Conditions: Resectable Pancreatic Ductal Adenocarcinoma
Keywords: Pancreatic Cancer Resectable
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 48
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the rate of pathologic complete response to neoadjuvant FOLFIRINOX in patients with resectable pancreatic cancer using a tissue collection component.

Detailed description:

Arms:
arm 1: FOLFIRINOX consists of the following combination of drugs:

1. Oxaliplatin, 85 mg/m2, IV over 2 hours prior to irinotecan, administered on days 1 and 15 of each 28 day cycle
2. Leucovorin, 400 mg/m2, IV over 2 hours with irinotecan, administered on days 1 and 15 of each 28 day cycle
3. Irinotecan, 180 mg/m2, IV over 90 minutes with leucovorin, administered on days 1 and 15 of each 28 day cycle
4. 5 FU, 400 mg/m2, IV bolus over 2 minutes after irinotecan, administered on days 1 and 15 of each 28 day cycle.
5. 5FU, 2400 mg/m2, IV infusion over 46 hours after 5FU bolus injection, administered on days 1 and 15 of each 28 day cycle.

Interventions: intervention 1: FOLFIRINOX
Intervention descriptions: intervention 1: FOLFIRINOX consists of the following combination of drugs:

1. Oxaliplatin, 85 mg/m2, IV over 2 hours prior to irinotecan, administered on days 1 and 15 of each 28 day cycle
2. Leucovorin, 400 mg/m2, IV over 2 hours with irinotecan, administered on days 1 and 15 of each 28 day cycle
3. Irinotecan, 180 mg/m2, IV over 90 minutes with leucovorin, administered on days 1 and 15 of each 28 day cycle 4.5 FU, 400 mg/m2, IV bolus over 2 minutes after irinotecan, administered on days 1 and 15 of each 28 day cycle.

5.5FU, 2400 mg/m2, IV infusion over 46 hours after 5FU bolus injection, administered on days 1 and 15 of each 28 day cycle.

Protocol document:
Prot_SAP_000.pdf: 
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A Phase II Study of Neoadjuvant FOLFIRINOX in Patients with Resectable Pancreatic 
Ductal Adenocarcinoma with Tissue Collection 
Protocol Number: 
IUCRO-0473 
Principal Investigator: 
Amikar Sehdev, M.D. 
Indiana University School of Medicine 
Department of Surgery 
545 Barnhill Drive, EH 543 
Indianapolis, IN 46202 
Phone: 317-274-0339 
Email: asehdev@iupui.edu 
Study Statistician: 
Susan Perkins, Ph.D. 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................................................................................... 4 
SCHEMA............................................................................................................................................................. 6 
1. 
BACKGROUND & RATIONALE..................................................................................................................... 6 
1.1 
RATIONALE FOR NEOADJUVANT THERAPY IN PDAC ..................................................................................................... 6 
1.2 
NEOADJUVANT THERAPY IN PDAC: (GEMCITABINE AND 5-FU +/- XRT)......................................................................... 7 
1.3 
NEOADJUVANT THERAPY: (FOLFIRINOX AND NAB-PACLITAXEL) ................................................................................... 7 
1.4 
STUDY RATIONALE ................................................................................................................................................ 8 
2. 
OBJECTIVES ............................................................................................................................................... 8 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................................. 8 
2.2 
SECONDARY OBJECTIVES ........................................................................................................................................ 8 
2.3 
TERTIARY OBJECTIVES............................................................................................................................................ 9 
2.4 
CORRELATIVE OBJECTIVES ...................................................................................................................................... 9 
3. 
OUTCOME MEASURES ............................................................................................................................... 9 
3.1 
PRIMARY OUTCOME MEASURE ............................................................................................................................... 9 
3.2 
SECONDARY OUTCOME MEASURES .......................................................................................................................... 9 
3.3 
TERTIARY OUTCOME MEASURES ............................................................................................................................. 9 
3.4 
CORRELATIVE OUTCOME MEASURES ........................................................................................................................ 9 
4. 
ELIGIBILITY CRITERIA ................................................................................................................................. 9 
4.1 
INCLUSION CRITERIA ............................................................................................................................................. 9 
4.2 
EXCLUSION CRITERIA ........................................................................................................................................... 10 
5. 
STUDY DESIGN ......................................................................................................................................... 11 
6. 
PATIENT REGISTRATION ........................................................................................................................... 11 
7. 
TREATMENT PLAN .................................................................................................................................... 11 
7.1 
TREATMENT DOSAGE AND ADMINISTRATION ........................................................................................................... 11 
7.2 
RECOMMENDED PRE-MEDICATIONS/PRECAUTIONS AND HYDRATION ........................................................................... 13 
7.3 
CONCOMITANT MEDICATIONS .............................................................................................................................. 13 
8. 
TOXICITIES TO BE MONITORED/DOSAGE MODIFICATIONS ........................................................................ 13 
9. 
STUDY PROCEDURES ................................................................................................................................ 17 
9.1 
EUS OR CT-GUIDED BIOPSY PROCEDURE................................................................................................................ 17 
9.2 
SURGICAL RESECTION .......................................................................................................................................... 17 
10. STUDY CALENDAR ....................................................................................................................................... 19 
11. 
CRITERIA FOR EVALUATION/REMOVAL FROM STUDY ............................................................................... 20 
11.1 
MEASURABLE ............................................................................................................................................... 20 
11.2 
NEW LESIONS ............................................................................................................................................... 20 
11.3 
EVALUATION OF BEST OVERALL RESPONSE ........................................................................................................... 20 
11.4 
METHODS OF MEASUREMENT ......................................................................................................................... 21 
11.5 
CRITERIA FOR REMOVAL FROM TREATMENT......................................................................................................... 22 
12. 
CORRELATIVE SAMPLE COLLECTION & ASSESSMENT, ANALYSIS ................................................................ 22 
12.1 
TISSUE COLLECTION ....................................................................................................................................... 22 
12.2 
BLOOD COLLECTION ....................................................................................................................................... 23 
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12.3 
NEXT GENERATION SEQUENCING METHODS (BLOOD AND TISSUE) .......................................................................... 23 
12.3 
ASSESSMENTS ............................................................................................................................................... 24 
12.4 
STUDY IDENTIFIERS ........................................................................................................................................ 24 
13. 
DRUG INFORMATION ............................................................................................................................... 24 
13.1 
OXALIPLATIN (ELOXATIN®) .............................................................................................................................. 24 
13.2 
IRINOTECAN (CAMPTOSAR®) ........................................................................................................................... 28 
13.3 
5FU............................................................................................................................................................ 30 
13.4 
LEUCOVORIN ................................................................................................................................................ 32 
14. 
STATISTICAL METHODS ............................................................................................................................ 33 
14.1 
SAMPLE SIZE ANALYSIS AND ACCRUAL................................................................................................................. 33 
14.2 
ANALYSIS DATASETS ....................................................................................................................................... 33 
14.3 
STATISTICAL ANALYSIS PLAN ............................................................................................................................. 33 
14.4 
CRITERIA FOR STOPPING STUDY ......................................................................................................................... 35 
15. 
DATA FORMS AND SUBMISSION SCHEDULE .............................................................................................. 35 
16. 
PATIENT CONSENT AND PEER JUDGMENT ................................................................................................ 35 
17. DATA AND SAFETY MONITORING ................................................................................................................ 36 
17.1 
DATA SAFETY MONITORING COMMITTEE ........................................................................................................... 36 
17.2 
DATA AND SAFETY MONITORING PLAN .............................................................................................................. 36 
18. 
REPORTING ADVERSE EVENTS .................................................................................................................. 38 
18.1 
DEFINITIONS OF ADVERSE EVENTS .................................................................................................................... 38 
18.2 
ADVERSE EVENT (AE) REPORTING .................................................................................................................... 40 
18.3 
RECORD RETENTION ....................................................................................................................................... 40 
20. 
REFERENCES ............................................................................................................................................. 40 
21. 
APPENDICES ............................................................................................................................................. 43 
APPENDIX I ................................................................................................................................................................. 43 
APPENDIX II ................................................................................................................................................................ 44 
APPENDIX III ............................................................................................................................................................... 45 
APPENDIX IV ............................................................................................................................................................... 46 
APPENDIX V ................................................................................................................................................................ 48 
 
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LIST OF ABBREVIATIONS 
 
Abbreviations 
Full Text 
5-FU 
5-Fluorouracil 
ATIII 
antithrombin III  
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANA 
antinuclear antigen  
AST 
Aspartate aminotransferase 
BP 
Blood pressure 
CA19-9 
Carbohydrate antigen 19-9 
CR 
Complete response 
CRO 
Clinical research office 
CRT 
Combined chemoradiation 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse 
Events 
CTSI 
Clinical and Translational Sciences Institute 
DCR 
Disease control rate 
DFS 
Disease free survival 
DSMC 
Data Safety Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDTA 
Ethylenediaminetetraacetic acid  
EUS 
Endoscopic ultrasound 
FAACT 
Functional Assessment of Anorexia/Cachexia 
Therapy 
FDP 
fibrogen degradation products 
FNA 
Fine needle aspirate 
FOLFIRINOX 
5-FU, leucovorin, irinotecan and oxaliplatin 
G-CSF 
Prophylactic filgrastim 
GGT 
Gamma-Glutamyl Transferase 
HFSR 
Hand Food Skin Reaction 
HIPAA 
Health Insurance Portability and 
Accountability Act 
HUS 
Hemolytic uremic syndrome 
IRB 
Institutional Review Board 
IV 
Intravenous 
ITT 
Intention to treat 
IUSCC 
Indiana University Simon Cancer Center 
LAPC 
locally advanced pancreatic cancer  
Mg 
Milligram 
mOS 
Mean overall survival 
MRI 
Magnetic resonance imaging 
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MRN 
Medical record number 
N 
Nausea 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NGS 
Next generation sequencing 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PAC 
Protocol Accrual Committee 
PD 
Progressive disease 
PDAC 
Pancreatic Ductal Adenocarcinoma 
PFS 
Progression free survival 
PG-SGA 
Scored Patient-Generated Subjective Global 
Assessment 
PO 
Oral 
PR 
Partial response 
PRN 
As needed 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RF 
rheumatoid factor  
RR 
Response rate 
SAE 
Serious Adverse Event 
SBRT 
stereotactic body radiotherapy  
SD 
Stable disease 
TTP 
thrombitic thrombycytopenic purpura 
ULN 
Upper limit of normal 
V 
Vomitting 
VOD 
veno-occlusive disease 
VWF 
vonWillebrand’s factor 
WOCBP 
Women of childbearing potential 
 
 
 
 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. BACKGROUND & RATIONALE 
Pancreatic Ductal Adenocarcinoma (PDAC) is the 4th leading cause of cancer related mortality in 
the USA. Approximately 45,000 Americans will be diagnosed with this disease annually and the 
majority of these patients will succumb to their disease. The incidence of PDAC has been on the 
rise for unknown reasons. Five year overall survival remains poor at 5% despite aggressive 
surgical interventions and adjuvant therapy (1). Fifteen to twenty percent of patients are 
diagnosed with locally resectable disease at the time of their initial presentation. There is no 
consensus regarding how to approach these patients, but a number of centers including Indiana 
University proceed with surgical resection first followed by adjuvant chemotherapy or 
chemoradiotherapy. Adjuvant therapy includes gemcitabine or 5-FU, based on improvement in 
disease free survival (DFS) and overall survival (OS) in patients receiving active therapy 
compared to observation alone (2). Even in patients who undergo Whipple surgery and adjuvant 
therapy, prognosis remains unfavorable with median overall survival (mOS) of less than 2 years 
(3).  As such, new approaches are needed.   
 
