Phase II Study of Peri-Operative Modified Folfirinox in Localized Pancreatic Cancer
Phase: PHASE2
Conditions: Acinar Cell Adenocarcinoma of the Pancreas, Duct Cell Adenocarcinoma of the Pancreas, Stage I Pancreatic Cancer, Stage IIA Pancreatic Cancer, Stage IIB Pancreatic Cancer
Sponsor: Yale University

1
   TITLE:  PHASE II STUDY OF PERI-OPERATIVE MODIFIED FOLFIRINOX IN 
LOCALIZED PANCREATIC CANCER 
HIC Protocol Number: 
1306012255 
Version Number: 
 
8.0 
 
Version Date: 
12-Sep-2018
Sponsor: 
Yale Comprehensive Cancer Center 
Principal Investigator: 
Jill Lacy, M.D. 
Yale University School of Medicine 
333 Cedar Street, 219 WWW  
PO Box 208032 
New Haven, CT 06520-8032 
Ph: 203-737-1600; Fax: 203-785-7531 
Jill.lacy@yale.edu 
Statistician: 
Daniel Zelterman, PhD 
Study Coordinator: 
Christina Wiess 
Data Manager:  
Kamile Pamorada 
Study Medications: 
Leucovorin, 5-fluorouracil, irinotecan, oxaliplatin 
Financial Support:  
Departmental 
NCT02047474   

 
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TABLE OF CONTENTS 
 
1.0  BACKGROUND/RATIONALE………………………………………………. 
3 
2.0  OBJECTIVES……………………………………………………………….... 
7 
3.0  STUDY DESIGN…………………………………………………………..…. 
8 
 
4.0  ON-STUDY GUIDELINES AND SAFETY PLAN………………………. . 
9 
5.0  ELIGIBILITY CRITERIA……………………………………………………… 
10 
6.0  TREATMENT PLAN…………………………………………………………. 
12 
7.0  STUDY DRUGS/DOSE MODIFICATIONS/TOXICITY MANAGEMENT.. 
13 
 
 
7.1 DOSES/SCHEDULE OF STUDY DRUGS………………...………. 
13 
 
7.2 DRUGS: FORMULATION/ADMINISTRATION/TOXICITY……….. 
14 
 
7.3 DOSE MODIFICATIONS AND TOXICITY MANAGEMENT……… 
21 
8.0  REQUIRED CLINICAL AND LABORATORY EVALUATIONS…………… 
26 
9.0  CRITERIA FOR RESPONSE AND PROGRESSION……………………... 
28 
10.0 SUBJECT DISCONTINUATION……………………………………………. 
33 
11.0 STUDY DISCONTINUATION……………………………………………….. 
34 
12.0 STATISTICAL METHODS………………………………………………....... 
34 
13.0 ADVERSE EVENT ANALYSIS, DEFINITION AND REPORTING……. … 
35 
14.0 YALE PRINCIPAL INVESTIGATOR SAE REPORTING  
         REQUIREMENTS……………………………………………………………. 
38 
15.0 YALE SAFETY REPORTING AND MONITORING (DSMP)…….……..... 
39 
16.0 RETENTION OF RECORDS ……………………………………………...... 
40 
17.0 RESEARCH ETHICS AND HUMAN SUBJECT PROTECTION…………. 
40 
18.0 REFERENCES……………………………………………………………….. 
42 
APPENDIX A: STANDARD PROCEDURE FOR COLLECTION AND STORAGE OF 
PLASMA AND BUFFY COAT SPECIMENS..................………………………...………45 
 
 
 
 
 

 
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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
BACKGROUND 
 
Pancreatic cancer is the fourth leading cause of cancer-related death in men and 
women. There were an estimated 43,140 new cases and 36,800 deaths from pancreatic 
cancer in United States in 2010, and the five year survival for all patients with pancreatic 
adenocarcinoma is <5% (1).   
 
While surgical resection (pancreaticoduodenectomy or distal pancreatectomy) is 
considered the only potentially curative treatment, only 20-25% of patients present with 
potentially resectable disease.  Among patients who are able to undergo surgical 
resection, the 5 year survival rate is just 4-21% due to the high rate of  metastatic and 
local-regional recurrence (2-4).   These disappointing results are likely attributable to 
early hematogenous dissemination such that sub-clinical metastastases are present at 
the time of diagnosis in most patients, as well as positive margins at the time of 
resection.  Patients with resectable disease who have positive margins (R1 or R2 
resection) have survival rates comparable to patients with locally advanced 
unresectable disease (5-7).   
 
At present, the standard of care for resectable pancreatic cancer supports the use of 
adjuvant chemotherapy with gemcitabine or leucovorin-modulated 5-fluorouracil (5-FU) 
for 6 months.  As reported in the CONKO-001 trial, the use of adjuvant gemcitabine for 
resectable pancreatic adenocarcinoma resulted in a significant improvement in disease- 
free survival compared to observation (13.4 months versus 6.9 months) (2).  However, 
gemcitabine was associated with only a modest improvement in survival (median overall 
survival 22.8 months versus 20.2 months; five-year survival 21% versus 9%) (8).  In the 
ESPAC-1 trial, both the two-year (40 versus 30 percent) and five-year (21 versus 8 
percent) survival rates were significantly greater among patients randomized to 
postoperative bolus leucovorin-modulated 5-FU for six months compared to those who 
did not receive it (3). The median survival for patients treated with 5-FU versus no 
chemotherapy was 20.1 versus 15.5 months, respectively. Subsequently, in the 
ESPAC-3 trial, adjuvant gemcitabine was compared to 5-FU (4).  These regimens were 
shown to be virtually identical in terms of efficacy (median survival 23.6 mo versus 23 

 
4
mo), although 5-FU was associated with more stomatitis and diarrhea.  Thus, the 
standard of care for patients who have undergone definitive resection of localized 
pancreatic cancer is the administration of six months of adjuvant gemcitabine, although 
5-FU is an acceptable alternative.   
 
 Although gemcitabine or bolus 5-FU remain the standard of care in the adjuvant 
setting, the most effective regimen for metastatic pancreatic adenocarcinoma is the 
combination regimen FOLFIRINOX (oxaliplatin 85 mg/m2 over 2 hrs, followed by 
irinotecan 180 mg/m2 over 90 min and leucovorin 400 mg/m2 over 2 hrs,  followed by 5-
fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 46h continuous infusion).  FOLFIRINOX 
was compared to gemcitabine in a randomized phase III trial in patients with metastatic 
pancreatic cancer (9).  This study showed significant improvements in overall survival 
(11.1 v 6.8 mo), progression free survival (6.4 v 3.3 mo) and response rate (31.6% v 
9.4%) with FOLFIRINOX compared to gemcitabine.  FOLFIRINOX was associated with 
significantly more grade 3/4 toxicity than gemcitabine (neutropenia, 45.7% v 21.0%; 
febrile neutropenia, 5.4% v 1.2%; fatigue, 23.6% v 17.8%; vomiting, 14.5% v 8.3%; 
diarrhea, 12.7% v 1.8%).  There was one toxic death in each arm.   Based on this study, 
FOLFIRINOX is considered the most effective regimen for metastatic pancreatic cancer, 
and it has emerged as the new standard of care in appropriate patients with a good 
performance status.    
 
Given concerns regarding excessive toxicity of FOLFIRINOX, most practitioners are 
reluctant to use full doses of all three chemotherapeutic agents.  A retrospective review 
of all patients treated at Smilow Cancer Center between June 2010 and June 2011 with 
FOLFIRINOX demonstrated that routine modest dose attenuations in combination with 
pegfilgrastim support was associated with improved tolerability and comparable 
efficacy compared to FOLFIRINOX-treated patients reported by Conroy et al (10,11).  In 
this retrospective review, 35 patients were treated (16 locally advanced unresectable; 
19 metastatic).  29 patients received dose attenuations with the first cycle. 
Median relative doses of irinotecan and bolus fluorouracil were less than those reported 
by Conroy (64% v 81% and 66% v 82%, respectively).  Response rate was 47% and 
did not differ significantly from the response rate of 32% reported by Conroy (p = 0.19).  
Overall survival (in the metastatic cohort) at 6 and 12 months was comparable to OS 
reported by Conroy.  The incidences of grade 3/4 toxicities (febrile neutropenia, anemia, 
thrombocytopenia, diarrhea, vomiting, fatigue [p=0.009], neutropenia [p<0.0001] were 
less than reported by Conroy et al, and we observed no treatment-related deaths.  

 
5
Based on this experience, dose-attenuated FOLFIRINOX (25% reduction in dose of 
irinotecan and bolus 5-FU), with routine use of pegfilgrastim, is being prospectively 
evaluated in patients with advanced pancreatic cancer (locally advanced unresectable 
or metastatic) in a Yale-sponsored multi-institutional Phase II trial.  Although this study 
is ongoing, preliminary analysis of 27 patients validates the tolerability and safety of this 
regimen.  Of note, at this institution, 6 patients with locally advanced pancreatic cancer 
have undergone successful surgical resection within one month of completion of 4 or 
more cycles of FOLFIRINOX.  In this small cohort of patients who received neoadjuvant 
FOLFIRINOX for locally advanced disease, we have observed no delays in moving to 
surgery and no unusual or unexpected post-operative complications in the post-
operative period.    
 
While FOLFIRINOX is clearly superior to gemcitabine in the metastatic setting, there are 
no data regarding its efficacy and tolerability in the neoadjuvant or adjuvant setting in 
patients with resectable disease.   Given the significant improvement in overall survival 
and progression free survival in the metastatic setting, the use of FOLFIRINOX in the 
neoadjuvant and/or adjuvant setting in patients with resectable pancreatic cancer may 
lead to substantial improvements in PFS and OS compared to adjuvant gemcitabine.  
 
