONIVYDE®, Ipsen Biopharmaceuticals) 
10.1.1  Identification 
Nal-IRI (irinotecan liposome injection, also known MM-398) is irinotecan in the form of the 
sucrosofate salt, encapsulated in liposomes for intravenous infusion.  Nal-IRI is developed by 
Ipsen Biopharmaceuticals for intravenous administration in the management of patients with 
metastatic adenocarcinoma of the pancreas.  Nal-IRI is irinotecan in the form of the sucrosofate 
salt, encapsulated in liposomes for intravenous infusion. It will be supplied in sterile, single-use 
vials containing 10 mL of nal-IRI at a concentration of 4.3 mg/mL. nal-IRI must be stored 
refrigerated at 2 to 8°C, with protection from light. 
10.1.2  Packaging and Labeling of Nal-IRI 
 
Twenty vials of nal-IRI will be packaged in a cardboard container. The individual vials, as well 
as the outside of the cardboard container, will be labeled in accordance with local regulatory 
requirements. 
10.1.3  Drug Supply 
 
The manufacturer (or designee) will ship Study Drug to the investigational sites.  The initial 
study drug shipment will be shipped after site activation (i.e., all required regulatory 
documentation has been received by the Sponsor and a contract has been executed). Subsequent 
study drug shipments will be made after site request for resupply. 
 
10.1.4  Storage, Handling and Dispensing 
 
Nal-IRI must be stored refrigerated at 2 to 8 °C, with protection from light. Light protection is 
not required during infusion. Nal-IRI must not be frozen. Responsible individuals should inspect 

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vial contents for particulate matter before and after they withdraw the drug product from a vial 
into a syringe. They must contact the manufacturer or its designee if they notice a problem with 
the study drug.  
 
Nal-IRI must be diluted prior to administration.  
• Withdraw the calculated volume of ONIVYDE® from the vial. Dilute ONIVYDE® in 
500 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP and mix 
diluted solution by gentle inversion.  
• Allow diluted solution to come to room temperature prior to administration. 
The diluted solution is physically and chemically stable for 4 hours at room temperature (15–
25°C), but it is preferred to be stored at refrigerated temperatures (2–8°C), and protected from 
light. The diluted solution must not be frozen. Because of possible microbial contamination 
during dilution, it is advisable to use the diluted solution within 24 hours if refrigerated (2–8°C), 
and within 4 hours if kept at room temperature (15–25°C). 
 
The Investigator (or assigned designee, i.e., study pharmacist) will dispense the proper diluted 
solution to the subject to satisfy dosing requirements for this trial.   
10.1.5    Administration of Nal-IRI 
• Infuse diluted solution intravenously over 90 minutes. Do not use in-line filters. Any 
unused portion is to be discarded. 
10.1.6    Drug Ordering and Accountability 
   
The investigator and investigational site staff are responsible for maintaining an accurate 
inventory and accounting of study drug. A record of all vials of study drug received and 
administered should be maintained on an investigational drug inventory form provided by the 
sponsor / site. The following information will be recorded: 
Date and quantity of study drug received 
Date and quantity of study drug dispensed from the pharmacy per patient 
Date and quantity of study drug administered to each patient 
Date and quantity of study drug destroyed (if prepared and dispensed, but not 
administered for any reason, the study drug may not be returned to inventory) 
Date and quantity of study drug returned to sponsor, if applicable 
Each shipment of study drug will contain an invoice describing the amount of drug shipped to 
the investigational site. The information on the invoice will be verified against the actual amount 
of drug received. 
 
The study pharmacist will reconcile the information on the investigational drug inventory form 
with the actual amount of study drug remaining at each site on a routine basis. At the conclusion 
of the study, the study pharmacist will either package and ship all unused vials of study drug 
back to Ipsen Biopharmaceuticals, Inc. or destruction or document the destruction, in accordance 

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with local regulations and institutional policy. Following use, empty vials of study drug may be 
destroyed according to local regulatory and environmental requirements. A record of any such 
destruction will be placed in the investigator’s regulatory file.                                    
10.1.7    Contraindications 
Avoid the use of strong CYP3A4 inducers if possible; substitute non-enzyme–inducing therapies 
at least 2 weeks prior to initiation of nal-IRI. Avoid the use of strong CYP3A4 or UGT1A1 
inhibitors, if possible; discontinue strong CYP3A4 inhibitors at least 1 week prior to starting 
therapy. 
 
The following drugs are noted in the irinotecan prescribing information as interacting with 
irinotecan: St. John’s Wort, CYP3A4 inducing anticonvulsants (phenytoin, phenobarbital, and 
carbamazepine), ketoconazole, itraconazole, troleandomycin, erythromycin, diltiazem and 
verapamil. Treatment with these agents and any others that interact with irinotecan or 5-FU 
should be avoided.  
 
Because 5-FU interacts with warfarin, caution should be exercised if concomitant use is 
necessary. Refer to the s package inserts of 5-FU and leucovorin for any other drug interactions. 
10.1.8     Adverse Event Profile 
 
Diarrhea 
 
Irinotecan can induce both early and late forms of diarrhea that appear to be mediated by 
different mechanisms. Early diarrhea (occurring during or shortly after infusion of irinotecan) is 
cholinergic in nature. It is usually transient and only infrequently severe. It may be accompanied 
by symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and 
intestinal hyper-peristalsis that can cause abdominal cramping. For patients who experienced 
early cholinergic symptoms during the previous cycle of nal-IRI, prophylactic administration of 
atropine will be given at the discretion of the investigator. Late diarrhea (generally occurring 
more than 24 hours after administration of irinotecan) can be life threatening since it may be 
prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Late diarrhea should be 
treated promptly with loperamide, and octreotide should be considered if diarrhea persists after 
loperamide, as described in Section 5.6.1 (Therapy for Diarrhea). Loss of fluids and electrolytes 
associated with persistent or severe diarrhea can result in life threatening dehydration, renal 
insufficiency, and electrolyte imbalances, and may contribute to cardiovascular morbidity. The 
risk of infectious complications is increased, which can lead to sepsis in patients with 
chemotherapy-induced neutropenia. Patients with diarrhea should be carefully monitored, given 
fluid and electrolyte replacement if they become dehydrated, and given antibiotic support if they 
develop ileus, fever, or severe neutropenia.  
 
Neutropenia 
Deaths due to sepsis following severe neutropenia have been reported in patients treated with 
irinotecan and nal-IRI. Neutropenic complications should be managed promptly with antibiotic 
support. G-CSF may be used to manage neutropenia at the investigator’s discretion or per 
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Hypersensitivity 
Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been 
observed with irinotecan, however, have not been observed with nal-IRI to date. This could be 
due to the limited cumulative patient exposure to date of nal-IRI, or the use of appropriate 
premedication and early recognition and treatment of expected adverse events. There is 
insufficient evidence to know whether these known adverse reactions of irinotecan are also 
associated with nal-IRI. Suspected drugs should be withheld immediately and aggressive therapy 
should be given if hypersensitivity reactions occur. 
 
Colitis/Ileus 
Cases of colitis complicated by ulceration, bleeding, ileus, and infection have been observed. 
Patients experiencing ileus should receive prompt antibiotic support. 
 
Thromboembolism 
Thromboembolic events have been observed in patients receiving irinotecan-containing 
regimens; the specific cause of these events has not been determined. 
 