Long before gemcitabine was established as an option for adjuvant therapy; it was approved in 
the metastatic setting based on clinical benefit in patients who had symptomatic advanced 
disease (4). Over the last 2 decades, several combinations of gemcitabine based chemotherapy 
have failed to improve outcome in patients with metastatic disease. Recently, both 
FOLFIRINOX (5-FU, leucovorin, irinotecan and oxaliplatin) and nab-paclitaxel/gemcitabine 
were proven superior to gemcitabine alone in patients with metastatic pancreatic cancer leading 
to improvement in response rate (RR), progression free survival (PFS) and OS (5, 6).  
1.1 
Rationale for neoadjuvant therapy in PDAC 
Several lines of evidence support a neoadjuvant approach in the treatment of patients with 
pancreatic cancer (7). This is based on the rationale that 70-80 % of patients who undergo 
resection with curative intent still experience relapse shortly after their recovery; perhaps 
neoadjuvant therapy might spare these patients with an aggressive biology a surgery that may not 
alter the course of their disease (8). Additionally, neoadjuvant chemotherapy provides the 
opportunity to evaluate response to therapy “in vivo”, and spares patients with poor biology a 
New 
diagnosis of 
resectable 
PDAC 
surgical 
consultation 
EUS guided 
biopsy 
r 
e 
g 
i 
s 
t
r
a
t 
i
o
n 
 
2 cycles of 
FOLFIRINOX 
C/A/P CT 
scan with 
contrast 
surgical  
reevaluation 
SOC surgery for 
patients with 
resectable 
disease 
SOC adjuvant 
therapy for 
progressive disease 
Complete 
SOC adjuvant 
therapy  (refer 
to section 7.1) 
 
Follow-up for  
progression 
and survival 
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large and potentially morbid operation. Prior to FOLFIRINOX (RR: 31%) and nab-
paclitaxel/gemcitabine (RR: 23%), the response rate to gemcitabine as a single agent was 
reported to be in a range of 6-7 %, which was unlikely to result in a meaningful R0 resection 
rate. Additionally, up to one-third of patients who undergo surgical resection may not recover 
well enough to undergo adjuvant therapy; therefore, ensuring adequate treatment in the form of 
neoadjuvant therapy theoretically results in better delivery of therapy.  
1.2 
Neoadjuvant therapy in PDAC: (Gemcitabine and 5-FU +/- XRT) 
In earlier studies to evaluate the safety and efficacy of combined chemoradiation (CRT) in the 
neoadjuvant setting, 28 patients with resectable PDAC received concurrent 5FU based CRT (9). 
All 28 patients completed treatment and 9 required hospitalization due to gastrointestinal 
toxicity.  Further studies evaluating this combination aimed at improving the resection rate, R0 
resection and evaluating OS (10, 11). Studies revealed that patients who completed their 
preoperative therapy and underwent resection experienced longer survival compared to patients 
who had surgery first (12), or who did not undergo resection due to progression or decline in 
functional status (13, 14). A retrospective study using 5FU and cisplatin in combination with 
radiotherapy concluded that local control was achieved in preoperative chemoradiation with no 
significant difference in OS between the two groups (15). Whether this is related to ineffective 
systemic therapy (cisplatin is ineffective in the treatment of pancreatic cancer) or local control 
(which does not correlate with overall survival) is unknown.  
While cisplatin is not commonly used in the treatment algorithm for patients with pancreatic 
cancer, a randomized phase II study with preoperative gemcitabine alone versus 
gemcitabine/cisplatin concluded that the combination arm achieved higher R0 resection rate, 
higher node negative rate and improved DFS at one year (16).  
1.3 
Neoadjuvant therapy: (FOLFIRINOX and nab-paclitaxel) 
Based on the higher response rate to FOLFIRINOX compared to gemcitabine, several clinical 
trials are evaluating FOLFIRINOX in a variety of settings (resectable, borderline resectable, and 
locally advanced unresectable) and in combinations with radiation therapy including intensity 
modulated radiotherapy (IMRT) and stereotactic body radiotherapy (SBRT). In a retrospective 
review of patients with locally advanced pancreatic cancer (LAPC), 19 received FOLFIRINOX. 
Five patients (28%) underwent R0 resection, and after a course of chemoradiotherapy, 3 more 
patients underwent R0 resection, improving the resectability rate to 44%. Another retrospective 
review using modified FOLFIRINOX in patients with non-metastatic (Stage II, III) PDAC 
resulted in a 30% response rate, 13.7 months of mPFS and 17.8 months of mOS (17). The 
incidence of grade 4 neutropenia, grade 3/4 diarrhea, and fatigue were 3%, 13%, and 13%, 
respectively. Twenty-one patients with borderline resectable and LAPC were treated with 
FOLFIRINOX. Six patients (29%) required dose reductions due to toxicity. Two patients (9%) 
were unable to tolerate treatment and three patients (14%) had disease progression on treatment. 
Seven patients (33%) underwent surgical resection following treatment with FOLFIRINOX 
alone, 2 (10%) of which were initially unresectable. Two patients underwent resection following 
FOLFIRINOX and SBRT. The R0 resection rate for patients treated with FOLFIRINOX + 
SBRT was 33% (55% borderline resectable, 10% unresectable). Five patients (24%) 
demonstrated a signiﬁcant pathologic response.  
Given the manageable toxicity of the nab-paclitaxel/gemcitabine regimen, studies evaluating its 
safety and efficacy have been conducted and other studies are ongoing. In a small study, 16 
patients received nab-paclitaxel/gemcitabine for 3 weeks, with one week off schedule. Two 
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patients had progressive metastatic disease during treatment (18). Nine patients had resection; 8 
with R0 resection. One patient had a pathologic complete response (CR) and 4 near CR. In a 
similar approach, 25 patients with localized PDAC received nab-paclitaxel/gemcitabine in a 
phase II study. Twenty patients had resection with 19/20 with R0 resection. Histologic down 
staging was evident in 30% of patients achieving G3/4 pathologic response (19). A phase II 
study is currently undergoing the evaluation of this combination based on risk stratification for 
resection incorporating IMRT for patients with higher risk of local recurrence (20).  
At Indiana University, we have been administering FOLFIRINOX for patients with good 
performance status who have borderline resectable pancreatic cancer or LAPC with the intention 
of inducing tumor response to convert their disease into a resectable disease. We have 
documented 4 cases of complete pathologic responses (pCR) and 4 cases of near (CR), which is 
very unusual in pancreatic carcinoma (unpublished data). One of the aims of the current study is 
to collect pre-treatment tissues in order to identify molecular/genetic factors that predict drug 
sensitivity.  
1.4 
Study Rationale 
Adjuvant treatment with gemcitabine or 5-FU improves DFS and mOS in patients with 
resectable pancreatic cancer with median improvement in OS of 2 months over observation 
alone. Further work is needed to identify patients who will benefit from surgery and spare the 
rest extensive surgery that may not alter the course of their disease. Incorporating the new 
combinations of chemotherapy (FOLFIRINOX and nab-paclitaxel/gemcitabine) into the 
treatment of early stage pancreatic cancer might improve the resectability rate, DFS and OS; 
however, only prospective clinical trials will tell. Collecting tissues to correlate benefit from 
therapy with molecular studies and explore mechanisms of resistance will be valuable.  
This proposal differs from what has been previously published or investigated because it will be 
targeting only patients with resectable pancreatic cancer, and will have a tissue collection 
component which will provide a great opportunity for translational research.  Our study will also 
provide important safety information about the use of preoperative FOLFIRINOX that will 
provide a foundation for future chemotherapy/targeted therapy combinations in this setting. 
2. OBJECTIVES 
2.1 
Primary Objective 
To evaluate the rate of pathologic complete response to neoadjuvant FOLFIRINOX in 
patients with resectable pancreatic cancer. 
2.2 
Secondary Objectives 
1. To describe the adverse events associated with FOLFIRINOX when administered 
preoperatively in patients with resectable pancreatic cancer. 
2. To estimate the fraction of patients who can successfully undergo surgery after 
neoadjuvant chemotherapy. 
3. To estimate the overall resectability rate, rate of R0 resection, disease free survival 
(DFS), overall survival (OS), overall response rate (ORR; complete response (CR) + 
partial response (PR)), and disease control rate (DCR; CR + PR + stable disease 
(SD)) after administration of FOLFIRINOX in patients with resectable pancreatic 
cancer. 
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2.3 
Tertiary Objectives 
1. Assess changes in quality of life (global assessment and functional assessment of 
anorexia/cachexia therapy) from baseline to 4 weeks (+/- 2 weeks) post-neoadjuvant 
chemotherapy. 
2.4 
Correlative Objectives 
1. Evaluate change in CA 19-9 and other tissue markers before and after treatment and 
correlate with outcomes. 
2. Correlate pathologic tumor response with findings from next generation sequencing 
(NGS).  
3. Outcome and survival data including DFS and OS will be correlated with NGS findings 
and other future research studies. 
4. Any residual tissue and other biologic samples (blood, serum and plasma) will be stored 
for future research 
3. OUTCOME MEASURES 
3.1 
Primary Outcome Measure 
 Rate of complete pathologic response  
3.2 
Secondary Outcome Measures 
 Percentage of patients to undergo surgical resection after receiving neoadjuvant 
FOLFIRINOX 
 Disease free survival and overall survival for patients with resected pancreatic 
cancer 
3.3 
Tertiary Outcome Measures 
 Patient-Generated Subjective Global Assessment (PG-SGA) score at baseline and 
4 weeks post neo-adjuvant therapy 
 Functional Assessment of Anorexia/Cachexia Therapy (FAACT) at baseline and 
4 weeks post neo-adjuvant therapy 
3.4 
Correlative Outcome Measures 
 Tissues pre (when feasible) and post therapy will be collected and stored for 
further analysis and future research.  
 Blood pre (when feasible) and post therapy will be collected and stored for further 
analysis and future research.  
 The planned analysis will include next generation sequencing on tissues collected 
before and after therapy. These tissues will be compared to germline evaluation 
from blood samples collected from peripheral blood.  
4. ELIGIBILITY CRITERIA 
All of the following criteria must be met in order to participate in this study: 
4.1 
Inclusion Criteria 
1. ≥ 18 years old at the time of informed consent 
2. Able to provide written informed consent and HIPAA authorization 
3. ECOG performance status of 0 or 1 
4. Patient must be eligible for abdominal surgery 
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5. Cytologically or histologically confirmed adenocarcinoma of the pancreas that has 
been documented to be resectable by standardized radiographic criteria by a 
pancreatic surgeon 
6. Women of childbearing potential definition (WOCBP) must have a negative serum or 
urine pregnancy test performed within 14 days prior to initiation of FOLFIRINOX. 
Any woman (regardless of sexual orientation, having undergone a tubal ligation, or 
remaining celibate by choice) is classified as WOCBP if she meets the following 
criteria: 
a. Has not undergone a hysterectomy or bilateral oophorectomy; or 
b. Has not been naturally postmenopausal for at least 24 consecutive months (i.e. 
has had menses at any time in the preceding 12 consecutive months). 
7. WOCBP and men must agree to use adequate contraception prior, to study entry, for 
the duration of study participation, and 8 weeks after the end of treatment. 
8. Patients must have adequate organ function as defined by the following laboratory 
values at study entry: 
a. Hemoglobin ≥ 9 g/dL (transfusions are acceptable) 
b. ANC ≥ 1.5 x 109/L 
c. Platelets ≥ 100 x 109/L 
d. Creatinine ≤ 1.5 x ULN, or creatinine clearance ≥ 50 mL/min (estimated by 
Cockcroft-Gault or measured) 
e. Total bilirubin ≤ 2 x ULN    
f. AST/ALT ≤ 3 x ULN 
4.2 
Exclusion Criteria 
1. Prior therapy for pancreatic adenocarcinoma  
2. Other malignancies within the past 3 years except for the following: adequately 
treated cervical or vulvar carcinoma in situ, treated basal cell or squamous carcinoma 
of the skin, superficial bladder tumors (Ta, Tis & T1), ductal carcinoma in situ 
(DCIS) of the breast and low grade prostate cancer. Any cancer curatively treated >3 
years prior to entry with no clinical evidence of recurrence is permitted. 
3. Hypersensitivity to 5FU, oxaliplatin (or other platinum agents), irinotecan (or to their 
excipients).  
4. Participation in any investigational drug study within 4 weeks preceding the start of 
study treatment. Patients are not permitted to participate in another investigational 
drug study while being treated on this protocol.  
5. Inability to receive a port or PICC line. 
6. History of or suspected Gilbert’s Disease (testing not required if presence is not 
suspected). 
7. Baseline peripheral neuropathy/paresthesia grade > 1. 
8. Active hepatitis B, unless patient has been on antiviral agents for at least 2 months 
(baseline testing not required). 
9. Active clinically serious infections (> grade 2). 
10. Major surgery or significant traumatic injury within 8 weeks of first study drug. A 
core pancreatic or liver biopsy does not preclude the patient from the study. 
11. Unable or unwilling to discontinue use of ketoconazole or St John’s wort. Use of 
phenytoin, carbamazepine, phenobarbital, rifampin and rifabutin is discouraged, but 
not contraindicated.  If patients require phenytoin, carbamazepine or phenobarbital 
monitoring of drug levels is suggested during the study. 
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12. Pregnant or lactating women. 
13. Psychological, familial, sociological or geographical condition potentially hampering 
compliance with the study protocol and follow-up schedule; those conditions should 
be discussed with the patient before registration in the trial. 
5. STUDY DESIGN 
This is a single arm, non-randomized, open label, prospective, phase II study for patients with 
resectable pancreatic cancer. 
6. PATIENT REGISTRATION 
All patients will be registered with the Indiana University Simon Cancer Center (IUSCC) 
Clinical Trials Office (CTO). Regulatory files will be maintained by the CTO and applicable 
regulatory documents must be completed and on file prior to registration of any patients. 
Potential patients will be identified in the Oncology surgery clinic, endoscopy suite and 
pancreatic cancer referral program. 
Patients who are interested in this study at the time of their work-up and appear to be eligible for 
this trial will undergo the Informed Consent Process and be screened for eligibility. The original 
signed IRB approved Informed Consent Document and completed eligibility checklist will be 
forwarded to the CTO designee for eligibility verification and registration in the OnCore® 
database.  
The expected duration of subject participation is 8-10 months (including time for surgery and 
recovery). Accrual is expected to be approximately 2 patients per month at Indiana University 
for a yearly accrual of approximately 24 patients and a total accrual of 48 patients. The 
approximate time to complete study enrollment will be approximately 24 months. 
7. TREATMENT PLAN 
7.1 
Treatment Dosage and Administration 
Patients on this trial will be treated with neoadjuvant FOLFIRINOX for 2 cycles (1 cycle = 28 
days). Patients will receive FOLFIRINOX on an outpatient basis on days 1 and 15 of each cycle. 
Following neoadjuvant treatment, patients will undergo repeat imaging (CT or MRI) to be 
reassessed for resectability of the tumor. Further adjuvant treatment will be determined at the 
treating physician’s discretion (i.e. chemoradiotherapy or adjuvant chemotherapy). It is 
important to note that post-neoadjuvant therapy is determined by the treating physician per their 
institutional guidelines and standard of care. While this study will collect data regarding disease 
progression and survival from the post-neoadjuvant period, this protocol does not dictate post-
neoadjuvant treatment which may be done at other institutions. 
For patients with an R1 resection, any chemoradiotherapy will be included in the 24 weeks of 
perioperative therapy. Chemoradiotherapy and the timing in which it will be given will be 
determined at the treating physician’s discretion based on margin status and the patient’s 
recovery. Furthermore, patients who receive chemoradiotherapy may also receive adjuvant 
chemotherapy; however, this will be based on the treating physician’s discretion. Recommended 
radiosensitization will be through 5FU 200 mg/m2/Day continuous infusions M-F of each week 
or capecitabine 825 mg/m2 PO BID M-F for the duration of radiation therapy. Patients who 
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receive adjuvant therapy will receive treatment based upon treating physician’s discretion with a 
recommended duration of therapy lasting 6 months accounting for preoperative therapy. 
 