There are several potential advantages in administering systemic chemotherapy pre-
operatively in patients with resectable pancreatic cancer, as follows: (1) early systemic 
therapy of micrometastatic disease may be more effective than delayed systemic 
therapy after surgery, due to lower burden of occult metastatic disease;  (2) the 
cytoreductive effect of pre-operative chemotherapy may increase the rate of margin-
negative R0 resections (v R1 or R2);  (3) adjuvant chemotherapy administration after 
pancreatectomy is often delayed for months due to post-operative recovery, potentially 
reducing efficacy; (4) 25% of patients never receive adjuvant chemotherapy  due to 
delayed post-operative recovery (12);  (5) the administration of pre-operative 
chemotherapy will identify patients with rapidly progressive disease who will not benefit 
from surgery. 
 
Potential disadvantages of neoadjuvant chemotherapy include the requirement for 
biliary decompression before chemotherapy and potential for complications associated 
with biliary stents, and delayed surgery allowing progression locally to a nonresectable 
stage in patients whose disease did not respond to chemotherapy.   Despite these 
theoretical disadvantages, multiple small phase II studies of neoadjuvant therapies with 

 
6
gemcitabine- or 5-FU-based regimens, usually with concurrent radiotherapy, have 
demonstrated the safety and feasibility of this approach in patients with resectable or 
borderline resectable disease (13-20).  In general, patients who undergo neoadjuvant 
therapies have not experienced increased pre- and peri-operative complications, and 
rates of hepatic toxicity and biliary stent-related complications are low.  Moreover, these 
studies demonstrated a negligible rate of local-only progression precluding surgery.   
For example, in a randomized phase 2 trial of neoadjuvant chemotherapy in resectable 
pancreatic cancer with gemcitabine alone versus gemcitabine combined with cisplatin, 
only one of 50 patients was unable to proceed to surgery due to local progression (16).   
 
While median survival durations from some of these small uncontrolled trials of 
neoadjuvant therapy for localized pancreatic cancer compare favorably to those 
reported with adjuvant therapy approaches, whether preoperative therapy is better than 
postoperative therapy remains unknown, as there are no randomized trials comparing 
the two approaches.  Notably, none of the published studies of neoadjuvant therapy 
have incorporated FOLFIRINOX.   At present, neoadjuvant therapy for resectable 
pancreatic cancer is not considered standard of care.    
 
Based on the superior efficacy of FOLFIRINOX compared to gemcitabine in metastatic 
pancreatic cancer, and the potential advantages of neoadjuvant chemotherapy, we 
propose to evaluate the efficacy of peri-operative (neoadjuvant and adjuvant) 
FOLFIRINOX in patients with resectable pancreatic adenocarcinoma.    
 
1.2       STUDY RATIONALE AND HYPOTHESIS 
In summary, patients with localized resectable pancreatic adenocarcinoma have a 5 
year survival rate of 4-21% after surgical resection (pancreaticoduodenectomy or distal 
pancreatectomy).  Although the use of adjuvant gemcitabine or bolus 5-FU is the 
current standard of care, these regimens have only a modest impact on overall survival 
compared to observation.  FOLFIRINOX has been shown to significantly increase 
survival, progression-free survival, and response rate compared to gemcitabine in 
metastatic pancreatic cancer.  Thus, it is likely that FOLFIRINOX will improve outcomes 
compared to gemcitabine in patients with resectable pancreatic cancer.  Based on the 
potential advantages of administration of systemic therapy pre-operatively in patients 
with resectable pancreatic cancer, we propose the utilization of peri-operative 
(neoadjuvant and adjuvant) FOLFIRINOX.  Finally, since modest dose reductions of 

 
7
bolus 5-FU and irinotecan in patients with advanced pancreatic cancer may be 
associated with improved tolerability and similar efficacy compared to full dose 
FOLFIRINOX, we will utilize dose-attenuated modification of FOLFIRINOX, or 
mFOLFIRINOX, with a 25% reduction in the doses of bolus 5-FU and irinotecan.    
We will evaluate peri-operative (neoadjuvant and adjuvant) mFOLFIRINOX in patients 
with resectable pancreatic adenocarcinoma.  We hypothesize that the use of peri-
operative mFOLFIRINOX will be associated with improved PFS compared to historical 
controls treated with adjuvant gemcitabine.  
 
2.0 
OBJECTIVES 
 
2.1 
PRIMARY 
The primary objective of this study is to determine the progression-free survival in 
patients with resectable non-metastatic pancreatic cancer treated with peri-operative 
mFOLFIRINOX.   
 
2.2 
SECONDARY 
1) Determine overall survival 
2) Determine objective response rate after neoadjuvant mFOLFIRINOX 
 
2.3 
EXPLORATORY 
1) Compare R0 resection rate and pathologic stage with institutional historical controls 
who did not receive neoadjuvant therapy 
2) Correlate early metabolic response, determined by changes in glucose metabolism 
using PET scanning, with pathologic response, R0 resection, and pathologic stage. 
3) Correlate early metabolic response, determined by changes in glucose metabolism 
using PET scanning, with progression-free and overall survival 
4) Correlate pre-operative response of CA19-9 with progression-free and overall 
survival 
5) Collect and bank serial serum and plasma specimens from subjects for future 
correlative biomarker studies.   
6) Collect and bank tumor tissue from subjects prior to treatment (from the diagnostic 
EUS-guided biopsy) and after treatment with six cycles of FOLFIRINOX (from the 
surgical specimen) for future correlative biomarker studies.  

 
8
3.0   
STUDY DESIGN 
 
3.1  
DESCRIPTION OF STUDY 
 
This is a Phase II open-label study to determine the anti-tumor efficacy of peri-operative 
(neoadjuvant and adjuvant) mFOLFIRINOX in patients with resectable pancreatic 
adenocarcinoma.  Patients will receive 6 cycles of mFOLFIRINOX every 2 weeks as 
follows: Oxaliplatin 85 mg/m2, followed by folinic acid 400 mg/m2 infused over 120 
minutes and irinotecan 135 mg/m2 infused over 90 minutes, followed by 5-fluorouracil 
300 mg/m2 IV bolus, followed by 2,400 mg/m2 continuous infusion for 46 hours.  
Levoleucovorin may be substituted for folinic acid at a dose of 200 mg/m2 infused over 
120 minutes. 
 
After the initial 6 cycles of mFOLFIRINOX, patients will undergo re-evaluation for 
resection with cross-sectional imaging (CAT scan or MRI scan); EUS is optional if 
deemed necessary to assess resectability.  Patients who are resectable will undergo 
surgical resection between 3 and 8 weeks after completion of neoadjuvant 
mFOLFIRINOX.  Post-operatively, patients will receive an additional 6 cycles of 
mFOLIFIRINOX.  Patients will be eligible to start the adjuvant treatment as part of the 
study for up to 12 weeks after surgery.   
 
Patients who complete the study treatment phase without disease progression will enter 
a post-study surveillance phase.  They will undergo history, physical exam, laboratory 
assessments at two month intervals and cross-sectional imaging at 4 months intervals 
for three years, and then at six month intervals for two additional years.  After five years, 
patients will be followed annually until death.    
 
3.2  
RATIONALE FOR STUDY DESIGN 
 
Since FOLFIRINOX has been shown to significantly increase progression-free and 
overall survival compared to gemcitabine in patients with metastatic pancreatic cancer, 
there is compelling rationale for utilizing FOLFIRINOX rather than gemcitabine in 
patients with resectable pancreatic cancer.  Our retrospective study and on-going 
prospective phase II study at Yale have shown improved tolerability and comparable 
efficacy of mFOLFIRINOX compared to FOLFIRINOX as reported by Conroy et al.  

 
9
Therefore, we propose an open label phase II study to evaluate the efficacy of peri-
operative (neoadjuvant and adjuvant) mFOLFIRINOX in patients with localized 
resectable pancreatic cancer. We hypothesize that the use of mFOLFIRINOX will be 
associated with a significant improvement in PFS when compared to historical controls 
treated with gemcitabine.   
 
3.3  
OUTCOME MEASURES 
 
3.3.1 PRIMARY OUTCOME MEASURES 
The primary outcome measure of this study is progression-free survival of patients with 
resectable non-metastatic pancreatic cancer treated with modified FOLFIRINOX in the 
neoadjuvant and adjuvant settings.   
 
3.3.2 SECONDARY OUTCOME MEASURES 
The secondary outcome measures are: 
1) Overall survival 
2) Objective response rate after neoadjuvant mFOLFIRINOX 
 
  
3.4  
EXPECTED ACCRUAL 
 
Expected accrual is 46 patients over five years (see Section 12, Statistical Methods). 
We anticipate accrual will be completed in five years, based on the number of 
pancreatic resections for adenocarcinoma that are performed annual at Yale New 
Haven Hospital annually (>40 per year).   
 
4.0 
ON-STUDY GUIDELINES AND SAFETY PLAN 
 
4.1 
GENERAL ON-STUDY GUIDELINES 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are 
enrolled.  All relevant medical and other considerations should be taken into account 
when deciding whether this protocol is appropriate for a particular patient.  Physicians 
should consider the risks and benefits of any therapy, and therefore only enroll patients 
for whom this treatment is appropriate.  Although they may not be considered as formal 

 
10 
subject selection criteria, as part of this decision making process, physicians should 
recognize that the following may seriously increase the risk to the patient entering this 
protocol: 
 
o Psychiatric illness that would prevent the patient from giving informed 
consent. 
 
o Patient is not deemed a candidate for mFOLFIRINOX based on overall 
condition and co-morbidities. 
 
o A medical condition such as active/uncontrolled infection or cardiac 
disease that would make this protocol unreasonably hazardous for the 
patient in the opinion of the treating physician.  
 
4.2 
mFOLFIRINOX-SPECIFIC SAFETY GUIDELINES 
 
See Section 7 for detailed instructions for safety guidelines and management of 
FOLFIRINOX–related toxicities. 
 