Pregnancy 
The pregnancy category of irinotecan is D. Women of childbearing potential should be advised 
to avoid becoming pregnant while receiving treatment with irinotecan. If a pregnancy is reported, 
treatment should be discontinued. The patient should be withdrawn from the study, and the 
pregnancy should be followed until the outcome becomes known. 
 
Patients at Particular Risk 
In clinical trials of the weekly schedule of irinotecan, it has been noted that patients with 
modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) have had a 
significantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those 
with bilirubin levels that were less than 1.0 mg/dL (50.0% [19/38] versus 17.7% [47/226]; 
p<0.001). Patients with abnormal glucuronidation of bilirubin, such as those with Gilbert’s 
syndrome, may also be at greater risk of myelosuppression when receiving therapy with 
irinotecan. 
 
Acute Infusion Associated Reactions 
Acute infusion-associated reactions characterized by flushing, shortness of breath, facial 
swelling, headache, chills, back pain, tightness of chest or throat, and hypotension have been 
reported in a small number of patients treated with liposome drugs. In most patients, these 
reactions generally resolve within 24 hours after the infusion is terminated. In some patients, the 
reaction resolves by slowing the rate of infusion. Most patients who experienced acute infusion 
reactions to liposome drugs are able to tolerate further infusions without complications. 
 
Other Anticancer Therapies 
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• 5-FU 
• Leucovorin 
• oxaliplatin 
 
Description of Combination Therapies 
A description of each anticancer therapy to be used in combination with nal-IRI is described 
below.  Please also refer to the package inserts for more details. 
 
Storage and Handling of Combination Therapies 
Refer to the country specific package inserts for details on storage and handling for 5-FU and 
leucovorin, and oxaliplatin, 
 
Packaging and Labeling of Combination Therapies 
Commercially available 5-FU and leucovorin (l + d racemic form, or the levoleucovorin l form) 
and oxaliplatin will be administered in accordance with the specific treatment regimen and 
package inserts. 
 
Potential Toxicities of Combination Therapies 
 
Potential Toxicities with 5-FU 
Stomatitis and esophagopharyngitis (which may lead to sloughing and ulceration), diarrhea, 
anorexia, nausea, emesis and leukopenia are commonly seen with treatment; alopecia and 
dermatitis, in the form of pruritic rash usually appearing on the extremities, may also be seen 
(see US package insert). Common adverse events (≥20 %) that were observed with nal- IRI in 
combination with 5-FU/LV in clinical trials considered to be related were: diarrhea, nausea, 
vomiting, decreased appetite, neutropenia, fatigue, anemia, stomatitis and pyrexia. 
 
Potential Toxicities with Oxaliplatin  
The following adverse events are relatively common (≥ 40%) with oxaliplatin treatment in 
combination with 5-FU/LV and are to be expected with the nal-IRI-containing regimen: 
peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increases in 
transaminases and alkaline phosphatase, diarrhea, fatigue, emesis, and stomatitis. In a phase 3 
study of the FOLFIRINOX regimen (5-FU/LV + irinotecan + oxaliplatin), the most common (> 
5%) Grade 3-4 adverse events were: neutropenia, fatigue, vomiting, diarrhea, thrombocytopenia, 
sensory neuropathy, anemia, elevated alanine aminotransferase (ALT) level, thromboembolism, 
and febrile neutropenia10, Grade ¾ hypersensitivity reactions, including anaphylactic reactions, 
have been observed in 2-3% of colon cancer patients receiving oxaliplatin; see package insert for 
more information.  

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11.    ADVERSE EVENTS 
11.1   Definitions 
11.1.1  Adverse Event 
 
The term “adverse event” (AE) includes any sign, symptom, syndrome, or illness that appears or 
worsens in a subject during the period of observation in the clinical study and that may impair 
the wellbeing of the subject. The term also covers laboratory findings or results of other 
diagnostic procedures that are considered to be clinically significant (e.g., that requires 
unscheduled diagnostic procedures or treatment measures, or result in withdrawal from the 
study).  An AE is therefore any unfavorable and unintended symptom or disease temporally 
associated with the administration of an investigational product, whether or not related to that 
investigational product. 
 
The adverse event may be: 
• A new illness/condition; 
• Worsening of a sign or symptom of the condition under treatment, or of a concomitant 
illness/condition; 
• An effect of the study drug; or 
• A combination of 2 or more of these factors. 
 
No causal relationship with the study drug or with the clinical study itself is implied by the use of 
the term “adverse event.” 
 
The Investigator will probe, via discussion with the subject, for the occurrence of Aes during 
each subject visit and record the information in the site’s source documents.  Aes will be 
recorded in the subject CRF.  Aes will be described by duration (start and stop dates and times), 
severity, outcome, treatment and relation to study drug, or if unrelated, the cause. 
 
Surgical procedures themselves are not adverse events; they are therapeutic measures for 
conditions that require surgery. The condition(s) for which the surgery is required may be an 
adverse event. Planned surgical measures permitted by the clinical study protocol and the 
condition(s) leading to these measures are not adverse events. 
 
When a clear diagnosis is available that explains the abnormal objective findings, this diagnosis 
will be recorded as an adverse event and not the abnormal objective findings (e.g., viral hepatitis 
will be recorded as the adverse event and not the transaminase elevation). If a definitive 
diagnosis is not available, then the sign(s) (e.g., clinically significant elevation of transaminase 
levels) or symptom(s) (e.g., abdominal pain) will be recorded as the adverse event. 
Adverse events fall into the categories “serious” and “non-serious.” 
11.1.2   Serious Adverse Event 
A serious adverse event is one that at any dose of the study drug or at any time during the period 
of observation: 

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• Results in death 
• Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
note below for exceptions) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event, defined as a medical event that may not be immediately 
life-threatening or result in death or hospitalization but, based on appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed above. Examples of 
such events include but are not limited to intensive treatment in an emergency department 
or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result 
in hospitalization. “Medically important” should be marked only if no other serious 
criteria are met. 
 
An “unexpected SAE” is any SAE for which the nature, specificity or severity is not consistent 
with the currently known adverse event profile of the investigational agent(s). 
 
NOTE: The following hospitalizations are not considered SAEs in UFHCC clinical studies: 
• a visit to the emergency room or other hospital department lasting less than 24 hours that 
does not result in admission (unless considered an “important medical event” or a 
life-threatening event) 
• elective surgery planned before signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy) 
• medical/surgical admission for purpose other than remedying ill health state that was 
planned before study entry. Appropriate documentation is required in these cases. 
• admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative). 
 
Clarification of the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). Any grade ≥ 3 adverse event per CTCAE is 
generally considered severe AE. This is not the same as “serious,” which is based on the 
outcome or action criteria usually associated with events that pose a threat to life or functioning. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
11.1.3   Non-Serious Adverse Event 
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criteria. 
11.2    Period of Observation 
 
Following the subject’s written consent to participate in the study, all SAEs must be collected, 
including those thought to be associated with protocol-specified procedures. Collection of all 
SAEs must continue until the post-op visit (or pre-op visit if the subject does not proceed with 
surgery). If applicable, SAEs must be collected that relate to any later protocol-specified 
procedure (e.g., protocol-specified resection surgery).   SAEs not related to a later protocol-
specified procedure will not be collected beyond 30 days post last dose of study treatment.  The 
investigator should notify the DISC of any SAE occurring after this time period that is believed 
to be related to the investigational product or protocol-specified procedure. 
 