The neoadjuvant FOLFIRINOX regimen starting doses are: oxaliplatin 85 mg/m2, followed by 
leucovorin 400 mg/m2 given simultaneously with irinotecan 180 mg/m2, followed by 5FU 400 
mg/m2 bolus and then 2400 mg/m2 (Table 1). Patients require a PORT, PICC or other IV access 
to allow administration of 5FU via a continuous infusion pump. All agents should be 
administered within SOC drug administration guidelines. Appropriate dose modifications for 
each agent are described in Section 9.0. See drug monographs/package inserts for full details on 
each agent. 
 
Table 1: Chemotherapy Drugs and Modes of Administration** 
Agent 
Dose* 
Route 
Schedule 
Oxaliplatin 
85 mg/m2 in  
250 cc D5W 
IV  before irinotecan 
Day 1,15 of each 28 day cycle 
Leucovorin 
400 mg/m2 in 
100 cc D5W 
with irinotecan. 
IV  with irinotecan 
infusion via Y-site 
connection  
Day 1, 15 of each 28 day cycle 
Irinotecan 
180 mg/m2 in 
500 cc D5W 
with leucovorin. 
IV with leucovorin 
infusion via Y-site 
connection 
Day 1, 15 of each 28 day cycle 
5FU 
400 mg/m2  
IV bolus after 
irinotecan 
Day 1, 15 of each 28 day cycle 
5FU 
2400 mg/m2  
IV after 5FU bolus 
Day 1, 15 of each 28 day cycle 
*Dose should be recalculated for patients with > 10% weight change  
** Information contained in this table is intended to be used as a guideline for administering 
FOLFIRINOX chemotherapy, and modifications to this table can be made based upon institutional 
guidelines or physician discretion. These modifications will not be recorded as deviations for this 
protocol. 
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7.2 
Recommended Pre-medications/Precautions and Hydration 
Table 2: Recommended Pre-medications, Hydration and Prophylactic Medications* 
Agent 
Dose/Precautions 
Route 
Schedule 
Ondansetron (or 
formulary equivalent) 
24 mg 
Instruct patient to avoid 
exposure to cold (food, 
liquids, air) for 5 days 
following oxaliplatin 
PO 30 minutes prior to 
oxaliplatin 
Days 1, 15 
Dexamethasone 
12 mg 
PO 30 minutes prior to 
oxaliplatin 
Days 1, 15 
Atropine 
0.4 mg 
IV PRN for abdominal 
cramping or diarrhea 
during or after irinotecan 
Days 1, 15 
Promethazine 
25 mg 
IV q6h PRN for nausea or 
vomiting 
Days 1-28 
D5W 
100 cc/h 
IV during treatment for 
infusions in D5W + to 
flush lines between 
medications. 
Days 1, 15 
0.9% Normal Saline 
2 L 
IV prior to/during/after 
treatment 
Days 1, 15 
Loperamide (home 
instructions) 
4 mg at onset of diarrhea, 
then 2mg q2h prn until 
diarrhea stops for at least 
12 hours 
PO 
Days 1-28 
Pegafilgrastim 
6 mg 
SQ 
Days 1, 15 
* Information contained in this table is intended to be used as a guideline, and modifications including 
any additions or omissions to this table can be made based upon institutional guidelines or physician 
discretion. These changes will not be recorded as deviations for this protocol. 
 
7.3 
Concomitant Medications 
All pre-medications, medications for hydration, prophylactic medications and medications given 
as a result of an adverse event will be recorded in the OnCore® system. Growth factors may be 
utilized at the investigator’s discretion. 
 
8. TOXICITIES TO BE MONITORED/DOSAGE MODIFICATIONS 
Adverse events will be recorded for all patients beginning at C1D1 (i.e. start of neoadjuvant 
treatment) through 30 days post completion of neoadjuvant therapy or progression. 
 
Each patient will be assessed for the development of any toxicity according to the Study 
Calendar (Section 10). Toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4. Dose adjustments should be made according to 
the system showing the greatest degree of toxicity. 
 
The treating physician may use his/her best clinical judgment when determining dose 
adjustments and/or holds. Dose adjustments of each agent may be made independently of dose 
modifications of the other agents (Table 3), and are based on the specific types of toxicities 
observed (Table 4). Agents held more than 14 days for toxicity should be discontinued.  If more 
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than 2 dose reductions of a single agent in a patient are required, that agent will be discontinued.  
Once a dose reduction has been performed, no intra-patient dose re-escalation is permitted. 
Patients that have treatment delays for more than 14 days during any of the 6 cycles of 
chemotherapy should be removed from the study.  
 
Additional detailed information on the potential adverse events and risks associated with each 
agent is included in Section 13. 
 
Table 3: Dose Levels for Toxicity 
Dose Level 
Irinotecan 
5FU 
Bolus / Infusion 
Oxaliplatin 
Leucovorin* 
Starting dose  
 (level 1) 
180 mg/m2 
400/2400 mg/m2 
85 mg/m2 
400 mg/m2 
-1 
150 mg/m2 
320/2000 mg/m2 
65 mg/m2 
400 mg/m2 
-2 
120 mg/m2 
240/1600 mg/m2 
50 mg/m2 
400 mg/m2 
*If 5FU is discontinued, leucovorin is simultaneously discontinued. 
 
 
Table 4: Dose Modifications for Toxicity 
On Day 1 or Day 15 
Toxicity at any 
point during cycle  
Dose Level for Subsequent 
Administration 
Hematologic Toxicities 
If ANC <1.5 on the day of 
treatment, treatment will be delayed2 
for 1 week. Resume treatment when 
ANC ≥1.5. 
Neutropenia 
Irinotecan 
5FU 
Oxaliplatin 
Grade 2 
Maintain 
dose 
Maintain 
dose 
Maintain 
dose 
Grade 3 
↓1 dose 
level 
↓1 dose 
level 
↓1 dose 
level 
Grade 4 
↓2 dose 
levels 
↓2 dose 
levels 
↓2 dose 
levels 
Febrile neutropenia 
↓2 dose 
levels 
↓2 dose 
levels 
↓2 dose 
levels 
 
 
If platelets <75K on the day of 
treatment, delay1 treatment for 1 
week Resume treatment when 
platelets ≥75K. 
Thrombocytopenia2 
Irinotecan 
5FU 
Oxaliplatin 
≤Grade 1 
Maintain 
dose 
Maintain 
dose 
Maintain 
dose 
Grade 2-3 
↓1 dose 
level 
↓1 dose 
level 
↓1 dose 
level 
Grade 4 
↓2 dose 
levels 
↓2 dose 
levels 
↓2 dose 
levels 
 
Non-Hematologic Toxicities 
 
If mucositis is >Grade 2 on the day 
of treatment, treatment will be 
delayed1 for 1 week.  Resume 
treatment when mucositis <Grade 2. 
Consider use of mouth wash/rinse. 
Mucositis 
Irinotecan 
5FU 
Oxaliplatin 
≤Grade 2 
Maintain 
dose 
Maintain 
dose 
Maintain 
dose 
Grade 3 
Maintain 
dose 
↓1 dose 
level 
Maintain 
dose 
Grade 4 
Maintain 
dose 
↓2 dose 
levels 
Maintain 
dose 
 
 
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Table 4: Dose Modifications for Toxicity 
If diarrhea is >Grade 2, on the day 
of treatment, treatment will be 
delayed1 1 week. Once diarrhea is 
<Grade 2, proceed with dose 
adjusted per table.   
Diarrhea 
Irinotecan 
5FU 
Oxaliplatin 
Grade 2 
↓1 dose 
level 
Maintain 
dose 
Maintain 
dose 
Grade 3 
↓1 dose 
level 
↓1 dose 
level 
Maintain 
dose 
Grade 4 
↓2 dose 
levels 
↓2 dose 
levels 
↓1 dose 
level 
 
 
Electrolyte abnormalities, regardless 
of grade, do not require dose 
reductions or dose delays but should 
be corrected with aggressive 
supplementation.  
Electrolyte 
Abnormalities 
Irinotecan 
5FU 
Oxaliplatin 
Any Grade  
Maintain dose. Treating physician may 
reduce dose for grade 3-4, if deemed 
appropriate 
 
Non-Hematologic Toxicities 
On Day 1 or Day 15 
Toxicity at any point during 
cycle  
Dose Level for Subsequent 
Administration 
If HFSR is >Grade 2, 
delay1 treatment for 1 
week.  Once HFSR is 
≤Grade 2, proceed with 
dose adjusted per table.   
HFSR 
Irinotecan 
5FU 
Oxaliplatin 
≤Grade 2 
Maintain 
dose 
Maintain 
dose 
Maintain dose 
Grade 3 
Maintain 
dose 
↓1 dose 
level 
Maintain dose 
Grade 4 
Maintain 
dose 
↓2 dose 
levels 
Maintain dose 
 
 
If neuropathy Grade 2 
and persisting between 
treatments, or ≥Grade 
3, delay1 treatment for 1 
week.  Once neuropathy 
is ≤Grade 2 and not 
persisting, proceed with 
dose adjusted per table.   
Neuropathy- motor and/or 
sensory 
Irinotecan 
5FU 
Oxaliplatin 
Grade 2 and persisting 
between treatments, OR new 
onset Grade 3 resolving to 
≤Grade 2 between treatments 
Maintain 
dose 
Maintain 
dose 
↓1 dose level 
First recurrence of Grade 3 
resolving to ≤Grade 2 
between treatments 
Maintain 
dose 
Maintain 
dose 
↓1 further dose 
level (i.e. to 
dose level -2) 
Second recurrence of Grade 3 
resolving to ≤Grade 2 
between treatments, OR 
 Grade 3 persistent between 
treatments, OR any Grade 4 
Maintain 
dose 
Maintain 
dose 
Discontinue 
 
 
If bilirubin is >2mg/dL, 
delay1 treatment for 1 
week. Once ≤2mg/dL, 
proceed with dose 
adjusted per table.   
Increased Bilirubin3 
Irinotecan 
5FU 
Oxaliplatin 
>2 mg/dL 
↓2 dose 
levels 
Maintain 
dose 
Maintain dose 
>3 mg/dL 
Discontinue 
Maintain 
dose 
Maintain dose 
 
 
Hypersensitivity Reaction 
Irinotecan 
5FU 
Oxaliplatin 
 
Grade 1-2  
Maintain 
dose 
Maintain 
dose 
Hypersensitivity 
treatment PRN. 
May retreat at 
next treatment 
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Table 4: Dose Modifications for Toxicity 
day (1 or 15)  
 
≥ Grade 3  
Or if recurrent >Grade 1 
Maintain 
dose 
Maintain 
dose 
Hypersensitivity 
treatment. 
Discontinue 
permanently  
 
 
Non-Hematologic Toxicities 
Delay1 dose of 
suspected offending 
agent(s) for 1 week, 
until toxicity resolves to 
≤Grade 2, then resume 
treatment with dose 
adjusted per table.     
Other Not-
Specified4 
Irinotecan 
5FU 
Oxaliplatin 
≥ Grade 3 
↓1 dose level (if 
suspected offending 
agent) 
↓1 dose 
level 
(if 
suspected 
offending 
agent) 
↓1 dose level 
(if suspected 
offending agent) 
Grade 4 
If suspected offending 
agent, ↓1-2 dose levels. If 
attribution not known, 
then decrease all agents. 
May discontinue at PI 
discretion. 
If suspected 
offending 
agent, ↓1-2 
dose levels. 
If 
attribution 
not known, 
then 
decrease all 
agents. May 
discontinue 
at PI 
discretion.  
If suspected 
offending agent, 
↓1-2 dose 
levels. If 
attribution not 
known, then 
decrease all 
agents. May 
discontinue at PI 
discretion.   
 
1 Delay offending agent(s) as identified in table.  If have to delay treatment >14 days on any of the 6 
cycles of chemotherapy, discontinue agent(s). May continue non-offending agents per investigator 
discretion. 
 