5.0 
ELIGIBILITY CRITERIA 
 
The eligibility criteria for this study are as follows.  
Disease Characteristics:  
• Pathologic or cytologic documentation of pancreatic adenocarcinoma 
• Resectable pancreatic adenocarcinoma disease as defined as follows: 
-No evidence of extrapancreatic disease by cross sectional imaging, PET 
scan, or laparoscopy, including nodal involvement beyond the 
peripancreatic tissues and/or distant metastases; 
-No evidence of tumor extension to superior mesenteric artery, hepatic 
artery, celiac axis, aorta, or inferior vena cava, and no evidence of 
occlusion or encasement of the superior mesenteric vein or superior 
mesenteric vein/portal vein confluence, as assessed by CT using 
pancreatic protocol (or MRI in patients who cannot undergo CT) and EUS  

 
11 
 
Prior Therapy: 
• No prior treatment (chemotherapy, biological therapy, or radiotherapy) for 
resectable pancreatic cancer  
• No prior treatment with oxaliplatin, irinotecan, fluoruouracil or capecitabine 
• Patients who received chemotherapy >5 years ago for malignancies other than 
pancreatic cancer are eligible  
• There is no evidence of the second malignancy at the time of study entry  
• >4 weeks since major surgery 
• No other concurrent anticancer therapy 
 
Patient Characteristics: 
• ECOG Performance Status:  0-1 
• Age > 18 
• No other malignancy within past five years except basal cell carcinoma of the 
skin, cervical carcinoma in situ, or nonmetastatic prostate cancer 
• Paraffin block or slides must be available 
• Adequate organ function 
• No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the 
lung 
• No > grade 2 sensory peripheral neuropathy 
• No uncontrolled seizure disorder, active neurological disease, or known CNS 
disease 
• No significant cardiac disease, including the following: unstable angina, New 
York Heart Association class II-IV congestive heart failure, myocardial infarction 
within six months prior to study enrollment 
• No history of chronic diarrhea 
• Not pregnant and not nursing 
• No other medical condition or reason that, in the opinion of the investigator, 
would preclude study participation 
• Laboratory parameters as follows: absolute neutrophil count ≥1,500/uL, platelet 
count ≥100,000/uL, hemoglobin ≥9 g,/dL, creatinine <1.5 X ULN or estimated 
GFR >30 ml/min, bilirubin <1.5 X ULN, AST and ALT <3 X ULN, negative 
pregnancy test in women of childbearing age 
 
 

 
12 
6.0 
TREATMENT PLAN 
 
This is an open-label non-randomized Phase II study. Patients will receive neoadjuvant 
treatment with mFOLFIRINOX every two weeks (initiated on day 1 of every 2 week 
cycle).  Therapy will be administered in an outpatient setting under medical supervision.  
Protocol treatment is to begin within 14 days of registration.  One cycle will be defined 
as 14 days or two weeks of treatment.   
 
Prior to surgery, patients will receive 6 cycles (12 weeks) of neoadjuvant 
mFOLFIRINOX.  An interval response assessment PET scan will be performed after 3 
cycles, and if there is no radiographic evidence of disease progression, patients will 
receive 3 additional cycles of mFOLFIRINOX.  After completion of 6 cycles, patients will 
undergo re-assessment for resection, including a pre-operative CT scan using 
pancreatic protocol (or MRI scan in patients who cannot undergo CT scan) and surgical 
evaluation; EUS and PET scan are optional if deemed necessary to assess 
resectability.  Patients who are deemed surgical candidates after re-assessment will 
undergo a pancreaticoduodenectomy or distal pancreatectomy within 3-8 weeks of 
completion of 6 cycles of neoadjuvant mFOLFIRINOX.  
 
Full pathologic evaluation and staging will be performed on resected disease.  Patients 
will continue to be seen every 2 weeks in the medical oncology setting to assess 
readiness to start adjuvant therapy. 
 
After surgery, patients will receive 6 cycles of adjuvant mFOLFIRINOX.  Patients will 
start adjuvant therapy with mFOLFIRINOX after they have returned to ECOG 
performance status of 0-1, have no open incisions, have normalization of labs and have 
demonstrated stable or increasing weight for >1 week.  Patients will be eligible to 
receive adjuvant treatment as part of the study if treatment is initiated within 12 weeks 
after surgery.    
 
Chemotherapy will consist of mFOLFIRINOX administered every two weeks. The details 
of administration of each drug in mFOLFIRINOX are described in section 7.  Treatment 
is initiated on day 1 of a two week cycle. The doses of drugs and sequence of 
administration are as follows: 
 
• Oxaliplatin 85 mg/m2 IV infused over two hours, followed by 

 
13 
 
• Leucovorin 400 mg/m2 IV (or levoleucovorin  200 mg/m2 IV) over two hours   
 
• Irinotecan 135 mg/m2 IV over 90 minutes (concurrent with leucovorin during the 
last 90 min of the leucovorin infusion) 
 
• 5-FU 300mg/m2 IV bolus, then 2400 mg/m2 continuous IV infusion over 46 hours 
 
 
All patients will receive supportive care as follows: 
 
• Pegfilgrastim (Neulasta) on day 3, 4, or 5.  
 
• Anti-emetics including palonosetron or ondansetron, aprepitant, and 
dexamethasone, according to standard protocols.  
 
• Atropine is administered per standard guidelines for cholinergic symptoms during 
irinotecan infusion of on day 1 
 
• Loperamide is administered per standard guidelines for chemotherapy-induced 
diarrhea. 
 
• Magnesium and calcium is administered pre- and post-oxaliplatin at the 
discretion of the treating physician per standard guidelines. 
 
Patients must be counseled regarding potential sides effects and their 
management, including the proper use of loperamide for chemotherapy-induced 
diarrhea. 
 
7.0 
STUDY DRUGS/DOSE MODIFICATIONS/ TOXICITY MANAGEMENT 
 
7.1 
DOSES AND SCHEDULE OF STUDY DRUGS  
 
Chemotherapy will consist of mFOLFIRINOX administered every two weeks, as 
described in detail Section 6 at the following doses.   
 

 
14 
• Oxaliplatin 85 mg/m2 IV infused over two hours, followed by 
• Leucovorin  400 mg/m2 (or levoleucovorin  200 mg/m2) IV over two hours  
• Irinotecan 135 mg/m2 IV over 90 minutes (concurrent with leucovorin during the 
last 90 min of the leucovorin infusion) 
• 5-FU 300mg/m2 IV bolus, then 2400 mg/m2 continuous IV infusion over 46 hours 
 
 
7.2.   STUDY DRUGS: FORMULATION, STORAGE, AVAILABILITY, PREPARATION, 
TOXICITY 
 
 
Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and 
safe disposal of chemotherapeutic agents in a self-contained, protective environment.   
 
Discard unused portions of injectable chemotherapeutic agents supplied as single-dose 
preparations within eight hours of vial entry to minimize the risk of bacterial 
contamination.  
 
The total administered dose of chemotherapy may be rounded up or down within a 
range of 5% of the actual calculated dose. 
 
 
7.2.1 OXALIPLATIN [ELOXATIN] 
 
Availability 
 
Oxaliplatin is commercially available as an aqueous solution in vials containing 50 mg 
and 100 mg at a concentration of 5 mg/mL.  The vials do not contain any preservative 
and they are intended for single use. 
 
Storage and Stability 
 
Intact vials should be stored at room temperature.  Solutions diluted in  
D5W are stable for 6 hours at room temperature or 24 hours under refrigeration. 
 
 
 

 
15 
Preparation 
 
The calculated dose of oxaliplatin should be diluted for infusion with 250 mL to 500 mL 
D5W.  Oxaliplatin should not be diluted with a sodium chloride solution.  Needles, 
syringes, catheters or IV administration sets containing aluminum should not be used 
with oxaliplatin.  As with other platinum compounds, contact with aluminum may result 
in a black precipitate. 
 
Administration 
 
Oxaliplatin will be administered by intravenous infusion over 120 minutes in patients 
receiving FOLFIRINOX.  Infusion time may be prolonged (up to 6 hours) in patients 
experiencing pharyngolaryngeal dysesthesia. 
 
Oxaliplatin is unstable in the presence of chloride or alkaline solutions.  Do NOT mix or 
administer oxaliplatin with saline or other chloride-containing solutions.  Do NOT 
administer other drugs or solutions in the same infusion line.  Flush IV lines/catheters 
with Dextrose 5% in Water both before and after oxaliplatin administration. 
 
Toxicity 
 
The most commonly observed oxaliplatin toxicities include neurotoxicity, GI toxicity, and 
myelosuppression.  Three neurotoxicity syndromes have been seen:   
 
Acute sensory neuropathy develops within hours to 2 days after oxaliplatin 
administration.  Symptoms include paresthesia, dysesthesia, and hypothesia of the 
hands, feet and perioral regions.  Jaw spasm, abnormal tongue sensation, dysarthria, 
eye pain and a sensation of chest pressure have also been noted.  Acute sensory 
neuropathy symptoms may be exacerbated by exposure to cold temperature or cold 
objects.  Symptoms are reversible, usually resolving within 14 days and commonly 
recurring with further dosing.  This syndrome has been observed in about 56% of 
patients receiving oxaliplatin with 5-FU and leucovorin. 
 
Acute pharyngolaryngeal dysesthesia is reported to occur in 1-2% of patients.  This 
syndrome is characterized by a subjective sensation of difficulty breathing or swallowing 
without laryngospasm or bronchospasm or objective evidence of hypoxia.  Avoidance of 

 
16 
cold drinks, food and air is suggested to order to minimize pharyngolaryngeal 
dysesthesia.  Antianxiety agents (e.g. lorazepam) may be used to treat 
pharyngolaryngeal dysesthesias once oxygen saturation has been documented to be 
normal. 
 
Peripheral neuropathy persisting > 14 days is characterized by paresthesias, 
dysesthesias, and hypothesia.  Abnormalities in proprioception may also be seen.  
Symptoms of persistent neuropathy may improve upon discontinuation of oxaliplatin. 
 