The investigator will begin collecting non-serious adverse event (NSAE) information once 
administration of the investigational product is initiated. This NSAE information should also be 
collected from the start of a placebo lead-in period or other observational period intended to 
establish a baseline status for the subjects.  Treated subjects, including those who were 
prematurely discontinued from the study, will be followed for any adverse events that occur 
during the study until the post-op visit (or pre-op visit if the subject does not proceed with 
surgery).  However, after 30 days post last dose of study treatment, only unexpected AEs related 
to a protocol-specified procedure (e.g. resection surgery and associated hospitalization) will be 
reported.  If another course of anti-cancer therapy is initiated prior to the that follow-up period 
visit, collection of adverse events will no longer be performed, with the exception of events that 
may be possibly, probably, or definitely related to the investigational agent or are clinically 
significant.   
11.3   Documenting / Reporting of Adverse Events by Investigator 
 
All adverse events collected per section 11 must be fully recorded in the subject’s case record 
form. 
 
Documentation must be supported by an entry in the subject’s file.  A laboratory test abnormality 
considered clinically relevant, e.g., causing the subject to withdraw from the study, requiring 
treatment or causing apparent clinical manifestations, or judged relevant by the investigator, 
should be reported as an adverse event.  Each event should be described in detail along with start 
and stop dates, severity, relationship to investigational product, action taken and outcome. 
 
Every attempt should be made to describe the adverse event in terms of a diagnosis that 
encompasses the component signs and symptoms. If only nonspecific signs or symptoms are 
present, then these should be recorded as separate diagnoses on the pages of the case report form. 
 
All subjects who have adverse events, whether considered associated with the use of study drug 
or not, must be monitored to determine the outcome. The clinical course of the adverse event will 
be followed according to accepted standards of medical practice, even after the end of the period 
of observation, until a satisfactory explanation is found or the Principal Investigator considers it 
medically justifiable to terminate follow-up. Should the adverse event result in death, a full 

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pathologist’s report should be supplied, if possible. 
11.3.1   Assessment of Causal Relationship of Study Drug 
 
The Investigator will provide an assessment of the potential causal relationship between adverse 
events and study medication by determining whether or not there is a reasonable possibility that 
the event was caused by the study medication. The relationship or association of the adverse 
event to the study medication will be characterized as not related, probably not related, possibly 
related, probably related, or related:   
 
Not Related: There is not a temporal relationship to the study drug administration or the 
adverse event is clearly due only to the progression of the underlying disease state, intercurrent 
illness, concomitant medication, concurrent therapy or other known cause. 
 
Probably Not Related:  There is little or no chance that the study drug administration caused the 
adverse event; the event is most likely due to another competing cause, including intercurrent 
illness, progression or expression of the disease state, or a reaction to a concomitant medication 
or concurrent therapy appearing to explain the reported adverse event.  
 
Possibly Related:  The association of the adverse event with the study drug administration is 
unknown; however, the adverse event is not reasonably attributed to any other condition.  
 
Probably Related:  When a reasonable temporal relationship exists between the adverse event 
and the study drug administration; significant symptoms abate upon discontinuation of the study 
drug and there is a reasonable explanation based on known characteristics of the study drug and 
there is no clear association with preexisting disease or therapy, intercurrent illness, concurrent 
therapy or other factor(s). 
 
Related:  When the adverse event is a known side effect of the study drug or there is a temporal 
relationship to the administration of the study drug; or the adverse event reappears upon re-
administration of the study drug (rechallenge); or the significant symptoms of the adverse event 
abate upon discontinuation of the study drug (dechallenge). 
11.3.2   Intensity of Adverse Events 
 
The intensity of adverse changes in physical signs or symptoms will be graded according to the 
CTCAE version 4. For all other adverse events not described in the CTCAE, the intensity will be 
assessed by the Investigator using the following categories: 
 
Mild (Grade 1) – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
 
Moderate (Grade 2) – mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention/therapy required. 
 
Severe (Grade 3) – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible. 

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Life-threatening (Grade 4) – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable. 
 
Death (Grade 5) – the event resulted in death. 
11.3.3   Action Taken with Study Drug 
 
The action the Investigator took with study drug as a result of the event should be recorded as 
one of the following: 
 
None – No action was taken with regard to the study drug as a result of the adverse event. 
 
Interrupted – Study drug was stopped due to the adverse event, but was later resumed at the 
same dose. 
 
Dose decreased – The dose of study drug was decreased as a result of the adverse event. 
 
Permanently discontinued – The subject was withdrawn from the study due to the adverse 
event. 
 
Only one item should be chosen. If multiple actions apply, the following “worst case” scenario 
hierarchy should be used to determine the preferred entry: 
 
Discontinued > dose decreased > therapy interrupted. 
11.3.4    Definition of Outcome 
 
The outcome of the AE should be recorded as one of the following: 
 
Resolved without sequelae – The subject fully recovered from the adverse event with no 
observable residual effects. 
 
Resolved with sequelae – The subject recovered from the adverse event with observable 
residual effects. 
 
Not resolved – The adverse event was present at the time of last observation. 
 
Death – The subject died as a result of the adverse event. 
11.4   Immediately Reportable Events 
11.4.1  Serious Adverse Events 
 
Serious adverse events (SAE’s) must be documented and reported to the UFHCC DISC Safety 
Team within 5 days of learning of the event.   The SAE Report and any email correspondence 
must be kept within the study files at the study site. The site investigator is responsible for 
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Follow-up information will be submitted to the UFHCC CRO stating that this is a follow-up to 
the previously reported SAE and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not (if 
applicable), and whether the participant continued or withdrew from study participation  
 
The UFHCC Project Management Office (PMO) must also be notified of the SAE within 24 
hours of knowledge of the event by email at pmo@cancer.ufl.edu. 
 
Ipsen Biopharmaceuticals Reporting Requirements 
 
SAEs must be reported to Ipsen Biopharmaceuticals within 24 hours of knowledge of the event 
using the contact information below: 
 
Ipsen Biopharmaceuticals SAE Reporting Contact Information 
Via email: drugsafety.USA@ipsen.com  or  fax: 855-631-0644 or phone: 855-463-5127 
 
11.4.2   Other Events Requiring Immediate Reporting 
 
All pregnancies, regardless of outcome, must be reported to the UFHCC DISC, including 
pregnancies that occur in the female partner of a male study subject. All pregnancies must be 
followed to outcome. 
 
Although overdose (dose variance of >25%) and cancer are not always serious by regulatory 
definition, these events should also be reported to the DISC in an expedited manner.  In case the 
overdose did not result in any adverse event, the Investigator should report this as “overdose, no 
adverse event” on the SAE form and provide the intended amount, as well as the actual amount, 
of drug administered.  In the event of overdose or exaggerated response, appropriate supportive 
measures should be employed.  Actual treatment should depend on the severity of the clinical 
situation and the judgment and experience of the treating physician. 
 
Pregnancies and overdoses should be documented and reported per the SAE reporting guidelines 
in section 11.4.1 above. 
 
11.5   IND Safety Reports Unrelated to this Trial 
 
IND safety reports not occurring on this trial but involving the study intervention (outside SAEs) 
received from outside sources will be forwarded to participating sites for submission to their 
Institutional Review Boards per their guidelines.  