2 If suspect hemolytic uremic syndrome (HUS) and/or thrombitic thrombycytopenic purpura (TTP), 
which is generally based on the presence of severe hemolysis, hemoglobinemia, and renal failure, draw 
the following lab tests: creatinine, BUN, CBC, INR, PTT, fibrinogen, (fibrogen degradation products 
(FDP), antithrombin III (ATIII), vonWillebrand’s factor (VWF), antinuclear antigen (ANA), 
rheumatoid factor (RF), C3, C4, CH50, antiplatelet antibodies, platelet-associated IgG, and circulating 
immune complexes; and urinalysis. In such cases, inpatient evaluation and referral to hematology are 
recommended. Oxaliplatin should be discontinued permanently. 
 
3 If any suspicion of veno-occlusive disease (VOD) of liver (including hyperbilirubinemia, ascites, 
unexplained weight gain, hepatomegaly, splenomegaly, esophageal varices, or other of signs portal 
hypertension), then hold chemotherapy. If diagnosed clinically, the discontinue chemotherapy 
completely. 
 
4 Do not adjust doses for alopecia or nausea (N) and vomiting (V) unless N&V persist for >48 hours 
despite maximum anti-emetic support. For all other ≥ Grade 3 non-hematologic toxicities not described 
above, hold suspected agent(s) and monitor toxicity at least weekly. For Grade 3 toxicities associated 
primarily with laboratory abnormalities only (e.g. elevation of ALT, AST, lipase, Grade 3 or Grade 4 
hypophosphatemia without clinical or other evidence of pancreatitis or other hepatic dysfunction (e.g. 
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Table 4: Dose Modifications for Toxicity 
concomitant elevated bilirubin), study treatment may continue without interruption if this is deemed 
medically acceptable by the investigator. 
 
9. STUDY PROCEDURES 
9.1 
EUS or CT-Guided Biopsy Procedure 
Pancreatic cancer is commonly staged by the means of endoscopic ultrasound (EUS). This is a 
standard of care procedure which includes minimal sedation and upper endoscopy. A linear 
echoendoscope will be utilized to identify the pancreatic mass. A fine needle aspirate (FNA) or 
core biopsy will be performed at the same time. As with standard practice, biopsy will be 
performed with on-site cytology review to confirm malignancy. All diagnostic biopsies must be 
reviewed by the Pathology Department per the institutional guidelines.  
 
If patients do not proceed to surgery after neoadjuvant treatment (may occur if the patient refuses 
surgery, is not eligible for surgery or has progression of disease), then an optional biopsy may be 
completed at the end of treatment. In these cases, a CT-guided biopsy will likely be performed. 
EUS biopsies are typically performed for patients who have localized disease while CT-guided 
biopsy is typically performed when metastatic disease is suspected.  
 
Biopsies may be performed prior to patient enrollment as they are standard of care for pancreatic 
cancer diagnosis. Therefore, tissue samples being stored with the Pathology Department (i.e. 
archival tissue) in lieu of fresh tissue collection may be requested after enrollment to satisfy the 
baseline tissue collection requirement of this study. Additionally, it may be difficult to 
coordinate fresh tissue collect at the time of surgical resection (see below) or biopsy; therefore, 
archival tissue may also be collected to satisfy the post-neoadjuvant treatment tissue collection 
requirement of this study. 
 
Additional details regarding tissue collection can be found in Section 12.1. 
9.2 
Surgical Resection  
Approximately 4 weeks (+/- 2 weeks) after the completion of the neoadjuvant treatment, patients 
will undergo standard of care operative exploration and complete extirpative surgery. Operative 
planning will be based on the original review of the patients’ initial (i.e. pre-treatment) staging 
CT or MRI scan and the scan obtained after completion of the neoadjuvant protocol. All patients 
will undergo two modalities of operative exploration for occult metastatic disease undetectable 
with conventional cross-sectional imaging. Prior to laparotomy, patients will undergo a formal 
two-port staging laparoscopy to exclude the presence of occult metastatic disease involving the 
liver or peritoneal surfaces. Suspicious nodules possibly representing metastatic disease will be 
biopsied to confirm a pathologic diagnosis of metastatic pancreatic adenocarcinoma. Proof of 
metastatic cancer (i.e. stage IV cancer) will exclude patients from operative resection of the 
primary pancreatic cancer. In the absence of metastatic disease detectable with staging 
laparoscopy, patients will undergo a formal laparotomy with abdominal exploration to exclude 
occult metastatic disease involving the peritoneal surfaces or liver.   
 
In the absence of occult metastatic disease, patients will undergo the planned operative procedure 
to resect the primary pancreatic adenocarcinoma completely. Based on preoperative imaging, 
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patients will undergo either a pancreatoduodenectomy (PD) or distal pancreatectomy and 
splenectomy (DPS). PD will be performed for patients with head and/or neck of pancreas 
cancers. DPS will be performed for patients with body and/or tail of pancreas cancers. PD and 
DPS will be performed according to standardized techniques which are employed routinely at 
Indiana University Hospital.  
All margins of resection will be sampled intraoperatively to ensure complete clearance. For PD, 
the neck of pancreas and bile margins will be reviewed with frozen section histopathologic 
analysis. For DPS, the proximal pancreatic margin (i.e. body or neck of pancreas) will be 
reviewed intraoperatively. Final margin status (R0 versus R1) of the resected specimens will be 
recorded in addition to the intraoperative margin status assessments. 
All complications within 30 days of operative resection will be recorded prospectively and 
comprehensively according to the data acquisition guidelines of the American College of 
Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). All patients 
undergoing pancreatectomy at Indiana University Hospital are included in the ACS-NSQIP 
database which has been modified to contain complications variables specific to pancreatic 
procedures. 
Patients will receive a routine, formal clinical evaluation by their respective surgeon as per 
institutional guidelines and standard of care. Postoperative complications will be recorded during 
this evaluation and will be treated according to standardized practices. Patients will be evaluated 
for post-operative adjuvant chemotherapy within 4-6 weeks from the date of the operation as is 
routinely done after surgery. Further adjuvant treatment will be determined at the treating 
physician’s discretion (i.e. chemoradiotherapy or adjuvant chemotherapy). 
 
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10. STUDY CALENDAR 
1 cycle = 2 treatments over 28 
days (treatments are given every 
2 weeks) 
D1=Day 1 
D15=Day 15 
Baseline1 
Cycles 
1-2 
Surgical 
Evaluation/EOT2 
Long-term 
Follow-up9 
Post-
neoadjuvant 
tx 
-28 days 
Day of Cycle 
(± 7 days) 
4 (+/- 2) weeks post 
neoadjuvant tx 
D1 
D15 
REQUIRED ASSESSMENTS 
Medical history 
X 
 
 
 
 
Height 
X 
 
 
 
 
Physical examination 
X 
X 
X 
 
 
BP, weight 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
X 
 
 
Complete metabolic panel 
X 
X 
X 
 
 
Calculated creatinine clearance 
X 
X 
X 
 
 
Platelets, ANC & Hgb 
X 
X 
X 
 
 
CA 19-9 
X 
 
 
 
 
Urine pregnancy3 
X 
 
 
 
 
AE and concomitant medication 
assessment 
X 
X 
X 
X10 
 
Overall survival 
 
 
 
 
X 
Disease progression 
 
 
 
 
X 
DISEASE ASSESSMENT 
MRI or CT chest, abdomen, 
pelvis 
X 
 
 
X5 
X4 
Surgical resection (if applicable) 
 
 
 
X 
 
TREATMENT 
Neoadjuvant FOLFIRINOX 
 
X 
X 
 
 
CORRELATIVE STUDIES 
Tissue collection 
X6 
 
 
X 
 
Blood collection 
X6 
 
 
X 
 
ASSESSMENTS 
PG-SGA questionnaire 
X7 
 
 
X8 
 
FAACT questionnaire 
X7 
 
 
X8 
 
 
Calendar Footnotes:  
1 Baseline assessments performed within 7 days of Cycle 1 Day 1 do not need to be repeated. 
2 All patients will have a surgical evaluation visit 4 (+/-2) weeks of completing or discontinuing 
neoadjuvant chemotherapy as part of their routine care. Information collected during this visit will be 
used for the EOT visit for this study. 
3 Required only for women of child-bearing potential. 
4 Disease progression will be assessed via radiology report from any MRI or CT scans done during the 
follow-up period per standard of care. 
5 Repeat imaging may be performed prior to surgical resection at the treating physician’s discretion. 
6 Whenever possible 
7 PG-SGA and FAACT assessments not completed at baseline can be completed on C1D1 as long as they 
are done before treatment begins. 
8 PG-SGA and FAACT assessments should be completed within 4 (+/-2) weeks of completing or 
discontinuing neoadjuvant chemotherapy. 
9 Follow-up for survival and disease progression will be done every 3-6 months years 1-3, every 6 months 
years 4-5, and every 12 months thereafter. 
10 May be done by telephone in lieu of an in-person visit. 
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11. CRITERIA FOR EVALUATION/REMOVAL FROM STUDY 
Definitions Associated with Response Evaluation Criteria in Solid Tumors (RECIST) version 1. 
Measurable disease - At baseline, tumor lesions/lymph nodes will be categorized 
measurable or non-measurable as follows: 
11.1 
Measurable  
Tumor lesions – Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
 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 slice thickness recommended to be no greater than 5 
mm). At baseline and in follow-up, only the short axis will be measured and followed.   
11.2 
New Lesions 
There are no specific criteria for the identification of new radiographic lesions; however, the 
finding of a new lesion should be unequivocal: i.e. not attributable to differences in scanning 
technique, change in imaging modality or findings thought to represent something other than tumor 
(for example, some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). 
This is particularly important when the patient’s baseline lesions show partial or complete 
response. For example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ 
cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline.  
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
11.3 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). 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. 
Target 
Lesions 
Non-Target 
Lesions 
New Lesion? 
Best Overall 
Response 
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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 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration”.  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  When 
the evaluation of complete response depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
11.3.1 Missing assessments and in-evaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response.  This would be most likely to happen in the case 
of PD. 
11.3.2 Definitions of Pathological Response 
Histopathologic response after neoadjuvant therapy will be evaluated according to the 
Evan’s criteria as detailed below. The evaluation includes assessment of the amount of 
variable carcinoma remaining in conjunction with cytologic changes. 
Evans’ criteria for pathologic response 
following neoadjuvant therapy (22) 
Grade 
Tumor regression 
I 
<10% to no tumor cells destroyed 
II 
IIa: 10-50% of tumor cells destroyed 
IIb: 50-90% of tumor cells destroyed 
III 
>90% of tumor cells destroyed 
IIIM: sizable pools of cellular mucin 
IV 
No viable tumor cells 
IVM: Acellular pools of mucin 
11.4 
Methods of Measurement 
Imaging based evaluation is preferred to evaluation by clinical examination.  The same imaging 
modality must be used throughout the study to measure disease.  All measurements should be 
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recorded in metric notation, using calipers if clinically assessed. All baseline evaluations should 
be performed as close as possible to the treatment start and never more than 4 weeks before the 
beginning of the treatment.  
11.4.1 CT and MRI 
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5mm or less. When CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans).  
11.4.2 Cytology and Histology 
All cytological and surgical pathology specimens will be prepared in the Indiana University 
Health Pathology Department. Cytologic and histologic techniques can be used to 
differentiate between complete and partial responses. Cytologic confirmation of the 
neoplastic nature of any effusion that appears or worsens during treatment is required when 
the measurable tumor has met response or stable disease criteria. All surgical pathologic 
specimens were re-reviewed and scored by an expert pathologist. 
11.4.3 Tumor markers 
Tumor markers alone cannot be used to assess objective tumor response. If markers are 
initially above the upper normal limit, however, they must normalize for a patient to be 
considered in complete response.  
11.5 
Criteria for removal from treatment 
A patient is considered discontinued from the study when the decision to permanently stop 
treatment is made. Patients will be removed from the study when any of the following criteria 
apply: 
Unacceptable adverse events, or change in underlying condition such that the patient can no 
longer tolerate therapy, including:  
a. Delay >14 days for administering scheduled chemotherapy due to toxicities 
b. Withdrawal of informed consent  
c. Investigator’s discretion 
d. Pregnancy 
 