Various agents have been used in an attempt to minimize neurotoxicity of oxaliplatin 
(e.g. carbamazepine, Mg++, Ca++).  Their routine use requires further confirmation of 
efficacy.  They may be used in this study at the discretion of the treating physician. 
 
Gastrointestinal toxicities include nausea, vomiting (oxaliplatin is considered to be 
moderately emetogenic) and diarrhea. 
 
Neutropenia is reported in 73% of patients receiving oxaliplatin with 5-FU and 
leucovorin (44% grade 3 or 4). Grade 3 or 4 thrombocytopenia is reported to occur in 
4% of patients receiving the combination. 
 
Allergic reactions, similar to those seen with other platinum compounds, have also been 
observed in patients treated with oxaliplatin.  Reactions range from rash to anaphylaxis 
 
Rarely, oxaliplatin has been associated with pulmonary fibrosis, which may be fatal.  
Oxaliplatin should be discontinued in the presence of unexplained pulmonary symptoms 
(e.g. nonproductive cough, dyspnea) or pulmonary infiltrates until interstitial lung 
disease or pulmonary fibrosis have been ruled out. 
 
Recent reports of oxaliplatin extravasation suggest that tissue necrosis may result and 
that oxaliplatin should be considered a vesicant.  No standard treatment exists for 
oxaliplatin extravasation although heat and sodium thiosulfate have both been 
suggested. 
 
Veno-occlusive disease (VOD) of the liver is a rare complication associated with 
oxaliplatin and 5-FU.  Clinical manifestations of VOD include hepatomegaly, ascites, 
and jaundice.  Histologically, VOD is characterized by diffuse damage in the 

 
17 
centrilobular zone of the liver.  Sequelae of VOD include hepatomegaly, splenomegaly, 
portal hypertension, and esophageal varices. A recent analysis of resected liver 
metastases in 153 patients indicated histological findings consistent with VOD in 6/27 
patients who received 5-FU alone, 4/17 patients who received 5-FU and irinotecan, 
20/27 patients who received 5-FU and oxaliplatin, and 14/16 who received 5-FU, 
oxaliplatin and irinotecan.  The remaining 66 patients had not received chemotherapy 
prior to resection.  There were no such findings in these patients. 
 
For more information on toxicities associated with oxaliplatin, please see the package 
insert. 
 
7.2.2 5-FLUOROURACIL (5-FU: FLUOROURACIL: ADRUCIL®) 
 
 
 
Please refer to the package insert for complete product information. 
 
Availability 
5-FU is commercially available as a 50 mg/mL solution for injection in 10 mL, 20 mL, 50 
mL and 100 mL vials 
 
Preparation 
Inspect for precipitate:  if found, agitate or gently heat in water bath.  
 
Bolus injections are prepared using undiluted drug. 
 
46-48 hour infusion of 5-FU should be prepared for administration via ambulatory 
infusion pump according to the individual institution’s standards.  These solutions may 
be prepared in D5W or 0.9% NaCl.  5 FU should not be mixed in the same solution with 
most parenteral antiemetics. 
 
Storage and Stability 
Intact vials should be stored at room temperature and protected from light.  Slight yellow 
discolor does not usually indicate decomposition.  Stability in ambulatory pumps varies 
according to the pump, manufacturer of drug, concentration and diluent.  Please refer to 
appropriate reference sources for additional information. 
 
 

 
18 
Administration 
In this study, 5-FU is administered as a 300 mg/m2 IV bolus followed by 2400 mg/m2 by 
IV infusion over 46 to 48 hours. 
 
Toxicity 
Nausea, diarrhea, vomiting (mild); stomatitis (5-8 days after treatment initiation); 
myelosuppression; granulocytopenia (9-14 days); thrombocytopenia (7-14 days); 
alopecia; loss of nails; hyperpigmentation: photosensitivity; maculopapular rash; palmar-
plantar erythrodysethesias: (42-82% receiving continuous infusion); CNS effects:  
cerebral ataxia (rare); cardiotoxicity:  MI, angina: asymptomatic S-T changes 68%; 
ocular effects: excessive lacrimation and less commonly, tear duct stenosis. 
 
Drug Interactions 
Leucovorin enhances the cytotoxicity of 5-FU by forming a more stable tertiary complex 
with thymidylate synthase.  Concomitant administration of 5-FU with warfarin has been 
reported to result in increased INR/prolonged prothrombin time.  Patients receiving both 
drugs should be followed with weekly INRs. 
 
7.2.3 LEUCOVORIN CALCIUM (FOLINIC ACID; CALCIUM FOLINATE; 
CITROVORUM FACTOR; N 5-FORMYLTETRAHYDROFOLATE; 5-FORMYL-
FH4; FOLINIC ACID). 
 
Levoleucovorin (200 mg/m2) may be substituted for leucovorin (400 mg/m2) in this 
study. 
 
Please refer to the package insert for complete product information for levoleucovorin 
and leucovorin. 
 
Availability 
Leucovorin calcium is commercially available in: 50 mg, 100 mg, 350 mg vials for 
reconstitution. 
 
Storage and Stability 
Intact vials should be stored at room temperature and protected from light.  Solutions 
reconstituted with BWI are stable for at least 7 days at room temperature. 
 

 
19 
Preparation 
Leucovorin may be reconstituted with Bacteriostatic Water for Injection (BWI) or with 
Sterile Water For Injection.  Solutions should be further diluted in D5W, 0.9% NaCl or 
Ringers solution for infusion over two hours. 
 
Administration 
Leucovorin will be administered as a 400mg/m2 IV infusion over 2 hours after oxaliplatin 
administration.  Leucovorin may also be administered concurrently with oxaliplatin as a 
separate IV infusion. 
 
Toxicity 
The only adverse reactions associated with leucovorin are allergic reactions.  These are 
extremely uncommon. 
 
7.2.4 IRINOTECAN (CPT-11, CAMPTOSAR). 
 
Availability 
Irinotecan is commercially available in a concentration of 20mg/mL in 2mL, 5mL, and 25 
mL vials.  
 
Storage and Stability  
Intact vials should be stored at controlled room temperature 59 to 86 degrees 
Fahrenheit (15 to 30 degrees Celsius) and protected from light. Solutions diluted in 
D5W are reported to be stable for 48 hours under refrigeration and protected from light. 
Irinotecan solutions should not be frozen as the drug may precipitate.  
 
Preparation  
Irinotecan is diluted in 5% dextrose (D5W) 500 mL to a final concentration of 0.12 – 1.1 
mg/mL.  
 
Administration 
 In this study, irinotecan is administered by IV infusion over 90 minutes 
 
Toxicity  
Virtually all phase I and II studies of irinotecan have reported neutropenia and/or late 
diarrhea (diarrhea occurring more than 24 hours after the irinotecan administration as 

 
20 
the dose limiting toxicities (depending on the schedule)). Other commonly observed 
adverse events include nausea and vomiting, anorexia, abdominal cramping, alopecia, 
asthenia, lymphocytopenia, and anemia. Dehydration has occurred as a consequence 
of diarrhea, particularly when associated with severe vomiting. Patients may have an 
acute syndrome of lacrimation, diaphoresis, abdominal cramping, and diarrhea (early 
diarrhea) during or shortly after irinotecan administration; this syndrome is thought to be 
cholinergically mediated, and may be treated and subsequently prevented with atropine. 
Sporadic cases of pulmonary toxicity, manifested as shortness of breath, non-
productive cough and transient infiltrates on chest x-ray have been reported. Infrequent 
occurrences of mucositis or colitis (sometimes with gastrointestinal bleeding) have been 
observed. Occasionally, abnormalities of serum creatinine, hepatic enzymes, or 
thrombocytopenia have been observed.  
 
Please refer to the package insert for further information regarding irinotecan. 
 
Concerns related to adverse effects: 
• Bone marrow suppression: [U.S. Boxed Warning]: May cause severe 
myelosuppression. Deaths due to sepsis following severe myelosuppression have been 
reported. Therapy should be temporarily discontinued if neutropenic fever occurs or if 
the absolute neutrophil count is <1000/mm3. The dose of irinotecan should be reduced if 
there is a clinically significant decrease in the total WBC (<200/mm3), neutrophil count 
(<1500/mm3), hemoglobin (<8 g/dL), or platelet count (<100,000/mm3). Routine 
administration of a colony-stimulating factor is generally not necessary, but may be 
considered for patients experiencing significant neutropenia. 
• Colitis: Colitis, complicated by ulceration, bleeding, ileus, and infection has been 
reported. 
• Diarrhea: [U.S. Boxed Warning]: Severe diarrhea may be dose-limiting and potentially 
fatal; two severe (life-threatening) forms of diarrhea may occur. Early diarrhea occurs 
during or within 24 hours of receiving irinotecan and is characterized by cholinergic 
symptoms (eg, increased salivation, diaphoresis, abdominal cramping); it is usually 
responsive to atropine. Late diarrhea occurs more than 24 hours after treatment which 
may lead to dehydration, electrolyte imbalance, or sepsis; it should be promptly treated 
with loperamide. Patients with diarrhea should be carefully monitored and treated 
promptly. 

 
21 
• Hypersensitivity reactions: Severe hypersensitivity reactions have occurred.  
• Renal toxicity: Renal impairment and acute renal failure have been reported, possibly 
due to dehydration secondary to diarrhea. 
Disease-related concerns: 
• Bowel obstruction: Patients with bowel obstruction should not be treated with 
irinotecan until resolution of obstruction.  
• Hepatic impairment: Use with caution in patients with hepatic impairment. 
• Hyperbilirubinemia: Patients with even modest elevations in total serum bilirubin levels 
(1-2 mg/dL) have a significantly greater likelihood of experiencing first-course grade 3 or 
4 neutropenia than those with bilirubin levels that were <1 mg/dL. Patients with 
abnormal glucuronidation of bilirubin, such as those with Gilbert's syndrome, may also 
be at greater risk of myelosuppression when receiving therapy with irinotecan. Use 
caution when treating patients with known hepatic dysfunction or hyperbilirubinemia; 
dosage adjustments should be considered. 
 