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12.    STATISTICAL METHODS 
The sections below provide an overview of the statistical considerations and analyses. 
12.1    Sample Size Determination 
For this prospective phase II pilot study, the sample size justification is based on the primary 
endpoint, the complication rate for evaluable patients who complete surgery. A sample size 
of 25 patients achieves ~80% to detect a reduction of 20% in the 30-day post-operative 
complication rate (from 30%16, 18 to 10%), using a one-sided exact test with a significance 
level of 0.05.  Assuming 10% drop-out rate, we will accrue a total of 28 patients for this 
study. The study expects a 20-month accrual period with an additional follow-up of 7 months 
after the last patient is enrolled.  The sample size calculation is conducted by PASS 16. 
12.2    Analysis of Primary Endpoint 
 
The primary analysis will use the modified Intention-to-Treat (mITT) population 
consisting of subjects who are enrolled and received any dose of study medication.  The 
mITT population will be included in summary tables of subject demographics and disease 
characteristics, and in analysis of efficacy.  Subjects who did not progress to surgery (for 
any reason) or are lost to follow-up will be censored at the day of their last objective tumor 
assessment and will be unevaluable for the primary endpoint. Subjects failing to proceed to 
surgery will be replaced, but all will support the secondary endpoints including feasibility, 
safety and correlative biologic analyses.  
 
Post-operative complications will be measured at the EOT visit 4-6 weeks after surgery.  
Complications occurring within 30 days after surgery and contributing to the primary 
endpoint are defined as hospital re-admission, death, second surgery or interventional 
procedure or major complications extending hospital stay. The proportion and its exact 
90% confidence interval of 30-day post-operative complication rate will be calculated. 
Statistical analyses will be conducted using SAS v9.4 (SAS institute, Cary, NC). 
 
12.3   Analysis of Secondary Endpoints 
            
Secondary endpoints will also be analyzed in a similarly descriptive manner.  Treatment 
completion rate is defined by the administration of all eight intended cycles of neoadjuvant 
chemotherapy.  The surgical complete resection rate (R0) will be determined from review 
of the pathology reports and inclusive of pathologic nodal status and TNM staging (AJCC 
8th Edition).  Pre-operative imaging will be compared to the baseline studies to assess 
radiographic response, in those who have RECIST measurable disease at baseline. The 
radiographic objective response rate (RR) is equal to the proportion of patients achieving a 
best overall response of partial or complete response (CR + PR), according to RECIST 
from the start of the treatment until disease progression/recurrence.  Clinical benefit rate is 
equal to the objective RR plus the proportion of patients attaining stable disease (CR + PR 
+ SD).  Patients with initially measurable disease who do not have a tumor response 
assessment for any reason will be considered non-responders and will be included in the 
denominator when calculating the response rate.  Biochemical response rate is measured as 

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the difference between baseline and maximal nadir of serum CA19-9 level.  Proportion and 
exact 95% CI based on binomial distribution will be estimated for each of the secondary 
endpoints described above. Subjects will further be characterized as those with 
normalization of CA19-9 during therapy, reduction without normalization or no reduction 
with assessment of the temporal nature of these changes and correlation to surgical 
resection rates.  Secondary and exploratory endpoints may be characterized between those 
with resectable vs. borderline resectable disease at study entry, but without any planned 
formal analyses between these two subsets. Mean and 95% CI, assuming a normal 
distribution, median (range) will be estimated for quality of life (QOL) parameters using 
the FACT-G validated patient reported outcome instrument.  
 
12.4   Analysis of Exploratory Endpoints 
 
Exploratory biomarkers and molecular assay results will be analyzed post-hoc.  These 
assessments are dependent upon funding support for determination including, but not 
limited to CTC enumeration and correlation with pathologic/radiographic response, 
pharmacogenomic determination of any relationship with toxicity/safety, tumor mutational 
profile assessments correlating with response vs. non-response as well as PDX 
development with supplemental correlative analyses to determine mechanisms of response 
and resistance. 
 
12.5   Analysis of Safety Data 
   
Safety analyses will be performed on all patients who receive any dose of study medication.  
Adverse events that occur more than 30 days after the administration of the last dose of 
treatment will not be included.  Safety evaluation will be performed based on the actual 
therapy received.  The safety and tolerability of study drug is determined by reported Aes, 
physical examinations, laboratory tests, and ECGs.  All patients will be assessed regularly 
for potential occurrence of Aes from the time that treatment starts until 30 days after the last 
dose of study therapy or 30 days post-operatively, whichever is longer.  Aes will be 
summarized with the incidence and percentage of patients with at least one occurrence of a 
preferred term (according to the most severe NCI-CTCAE Version 4.0 grade) will be 
included.  The number of Aes reported will also be summarized.  Causality (relationship to 
study drug) will be summarized separately.  Duration of AE will be determined and 
included in listings along with action taken and outcome.  Laboratory results will be 
classified according to NCI-CTCAE, Version 4.0.  Incidence of laboratory abnormalities 
will be summarized; laboratory results not corresponding to an NCI-CTCAE Version 4.0 
term will not be graded.  Laboratory toxicity shifts from baseline to worst grade will also be 
provided.  The results from physical examination and vital sign measurement will be 
tabulated. Descriptive statistics will be provided as appropriate. 
 
12.6   Enhanced AE Safety Monitoring 
 
When accrual is greater than 10 subjects, if at any time, 5 of the initial 10 treated subjects or 
50% or more of all treated subjects have experienced a non-hematologic grade >= 3,4, 5 
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definite), accrual will be temporarily suspended to this study for a review by the PI and the 
Data Integrity and Safety Committee.  Grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related” will be reviewed and monitored, to assess for the emergence of a 
previously unrecognized treatment-related adverse event. 
 
 
13.  DATA AND SAFETY MONITORING 
13.1   Data Integrity and Safety Committee 
 
This protocol will be reviewed and monitored by the University of Florida Health Cancer Center 
(UFHCC) DISC in accordance with their policies and procedures.  They will review and monitor 
study progress, toxicity, safety and other data from this trial. Questions about subject safety or 
protocol performance will be addressed with the sponsor-investigator, statistician and study team 
members. Should any major concerns arise; the DISC will offer recommendations regarding 
whether or not to suspend the trial. 
 
UFHCC DISC data and safety monitoring activities include:  
• Review of clinical trial conducted for progress and safety  
• Review of all adverse events requiring expedited reporting as defined in the protocol  
• Review of reports generated by data quality control review process  
• Notification of the sponsor-investigator of recommended action  
• Notification of sites coordinated by the UFHCC of adverse events requiring expedited 
reporting and subsequent committee recommendations for study modifications 
 
13.2    Monitoring 
 
UFHCC monitors will utilize on-site and/or remote monitoring periodically during the trial to 
determine whether sites are complying with the protocol. Source documents will be reviewed for 
verification of agreement with data as submitted via the data collection system. The site 
investigator/institution guarantee access to source documents by UFHCC or its designee and 
appropriate regulatory agencies.   
 
The trial site may also be subject to quality assurance audit by any collaborating sponsors or their 
designee as well as inspection by appropriate regulatory agencies.  
 
It is important for the site investigator and their relevant personnel to be available during the 
monitoring visits and possible audits and for sufficient time to be devoted to the process. 
13.3   Principal Investigator Responsibilities 
 
As part of the responsibilities assumed by conducting this study, the Principal Investigator (PI) 
agrees to maintain and have available for monitoring adequate case records (accurate source 
documents and CRFs) for the subjects treated under this protocol.  
 