This decision should be made by the principal investigator and co-investigators. The reason for 
study removal and the date the patient was removed should be documented in the electronic case 
report form (eCRF). The patient should be followed per protocol. 
12. CORRELATIVE SAMPLE COLLECTION & ASSESSMENT, ANALYSIS 
12.1 
Tissue Collection 
The collection of the pancreatic tumor tissue pre- and post-neoadjuvant treatment is an important 
part of this trial. The goal of these collections is to generate findings from next generation 
sequencing (NGS) (see 12.2.1 for more details) to predict the pathological response versus 
progression. Additionally, future, yet undetermined, research studies will be done on any unused 
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tissue samples that were collected as part of this study. The outcome and survival data will be 
correlated with next generation sequencing and other future research. 
The tissue will be obtained at the time of diagnosis as a standard of care to establish the 
diagnosis. If there is additional tissue available from the diagnostic biopsy samples, we plan on 
requesting them either at the time of biopsy (i.e. fresh tissue sample collection for patients who 
are already enrolled to this study) or from the Pathology Department (i.e. archival tissue). For 
patients who have biopsies at institutions outside of IUH, the PI and/or his designee will make 
requests for any additional tissue from those respective institutions’ pathology departments.  
After the second cycle of neoadjuvant chemotherapy, additional tumor tissue samples that would 
otherwise be discarded, will be obtained at the time of surgical resection or biopsy (if 
applicable). If patients do not proceed to surgery (may occur if the patient refuses surgery, is not 
eligible for surgery or has progression of disease), then an optional biopsy may be completed at 
the end of neoadjuvant treatment. All research tissue samples will be stored in the IUSCC Tissue 
Bank or IU CTSI Specimen Storage Facility.  
Please refer to the study laboratory manual for complete instructions regarding tissue collection, 
processing, transfer and storage. 
12.2 
Blood Collection 
Blood samples for future, yet undetermined, research studies (in addition to the blood samples 
taken as part of standard of care) will be collected prior to treatment (i.e. at baseline or C1D1 as 
long as completed before treatment begins) whenever possible and at the time of surgical 
evaluation (i.e. 4 weeks [+/-2 weeks] post neoadjuvant chemotherapy). These blood samples will 
be stored in the IUSCC Tissue Bank or IU CTSI Specimen Storage Facility.  
Please refer to the study laboratory manual for complete instructions regarding tissue collection, 
processing, transfer and storage. 
12.3 
Next Generation Sequencing Methods (Blood and Tissue) 
Genomic sequencing of samples derived from this trial will be performed at IU to ascertain 
markers of response as well as to inform future studies. From the tumor biopsies, Next-
generation DNA and RNA sequencing will be performed per available technologies at the time 
of analysis. One such method that may be used is described below. 
For each sample, DNA & RNA will be extracted from tumor biopsies along with DNA from 
matched whole blood. Briefly, 40ng of DNA will undergo a highly multiplexed PCR reaction to 
amplify all exons of 409 genes known to be mutated in cancer (Sanger Gene Census) using the 
Ion Ampliseq Comprehensive Cancer Panel. This panel is specifically designed for amplification 
of both formalin-fixed paraffin embedded samples as well fresh/frozen tissue. Subsequent to 
amplification, libraries will be sequenced on an Ion Proton Sequencer using 200bp fragment 
chemistry and an Ion Proton I chip. It is estimated that each sample will have 1500-2000X 
average coverage of each cancer gene, enabling low allele frequency somatic mutation detection. 
Each sequencing run will be evaluated for technical quality control metrics. For bioinformatics 
analysis, reads will be mapped to the human genome using the TMAP algorithm. After mapping, 
somatic variants will be called (point mutations, indels, and copy number variation), using the 
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Ion Reporter pipeline (Life Technologies). Annotation of identified variants will be performed 
by cross-referencing the following databases: NIH dbSNP, 1000 genomes project, COSMIC 
(Catalog of Somatic Mutations in Cancer), and TCGA (The Cancer Genome Atlas). 
Identification of cancer driver variants, association with therapeutic interventions, and mutational 
network analyses will be performed using Ingenuity Variant Analysis (Ingenuity Systems). All 
data and analyses will be stored on the HIPPA-compliant Indiana University Scholarly Data 
Archive. 
For expression analysis 10ng of RNA (extracted as described above) will undergo library 
preparation using the Ion Ampliseq Transcriptome Human Gene Expression Kit. This will allow 
for accurate quantitative expression of ~20,000 genes in the human genome. Standard workflow 
for gene-level expression will be conducted using Torrent Suite Version 5.0. The AmpliSeq 
Transcriptome Plugin tool will be used to generate standard expression files. 
12.3 
Assessments 
Patients will be given the following questionnaires to complete via paper or in electronic format 
(online, email, or on a tablet) prior to treatment (i.e. at baseline or C1D1 as long as completed 
before treatment begins) and at the time of surgical evaluation (i.e. 4 weeks [+/-2 weeks] post 
neoadjuvant chemotherapy). 
12.3.1 Scored Patient-Generated Subjective Global Assessment (PG-SGA) 
The Scored Patient-Generated Subjective Global Assessment (PG-SGA) includes the 
four patient-generated historical components (Weight History, Food Intake, Symptoms 
and Activities and Function), the professional part (Diagnosis, Age, Metabolic stress, 
and Physical Exam), the Global Assessment (A = well nourished, B = moderately 
malnourished or suspected malnutrition, C = severely malnourished), the total 
numerical score, and nutritional triage recommendations. Subsequently, the Scored PG-
SGA allows for triaging of specific nutrition interventions, as well as facilitating 
quantitative outcomes data collection.23 
12.3.2 Functional Assessment of Anorexia/Cachexia Therapy (FAACT) 
The Functional Assessment of Anorexia/Cachexia Therapy (FAACT) is a comprehensive 
questionnaire used for patient self-report of anorexia and appetite assessment that 
contains general core questions of the Functional Assessment of Chronic Illness 
Treatment (FACIT) plus questions about nutritional issues including appetite.24 
12.4 
Study Identifiers 
The PI will have ownership of any tissue or blood samples that are stored for future research. 
Distribution of samples will be at PI discretion; however, samples will not be sold. Any samples 
that are distributed to researchers outside of the study team, will anonymized and only identified 
by a coded number.   
13. DRUG INFORMATION 
13.1 
Oxaliplatin (Eloxatin®)  
Oxaliplatin is a platinum-based drug that forms crosslinks of guanine that inhibit DNA 
replication and transcription. Cytotoxicity is cell-cycle nonspecific. It is indicated for the 
treatment of metastatic CRC in combination with 5FU and leucovorin. 
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Supply and Supplier  
Oxaliplatin as Eloxatin® is available from Sanofi-Aventis in powder form in two strengths (50 
mg or 100 mg), and as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/ml 
in 3 sizes: 50 mg, 100 mg or 200 mg. It must be diluted prior to intravenous infusion. See Full 
Prescribing Information at:  http://products.sanofi-aventis.us/eloxatin/eloxatin.html for complete 
information. Commercially available supplies of either Eloxatin® or generic oxaliplatin will be 
used for this study.   
Preparation, Storage and Stability  
The appropriate dose of oxaliplatin (see Section 7.1) should be reconstituted, diluted and stored 
according to the package insert provided by the manufacturer and according to local 
pharmaceutical regulations. Reconstitution or final dilution must never be performed with a 
sodium chloride solution or other chloride containing solutions. 
Premedication  
Patients should be prescribed medications to prevent and treat nausea and vomiting as per 
institutional guidelines.  
Dosage and Administration  
See Section 7.1.   
Handling and Disposal 
As with other potentially toxic anticancer agents, care should be exercised in the handling and 
preparation of infusion solutions prepared from oxaliplatin. The use of gloves is recommended. If 
a solution of oxaliplatin contacts the skin, wash the skin immediately and thoroughly with soap 
and water. If oxaliplatin contacts the mucous membranes, flush thoroughly with water. Procedures 
for the handling and disposal of anticancer drugs should be considered.   
Adverse Events  
Incidence rates of adverse events associated with oxaliplatin are provided in the products’ Full 
Prescribing Information (http://products.sanofi-aventis.us/eloxatin/eloxatin.html). Some of the 
adverse events expected with oxaliplatin treatment are listed below. 
 
More than 1100 patients with stage II or III colon cancer and >4000 patients with advanced CRC 
have been treated in clinical studies with Eloxatin®.  The most common adverse reactions in 
these trials (incidence ≥ 40% of patients) were peripheral sensory neuropathy, neutropenia, 
thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, 
emesis, fatigue and stomatitis.  
 
Hematologic: When oxaliplatin was used in combination with 5FU and leucovorin in previously 
untreated advanced CRC, the percent of patients who experienced hematological toxicities (all 
grades/grade ≥3) were: anemia (27%/3%)  leukopenia (85%/20%), neutropenia (81%/53%), 
infection with grade ≥3 neutropenia (8%), febrile neutropenia (4%) and thrombocytopenia 
(71%/5%).  Epistaxis occurred in 10% of patients, versus 1% in those receiving irinotecan plus 
5FU and leucovorin. 
 
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Gastrointestinal: When oxaliplatin was used in combination with 5FU and leucovorin in 
previously untreated advanced CRC, the percent of patients who experienced gastrointestinal 
toxicities (all grades/grade ≥3) were: nausea (71%/6%), diarrhea (56%/12%), vomiting 
(41%/4%), and stomatitis (38%/0%).  Premedication with antiemetics, including 5-HT3 blockers, 
is recommended. Diarrhea and mucositis may be exacerbated by the addition of oxaliplatin to 
5FU/leucovorin, and should be managed with appropriate supportive care. Since cold 
temperature can exacerbate acute neurological symptoms, ice (mucositis prophylaxis) should be 
avoided during the infusion of oxaliplatin. 
 
Dermatologic: When oxaliplatin was used in combination with 5FU and leucovorin in previously 
untreated advanced CRC, the percent of patients who experienced hand-foot syndrome was 7%. 
 
Intravenous Site Reactions: Extravasation, in some cases including necrosis, has been reported. 
Injection site reaction, including redness, swelling, and pain, has been reported. 
 
Anticoagulation and Hemorrhage: There have been reports while on study and from post-
marketing surveillance of prolonged prothrombin time and INR occasionally associated with 
hemorrhage in patients who received oxaliplatin plus 5FU/leucovorin while on anticoagulants. 
Patients receiving oxaliplatin plus 5FU/leucovorin and requiring oral anticoagulants may require 
closer monitoring. 
Renal: About 5-10% of patients in all clinical trial groups in the oxaliplatin trials in CRC had some 
degree of elevation of serum creatinine. 
Thromboembolism: When oxaliplatin was used in combination with 5FU and leucovorin in 
previously untreated advanced CRC, the percent of patients who experienced thromboembolic 
events was 6%. 
 
The following toxicities are noted with particular Warnings and Precautions in the prescribing 
information for Eloxatin®: 
 
1. Neuropathy: Oxaliplatin is associated with two types of neuropathy: 
a. An acute, reversible, primarily peripheral, sensory neuropathy that is of early 
onset, occurring within hours or one to two days of dosing, that resolves within 14 
days, and that frequently recurs with further dosing. The symptoms may be 
precipitated or exacerbated by exposure to cold temperature or cold objects and they 
usually present as transient paresthesia, dysesthesia and hypoesthesia in the hands, feet, 
perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, 
and a feeling of chest pressure have also been observed. The acute, reversible pattern 
of sensory neuropathy was observed in about 56% of study patients who received 
oxaliplatin with 5FU/leucovorin. In any individual cycle acute neurotoxicity was 
observed in approximately 30% of patients. In adjuvant patients the median cycle of 
onset for grade 3 peripheral sensory neuropathy was 9 in the previously treated patients 
the median number of cycles administered on the oxaliplatin with 5FU/leucovorin 
combination arm was 6. 
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An acute syndrome of pharyngolaryngeal dysesthesia seen in 1–2% (grade 3/4) of 
patients previously untreated for advanced colorectal cancer, and the previously treated 
patients, is characterized by subjective sensations of dysphagia or dyspnea, without any 
laryngospasm or bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) 
should be avoided during the infusion of oxaliplatin because cold temperature can 
exacerbate acute neurological symptoms. 
b. A persistent (>14 days), primarily peripheral, sensory neuropathy that is usually 
characterized by paresthesias, dysesthesias, hypoesthesias, but may also include 
deficits in proprioception that can interfere with daily activities (e.g. writing, 
buttoning, swallowing, and difficulty walking from impaired proprioception). 
These forms of neuropathy occurred in 48% of the study patients receiving oxaliplatin 
with 5FU/leucovorin. Persistent neuropathy can occur without any prior acute 
neuropathy event. The majority of the patients (80%) who developed grade 3 persistent 
neuropathy progressed from prior Grade 1 or 2 events. These symptoms may improve 
in some patients upon discontinuation of oxaliplatin. 
Overall, neuropathy was reported in patients previously untreated for advanced 
colorectal cancer in 82% (all grades) and 19% (grade 3/4), and in the previously treated 
patients in 74% (all grades) and 7% (grade 3/4) events. Information regarding 
reversibility of neuropathy was not available from the trial for patients who had not 
been previously treated for colorectal cancer. 
The following warnings and precautions are less common but serious adverse events associated 
with oxaliplatin: 
2. Anaphylactic Reactions: These have been reported, and may occur within minutes of 
oxaliplatin administration. Epinephrine, corticosteroids, and antihistamines have been 
employed to alleviate symptoms. Grade 3/4 hypersensitivity, including 
anaphylactic/anaphylactoid reactions, to oxaliplatin has been observed in 2–3% of colon 
cancer patients. These allergic reactions which can be fatal, can occur within minutes of 
administration and at any cycle, and were similar in nature and severity to those reported 
with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, 
rarely, bronchospasm and hypotension. The symptoms associated with hypersensitivity 
reactions reported in the previously untreated patients were urticaria, pruritus, flushing of the 
face, diarrhea associated with oxaliplatin infusion, shortness of breath, bronchospasm, 
diaphoresis, chest pains, hypotension, disorientation and syncope. These reactions are usually 
managed with standard epinephrine, corticosteroid, antihistamine therapy, and may require 
discontinuation of therapy. Drug-related deaths associated with platinum compounds from 
anaphylaxis have been reported. 
3. Pulmonary Toxicity: Oxaliplatin has been associated with pulmonary fibrosis (<1% of study 
patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (any 
grade) and <1% (grade 3) with no grade 4 events in the oxaliplatin plus infusional 
5FU/leucovorin arm compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in 
the infusional 5FU/leucovorin alone arm in adjuvant colon cancer patients. In this study, one 
patient died from eosinophilic pneumonia in the oxaliplatin combination arm. The combined 
incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the 
oxaliplatin plus 5FU/leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in 
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the irinotecan plus 5FU/leucovorin arm of unknown duration for patients with previously 
untreated colorectal cancer. In case of unexplained respiratory symptoms such as non-
productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, oxaliplatin should 
be discontinued until further pulmonary investigation excludes interstitial lung disease or 
pulmonary fibrosis. 
4. Hepatotoxicity: Hepatotoxicity appears to be related to oxaliplatin combination therapy. When 
oxaliplatin was used in combination with 5FU and leucovorin in previously untreated advanced 
CRC, the percent of patients who experienced hepatotoxicity (all grades/grade ≥3) were ALT 
elevation (6%/1%), AST elevation (17%/1%), alkaline phosphatase elevation (16%/0%), and 
total bilirubin elevation (6%/1%).   In the study of oxaliplatin and 5FU/leucovorin versus 
5FU/leucovorin alone in patients with colon cancer receiving chemotherapy as adjuvant 
treatment,  hepatotoxicity was observed more frequently in the oxaliplatin arm, as evidenced 
by increases in transaminases (57% vs. 34%) and alkaline phosphatase (42% vs. 20%). The 
incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies 
include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal 
fibrosis, and veno-occlusive lesions. Hepatic vascular disorders should be considered, and if 
appropriate, should be investigated in case of abnormal liver function test results or portal 
hypertension, which cannot be explained by liver metastases. 
Drug Interactions 
No specific cytochrome P-450-based drug interaction studies have been conducted. No 
pharmcokinetic interaction between 85 mg/m2 oxaliplatin and 5FU/leucovorin has been observed 
in patients treated every 2 weeks. Increases of 5FU plasma concentrations by approximately 20% 
have been observed with doses of 130 mg/m2 oxaliplatin dosed every 3 weeks. Because 
platinum-containing species are eliminated primarily through the kidney, clearance of these 
products may be decreased by co-administration of potentially nephrotoxic compounds; 
although, this has not been specifically studied   
 