7.3 
DOSE MODIFICATIONS AND TOXICITY MANAGEMENT 
 
All dose adjustments should be based on the worst preceding toxicity, graded using the 
National Cancer Institute (NCI)Common Terminology Criteria for Adverse Events 
(CTCAE) (version 4.0).   
 
If more than one of the dose modifications apply, use the most stringent (i.e., the 
greatest dose reduction).  Dose modifications are cumulative and permanent.   
 
If treatment is held for any treatment-related toxicities for > 3 weeks, patients should 
discontinue all protocol therapy.  
 
The dose of leucovorin is not modified for toxicity, but is omitted if fluorouracil is omitted.  
 
Dose modifications for toxicity are adapted from Conroy, T et al. FOLFIRINOX versus 
Gemcitabine for Metastatic Pancreatic Cancer. N Engl J Med 2011; 364:1817-1825.  
 
 
 

 
22 
7.3.1 HEMATOLOGIC TOXICITY 
 
On day 1 of treatment, hold all chemotherapy until the granulocyte count is ≥ 1500/ul 
and the platelet count is ≥75000/ul. 
 
Doses according to the blood counts at the beginning of a cycle (Day 1) 
Blood counts 
on Day 1 
DELAY OF 
CYCLE 
DOSE REDUCTION 
 
 
irinotecan 
oxaliplatin 
fluorouracil 
Granulocytes 
<1500/ul 
Hold treatment 
until 
granulocytes > 
1500/ul  
 
 
 
1st  occurrence: 
reduce to 75% 
of previous dose 
 
2nd occurrence: 
maintain 
previous dose 
 
3rd occurrence: 
treatment 
discontinuation 
1st  occurrence : 
no reduction  
 
 
2nd occurrence: 
reduce to 75% 
of previous dose 
 
3rd occurrence: 
treatment 
discontinuation 
1st  occurrence: 
delete bolus 5FU 
Platelets 
<75000/ul 
Hold the 
treatment until 
platelets 
>75000 
 
 
1st occurrence: 
no reduction 
 
 
2nd occurrence: 
reduce to 75% 
or original dose 
 
3rd occurrence: 
treatment 
discontinuation 
1st  occurrence: 
reduce to 75% 
of previous dose 
 
2nd occurrence: 
maintain 
previous dose 
 
3rd occurrence: 
treatment 
discontinuation 
1st occurrence: 
reduce bolus and  
infusion to 75% 
of previous 
doses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
23 
Doses for neutropenic fever or nadir cytopenias 
 
ADVERSE EVENTS 
REDUCTION OF DOSE FOR 
SUBSEQUENT CYCLES 
Febrile neutropenia 
or 
Grade 4 neutropenia  
 
1st occurrence: reduce irinotecan to 75% of 
previous dose and delete the bolus 5FU 
dose 
 
2nd occurrence: reduce oxaliplatin to 75% of 
previous dose 
 
3rd occurrence: treatment discontinuation 
Grade 4 Thrombocytopenia 
1st occurrence: reduce oxaliplatin and 5FU 
(bolus and infusion) to 75% of previous dose 
 
2nd occurrence: reduce irinotecan and 5FU 
(bolus and infusion) to 75% of previous dose 
 
3rd occurrence: treatment discontinuation 
 
 
7.3.2.  DIARRHEA 
 
Patients must be instructed in the use of loperamide for diarrhea, and must have a supply of 
this drug upon starting FOLFIRINOX.  Patients should not be retreated with irinotecan until 
recovery from diarrhea to < grade1 (without loperamide for at least 24 h) has occurred.  
Diarrhea is attributed to chemotherapy UNLESS a specific infectious agent is isolated. 
 
ADVERSE EVENTS 
 
REDUCTION OF DOSE FOR 
SUBSEQUENT CYCLES 
 
Diarrhea grade 3-4 
or 
Diarrhea + fever 
and/or 
neutropenia grade 3-4 
1st occurrence: reduce irinotecan to 75% of 
previous dose and delete bolus 5FU dose 
 
2nd occurrence: reduce oxaliplatin and 
continuous infusion 5FU to 
75% of previous doses 
 
3rd occurrence: treatment discontinuation 
Diarrhea ≥ 48 h despite high 
doses loperamide 
Hold FOLFIRINOX until resolves to < 
grade1 for at least 24 hrs. 
 
No dose reductions after complete recovery, 
unless gr 3-4 diarrhea, or diarrhea + fever 
and/or concomitant neutropenia gr 3-4 

 
24 
7.7.3.  MUCOSITIS OR HAND-FOOT SYNDROME 
 
Grade > 2:  Hold treatment until toxicity resolves to a < grade1, then resume oxaliplatin, 
irinotecan, and leucovorin at 100% of the previous dose and fluorouracil (bolus + 
infusional 5-FU) at 75% of the previous dose for all subsequent doses.   For subsequent 
grade > 2 recurrence(s), hold treatment until toxicity resolves to a < grade1, then 
resume oxaliplatin, irinotecan, and leucovorin at 100% of the previous dose and 
fluorouracil (bolus + infusional 5-FU) at 75% of the previous dose. 
 
7.3.4.  CARDIAC TOXICITY 
 
For any cardiac arterial thrombotic event or ischemic event (angina, myocardial 
infarction) discontinue all protocol therapy. 
 
7.3.5.  INCREASED BILIRUBIN 
 
In case of elevation of bilirubin, evaluation to exclude biliary obstruction or progressive 
disease is recommended.  For bilirubin is >1.5x ULN, omit irinotecan until bilirubin is 
<1.5xULN. 
 
7.3.6.  NEUROTOXICITY 
 
Toxicity Scale for the Sensory Neuropathies Associated with Oxaliplatin 
 
                    Symptoms 
Grade 1 
Paresthesias/dysesthesias* of short duration that resolve and do not 
interfere with function 
Grade 2 
Paresthesias/dysesthesias* interfering with function, but not with 
activities of daily living (ADL) 
Grade 3 
Paresthesias/dysesthesias* with pain or with functional impairment that 
also interfere with ADL. 
Grade 4 
Persistent paresthesias/dysesthesias* that are disabling or life 
threatening. 
 
* May be cold-induced 
 
 
For grade 2 neurotoxicity persisting between treatments: Reduce   
 
oxaliplatin to75% of the previous dose for all subsequent cycles. 

 
25 
 
 
For grade 3 neurotoxicity resolving to < grade 2 between treatments:   
 
Reduce oxaliplatin to 75% of the previous dose for all subsequent cycles. 
 
 
For grade 3 neurotoxicity persisting between treatments:  Discontinue  
 
Oxaliplatin.  Patients should continue to receive other protocol therapy. 
 
 
For grade 4 neurotoxicity:  Discontinue oxaliplatin.  Patients should 
 
continue to receive other protocol therapy. 
 
 
7.3.7.  OTHER TOXICITIES 
 
For > grade 2 toxicity attributed to treatment and not described above (except anemia 
and alopecia), hold treatment until toxicity resolves to < grade 1 and resume treatment 
with the agent that is thought to be causing the toxicity at 75% of the previous dose and 
all other agents at full dose. 
 
If grade 3-4 toxicity is clearly secondary to a single agent and is thought to be 
cumulative, the causative agent may be discontinued with the approval of the principal 
investigator.  Similarly, a causative agent may be discontinued for grade 2 allergic 
reaction and must be discontinued for grade 3-4 allergic reaction. 
 
7.3.8.  EXTRAVASATION 
 
Extravasation of oxaliplatin is reported to cause necrosis.  Extravasation should   be 
treated according to institutional guidelines. 
 
7.3.9.  DOSE MODIFICATION FOR OBESE PATIENTS 
 
There is no clearly documented adverse impact of treatment of obese patients when 
dosing is performed according to actual body weight.  Therefore, all dosing is to be 
determined solely by the patient’s BSA as calculated from actual weight. 
 
7.4 
CONCOMITANT MEDICATIONS 
7.4.1 Anti-emetics: Due to the emetogenic nature of this regimen, Emend will be 
administered with each cycle in addition to concomitant antiemetics at the 
discretion of the treating physician 

 
26 
 
7.4.2 Loperamide:  For symptoms of diarrhea and/or abdominal cramping that occur at 
any time during a treatment cycle patients will be instructed to begin taking 
loperamide.  Loperamide should be started at the earliest sign of (1) a poorly 
formed or loose stool or (2) the occurrence of 1 to 2 more bowel movements than 
usual in 1 day or (3) an increase in stool volume or liquidity.  Loperamide should 
be taken in the following manner: 4 mg at the first onset of diarrhea, then 2 mg 
every 2 hours around the clock until diarrhea-free for at least 12 hours.  Patients 
may take loperamide 4 mg every 4 hours during the night.  The maximum daily 
dose of loperamide is 16 mg/day. 
 
7.4.3 Antibiotics: Oral fluoroquinolone treatment may be initiated for ANC<500 or 
diarrhea for >24 hours despite loperamide, at the discretion of the treating 
physician. 
 
 
7.4.4 Anticoagulants: Prophylactic or therapeutic doses of Coumadin or low-molecular 
weight heparin are permitted. 
7.4.5 Low-dose aspirin (≤ 325 mg/d):  Aspirin may be continued if the patient was on 
this prior to enrollment. 
7.4.6 Growth Factors:  Pegfilgrastim (Neulasta) will be administered with each cycle of 
therapy but can be omitted after the first cycle at the discretion of the treating 
physician for hyper-leukocytosis on day 1 of treatment. 
 
7.4.7 Ca++/Mg++:  Patients will receive supplemental calcium and magnesium 
infusions pre- and post-oxaliplatin at the discretion of the treating physician. 
 