The PI will be primarily responsible for monitoring of adverse events, protocol violations, and 
other immediate protocol issues. The study coordinator will collect information on subjects 

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enrolled through the use of electronic or paper adverse event (AE) forms, CRFs, and Informed 
Consent forms.  
14.    EMERGENCY PROCEDURES 
14.1    Emergency Contact 
In emergency situations, the treating physician should contact the Principal Investigator by 
telephone at the number listed on the title page of the protocol. 
14.2    Emergency Identification of Investigational Products 
 
This is a non-blinded, non-randomized study. Thus, there will be no need for unmasking 
procedures, and the identification of the investigational product can be made by simple inquiry to 
the investigational pharmacy. 
14.3    Emergency Treatment 
 
During and following a subject’s participation in the study, the treating physician and/or 
institution should ensure that adequate medical care is provided to a subject for any adverse 
events, including clinically significant laboratory values, related to the study. 
15.  ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS 
 
15.1   Good Clinical Practice 
 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Principal Investigator and Co-
Investigators abide by Good Clinical Practice (GCP), as described in International Conference on 
Harmonization (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki.  
 
The study will be conducted in compliance with the protocol. The protocol, any amendments, 
and the subject informed consent will receive Institutional Review Board (IRB) approval before 
initiation of the study.  
 
The Principal Investigator will conduct all aspects of this study in accordance with applicable 
national, state, and local laws of the pertinent regulatory authorities. 
 
All potential serious breaches must be reported immediately to the UFHCC DISC and IRB of 
record, if applicable. A serious breach is a breach of the conditions and principles of GCP in 
connection with the study or the protocol, which is likely to affect, to a significant degree, the 
safety or physical or mental integrity of the subjects of the study or the scientific value of the 
study. 

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15.2   Institutional Review Board 
 
Before study initiation, the investigator must have written and dated approval from the IRB for 
the protocol, consent form, subject recruitment materials/process (e.g., advertisements), and any 
other written information to be provided to subjects. The investigator should also provide the 
IRB with a copy of the Investigator Brochure or product labeling, information to be provided to 
subjects, and any updates. The investigator should provide the IRB with reports, updates, and 
other information (e.g., amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 
15.3   Delegation of Investigator Responsibilities 
 
The Principal Investigator will ensure that all persons assisting with the study are adequately 
informed about the protocol, any amendments to the protocol, the study treatments, and their 
study-related duties and functions. The Principal Investigator will maintain a list of Co-
Investigators and other appropriately qualified persons to whom he has delegated significant 
study-related duties.  
 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. This study will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct or 
fraud (e.g., loss of medical licensure; debarment). Systems with procedures that ensure the 
quality of every aspect of the study will be implemented. 
 
15.4   Subject Information and Informed Consent 
 
Before being enrolled in this clinical trial, the subject must consent to participate after the nature, 
scope, and possible consequences of the clinical study have been explained in a form 
understandable to him or her. An informed consent document that includes both information 
about the study and the consent form will be prepared and given to the subject. This document 
will contain all ICH, GCP, and locally required regulatory elements. The document must be in a 
language understandable to the subject and must specify the person who obtained informed 
consent. 
After reading the informed consent document, the subject must give consent in writing. The 
written informed consent will be obtained prior to conducting any study-related procedures or 
tests. The subject’s consent must be confirmed at the time of consent by the personally dated 
signature of the person conducting the informed consent discussions. A copy of the signed 
consent document must be given to the subject. 
The PI will retain the original signed consent document. The PI will not undertake any measures 
specifically required only for the clinical study until valid consent has been obtained. 
15.5   Confidentiality 
 

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All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual.   
 
Subjects will be told that the IRB, UF Health DISC, or regulatory authorities may inspect their 
medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in strictest confidence and in accordance with local data 
protection law. 
15.6   Protocol Amendments 
 
Once the study has started, amendments should be made only in exceptional cases.  Protocol 
amendments cannot be implemented without prior written IRB approval except as necessary to 
eliminate immediate safety hazards to subjects.  A protocol amendment intended to eliminate an 
apparent immediate hazard to subjects may be implemented immediately, provided the IRB and 
CRO are notified within five business days.   All amendments will be submitted to the IRB and 
written verification that the amendment was submitted and subsequently approved is to be 
obtained.   
 
15.7    Case Report Forms 
 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into OnCore® via standardized 
CRFs in accordance with the CTMS study calendar, using single data entry with a secure access 
account.   
An electronic case report form (eCRF) is required and must be completed for each included 
subject. The completed dataset is the sole property of UFHCC and should not be made available 
in any form to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without written permission from UFHCC. 
15.8     Record Retention 
 
Study documentation includes all eCRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical trial must be retained by the study investigator. In the case of a study 

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with a drug seeking regulatory approval and marketing, these documents shall be retained for at 
least two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
 
UF Health Cancer Center requires that all study documentation be maintained for at least 6 years 
from the date of final study publication.  No study records may be destroyed without prior 
authorization from UF. 
15.9     Sub-Site Management and Communication Plan 
 
On a weekly basis for the duration that the site has subjects on study treatment, the UFHCC 
Project Management Office will be in communication with each sub-site to receive updates on 
study and subject status.  Communication will be in the form of e-mail, phone, and weekly study 
meetings that include at least one representative from each site.  Adverse events and regulatory 
status approvals / updates will be standing agenda items at these meetings.  Once all site subjects 
are completed with the treatment phase of the study (ie., in the 5 year survival follow up phase), 
meeting frequency may be decreased. 
De-identified site data, as well as site study team records, will be reviewed (at a minimum) 
approximately every 12-16 weeks (at a minimum) to ensure accuracy and up-to-date 
certifications / local approvals are on file.  All local approval documentation by IRB or otherwise 
must be provided to UFHCC and contained in the site’s regulatory files.   
Protocol amendments with red-lined, clean versions and a summary of changes will be provided 
to sites for IRB submission.  Consent form (ICF) amendments will be provided in the study’s 
model consent and will contain tracked changes.  Updates to the local ICF must be approved by 
UFHCC PMO prior to submission to the local IRB.  Other document updates such as to the 
Investigator Brochure and lab manual must be submitted to the local IRB as per their guidelines.   
Activated secondary sites are expected to submit modifications to their local IRBs, per local 
guidelines within 4 weeks of receipt unless otherwise noted.  All approval documentation must 
be forwarded to UFHCC PMO within 2 weeks of approval.   If the IRB of record for a sub-site is 
UF-IRB-01, UFHCC PMO will submit updates on the site’s behalf with input from the sub-
site(s).  Approval will be provided via email to the sub-site(s) as soon as possible when obtained. 
The University of Florida IRB requires that all events meeting the definition of unanticipated 
problem or serious noncompliance be reported as outlined.  
Documentation of participating site’s IRB approval of annual continuing reviews, protocol 
amendments, SAE reports, and protocol deviations, regulatory violations and unanticipated 
events must be kept on file at UFHCC PMO.   
 
 

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17.  Ferrone, Cristina R., et al. Radiological and surgical implications of neoadjuvant treatment  
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      K.S., Hirose, R., Tempero, M.A. and Ko, A.H., 2016. Preoperative FOLFIRINOX for 
      borderline resectable pancreatic cancer: Is radiation necessary in the modern era of  
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20.  F. Bellanti, B. Kågedal, and O. Della Pasqua, “Do pharmacokinetic polymorphisms explain 
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21.  R. H. J. Mathijssen, R. J. van Alphen, J. Verweij, W. J. Loos, K. Nooter, G. Stoter, and A.  
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38. Wainberg ZA, Bekaii-Saab T, Boland PM, Dayyani F, Macarulla T, Mody K, Belanger B, 
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17.     APPENDICES 
 
 
 
 
 
 
 
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following page.) 
 