13.2 
Irinotecan (Camptosar®)  
Irinotecan hydrochloride is a semisynthetic derivative of camptothecin and is an antineoplastic 
agent of the topoisomerase I inhibitor class.  It is a prodrug of the active metabolite, SN38, that 
produces DNA breakage and cell death.(21). It is indicated for the treatment of metastatic CRC 
in combination with 5FU and leucovorin.  
Supply and Supplier 
Irinotecan as Camptosar® is available from Pfizer in single-dose amber glass vials containing 40 
mg/2 mL or 100mg/5mL, and must be diluted prior to intravenous infusion.  See Full Prescribing 
Information at: https://www.pfizeroncology.com/sites/pop/PDFs/uspi_camptosar.pdf for 
complete information. Commercially available supplies of either Camptosar® or generic 
irinotecan will be used for this study.   
Preparation, Storage and Stability 
The appropriate dose of irinotecan (see Section 7.1) should be reconstituted, diluted and stored 
according to the package insert provided by the manufacturer and according to local 
pharmaceutical regulations. 
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Premedication 
Patients should be prescribed medications to prevent and treat nausea and vomiting as per 
institutional guidelines.      
Dosage and Administration 
See Section 7.1. 
Handling and Disposal 
To minimize the risk of dermal exposure, always wear impervious gloves when handling vials 
containing irinotecan. This includes all handling activities in clinical settings, pharmacies, 
storerooms, and home healthcare settings, including during unpacking and inspection, transport 
within a facility, and dose preparation and administration.  If a solution of irinotecan contacts the 
skin, wash the skin immediately and thoroughly with soap and water.  If irinotecan contacts the 
mucous membranes, flush thoroughly with water.  Procedures for proper handling and disposal 
of anti-cancer drugs should be considered.  
Adverse Events  
Incidence rates of adverse events associated with irinotecan are provided in the products’ Full 
Prescribing Information (https://www.pfizeroncology.com/sites/pop/PDFs/uspi_camptosar.pdf). 
Some of the adverse events expected with irinotecan treatment are listed below. 
 
Nausea, vomiting and diarrhea are common adverse events following treatment with irinotecan, 
and can be severe.  When observed, nausea and vomiting usually occur during or shortly after 
infusion of irinotecan. 
 
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 is severe. It may be 
accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, 
diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Early 
diarrhea and other cholinergic symptoms may be prevented or ameliorated by administration of 
atropine.  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.  
Patients with diarrhea should be carefully monitored, should be given fluid and electrolyte 
replacement if they become dehydrated, and should be given antibiotic support if they develop 
ileus, fever, or severe neutropenia.  
 
Hepatic:  In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4 liver 
enzyme abnormalities were observed in fewer than 10% of patients.  These events typically 
occur in patients with known hepatic metastases.   
 
Hematologic: Irinotecan commonly causes neutropenia, leucopenia (including lymphocytopenia) 
and anemia.  Deaths due to sepsis following severe neutropenia have been reported in patients 
receiving irinotecan.    Individuals who are homozygous for the UGT1A1*28 allele 
(approximately 10% of North American population) are at increased risk for neutropenia 
following initiation of irinotecan treatment.  Serious thrombocytopenia is uncommon. SN-38, the 
active metabolite of irinotecan, is predominantly converted to its glucuronide metabolite, which 
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is essentially inactive, and subsequently eliminated in bile and feces. Based on this, patients with 
known defective UGT1A1 (Gilbert’s syndrome) will be excluded from this trial.   
 
Body as a Whole: Asthenia, fever, and abdominal pain are generally the most common events of 
this type. 
 
Hypersensitivity:  Hypersensitivity reactions including severe anaphylactic or anaphylactoid 
reactions have been observed. 
 
Colitis/Ileus:  Cases of colitis complicated by ulceration, bleeding, ileus, and infections have 
been observed.  Patients experiencing ileus should receive prompt antibiotic support. 
 
Renal Impairment/Renal Failure:  Rare cases of renal impairment and acute renal failure have 
been identified, usually in patients who became volume depleted from severe vomiting and/or 
diarrhea.   
 
Thromboembolism: Thromboembolic events have been observed in patients receiving irinotecan; 
the specific cause of these events has not been determined. 
 
 
Respiratory: In clinical studies, ≥Grade 3 dyspnea was reported in 4% of patients.  Of note, over 
half of these patients had lung metastases.    Interstitial pulmonary disease, which can be fatal, is 
uncommon.  Risk factors include pre-existing lung disease, use of pneumotoxic drugs, radiation 
therapy, and colony stimulating factors.   
Drug Interactions 
Exposure to irinotecan and its active metabolite SN-38 is substantially reduced when patients are 
concomitantly receiving CYP3A4 enzyme-inducing drugs such as the anti-convulsants 
phenytoin, phenobarbital or carbamazepine, as well as other agents such as St. John’s Wort.  
Strong inhibitors of CYP3A4 enzymes such as the anti-fungal ketoconazole and the HIV anti-
retrovirals (e.g. atazanavir), have increased exposure to irinotecan and SN-38 and should be 
avoided in patients receiving irinotecan.  See https://www.pfizeroncology.com/sites/pop/ 
PDFs/uspi_camptosar.pdf for further information. See Section 7.3 for further information on 
prohibited concomitant drugs, and drugs to be used with caution.   
13.3 
5FU 
5FU is an antineoplastic anti-metabolite that interfers with the synthesis of DNA and to a lesser 
extent RNA by blocking the methylation reaction of deoxyuridylic acid to thymidylic acid.  It is 
indicated for the treatment of metastatic CRC.   
Supply and Supplier 
The following information was taken from the prescribing information for Teva USA’s Adrucil® 
(5FU).  Additional details may be found at: 
http://www.tevausa.com/assets/base/products/pi/Adrucil_PI.pdf.   
 
Each 10 mL contains 500 mg of FU (50 mg/mL) and sodium hydroxide to adjust pH to 
approximately 9.2.  Commercially available supplies of either Adrucil® or another generic 5FU 
will be used for this study based on cost and availability.   
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Preparation, Storage and Stability 
The appropriate dose of 5FU (see Section 7.1) should be reconstituted, diluted and stored 
according to the package insert provided by the manufacturer and according to local 
pharmaceutical regulations. 
 
Premedication/Hydration 
Patients should receive premedication and hydration as described earlier.  
Dosage and Administration 
See Section 7.1. 
Handling and Disposal 
To minimize the risk of dermal exposure, always wear impervious gloves when handling vials 
containing 5FU. This includes all handling activities in clinical settings, pharmacies, storerooms, 
and home healthcare settings, including during unpacking and inspection, transport within a 
facility, and dose preparation and administration.  If a solution of 5FU contacts the skin, wash 
the skin immediately and thoroughly with soap and water.  Procedures for proper handling and 
disposal of anti-cancer drugs should be considered.  
Adverse Events  
The most common toxicities seen with 5FU therapy include stomatitis, esophagopharyngitis 
(which may result in sloughing and ulceration), diarrhea, anorexia, nausea and vomiting.  
Neutropenia commonly follows treatment with white count nadir observed between days 9 and 
14 following therapy.  Mild alopecia has been reported, though is usually not complete.  
Dermatitis, in the form of a pruritic maculopapular rash that usual appears on the extremities and 
(less frequently) trunk, is generally reversible and responsive to symptomatic treatment.  This 
dermatitis may be increased with sun exposure.  
  
Other less common adverse reactions are: 
Hematologic: pancytopenia, thrombocytopenia, agranulocytosis, anemia. 
 
Cardiovascular: myocardial ischemia, angina. 
 
Gastrointestinal: gastrointestinal ulceration and bleeding. 
 
Allergic Reactions: anaphylaxis and generalized allergic reactions. 
 
Neurologic: acute cerebellar syndrome (which may persist following discontinuance of 
treatment), nystagmus, headache. 
 
Dermatologic: dry skin; fissuring; photosensitivity, as manifested by erythema or increased 
pigmentation of the skin; vein pigmentation; palmar-plantar erythrodysesthesia syndrome, as 
manifested by tingling of the hands and feet followed by pain, erythema and swelling. 
 
Ophthalmic: lacrimal duct stenosis, visual changes, lacrimation, photophobia. 
 
Psychiatric: disorientation, confusion, euphoria. 
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Miscellaneous: thrombophlebitis, epistaxis, nail changes (including loss of nails) 
 
13.4 
Leucovorin 
Leucovorin, also known as folinic acid or citrovorum factor is a chemically reduced derivative of 
folic acid.  Leucovorin is readily converted to another rduced folate, 5,10-
methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyuridylic acid to 
thymidylate synthase, thereby enhancing the inhibition of this enzyme.   It is used to enchance 
the effects of fluoropyrimdines such as 5FU.   
Supply and Supplier 
The following information was taken from the prescribing information for Sagent 
Pharmaceutical’s leucovorin calcium. 
 
Leucovorin calcium is commercially available as a sterile, single-use vial containing either 
100mg or 350mg each. Commercially available supplies of generic leucovorin calcium will be 
obtained from Sagent or another manufacturer and used for this study.  
Preparation, Storage and Stability 
The appropriate dose of leucovorin (see Section 7.1) should be reconstituted and diluted and 
stored according to the package insert provided by the manufacturer and according to local 
pharmaceutical regulations. 
Dosage and Administration 
See Section 7.1. 
Adverse Events Associated with Leucovorin 
Leucovorin should not be used for pernicious anemia and other megalobastic anemias secondary 
to the lack of vitamin B12.  A hematologic remission may occur while neurologic manifestations 
continue to progress.   
 
Leucovorin enhances the toxicity of 5FU.  When these drugs are administered concurrently in 
the treatment of advanced colorectal cancer, as they are in this study, gastrointestinal toxicities 
(particularly stomatitis and diarrhea) are observed more commonly and may be more severe and 
of prolonged duration.  Seizures and/or syncope have been reported rarely in cancer patients 
receiving leucovorin, usually in combination with fluoropyrimidine administratiaon, and most 
commonly in those with CNS metastases or other predisposing factors, however, a causal 
relationship has not been established.  
 
Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported 
following administration of leucovorin.   
Drug Interactions 
Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin 
and primidone, and increase the frequency of seizures in susceptible pediatric patients. 
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14. STATISTICAL METHODS 
14.1 
Sample size analysis and accrual 
The pathological complete response with traditional chemotherapy in pancreatic cancer is very 
low (no reported complete response in neoadjuvant studies). We aim to evaluate the complete 
response rate and the correlation with outcome. So we assume the pathological complete 
response in traditional chemotherapy to be 1%. We expect that the pathological complete 
response after 2 cycles of FOLFIRINOX therapy is about 10%. We plan to enroll 48 patients 
over a 24 months period. Assuming 90% of patients are evaluable for response, we will have 43 
patients evaluable for pathological complete response. Patients will be considered non-evaluable 
and be replaced with new subjects per analysis datasets section below. With evaluable patients, 
we have 82% power detect a significant difference from the traditional chemotherapy with a 5% 
Type I error rate using a two sided one-sample test for proportion. 
14.2 
Analysis datasets 
 
Population 
Definition 
Enrolled 
This will comprise all patients who meet the eligibility 
criteria and are registered onto the study.  
Efficacy Evaluable 
This will comprise all patients who complete at least 2 
treatments and either undergo at least one post-baseline 
assessment or die before any evaluation.   
Not Evaluable for 
Efficacy 
This will comprise of patients who do not complete 2 out 
of 4 treatments unless it is related to profound toxicity 
leading to treatment discontinuation. 
Safety 
This will comprise all patients that contribute data to the 
safety analysis. This population should be specifically 
defined in the protocol.  
 