 
8.0 
REQUIRED CLINICAL AND LABORATORY EVALUATIONS 
 
To be completed within 14 DAYS (2 WEEKS) before the first dose of study drug: 
-All blood work, History, Physical Examination, and Performance Status 
To be completed within 21 DAYS (3 WEEKS) before the first dose of study drug: 
-Imaging studies (CT or MRI, and PET scans) 
-CT with pancreatic protocol is recommended at baseline and pre-
operatively; for patients who cannot undergo CT, MRI is allowed 

 
27 
To be completed within 42 DAYS (6 WEEKS) before the first dose of study drug: 
-Endoscopic Ultrasound (EUS) 
 
Tests & 
Observations 
Prior to 
Registr-
ation 
Day 1 of  
each 
cycle* (-1/ 
+3 day 
window) 
 
Day 8 of 
each 
cycle* (+/- 
1 day 
window) 
Pre-
Operative  
(within 4 
weeks  
prior to 
surgery) 
Day 1 of 
cycle 7 
(within 12 
weeks of 
surgery)  
Post  
Treatment 
Follow-UpC (+/- 
14 day window) 
Surgical evaluation 
History   
Physical Exam  
Height 
Weight/BSA 
Performance Status 
Toxicity 
AssessmentVital 
SignsK  
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
x 
x 
 
 
 
xJ 
 
 
xJ 
xJ 
xJ 
x 
 
x 
x 
 
x 
x 
xx 
 
x 
x 
 
x 
x 
x 
Laboratory StudiesG: 
 CBC, Diff, Platelets 
 Serum Chemistries+ 
 PT/INR++ 
 CA 19-9, CEA 
 Pregnancy test # 
 
Plasma samples## 
Archival Tissue 
 
x 
x 
x 
x 
x 
 
x 
 
xI 
 
x 
x 
 
 
 
 
x 
x 
 
x 
x 
x 
x 
 
 
xF 
 
x 
x 
 
x 
 
 
x 
 
x 
x 
 
x 
 
 
xD 
Staging: 
CT (or MRI)^ 
PET 
Endoscopic 
Ultrasound (EUS) 
 
x 
x 
x 
 
 
xA 
 
 
 
XH 
 
xB 
 
 
xE 
 
* 
Laboratory studies must be drawn within 24 hours of administration of drugs) 
+ 
Serum chemistry panel will include serum creatinine, BUN, electrolytes (Na, K, Cl, Bicarb), 
AST/ALT, Alk Phos, Bili, and albumin  
++ 
PT/INR should be monitored weekly for those taking coumadin or warfarin 
# 
For women of child-bearing potential only 
## 
10-15 ml plasma for cryopreservation. This is an optional procedure. See Appendix A for 
additional information. 
^ 
CT prior to surgery should be performed using pancreatic protocol.  For patients who are unable 
to undergo CT, MRI may be used 
A 
After initial 3 cycles of neoadjuvant chemotherapy, prior to cycle 4 
B 
Endoscopic ultrasound is optional if deemed necessary for surgical assessment 
C 
Initiated within 4 weeks of completing all treatment and continue every 3 months for three years, 
then every six months for two years, then annually or until disease recurrence or death  

 
28 
D 
Plasma samples will be drawn during follow-up every 3 months for three years, then every 6 
months for two years, then annually until disease progression. A sample will also be drawn at the 
time of disease progression. 
E  
Initiated within 4 weeks of completing all treatment, then every 6 months for three years, and then 
annually for 2 years or until disease recurrence 
F 
Plasma samples will be done post-cycle 6 and within 3-8 weeks of surgery 
G 
Cycle 1 Day 1 laboratory studies must be done within 24 hours of the start of study drug 
H 
CT scan will be done post-cycle 6 and within 2-8 weeks of surgery 
I 
Archival tissue from a prior biopsy may be accessed by the researchers at any time during 
participation on study. This is an optional procedure. 
J 
Cycle 1 only 
K 
Temperature, heart rate and blood pressure will be measured 
 
 
9.0  CRITERIA FOR RESPONSE AND PROGRESSION 
 
At baseline, tumor lesions will be characterized as either measurable or non-
measurable. 
 
Treating physicians and investigators will utilize RECIST version 1.1 (Eisenhauer et al. 
New response evaluation criteria in solid tumors: Revised RECIST guideline [version 
1.1]. European Journal of Cancer 45 (2009) 228-247) in assessing response in all 
patients enrolled in this study, as detailed herein: 
 
 
9.1  
DEFINITIONS  
 
Measurable disease: 
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: 
• 10mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 20mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be >15mm in short axis when assessed by CT scan (CT scan slice 

 
29 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed.  
 
Non-measurable disease: 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph 
nodes with >10 to <15mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
 
9.2   METHODS OF MEASUREMENT 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging based evaluation should always be done rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
exam. 
 
Computed tomography (CT)/MRI - CT and MRI might be the best currently 
available and reproducible methods to measure target lesions selected for response 
assessment. Conventional CT and MRI should be performed with cuts of 5 mm or 
less in slice thickness contiguously. Spiral CT should be performed using a 5-mm 
contiguous reconstruction algorithm. 
 
9.3  
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
 
Target lesions:  
When more than one measurable lesion is present at baseline all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline (this means in instances where patients have only one or two 
organ sites involved a maximum of two and four lesions respectively will be recorded). 
 
Lymph nodes: These merit special mention since they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. Pathological nodes 

 
30 
which are defined as measurable and may be identified as target lesions must meet the 
criterion of a short axis of >15mm by CT scan. Only the short axis of these nodes will 
contribute to the baseline sum. The short axis of the node is the diameter normally used 
by radiologists to judge if a node is involved by solid tumor. Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan this 
is almost always the axial plane; for MRI the plane of acquisition may be axial, saggital 
or coronal). The smaller of these measures is the short axis. All other pathological 
nodes (those with short axis >10mm but <15 mm) should be considered non-target 
lesions. Nodes that have a short axis <10mm are considered non-pathological and 
should not be recorded or followed. 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for 
all target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added 
into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the 
disease. 
 
Non-target lesions:  
All non-measurable lesions (or sites of disease) plus any 
measurable lesions over and above the 5 listed as target lesions. Measurements 
are not required but these lesions should be noted at baseline and should be followed 
as “present” or “absent.” 
 
9.4  
EVALUATION OF BEST OVERALL RESPONSE 
 
In general, the patient’s best response assignment will depend on the achievement 
of both measurement and confirmation criteria as outlined below and summarized in 
Table 1: 
 
Complete Response (CR): Disappearance of all target lesions. 
Any pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 

 
31 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 
one or more new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of diameters while on 
study. 
 
 
   Table 1: Response Assessment in Patients with Measurable Disease
 
 
 
Every effort should be made to document the objective progression even after 
discontinuation of treatment 
 
Response duration will be measured from the time measurement criteria for CR/PR 
(whichever is first recorded) are first met until the first date that recurrent or PD is 
objectively documented. 
 

 
32 
Stable disease duration will be measured from the time of start of therapy until the 
criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started. 
 
9.5  
EVALUATION OF RESPONSE FOR NON-MEASURABLE DISEASE 
 
When the patient has only non-measurable disease, the same general concepts apply 
here as noted above. However, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified (by 
definition: if all lesions are truly non-measurable) a useful test that can be applied when 
assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease: 
i.e. an increase in tumor burden representing an additional 73% increase in ‘volume’ 
(which is equivalent to a 20% increase diameter in a measurable lesion). Examples 
include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as 
‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be 
ideal to have objective criteria to apply to non-measurable disease, the very nature of 
that disease makes it impossible to do so, therefore the increase must be substantial. 
 
It is assumed that at each protocol specified time point, a response assessment occurs.  
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used. 
 
 

 
33 
 
 
 
 
10.0  SUBJECT DISCONTINUATION 
 
Treatment will continue for 6 cycles (12 weeks) pre-operatively and 6 cycles (12 weeks) 
post-operatively, or until disease progression, or until unacceptable toxicity as specified 
in the protocol (section 7.3).   Patients who are deemed unresectable at the time of 
surgery will be discontinued from study treatment. 
 
Patients who complete the study treatment phase without disease progression will enter 
a post-study surveillance phase.  They will undergo history, physical, and lab 
assessments at three month intervals and cross-sectional imaging at 6 months intervals 
for three years, and then at six month intervals for two additional years.  After five years, 
patients will be followed annually until death; surveillance imaging and lab assessments 
are optional after five years.   
 
In addition, subjects who meet the following criteria should be discontinued from study 
treatment:  

 
34 
o Any grade 3 or 4 toxicity that does not resolve within 3 weeks of holding 
treatment. 
o Unwillingness or inability of subject to comply with study requirements  
o Determination by the investigator that it is no longer safe for the subject to 
continue therapy, or that the constraints of this protocol are detrimental to the 
patient’s health 
o The patient no longer wishes to continue protocol therapy 
All subjects will be followed for survival. 
 
11.0   
STUDY DISCONTINUATION 
 
The Principal Investigator has the right to terminate this study at any time if the 
incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to subjects.  
 
12.0  STATISTICAL METHODS 
 
The primary objective of this phase II study is to determine the proportion of patients 
who are alive and free from progression of disease at 12 months from the first cycle of 
neoadjuvant mFOLFIRINOX. Thus, the primary endpoint of this study is 12-month PFS 
rate in patients with resectable non-metastatic pancreatic cancer after receiving 
modified FOLFIRINOX in the neoadjuvant and adjuvant settings.  With the current 
standard of care (adjuvant gemcitabine) patients would be expected to have a 
progression-free survival rate at 12 months of 54% (the corresponding median PFS is 
13.4 months) (2).  Alternatively, the regimen (peri-operative mFOLFIRINOX) will be 
considered worthy of further study if its true progression-free survival rate at 12 months 
is 66% or better (the corresponding median PFS is 19.7 months).  
 
We will enroll 46 patients in this trial. Using a one-sided 0.10-alpha level exact test, we 
will have approximately 82% power to detect a survival proportion at 12 months of 0.66 
assuming that the PFS proportion at 12 months under the null hypothesis is 0.50. 
Therefore, this treatment can be considered for further investigation if at least 28 of the 
46 patients are alive at 12 months without progression. 