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Appendix A: SCHEDULE OF EVENTS 
                                      Visit: 
 
Procedure: 
SCREENING 
ON-TREATMENT 
PRE-SURGICAL7  
FOLLOW-UP/SURVIVAL9 
(Day -28 to one day prior to 
Cycle 1/ Day 1)3 
(Cycle 1/ Day 1) 
+/- 3 days 
(Cycles 2-8/ Day 1) 
+/- 3 days 
(within 4 weeks prior 
to surgery) 
(within 4-6 weeks post-op) 
Informed Consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Interim Medical History 
 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
Vital Signs1 
X 
X 
X 
X 
X 
Height  
X 
X 
X 
X 
X 
Weight  
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
FACT-G 
 
X 
X6 
X 
X 
CMP 
X 
X 
X 
X 
X 
CBC w/Diff 
X 
X 
X 
X 
X 
CA 19-9 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
Pregnancy Test (Urine)3,4 
X 
X 
X 
 
 
Diagnostic Imaging Scan/TA2,5,7 
X 
 
 
X7 
 
Microbiome Samples11 
 
X11 
X11 
X11 
X11 
ECG 
X12 
X12 
X12 
X12 
 
Administration of Study Drug 
 
X 
X 
 
 
Concomitant Medication Review 
X 
X 
X 
X10 
X10 
Adverse Event Review 
 
X 
X 
X10 
X10 
Tumor specimen8 
X 
 
 
 
X 
Research blood collection 
 
X 
X 
X 
X 
1) 
Vital signs include temperature, resting pulse, blood pressure, and respiratory rate.  
2) 
CBC/diff=complete blood count and white blood cell differential; CMP=12 item complete metabolic profile (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, alkaline phosphatase, 
AST, ALT, total bilirubin, albumin); TA= Tumor assessment 
3) 
Screening studies are repeated if there are more than 28 days prior to the initiation of study treatment; with the exception of the urine pregnancy test, which must be completed within seven days of study treatment 
initiation. 
4) 
 Pregnancy test on Day 1 of Cycles 1-8 can be either serum or urine. 
5) 
TA= Tumor assessment by RECIST. Diagnostic CT scan and/or MRI scan.  
6) 
FACT-G collected only on Day 1 of Cycles 1, 5, and 8. 
7) 
Pre-surgical imaging should be obtained within 4 weeks of administering last planned cycle (8) of chemotherapy.  In the event radiotherapy (RT) is used in the interim between chemotherapy and surgery, an additional 
pre-surgical imaging assessment may be required after RT is completed.   

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8) 
Submission of initial tumor specimen (FFPE) obtained prior to enrollment as part of diagnostic workup, as well as tumor tissue at the time of surgical resection, are both required for this study. In the event a FFPE block 
is not available at study entry, slides or cytology specimens may be acceptance with permission from the study PI. 
9) 
Subjects will be followed for overall survival approximately every 6 months for 5 years after this visit. 
10)  Adverse Events and Concomitant Medications are to be collected in accordance with sections 11.2 and  7.2.2 of this protocol, respectively.  
11)  Microbiome samples will be collected up to 5 timepoints: enrollment, after 4 cycles, at completion of chemotherapy, after completion of radiation if applicable, and at post-surgical EOT. There will be no reportable 
protocol deviation for microbiome specimens not collected or collected outside of collection window. Such variance poses no risk to patient safety or primary study endpoints. 
12) ECGs will be done at baseline and as medically indicated 

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Appendix B: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
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 to bed or chair more 
than 50% of waking hours 
40 
Disabled, requires special care and 
assistance 
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 
 
 
 
 
 
 

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Appendix C: RECIST GUIDELINES (VERSION 1.1) 
 
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumors (RECIST): Revised RECIST 
Guideline (version 1.1). 
 
Measurability of Tumor at Baseline 
Tumor lesions/lymph nodes will be categorized at baseline as measurable or non-measurable. 
Measurable disease is defined by the presence of at least 1 measurable lesion. 
 
Measurable 
Tumor lesions: Measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of: 
• 10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan (slice 
thickness ≤5 mm) 
• 10 mm caliper measurement by clinical exam (non-measurable lesions if cannot be 
accurately measured with calipers) 
• 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan thickness recommended 
to be ≤5 mm). 
 
Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measureable by reproducible imaging techniques. 
 
Special Considerations for Lesion Measurability 
Bone Lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft t issue 
components, that can be evaluated by cross sectional imaging techniques such as CT or 
MRI, can be considered measurable lesions if the soft tissue component meets the 
definition of measurability. 
• Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
• Simple cysts should not be considered as malignant lesions (neither measurable nor non-
measurable) 
• Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability. If non-cystic lesions are presented in 
the same patients, these are preferred for selection as target lesions. 

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Lesions with Prior Local Treatment: 
• Tumor lesions situated at a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are non-measurable unless there has been demonstrated 
progression in the lesion. 
 
Baseline Documentation of Target and Non-Target Lesion 
 
Target Lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Non-nodal 
target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and can be reproduced in repeated measurements. 
Measurable lymph nodes are target lesions if they meet the criteria of a short axis of ≥15 mm by 
CT scan. All measurements are to be recorded in the CRF in millimeters (or decimal fractions of 
centimeters [cm]). 
 
Non-target Lesions 
All other lesions (or sites of disease) are identified as non-target lesions (chosen based on the 
representativeness of involved organs and the ability to be reproduced in repeated measurements) 
and should be recorded at baseline. Measurement of these lesions are not required but should be 
followed as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal progression.’ In addition, it is 
possible to record multiple non-target lesions involving the same organ as a single item on the 
CRF (for example, multiple liver metastases recorded as 1 liver lesion). 
Lymph nodes with short axis ≥10 mm but <15 mm should be considered non-target lesions. 
Nodes that have a short axis <10 mm are considered non-pathological and are not recorded or 
followed. 
 
Specifications by Methods of Measurement 
 
All measurements should be recorded in metric notation, using a ruler or calipers if clinically 
assessed. 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 should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessed by clinical exam. 
 
An adequate volume of a suitable contrast agent should be given so that the metastases are 
demonstrated to best effect and a consistent method is used on subsequent examinations for any 
given patient. If prior to enrollment it is known a patient is not able to undergo CT scans with 
intravenous contrast due to allergy or renal insufficiency, the decision as to whether a non-
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CT or MRI (with or without intravenous contrast) should be used to evaluate the patient at 
baseline and follow-up should be guided by the tumor type under investigation and the anatomic 
location of the disease. 
 
Clinical Lesions: Clinical lesions will be considered measurable only when they are superficial 
and ≥10 mm diameter as assessed using calipers (for example, skin nodules). For the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size of the lesion 
is recommended. When lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may be reviewed at the end of the 
study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray when progression is an important endpoint. 
Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung. 
 
CT and MRI: CT scan is the best currently available and reproducible method to measure lesions 
selected for response assessment. Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is ≤5 mm. When CT scan have slice thickness >5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable 
in certain situations (for example, for body scans). If there is concern about radiation exposure at 
CT, MRI may be used instead of CT in selected instances. 
 
Ultrasound: Ultrasound should not be used to measure lesion size. Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a later date and, because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in the course 
of the study, confirmation by CT or MRI is advised. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques can be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
 
Tumor Markers: Tumor markers alone cannot be used to assess tumor response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete response (CR). 
 