14.3 
Statistical analysis plan 
Primary Outcome: 
 Pathologic complete response: the proportion of the 48 patients having a pathologic 
complete response with a 95% confidence interval (using normal approximation) will 
be calculated.   
 
Secondary Outcomes: 
 Safety: Adverse events of grades 3, 4, 5 by the CTCAE v4.3 criteria for each category 
listed in section 2.1.6 will be summarized. The proportion of patients with each 
category of AE will be calculated with a 95% confidence interval. After the 
enrollment of the first 20 patients, we will evaluate the rate of surgical resection. If >6 
patients are not able to proceed with surgery due to excessive toxicity or progression 
(not including occult metastatic peritoneal disease that was found during surgery and 
not on imaging) the study will discontinue due to unacceptable toxicity. 
 
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 Ability of patients to undergo surgical resection after receiving neoadjuvant 
FOLFIRINOX: the proportion of patients who are able to go through surgery among 
those who have resectable tumor will be calculated accompanied with a 95% 
confidence interval.   
 
 Rate of resectability will be evaluated by determining the proportion of patients who 
are able to undergo surgery with resection of their primary tumor (R0 vs R1) 
resection. A 95% confidence interval will be constructed for the rate. 
 
 Disease free survival (DFS): DFS is defined as time from registration to evidence of 
tumor recurrence (including clinical deterioration related to the underlying pancreatic 
cancer, as assessed by the investigator) or death from any cause. Kaplan-Meier curve 
for DFS will be plotted. Median DFS time will be calculated accompanied with a 
95% confidence interval. 
 
 Overall survival: time from registration to death for 48 patients with right censoring 
will be analyzed using Kaplan-Meier estimate. Median survival time will be obtained 
accompanied with a 95% confidence interval. 
 
 Objective response rate: proportion of patients with complete responses (CR) or 
partial responses (PR) after 4 cycles of FOLFIRINOX treatment will be constructed 
with a 95% confidence interval. 
 
 Disease control rate: Proportion of patients with complete responses (CR), partial 
responses (PR), or stable disease (SD) after 4 cycles of FOLFIRINOX treatment will 
be obtained with a 95% confidence interval. 
 
Tertiary Outcomes: 
 Quality of life measures (from PG-SGA and FAACT) will be summarized with 
descriptive statistics and compared between baseline and 4 weeks post neo-adjuvant 
therapy with paired t-tests. 
 
Correlative Outcomes: 
 Change of biomarkers (including Ca19-9 and other tissue markers) from baseline to 
after 2 cycles of therapy will be calculated. Paired t-test will be used to test the 
change. We will correlate the change of Ca19-9 with patients’ pathologic complete 
response using logistic regression model or overall survival using Cox proportional 
hazards model as appropriate. Biomarkers will also be correlated with PFS and other 
response outcomes similarly. 
 
 Differential expression will be performed in R using DESeq2. These files will be 
downloaded and uploaded to Partek Genomics Suite v6.6 for visualization.  Pathway 
analysis will be performed using Ingenuity Pathway Analysis.  CIBERSORT analysis 
to identify the immune cell make up based on gene expression will also be performed. 
Selected differentially expressed markers will be correlated with outcomes as 
describe above.  
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14.4 
Criteria for stopping study  
The study will be discontinued if 25-30% of patients are unable to complete surgery due to 
toxicity. Analysis will be conducted after the first 20 patients are enrolled onto the study. If >6 
patients are not able to proceed with surgery due to excessive toxicity the study will discontinue 
due to unacceptable toxicity. 
15. DATA FORMS AND SUBMISSION SCHEDULE 
This study will utilize electronic Case Report Form completion in the OnCore® database. A 
calendar of events and required forms are available in OnCore®. The OnCore® database is a 
comprehensive database used by the IUSCC Clinical Trials Office (CTO) and supported by the 
Indiana Clinical and Translational Sciences Institute (CTSI).   
Access to data through OnCore® is restricted by user accounts and assigned roles.  Once logged 
into the OnCore® system with a user ID and password, OnCore® defines roles for each user 
which limits access to appropriate data.  New username and passwords can be obtained by going 
to the following link: https://redcap.uits.iu.edu/surveys/?s=sYN36a9U5c.  For further questions 
regarding your oncore account you can contact the CTO Cancer Center Oncore Support via 
email at: oncorecc@iupui.edu.   
All source documents are to remain in the patient’s clinic file.  All documents should be kept 
according to applicable federal guidelines.  Clinical trial data in OnCore® are periodically 
monitored by the IU Simon Cancer Center Data Safety Monitoring Committee.   
Generally, clinical and correlative data will be electronically captured in OnCore®. If procedures 
on the study calendar are performed for standard of care, at minimum, that data will be captured 
in the medical record. Select standard of care data will also be captured in OnCore®, according to 
study-specific objectives. Please see the OnCore® data collection guidelines for further details. 
Tissues will be stored in the IUSCC and data will be kept in OnCore® in a BSM. 
16. PATIENT CONSENT AND PEER JUDGMENT 
The protocol and informed consent form for this study must be approved in writing by the 
appropriate Institutional Review Board (IRB) prior to any patient being registered on this study.   
Changes to the protocol, as well as a change of principal investigator, must also be approved by 
the Board.  Records of the Institutional Review Board review and approval of all documents 
pertaining to this study must be kept on file by the investigator (housed in the Clinical Trials 
Office) and are subject to inspection at any time during the study.  Periodic status reports must be 
submitted to the Institutional Review Board at least yearly, as well as notification of completion 
of the study and a final report within 3 months of study completion or termination.   
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
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17. DATA AND SAFETY MONITORING 
17.1 
Data Safety Monitoring Committee  
The Data Safety Monitoring Committee (DSMC) of the Indiana University Simon Cancer Center 
(IUSCC) is responsible for patient safety and privacy protection, compliance with required 
reporting, and study integrity for all trials conducted at IUSCC. Members are subject matter 
experts from multiple disciplines including medical oncology, pediatrics, biostatistics, behavioral 
oncology, radiation oncology, urology, surgery, gynecologic oncology, data and project 
management and research administration who are appointed by the DSMC Chair. The DSMC 
will provide independent oversight of the clinical trial so that study integrity is assured. 
However, the DSMC is not serving as a Data and Safety Monitoring Board (DSMB) for this 
study.  The DSMC will meet per the currently approved DSMP, led by the DSMC Chair and 
Coordinator, and will review all adverse events, monitoring and auditing reports, unanticipated 
problems and study non-compliance events that require expedited reporting.  Meeting minutes 
will be maintained in the IUSCC Clinical Trials Office (CTO). Specifically the DSMC has the 
following responsibilities:  
 Assessment of the adequacy of trial-specific Data Monitoring and Safety Plan (DSMP) of 
studies that are not subject to external monitoring, including investigator initiated studies, 
and establish risk based monitoring determination of trial specific DSMB. 
 Review safety data for investigator initiated trials including all adverse events, unanticipated 
problems and study non-compliance events requiring expedited reporting. 
 Conduct routine study monitoring and auditing in compliance with the IUSCC data quality 
control review process.  
17.2 
Data and Safety Monitoring Plan 
This trial will comply with the current requirements of the Data and Safety Monitoring Plan 
(DSMP) of the IUSCC. The CTO of the IUSCC will be the Coordinating Center for this phase 2 
trial. Investigators will conduct continuous review of data and patient safety.  Monthly review 
meetings are required and will include the Principal Investigator, clinical research specialist 
and/or study nurse (or other members will be present at the Principal Investigator’s discretion).  
Monthly meeting summaries should include review of data, the number of patients, significant 
toxicities as described in the protocol, and responses observed.  Summaries will be submitted to 
DSMC@iupui.edu and reviewed monthly by DSMC. Monthly meeting summaries will include 
and document review of data and patient safety by including:  the number of patients, significant 
toxicities as described in the protocol, responses observed, eligibility of patients enrolled at each 
site, serious adverse events (SAEs) or unanticipated problems (UPs) (both IUSCC and those 
reported from other institutions), dose adjustments, and protocol deviations.  Meeting minutes 
will be submitted and reviewed by the DSMC.  
 
 
 
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Study Monitoring for Moderate Risk Trials 
All trials conducted at the IUSCC are subject to auditing and/or monitoring. Reports will be 
reviewed by the full DSMC at the time of study review (Reference Risk Table in full DSMC 
Charter). 
 
 
Early Study Closure 
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks 
(or benefits) to the patient warrant early closure of the study, this recommendation should be 
made in writing to the Data Safety Monitoring Committee.  Alternatively, the DSMC may 
initiate suspension or early closure of the study based on its review. 
 
Reporting Guidelines 
The DSMC has streamlined the reporting process by utilizing reports from OnCore®. This has 
allowed direct view of reports within the Clinical Trials Management System (CTMS); thus, 
discontinuing all paper reports. SAE reports are entered into OnCore® monthly and reviewed by 
the DSMC chair and/or coordinator monthly. Findings will be reported to the full DSMC at the 
time of the studies DSMC review. 
 
Reporting Death  
Death will be captured in the Case Report Form and reported per local IRB reporting guidelines. 
 
Study Accrual Oversight 
Accrual data will be entered into the IU Simon Cancer Center OnCore® system. The Protocol 
Progress Committee (PPC) will review study accrual twice per year while the PPC coordinator 
will review accrual quarterly. 
 
Continuing Review   
All Continuing Reviews (CR) will be reviewed annually or as dictated by the Institutional 
Review Board.  Participating sites will submit a copy of the CR with attachments to the IUSCC 
Multicenter Network Associate Administrator, or designee. 
 
Protocol Deviations 
Protocol deviations will be entered into OnCore® and reviewed by the DSMC chair and/or 
coordinator. Findings will be reported to the full DSMC at the time of DSMC review.  
 
Unanticipated Problems 
Investigators are required to submit unanticipated problems to the DSMC (through OnCore®) 
concurrent with their submission of them to the IRB.  Prompt reporting of unanticipated 
problems to the IRB is defined as within 5 days for on-site studies. 
 
Unanticipated problems that will be reported promptly to the IRB include: 
 Major protocol deviation/violation 
 Change to the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research subject (e.g. purposeful and for subject safety) 
 Complaint of a subject that indicates unexpected risks, or complaint that cannot be resolved 
by the research team 
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 Publication in the literature, safety monitoring report, interim result or other finding that 
indicates an unexpected change to the risks or potential benefits of the research, in terms of 
severity or frequency 
 Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in 
a research study 
 Investigator- or sponsor-initiated suspension or hold 
 Serious or continuing non-compliance 
 Adverse events 
18. REPORTING ADVERSE EVENTS 
18.1 
Definitions of Adverse Events 
18.1.1 Adverse Event (AE) 
An adverse event is defined as an unplanned, unwanted medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related. An adverse 
event can be ANY unfavorable and unintended sign (e.g. an abnormal laboratory 
finding), symptom, or disease temporarily associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal 
(investigational) product (attribution of ‘unrelated’, ‘unlikely’, ‘possible’, ‘probable’, or 
‘definite’).  An AE may also include a newly occurring event or a previous condition that 
has increased in severity or frequency since the administration of the investigational 
product. Adverse events will be graded according to the NCI Common Toxicity Criteria, 
Version 4.0. A copy of the current CTCAE version 4 is available at 
http://ctep.cancer.gov/reporting/. 
18.1.2 Unexpected Adverse Event 
An adverse event not mentioned in the Investigator's Brochure or package insert or the 
specificity or severity of which is not consistent with the Investigator's brochure or 
package insert. 
18.1.3 Unanticipated Problem (UP) 
An unanticipated problem is any incident, experience, or outcome that meets all of the 
following criteria: 
1) unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being study; 
2) related or possibly related to participation in the research; and  
3) suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) related to the 
research than was previously known or recognized. 
Only a small subset of adverse events occurring in human subjects participating in 
research will meet these three criteria for an unanticipated problem. Furthermore, there 
are other types of incidents, experiences, and outcomes that occur during the conduct of 
human subjects research that represent unanticipated problems but are not considered 
adverse events. For example, some unanticipated problems involve social or economic 
harm instead of the physical or psychological harm associated with adverse events. In 
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other cases, unanticipated problems place subjects or others at increased risk of harm, but 
no harm occurs. 
18.1.4 Determining Attribution to the Investigational Agent(s) 
Attribution: An assessment of the relationship between the AE and the medical 
intervention. CTCAE does not define an AE as necessarily “caused by a therapeutic 
intervention”. AEs will be monitored until they are resolved or are clearly determined to 
be due to a subject’s stable or chronic condition or intercurrent illness.  
 