 
35 
 
Upon completion of the study we will summarize PFS and overall survival using Kaplan-
Meier curves.  Rates of toxicity will be reported along with exact binomial confidence 
intervals.  We will use proportional hazards regression to determine if overall survival 
and PFS are related to the occurrence of toxicity or demographic variables. 
 
Any additional correlative studies (PET scan) will include proportional hazards 
regressions to determine if there are demographic or clinical parameters that can be 
used to identify patients with longer or shorter anticipated PFS or OS.  This trial is not 
powered for these correlative secondary outcomes. 
 
We anticipate accrual will be completed in five years, based on the number of 
pancreatic resections for pancreatic adenocarcinoma that are performed annual at Yale 
New Haven Hospital annually (>40 per year).   
 
 
13.0  ADVERSE EVENT ANALYSIS, DEFINITION, AND REPORTING 
 
13.1  SAFETY ANALYSIS 
 
Safety will be analyzed for patients treated in this study.   
 
At each visit, a brief focused history will be obtained and any indication of treatment 
related toxicity will be evaluated by appropriate examination and/or 
laboratory/radiographic studies. 
 
Safety analyses will include summaries of adverse event rates and changes in 
laboratory results, as well as number of CTCAE toxicity grades for both laboratory and 
non-laboratory data. 
 
The evaluation period should extend from date of first treatment until at least 30 days 
(or longer if so specified) from the last dose or until resolution from all acute toxicities 
associated with the drug administration. 
 
 
 

 
36 
13.2  DEFINITION OF ADVERSE EVENT TERMS 
 
Adverse Event – Any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medical treatment or procedure regardless of whether it is considered related to the 
medical treatment or procedure (attribution of unrelated, unlikely, possible, probable, or 
definite). [NIH Guidelines, January 2001] 
 
Serious Adverse Event (SAE) – Any adverse drug experience occurring at any dose 
that results in any of the following outcomes: 
• death, 
• a life-threatening adverse drug experience, 
• in patient hospitalization or prolongation of existing hospitalization, 
• any persistent or significant disability/incapacity, 
• or a congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  
 
“Serious” Versus “Severe” Adverse Events – There is a distinction between serious and 
severe AEs.  Assessment of seriousness will be made solely by the serious criteria 
listed above.  Severity of AEs will be graded according to the NCI Common Terminology 
Criteria for Adverse Events v3.0.  Therefore, serious events will not be automatically 
considered severe.  For example, a stroke that results in only a limited degree of 
disability may be considered a mild (not severe) stroke, but it would still meet serious 
criteria and thus, be captured as an SAE.  Similarly, severe events may not always be 
serious.  An example would be an episode of severe, transient nausea which persists 
for several hours.  This would be classified as a “severe” episode of nausea, but if it did 
not require treatment, intervention, or somehow meet other serious criteria, it would not 
be considered an SAE. 
 
Life-threatening Adverse Drug Experience – Any adverse drug experience that places 
the patient or subject, in the view of the investigator, at immediate risk of death from the 

 
37 
reaction as it occurred, i.e. it does not include a reaction that, had it occurred in a more 
severe form, might have caused death.  
 
Unexpected Adverse Drug Experience – Any adverse drug experience, the specificity or 
severity of which is not consistent with the current investigator brochure; or, if an 
investigator brochure is not required or available, the specificity or severity of which is 
not consistent with the risk information described in the general investigational plan.  
“Unexpected” as used in this definition, refers to an adverse drug experience that has 
not been previously observed (e.g., included in the investigator brochure) rather than 
from the perspective of such experience not being anticipated from the pharmacological 
properties of the pharmaceutical product. 
 
13.3  TOXICITY GRADING 
 
Toxicities will be graded according to the current version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0.  The full text of the NCI 
CTCAE is available online at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
 
If a certain event or symptom is not described in the CTCAE grades, use the following 
grading scale: 
• Mild: awareness of event but easily tolerated 
• Moderate: discomfort enough to cause some interference with usual activity 
• Severe: inability to carry out usual activity 
• Very Severe: debilitating, significantly incapacitates patient despite symptomatic 
therapy 
 
13.4  TOXICITY ATTRIBUTION 
 
Assessment of attribution is made by consideration of all clinically relevant data prior to, 
during, and after occurrence of the event, including diagnostic tests to assess the cause 
of the event.  Clinically relevant data include, but are not limited to; underlying disease, 
past and present medical history (all concurrent non-malignant disease), concurrent 
medications, and timing between event and drug administration.  The mechanism of 
action and prior toxicology of the study drug should be considered. 
 

 
38 
An adverse event is associated with the use of the drug when there is a reasonable 
possibility that the experience may have been caused by the drug.  
 
Attribution Standards per NCI – CTEP: 
 
Unrelated: The Adverse Event is clearly not related to the investigational agent(s) Unlikely:    
The Adverse Event is doubtfully related to the investigational agent(s) 
Possible:   The Adverse Event may be related to the investigational agent(s) 
Probable:   The Adverse Event is likely related to the investigational agent(s) 
Definite:     The Adverse Event is clearly related to the investigational agent(s) 
 
14.0   YALE PRINCIPAL INVESTIGATOR SAE REPORTING REQUIREMENTS 
 
14.1  EXPEDITED REPORTING OF UNEXPECTED SAES 
 
AEs classified as “serious” and “unexpected” that are possibly, probably, or definitely 
attributed to drug administration, or SAEs whose frequency exceeds expectations, 
require expeditious handling and reporting. 
 
The PI will promptly investigate all safety information related to an adverse experience.  
If the results of the PI’s investigation show an adverse drug experience not initially 
determined to be reportable (based on whether the event is serious, unexpected, and 
associated with drug administration) is so reportable, the PI will report such experience.  
Follow-up information to a safety report shall be submitted as soon as the relevant 
information is available. 
 
Reporting to the Yale Human Investigation Committee 
 
All SAEs, whether originating at Yale or a collaborating center, meeting the 
criteria for expedited reporting will be reported to the Yale University Human 
Investigation Committee (HIC) using HIC Form 710 FR 4 as per IRB Policy 710. 
 
The Yale University Human Investigation Committee expedited reporting criteria 
are: 
a.   Serious AND unanticipated AND possibly, probably or definitely 
related events; 

 
39 
and 
b.   Anticipated Adverse Events occurring with a greater frequency than 
expected. 
 
The HIC does not require reporting of any other Adverse Event type.  A copy of 
the Yale IRBPolicy 710 Reporting Unanticipated Problems Involving Risks to 
Subjects or Others, including Adverse Events is available at:  
http://www.yale.edu/hrpp/policies/documents/NewIRBPolicy710_UPIRSOSAE_4.
3.2014_withflowchart_vF.PDF 
 
 
14.2  DURATION OF REPORTING OF SAES 
 
From the date of first treatment until 30 days (unless otherwise specified) subsequent to 
last treatment or withdrawal of subject, new onset adverse events will be captured.  
Follow-up and reporting of these events will follow the same procedure as for AEs 
observed during the study period.  In addition, any unexpected Serious Adverse Event 
that occurs more than 30 days after drug administration but is possibly, probably or 
definitely attributed to drug administration will be recorded and reported. 
 
 
15.0   YALE SAFETY REPORTING AND MONITORING (DSMP) 
 
The principal investigator at the Yale Cancer Center will monitor the clinical trial for 
safety. The principal investigator will assess all expedited adverse events and will 
periodically review all adverse events observed on the trial.  Yale Cancer Center 
standard operating procedures (SOPs) for assessment and reporting of adverse events 
are followed which are in compliance with FDA 21 Code of Federal Regulations Part 
312.32 and 312.33.  
 
The clinical trial data consisting of all required observations, AEs, and laboratory data 
will be entered into a computerized database (OnCore) in a timely manner.  The 
accuracy and completeness of the database, timely submission of SAEs and 
compliance with the protocol, is assured by periodic auditing conducted by the Yale 
Cancer Center Office of Protocol Review and Monitoring, which reports to the Yale Data 
and Safety Monitoring Committee (DSMC).  Safety data will be submitted to DSMC at 

 
40 
least once yearly or more often as required by the DSMC.  On a regular interval basis, 
status reports of all laboratory parameters, AEs and SAEs are reviewed by the PI to 
view composite data across subjects.  Regular meetings are held to discuss ongoing 
patient treatment and adverse events. 
 
The Yale DSMC will perform an interim safety analysis after enrollment of 20 patients to 
determine whether there are any safety issues and to assess whether it is safe to 
continue enrollment.  Enrollment will be suspended until approval is granted from the 
DSMC to proceed completion of enrollment.   
 
Possible actions taken by the PI or the Yale DSMC if a new unexpected toxicity is 
identified from the above safety review, or if the periodic review of all adverse events 
and laboratory data indicates a pattern of incidence or severity of toxicity that raises a 
safety concern, can be to: 
• Revise consent form 
• Amend the protocol 
• Suspend the protocol 
 
All AEs found to be expected or non-serious, will be included in the Annual Report. 
 
16.0 RETENTION OF RECORDS 
 
U.S. FDA regulations (21 CFR 312.62[c]) require that records and documents pertaining 
to the conduct of this study and the distribution of investigational drug, including CRFs, 
consent forms, laboratory test results, and medication inventory records, must be 
retained by the principal investigator for 2 years after the investigation is discontinued. 
17.0  RESEARCH ETHICS AND HUMAN SUBJECT PROTECTION 
17.1 SUBJECT SELECTION 
 
 
This protocol will seek to accrue patients 18 years of age or older as described in 
the study inclusion criteria.   
17.2 INFORMED CONSENT PROCESS 
 
 
The informed consent dialogue with the research subjects will include a 
discussion of the natural history of their condition and alternative therapies that a 

 
41 
person might consider (e.g. supportive care only, administration of conventional 
chemotherapy agents, or participation in a research study). 
17.3 CONFIDENTIALITY 
 
 
Data collected on each patient will be maintained in a research folder kept in a 
locked room.  Data entered into a computerized database will be kept on a 
computer that is password protected and kept in a locked room.  In all 
publications and presentations resulting from this research project, the research 
subject’s anonymity will be protected to the maximum extent possible.  
Authorized Medical Department personnel and personnel from the cancer center 
and IRB may have access to their research file in order to verify that the research 
subject’s rights have been safeguarded.  In addition, their name will be given to 
the Clinical Studies Unit, a contracting office who will register the research 
subject onto this study and verify their eligibility.  
 