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete response (CR) in rare cases if required by protocol (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors can 
remain). When effusions are known to be a potential adverse effect of treatment (for example, 
with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be considered if 
the measurable tumor has met criteria for response or stable disease (SD) in order to differentiate 
between response (or SD) and progressive disease (PD). 
 

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PET scan (FDG-PET, PET CT): PET is not recommended for lesion assessment. If a new lesion 
is found by PET, another assessment must be done by CT, unless the PET CT is of diagnostic 
quality. If CT is done to confirm the results of the earlier PET scan, the date of progression must 
be reported as the earlier date of the PET scan. 
 
Bone Scan: If lesions measured by bone scan are reported at baseline, it is necessary to repeat the 
bone scan when trying to identify a complete response (CR) or partial response (PR) in target 
disease or when progression in bone is suspected. 
 
Response Criteria 
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker 
results must have normalized. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameter of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (including the baseline sum if that is the smallest). 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm. The appearance of 1 or more new lesions is also considered progression. 
For equivocal findings of progression (for example, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Not Evaluable (NE): When an incomplete radiologic assessment of target lesions is performed or 
there is a change in the method of measurement from baseline that impacts the ability to make a 
reliable evaluation of response. 
 
Evaluation of Non-target Lesions 
 
Complete Response: Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological or normal in size (<10 mm short axis). 
 
Non-CR/ non-PD: Persistence of 1 or more non-target lesions and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease: Unequivocal progression of existing non-target lesions. The appearance of 
1 or more new lesions is also considered progression. 

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Not Evaluable: When a change in method of measurement from baseline occurs and impacts the 
ability to make a reliable evaluation of response. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the study treatment until 
the earliest of objective progression or start of new anticancer therapy, taking into account any 
requirement for confirmation. The patient’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. The best overall response will be calculated via an algorithm using 
the assessment responses provided by the investigator over the course of the trial. 
 
Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs. (When no 
imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point.) Table 17.2.1 provides a summary of the overall response status calculation at 
each time point for patients who have measurable disease at baseline. 
 
Table 17.2.1- Time Point Response: Patients with Target or Measureable Disease 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
   Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response;  
SD = stable disease 
 
Table 17.2.2 is to be used when patients have non-measureable disease only. 
 
Table 17.2.2- Time Point Response: Patients with Non-Target or Non-Measureable Disease 
 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluable 
No 
NE 
Unequivocal 
Yes or No 
PD 
Any 
Yes 
PD 
   Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; SD = stable disease. 
   a non-CR/non-PD is preferred over SD for non-target disease due to SD being increasingly used as an endpoint      
      for assessment in trials; to assign this category when no lesions can be measured is not advised. 

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Frequency of Tumor Re-Evaluation 
 
A baseline tumor evaluation must be performed within 4 weeks before patient begins study 
treatment. Frequency of tumor re-evaluation while on and adapted to treatment should be 
protocol-specific and adapted to the type and schedule of treatment. Normally, all target and non-
target sites are evaluated at each assessment using the same method. However, bone scans may 
need to be repeated only when CR is identified in target disease or when progression in bone is 
suspected. 
 
Duration of Response 
 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective 
progression is observed (taking as reference for PD the smallest measurements recorded on 
study). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, that is the reference for calculation of 
PD). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix D: FACT-G (VERSION 4):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix E: SUMMARY OF CHANGES FROM PROTOCOL VERSION 4.0 TO VERSION 5.0 
 
Version 4.0  
 
Eligibility was limited to subjects with borderline resectable 
carcinoma only 
 
Version 5.0  
 
Updates were made throughout to include resectable subjects, in 
addition to borderline resectable subjects. 
Affected sections include protocol synopsis, 2.1, 3.1, 4.2, and 12.3. 
 
Additionally, minor administrative edits were made to the cover 
page, protocol signature page, and to clarify that OnCore is UF’s 
Clinical Trial Management System in section 5. 
 
Below text in 12.1 was replaced: 
For this prospective phase 2 pilot study, a total of 28 evaluable 
patients will be needed to achieve the primary endpoint. Evaluable 
patients are defined as those who complete surgery. This is based on 
the assumption of a 66% reduction (HR 0.34) in the 30-day post-
operative complication rate from 30% (historical data) to 10% 
(expected). (alpha = 0.05; beta = 0.20), using a one-sided exact test 
of binomial proportion. The study assumes a 20-month accrual 
period with an additional follow-up of 7 months after the last patient 
is enrolled.  This pilot phase II study and this sample size, while not 
definitive, will allow determination of safety, feasibility, 
compliance, toxicity, and generation of robust clinicopathologic 
outcome assessment to serve as a benchmark control for subsequent 
comparative studies. 
 
Section 12.1 now reads: 
For this prospective phase II pilot study, the sample size justification 
is based on the primary endpoint, the complication rate for evaluable 
patients who complete surgery. A sample size of 25 patients 
achieves ~80% to detect a reduction of 20% in the 30-day post-
operative complication rate (from 30% to 10%), using a one-sided 
exact test with a significance level of 0.05.  Assuming 10% drop-out 
rate, we will accrue a total of 28 patients for this study. The study 
expects a 20-month accrual period with an additional follow-up of 7 
months after the last patient is enrolled.  The sample size calculation 
is conducted by PASS 16. 
 
Note: The Sample Size Considerations section of the synopsis was 
also updated to reflect this change. 
Below text in Section 12.2 was removed: 
Statistical analyses will be conducted by the study biostatistician 
using SAS v9.1 (SAS institute, Cary, NC). 
 
Below text in Section 12.2 was added: 
The proportion and its exact 95% confidence interval of 30-day 
post-operative complication rate will be calculated. Statistical 
analyses will be conducted using SAS v9.4 (SAS institute, Cary, 
NC). 

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Below text in 12.3 was replaced: 
The number of patients achieving a response will be divided by the 
total of patients treated to yield the proportion responding.  Exact 
confidence bounds (95% CI) will be calculated.  Proportion and 
exact confidence boundaries (95% CI) will be estimated for toxicity 
and compliance with therapy.  Similar calculations will be 
performed for the biochemical response rate measured as the 
difference between baseline and maximal nadir of serum CA19-9 
level.  Subjects will further be characterized as those with 
normalization of CA19-9 during therapy, reduction without 
normalization or no reduction with assessment of the temporal 
nature of these changes and correlation to surgical resection rates.  
Secondary and exploratory endpoints may be characterized between 
those with resectable vs. borderline resectable disease at study entry, 
but without any planned formal analyses between these two subsets. 
Mean and 95% confidence interval will be estimated for quality of 
life (QOL) parameters using the FACT-G validated patient reported 
outcome instrument. 
Section 12.3 now reads: 
Biochemical response rate is measured as the difference between 
baseline and maximal nadir of serum CA19-9 level.  Proportion and 
exact 95% CI based on binomial distribution will be estimated for 
each of the secondary endpoints described above. Subjects will 
further be characterized as those with normalization of CA19-9 
during therapy, reduction without normalization or no reduction with 
assessment of the temporal nature of these changes and correlation 
to surgical resection rates.  Secondary and exploratory endpoints 
may be characterized between those with resectable vs. borderline 
resectable disease at study entry, but without any planned formal 
analyses between these two subsets. Mean and 95% CI, assuming a 
normal distribution, median (range) will be estimated for quality of 
life (QOL) parameters using the FACT-G validated patient reported 
outcome instrument. 
 