After naming and grading the event, the clinical investigator must assign an attribution; 
or the determination of whether an adverse event is related to a medical treatment or 
procedure. The categories of attribution are described below:  
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related 
Unlikely 
The AE is doubtfully related 
Related to investigational 
agent/intervention 
Possible 
The AE may be related 
Probable 
The AE is likely related 
Definite 
The AE is clearly related 
18.1.5 Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence resulting in one or more of 
the following: 
 
Results in death or ANY death occurring within 28 days of last dose of study 
drug (even if it is not felt to be drug related)  
 
Is life-threatening (defined as an event in which the patient 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 prolongation of existing hospitalization 
NOTE: Hospitalizations that are not considered SAEs are:  
 Hospitalization planned prior to first administration of study drug 
 Hospitalization for elective treatment of a pre-existing condition 
unrelated to the study medication 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may 
require intervention (e.g. medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above).  Examples of such events include, but 
are not limited to, intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions not resulting in 
hospitalization; or the development of drug dependency or drug abuse. 
 
 Pregnancy 
Pregnancy of a patient or of the female partner of a male patient during the study 
or within 30 days after the last dose of study drug should be reported via an SAE 
report.  Should pregnancy occur in a female participant during the treatment 
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period, study drug should be discontinued immediately.  Should a pregnancy 
occur in a female companion of a male participant during the treatment period, 
the male participant can continue treatment immediately. Any such pregnancy is 
to be followed until final outcome.   
18.2 
Adverse Event (AE) Reporting 
Adverse events (AEs) will be recorded from the time of first study drug administration and for at 
least 30 days after treatment discontinuation, regardless of whether or not the event(s) are 
considered related to trial medications.  All AEs considered related to trial medication will be 
followed until resolution, return to baseline, or deemed clinically insignificant, even if this 
occurs post-trial.  
18.2.1 Reporting to the Data Safety Monitoring Committee (DSMC): 
Regardless of study sponsorship, the DSMC chair and/or coordinator will review all 
expedited SAE reports through OnCore®. Expedited reports are completed per IRB 
guidelines and may include the IRB Prompt Reporting form, and/or non-compliance 
form. Submission of this information to the DSMC is additional to any other protocol-
specified regulatory bodies (e.g. FDA, pharmaceutical company) to be notified.  When 
follow-up information is received, a follow-up report should also be created in OnCore®.  
The DSMC chair and/or coordinator will review expedited SAE reports monthly. 
18.2.2 Reporting to the IRB  
Each participating site will report adverse events and unanticipated problems to their IRB 
per local guidelines. Any event that requires expedited reporting to the local IRB will 
also be submitted to the IU Simon Cancer Center. 
Unanticipated problems involving risks to subjects or others will be reported promptly to 
the IRB if they:  
 caused harm;  
 were unexpected; AND 
 were related or possibly related to the research intervention. 
 
If the serious adverse event does not meet all three (3) criteria listed above, the event 
does not have to be promptly reported to the Indiana University IRB.  However, it should 
be reported at the time of continuing review. 
Prompt reporting of unanticipated problems to the IRB is defined as within 5 business 
days from becoming aware of the event. 
18.3 
Record Retention 
All documentation of adverse events and records of all IRB correspondence will be stored in 
accordance with all applicable federal guidelines. 
20. REFERENCES 
1. 
Hidalgo M. Pancreatic cancer. The New England journal of medicine. 2010 Apr 
29;362(17):1605-17. PubMed PMID: 20427809. 
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2. 
Neoptolemos JP, Stocken DD, Tudur Smith C, Bassi C, Ghaneh P, Owen E, et al. 
Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite 
data from the ESPAC-1 and -3(v1) trials. British journal of cancer. 2009 Jan 
27;100(2):246-50. PubMed PMID: 19127260. Pubmed Central PMCID: 2625958. 
3. 
Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, et al. Adjuvant 
chemotherapy with gemcitabine and long-term outcomes among patients with resected 
pancreatic cancer: the CONKO-001 randomized trial. JAMA : the journal of the 
American Medical Association. 2013 Oct 9;310(14):1473-81. PubMed PMID: 24104372. 
4. 
Burris HA, 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. 
Improvements in survival and clinical benefit with gemcitabine as first-line therapy for 
patients with advanced pancreas cancer: a randomized trial. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. 1997 Jun;15(6):2403-13. 
PubMed PMID: 9196156. 
5. 
Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. 
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. The New England 
journal of medicine. 2011 May 12;364(19):1817-25. PubMed PMID: 21561347. 
6. 
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased 
survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. The New England 
journal of medicine. 2013 Oct 31;369(18):1691-703. PubMed PMID: 24131140. 
7. 
Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. 
Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-
analysis of response and resection percentages. PLoS medicine. 2010 Apr;7(4):e1000267. 
PubMed PMID: 20422030. Pubmed Central PMCID: 2857873. 
8. 
White RR, Hurwitz HI, Morse MA, Lee C, Anscher MS, Paulson EK, et al. Neoadjuvant 
chemoradiation for localized adenocarcinoma of the pancreas. Annals of surgical 
oncology. 2001 Dec;8(10):758-65. PubMed PMID: 11776488. 
9. 
Evans DB, Rich TA, Byrd DR, Cleary KR, Connelly JH, Levin B, et al. Preoperative 
chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. 
Archives of surgery. 1992 Nov;127(11):1335-9. PubMed PMID: 1359851. 
10. 
Le Scodan R, Mornex F, Partensky C, Mercier C, Valette PJ, Ychou M, et al. 
Histopathological response to preoperative chemoradiation for resectable pancreatic 
adenocarcinoma: the French Phase II FFCD 9704-SFRO Trial. American journal of 
clinical oncology. 2008 Dec;31(6):545-52. PubMed PMID: 19060585. 
11. 
Satoi S, Yanagimoto H, Toyokawa H, Takahashi K, Matsui Y, Kitade H, et al. Surgical 
results after preoperative chemoradiation therapy for patients with pancreatic cancer. 
Pancreas. 2009 Apr;38(3):282-8. PubMed PMID: 19142173. 
12. 
Papalezova KT, Tyler DS, Blazer DG, 3rd, Clary BM, Czito BG, Hurwitz HI, et al. Does 
preoperative therapy optimize outcomes in patients with resectable pancreatic cancer? 
Journal of surgical oncology. 2012 Jul 1;106(1):111-8. PubMed PMID: 22311829. 
13. 
Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW, et al. Preoperative 
gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the 
pancreatic head. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2008 Jul 20;26(21):3496-502. PubMed PMID: 18640930. 
14. 
Turrini O, Ychou M, Moureau-Zabotto L, Rouanet P, Giovannini M, Moutardier V, et al. 
Neoadjuvant docetaxel-based chemoradiation for resectable adenocarcinoma of the 
pancreas: New neoadjuvant regimen was safe and provided an interesting pathologic 
response. European journal of surgical oncology : the journal of the European Society of 
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Surgical Oncology and the British Association of Surgical Oncology. 2010 
Oct;36(10):987-92. PubMed PMID: 20828979. 
15. 
Barbier L, Turrini O, Gregoire E, Viret F, Le Treut YP, Delpero JR. Pancreatic head 
resectable adenocarcinoma: preoperative chemoradiation improves local control but does 
not affect survival. HPB : the official journal of the International Hepato Pancreato 
Biliary Association. 2011 Jan;13(1):64-9. PubMed PMID: 21159106. Pubmed Central 
PMCID: 3019544. 
16. 
Palmer DH, Stocken DD, Hewitt H, Markham CE, Hassan AB, Johnson PJ, et al. A 
randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: 
gemcitabine alone versus gemcitabine combined with cisplatin. Annals of surgical 
oncology. 2007 Jul;14(7):2088-96. PubMed PMID: 17453298. 
17. 
Mahaseth H, Brutcher E, Kauh J, Hawk N, Kim S, Chen Z, et al. Modified 
FOLFIRINOX regimen with improved safety and maintained efficacy in pancreatic 
adenocarcinoma. Pancreas. 2013 Nov;42(8):1311-5. PubMed PMID: 24152956. 
18. 
Rafael Alvarez-Gallego AC, Jesus Rodriguez-Pascual, Yolanda Quijano, Emilio De 
Vicente, Lina García, Fernando López-Ríos, Carlos Plaza, Elena García-García, María 
Pia Morelli, Manuel Hidalgo. Antitumor activity of nab-paclitaxel and gemcitabine in 
resectable pancreatic cancer. J Clin Oncol 30, 2012 (suppl; abstr 4040). 2012. 
19. 
Shawn MacKenzie HZ, Laurence E. McCahill, Timothy D. Sielaff, Nathan Bahary, 
Thomas Edward Gribbin, John E. Seng, Joseph W. Leach, Jocelyn Harmon, Michael J. 
Demeure, Daniel D. Von Hoff, A Jim Moser, Ramesh K. Ramanathan. A pilot phase II 
multicenter study of nab-paclitaxel (Nab-P) and gemcitabine (G) as preoperative therapy 
for potentially resectable pancreatic cancer (PC). J Clin Oncol 31, 2013 (suppl; abstr 
4038). 2013. 
20. 
Neelam Vijay Desai SH, Alison Ivey, Steven N. Hochwald, Carmen Joseph Allegra, Jose 
Gilberto Trevino, Long H. Dang, Kevin Behrns, Judith L. Lightsey, Robert Zlotecki, 
Chen Liu, Shailendra Chauhan, Maria Zajac-Kaye, Tania Zuluaga Toro, Wei Hou, 
Thomas J. George. Gemcitabine with nab-paclitaxel in neoadjuvant treatment of 
pancreatic adenocarcinoma: GAIN-1 study. J Clin Oncol 30, 2012 (suppl; abstr 
TPS4136). 2012. 
21. 
Lexi-Comp. Fluorouracil: Drug Information 2010 [cited 2010 Sept 29, 2010]. 
22. 
Douglas B. Evans; Tyvin A. Rich; David R. Byrd; Karen R. Cleary; John H. Connelly; 
Bernard Levin; Chusilp Charnsangavej; Claudia J. Fenoglio; Frederick C. Ames,   
Preoperative Chemoradiation and Pancreaticoduodenectomy for Adenocarcinoma of the 
Pancreas Arch Surg. 1992;127(11):1335-1339.  
23. 
Ottery, Faith & Jager-Wittenaar, Harriët.  PG-SGA.  http://www.pt-global.org. 
24.  
Chang VT, Xia Q, Kasimis B. The Functional Assessment of Anorexia/Cachexia Therapy 
(FAACT) Appetite Scale in veteran cancer patients. J Support Oncol. 2005 Sept-
Oct;3(5):377-82. 
 
 
 
 
 
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21. APPENDICES 
 
Appendix I 
 
NCI Common Toxicity Criteria  
 
Version 4.0 
Due to the size of the latest version of the Common Toxicity Criteria, copies of this appendix are 
not included with this protocol document. 
An electronic copy is available on the CTEP web site, http://ctep.cancer.gov/reporting/ctc.html 
 
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Appendix II 
Performance Status Scales/Scores 
 
       ECOG or Zubrod                              Karnofsky  
                Lansky 
 
 
 
 
Score        Activity               Score                Activity                      Score               Activity 
0 
Fully active, able 
to carry on all pre-
disease 
performance 
without restriction. 
100 
 
 
90 
Normal, no complaints, no 
evidence of disease. 
 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
 
100 
 
 
90 
Fully active, normal. 
 
 
Minor restrictions in physically 
strenuous activity. 
1 
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 
 
 
 
 
70 
Normal activity with effort; 
some signs or symptoms of 
disease. 
 
Cares for self, unable to 
carry on normal activity or 
do active work. 
80 
 
 
 
 
70 
Active, but tires more quickly. 
 
 
 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and 
capable of all 
selfcare but unable 
to carry out any 
work activities.  
Up and about more 
than 50% of 
waking hours. 
 
 
60 
 
 
 
50 
Requires occasional 
assistance, but is able to 
care for most of his/her 
needs. 
 
Requires considerable 
assistance and frequent 
medical care. 
 
 
60 
 
 
 
50 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
 
 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only 
limited selfcare, 
confined to bed or 
chair more than 
50% of waking 
hours. 
40 
 
 
 
30 
Disabled, requires special 
care and assistance. 
 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
40 
 
 
 
30 
Mostly in bed; participates in 
quiet activities. 
 
In bed; needs assistance even 
for quiet play. 
4 
Completely 
disabled.  Cannot 
carry on any 
selfcare. Totally 
confined to bed or 
chair. 
20 
 
 
10 
Very sick, hospitalization 
indicated.  Death not 
imminent. 
Moribund, fatal processes 
progressing rapidly. 
20 
 
 
10 
 
Often sleeping; play entirely 
limited to very passive 
activities. 
No play; does not get out of 
bed. 
 
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Appendix III 
DSMC Check Sheet 
 
 
 
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Appendix IV 
Scored Patient-Generated Subjective Global Assessment (PG-SGA) 
Patient ID__________            Patient Initials___________                     Date_______________ 
 
 
 
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Appendix V 
Functional Assessment of Anorexia/Cachexia Therapy (FAACT) 
Patient ID__________            Patient Initials___________                     Date_______________ 
 
 
Protocol 1404646947 IRB Approved for re-consenting only


IUCRO-0473 
Protocol Version Date:   
October 2, 2019 
 
Page 49 
 
Protocol 1404646947 IRB Approved for re-consenting only


IUCRO-0473 
Protocol Version Date:   
October 2, 2019 
 
Page 50 
 
Protocol 1404646947 IRB Approved for re-consenting only