17.4 PATIENT’S RIGHTS 
 
 
 
If the research subject suffers any physical injury as a result of their participation 
in this study, immediate medical treatment is available at the treating institution. 
Although no compensation is available, any injury as a result of his participation 
will be evaluated and treated in keeping with the benefits or care to which he is 
entitled under applicable regulations.  
 
  
If the research subject has any questions regarding this research project, he may 
contact Dr. Jill Lacy or site investigator or coordinator or IRB.  If he has any 
questions regarding his rights as an individual while participating in a research 
project at the Yale Cancer Center (YCC), he can contact one of the Research 
Administrators, Clinical Investigation Department, who will answer the research 
subject’s questions or refer him to a member of the committee for the Protection 
of Human Subjects for further information.  If the patient believes that he has 
been injured as a result of this project, he may call the legal office of YCC. 
 
Participation in this research project is voluntary.   A patient’s refusal to 
participate will involve no penalty or loss of benefits to which he is entitled under 
applicable regulations.  If the chooses to participate, he is free to ask questions 
or to withdraw from the project at any time.  If he should decide to withdraw from 

 
42 
the research project, he will notify the PI either directly or indirectly through the 
research nurse, to make sure the reasons for withdrawal are recorded and to 
ensure that everything is in order.  A patient’s withdrawal will involve no loss of 
benefits to which he is entitled. 
 
 
The investigators may terminate the research subject’s participation in this 
project for the following reasons:  growth of his cancer, intolerance of treatment, 
inability to comply with the protocol guidelines for treatment and follow-up, or if 
the patient chooses to stop protocol therapy, or at the specific request of MEI.  
Any new significant finding developed during the course of the research which 
may affect his willingness to participate further will be explained to the research 
subject. 
 
18.0   REFERENCES  
 
1.  Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 
2010;60:277-300. 
 
2. Oettle H et al. Adjuvant chemotherapy with gemcitabine vs observation in patients 
undergoing curative-intent resection of pancreatic cancer. JAMA 2007; 297(3)267-277. 
 
3. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of 
chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J 
Med. 2004 Mar 18;350(12):1200-10. 
 
4. Neoptolemos, JP et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs 
gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 
2010:304(10) 1073-81.  
 
5.  Takai S, Satoi S, Toyokawa H, Yanagimoto H, Sugimoto N, Tsuji K, et al. 
Clinicopathologic evaluation after resection for ductal adenocarcinoma of the pancreas: 
a retrospective, single-institution experience. Pancreas. 2003;26:243–9. 
 
6.  Neoptolemos JP, Stocken DD, Dunn JA, Almond J, Beger HG, Pederzoli P, et al. 
Influence of resection margins on survival for patients with pancreatic cancer treated by 

 
43 
adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled 
trial. Ann Surg. 2001;234:758–68.  
 
7. Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, et al. Resected 
adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic 
indicators. J Gastrointest Surg. 2000;4:567–79.  
 
8. Neuhaus P, Riess H, Post S, et al. CONKO-001: Final results of the randomized, 
prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine vs. 
observation in patients with resected pancreatic cancer (abstract). J Clin Oncol 2008; 
26:1009s 
 
9.  Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for 
metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25. 
 
10. Gunturu KS, Thumar  JR, Hochster HS, Stein S, Yao X, Cong X, Hahn C, Kaley K, 
Lacy J.  Single-institution experience with FOLFIRINOX in advanced pancreatic cancer 
(PC). J Clin Oncol 30, 2012 (suppl 4; abstr 330) 
 
11. Gunturu KS, Yao X, Cong X, Thumar JR, Hochster HS, Stein SM, Lacy J.   
FOLFIRINOX for Locally Advanced and Metastatic Pancreatic Cancer: Single Institution 
Retrospective Review of Efficacy and Toxicity Medical Oncology (in press) 
 
12. Spitz FR, Abbruzzese JL, Lee JE, Pisters PW, Lowy AM, Fenoglio CJ, Cleary KR, 
Janjan NA, Goswitz MS, Rich TA, Evans DB. Preoperative and postoperative 
chemoradiation strategies in patients treated with pancreaticoduodenectomy for 
adenocarcinoma of the pancreas. J Clin Oncol. 1997 Mar;15(3):928-37. 
 
13. Varadhachary GR,  Tamm EP,  Abbruzzese JL, et al. Borderline resectable 
pancreatic cancer: definitions, management, and role of preoperative therapy. Ann Surg 
Oncol 2006;8:1035-1046 
 
 

 
44 
14. Varadhachary GR et al. Preoperative gemcitabine and cisplatin followed by 
gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic 
head. J Clin Oncol 2008; 26(21): 3487-3495. 
 
15. Evans DB et al. Preoperative gemcitabine-based chemoratiation for patients with 
resectable adenocarcinoma of the pancreatic head. J Clin Oncol 2008; 26(21) 3496-
3502. 
 
16. Palmer DH, Stocken DD, Hewitt H, Markham CE, Hassan AB, Johnson PJ, Buckels 
JA, Bramhall SR. A randomized phase 2 trial of neoadjuvant chemotherapy in 
resectable pancreatic cancer: gemcitabine alone versus gemcitabine combined with 
cisplatin. Ann Surg Oncol. 2007 Jul;14(7):2088-96. Epub 2007 Apr 24.  
 
17. Heinrich S, Pestalozzi BC, Schäfer M, Weber A, Bauerfeind P, Knuth A, Clavien PA. 
Prospective phase II trial of neoadjuvant chemotherapy with gemcitabine and cisplatin 
for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008 May 
20;26(15):2526-31. 
 
18. Varadhachary GR. Preoperative therapies for resectable and borderline pancreatic 
cancer. J Gastrointest Oncol 2011; 2:136-142.  
 
19. Le Scodan R, Mornex F, Girard N, Mercier C, Valette PJ, Ychou M, Bibeau F, Roy 
P, Scoazec JY, Partensky C. Preoperative chemoradiation in potentially resectable 
pancreatic adenocarcinoma: feasibility, treatment effect evaluation and prognostic 
factors, analysis of the SFRO-FFCD 9704 trial and literature review. Ann Oncol. 2009 
Aug;20(8):1387-96. Epub 2009 Jun 5. 
 
20. Talamonti MS, Small W Jr, Mulcahy MF, Wayne JD, Attaluri V, Colletti LM, Zalupski 
MM, Hoffman JP, Freedman GM, Kinsella TJ, Philip PA, McGinn CJ.  A multi-
institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation 
for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol. 2006 
Feb;13(2):150-8. Epub 2006 Jan 19. 
 

 
45 
 
 
 
 
APPENDIX A: STANDARD PROCEDURE FOR COLLECTION AND STORAGE OF 
PLASMA AND BUFFY COAT SPECIMENS 
 
1. PURPOSE 
Whole blood is collected from patients to bank plasma in 200ul and 1ml aliquots along with 
white blood cells (buffy coat).  Collection will occur at baseline (3 tubes or 30 mls) and then 
1-2 tubes (or 10-20 mls) each at the specified Pre-Operative visit, the specified Post-
Operative, and at each specified Follow Up visit.    
 
2. MATERIALS 
• Becton-Dickinson Vacutainer K2 EDTA (10 ml) Ref 3666432ml and 0.5 ml micro 
tubes (Sarstedt Ref 72.730.005 and 72.694.005) P200 and P1000 micro pipettes and 
aerosol barrier tips low speed tabletop centrifuge 
 
 
3. PROTOCOL 
1.) Collect 3 tubes of blood at baseline and 1 or 2 tubes at the subsequent visits from 
consented patients. Once blood tubes are back in the lab, allow them to sit until 
separation of the two layers begins to occur. 
a. Store at room temperature until preparing the samples. 
b. Process the samples within 4 hours of being drawn. 
c. Enter information regarding time/day etc. of obtaining into a plasma tracking 
sheet form. 
 
2.) Within 4 hours of collection spin the purple top blood collection tubes in the centrifuge 
(1000 - 1200g) for 10 minutes. 
 
3.) While the blood is spinning, label cryotubes for 10 of the 1ml tubes of plasma, 3 of the 
2ml tubes for buffy coats and 3 of the 10 of the 2ml tubes for plasma, depending on the 
volume of blood. 
 Include the following information: 
a. 
Study HIC# 2255 
b. 
Patient ID  PT xxxxxx 
c. 
Plasma or buffy coat 
d. 
Visit name and date of collection 
e. 
How much is in the tub e.g. 200µl or 1.8 ml  
f. 
The number of the tube 001, 002 etc. 
 
  
 

 
46 
4.) Gently remove EDTA tubes from the centrifuge so as not to disturb the buffy coat. 
 
 
5.) Pipette 1000µl into each 2 ml tube for a final volume of 1ml (2-3 aliquots). 
 
6.) Pipette 200µl of plasma into each of the 1 ml tubes. 
 
7.) Once all possible aliquots are removed from blood collection tubes, take the P200 and 
pipette the remaining plasma without disturbing the white buffy coat layer.  
 
8.) Using the P200 carefully remove the buffy coat (white layer) from each blood collection 
tube without removing too many red blood cells below.  
 
9.) Once the buffy coat is removed, place the cap back on the EDTA tube and place in sharps 
container.   
 
Place the plasma and buffy coat aliquots in the appropriate box in the -80°C freezer.