 
 

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Appendix F: SUMMARY OF CHANGES FROM PROTOCOL VERSION 5.0 TO VERSION 5.1 
 
Version 5.0  
 
Version 5.1  
 
Clarifications throughout  
• Updated the chemotherapy regimen name from “FOLNal-IRINOX” to 
“NAPOLI-OX” to be in better alignment with the nomenclature that the rest 
of the field is moving towards.  This will help keep the study results relevant 
when published. 
• Survival follow up was required in previous versions, but this version notes 
these visits throughout to be more clear about when study participation ends 
(and be consistent with the ICF). 
 
Eligibility Criteria 
Inclusion criteria E included guidelines for 
determining “borderline resectable” or “resectable.”  
 
The ultimate determination of whether a potential subject meets the criteria of 
“resectable or borderline resectable” lies in the consensus of the UF GI 
Multidisciplinary Tumor Board, or equivalent body (if applicable for external sites). 
The Inclusion Criteria E as previously written contained current guidance for this 
determination, but this guidance is not comprehensive, is subject to change based on 
most up-to-date best practices, and is not at any point intended to supercede the 
consensus decision of “resectable or borderline resectable” as documented by the 
tumor board.  Language was updated to clarify. 
 
Section 7.2.4 Radiotherapy 
Section 7.2.4 now explicitly allows proton therapy upon review of the case and at the 
discretion of the PI.  The section also clarifies the update to the schedule of events 
which notes that, in the event radiotherapy (RT) is used in the interim between 
chemotherapy and surgery, an additional pre-surgical imaging assessment may be 
required after RT is completed.   
 
Section 12.6 absent 
Section 12.6 now reads: 
12.6   Enhanced AE Safety Monitoring 
When accrual is greater than 10 subjects, if at any time, 5 of the initial 10 treated 
subjects or 50% or more of all treated subjects have experienced a non-hematologic 
grade >= 3, 4, 5 adverse event considered at least possibly related to treatment 
(possible, probable, or definite), accrual will be temporarily suspended to this study 

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for a review by the PI and the Data Integrity and Safety Committee.  We will review 
Grade 4 and 5 adverse events deemed “unrelated” or “unlikely to be related,” to 
assess for the emergence of a previously unrecognized treatment-related adverse 
event. 
Section 15.9 absent 
 
Section 15.9 now reads: 
On a weekly basis for the duration that the site has subjects on study treatment, the 
UFHCC Project Management Office will be in communication with each sub-site to 
receive updates on study and subject status.  Communication will be in the form of e-
mail, phone, and weekly study meetings that include at least one representative from 
each site.  Adverse events and regulatory status approvals / updates will be standing 
agenda items at these meetings.  Once all site subjects are completed with the 
treatment phase of the study (ie, in the 5 year survival follow up phase), meeting 
frequency may be decreased. 
De-identified site data, as well as site study team records, will be reviewed (at a 
minimum) approximately every 12-16 weeks (at a minimum) to ensure accuracy and 
up-to-date certifications / local approvals are on file.  All local approval 
documentation by IRB or otherwise must be provided to UFHCC and contained in 
the site’s regulatory files.   
Protocol amendments with red-lined, clean versions and a summary of changes will 
be provided to sites for IRB submission.  Consent form (ICF) amendments will be 
provided in the study’s model consent and will contain tracked changes.  Updates to 
the local ICF must be approved by UFHCC PMO prior to submission to the local 
IRB.  Other document updates such as to the Investigator Brochure and lab manual 
must be submitted to the local IRB as per their guidelines.   
Activated secondary sites are expected to submit modifications to their local IRBs, 
per local guidelines within 4 weeks of receipt unless otherwise noted.  All approval 
documentation must be forwarded to UFHCC PMO within 2 weeks of approval.   If 
the IRB of record for a sub-site is UF-IRB-01, UFHCC PMO will submit updates on 
the site’s behalf with input from the sub-site(s).  Approval will be provided via email 
to the sub-site(s) as soon as possible when obtained. The University of Florida IRB 
requires that all events meeting the definition of unanticipated problem or serious 
noncompliance be reported as outlined.  

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Documentation of participating site’s IRB approval of annual continuing reviews, 
protocol amendments, SAE reports, and protocol deviations, regulatory violations and 
unanticipated events must be kept on file at UFHCC PMO. 
Appendix A: Schedule of Events 
Update footnote to clarify that “In the event radiotherapy (RT) is used in the interim 
between chemotherapy and surgery, an additional pre-surgical imaging assessment 
may be required after RT is completed.”  
 
 
 
 

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Appendix G: SUMMARY OF CHANGES FROM PROTOCOL VERSION 5.1 TO VERSION 5.2 
 
Version 5.1  
 
Version 5.2  
 
Updated name of chemotherapy regimen 
• Updated the chemotherapy regimen name from “FOLNal-IRINOX” to 
“NAPOLI-OX” to NALIRIFOX as indicated by the sponsor (Ipsen) 
Section 12.1 
• Added references for the estimation of 30% post-operative complication rate  
based on historical data 
Section 12.2 
• Corrected 95% to 90%, to specify that the 30-day post-operative complication 
rate and its 90% exact confidence interval (CI) will be calculated. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix H: SUMMARY OF CHANGES FROM PROTOCOL VERSION 5.2 TO VERSION 5.3 
 
Version 5.2 
 
Version 5.3  
 
Cover Page 
• Added NCT # 
Protocol Synopsis 
4.1 Inclusion Criteria 
• Updated inclusion criteria to include bilirubin 1.5 ULN, with values trending 
down 
Protocol Synopsis 
Section 2.3 
• Added microbiota samples as an exploratory objective 
Sections 6.2, 6.3, 9.2, 9.3 
• Added Microbiota collection information 
Section 7.2.2 
• Added routine pre-treatment Supportive Care meds need not be captured 
Section 8.3 
• Updated replacement of subjects criteria to include anti-cancer therapy 
addition. 
Section 9.2 
• Added Tempus as a research location for sending de-identified samples for 
analysis. 
Section 10 
• Updated Ipsen name to Ipsen Biopharmaceuticals 
Appendix A Footnote 8 
• Added FFPE block study entry guidelines 
Appendix A Footnote 10 
• Added AE and Concomitant Medications collection clarifications after end of 
treatment. 
Appendix A Footnote 11 
• Added microbiome collection timepoints. 
 

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Appendix I: SUMMARY OF CHANGES FROM PROTOCOL VERSION 5.3 TO VERSION 6 
 
Version 5.3 
 
Version 6 
 
Title Page 
• Added Dr. Sherise Rogers as Junior PI 
Protocol Synopsis, Section 4.2, 4.3 
• Updated reproductive risk contraceptive timeline based on IBv15 
Section 1.4 Table B 
• Deleted NCT02785068 study  
Section 1.4.2  
• Added results of NCT 02551991 study 
Section 6.1, 6.2, 6.3, Appendix A 
• Updated so ECGs past baseline/screening will only be performed if medically 
indicated, and to document any abnormalities at the screening ECG 
Sections 6.4, 9.2, Appendix A Footnote 11 
• Added Microbiota collection information 
Section 7.2.2, 11.2, 11.3, Appendix A Footnote 10 
• Updated collection of Concomitant Medications and Adverse Events after 30 
days post last dose to capture complications of surgery 
Section 7.3  
• Added language that Oxaliplatin may be discontinued while subject remains 
on study 
Section 16 
• Added reference #38 for NCT 02551991 study 
Appendix A Footnote 2 
• Removed uric acid, added albumin