A Pilot Study of Neoadjuvant and Adjuvant mFOLFIRINOX in Localized, Resectable Pancreatic Adenocarcinoma
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma
Sponsor: Endeavor Health

 
1
 
 
Local Protocol #:11-01  
 
 
 
 
 
 
 
 
 
 
Version Date 5/13/2013  
 
       A Pilot Study of neoadjuvant and adjuvant mFOLFIRINOX in localized, resectable 
pancreatic adenocarcinoma. 
 
 
Coordinating Center: 
 
 
NorthShore University Health System 
 
 
 
*Principal Investigators: 
Name: Robert de W Marsh MD FACP 
 
 
Address:  NorthShore University HealthSystem 
                                                                    Kellogg Cancer Center 2650 Ridge Avenue 
                                                                   Evanston Il 60201 
 
Telephone; 847-5702112 
 
Fax: 847-5702336 
 
e-mail address: rmarsh@northshore.org 
 
                                                      Name: Hedy Lee Kindler MD 
 
                                          Address:  University of Chicago Medical Center 
                                                                      Section of Hematology/Oncology 
                                                                      5841 South Maryland Ave., MC 2115 
                                                                      Chicago, IL 60637  
 
Telephone:773-7020360 
 
Fax: 773-7023163 
 
e-mail address: hkindler@medicine.bsd.uchicago.edu 
 
Co-Investigators: 
Name: Daniel Virgil Catenacci MD 
 
                                          Address:  University of Chicago Medical Center 
                                                                      Section of Hematology/Oncology 
                                                                      5841 South Maryland Ave., MC 2115 
                                                                      Chicago, IL 60637  
 
Telephone:773-7024400 
 
Fax: 773-7023163 
 
e-mail address: daniel.catenacci@uchospitals.edu 
 
 
Name: Mark Kozloff MD 
 
                                          Address:  University of Chicago Medical Center 
                                                                      Section of Hematology/Oncology 
                                                                      5841 South Maryland Ave., MC 2115 
                                                                      Chicago, IL 60637  
 
Telephone:773-7020360 
 
Fax: 773-7023163 
 
e-mail address: mkozloff@aol.com 
 
 
 
 
 

 
2
                                                       Name: Blase Polite MD MPH 
 
                                          Address:  University of Chicago Medical Center 
                                                                      Section of Hematology/Oncology 
                                                                      5841 South Maryland Ave., MC 2115 
                                                                      Chicago, IL 60637  
 
Telephone:773-702-0360 
 
Fax: 773-702-3163 
 
e-mail address: bpolite@medicine.bsd.uchicago.edu 
 
 
Name: Mark S Talamonti MD 
 
                                          Address:  NorthShore University HealthSystem 
                                                                      Department of Surgery 
                                                                      Walgreens Building 2507 
                                                                      2650 Ridge Ave 
                                                                      Evanston, IL 60201 
 
Telephone:847-570-2560 
 
Fax: 847-570-2930 
 
e-mail address: mtalamonti@northshore.org 
 
 
Name: Mitchell Posner MD 
 
                                          Address:  University of Chicago Medical Center 
                                                                     Department of Surgery MC 5031 
                                                                     5841 South Maryland Ave.,  Rm G209 
                                                                     Chicago, IL 60637  
 
Telephone:773-8340156 
 
Fax: 773-7026120 
 
e-mail address: mposner@surgery.bsd.uchicago.edu 
 
 
Name: Kevin Roggin MD 
 
                                          Address:  University of Chicago Medical Center 
                                                                     Department of Surgery MC 5094 
                                                                     5841 South Maryland Ave.,  Rm G-216 
                                                                     Chicago, IL 60637  
 
Telephone:773-795-4595 
 
Fax: 773-702-6120 
 
e-mail address: kroggin@surgery.bsd.uchicago.edu 
 
 
           
Name: Richard Gore MD 
 
Address: NorthShore University HealthSystem  
                                                                    Department of Radiology 
 
             2650 Ridge Avenue Evanston Il 60201 
 
Telephone: 847-5702112 
 
Fax: 847-5702336 
 
e-mail address: rmgore1953@aol.com 
 
 
 

 
3
 
 
 
 
                                                       Name: Michael Vannier MD 
 
                                          Address:  University of Chicago Medical Center 
                                                                     Department of Radiology MC 2026 
                                                                     5841 South Maryland Ave.,   
                                                                     Chicago, IL 60637  
 
Telephone:773-703-3220  
 
Fax: 773-702-2523 
 
e-mail address: mvannier@.uchicago.edu 
 
 
 
 
 
Participating Institutions:         NorthShore University HealthSystem 
 
P.I. Robert de W Marsh MD FACP 
 
 
University of Chicago 
 
P.I. Hedy Lee Kindler MD 
 
 
Statistician: 
 
                              Study Coordinator: 
 
 
Name: Kristen Wroblewski 
                   Name: Michele Britto 
     Address: University of Chicago                                               Address: Kellogg Cancer Center 
                   5841 South Maryland Ave., MC 2007                                     2650 Ridge Avenue                    
 
             Chicago, IL 60637                                                                  Evanston Il 60201                    
 
Telephone: 773-702-7173 
                   Telephone: 847-570-2109 
 
Fax: 773-702-1979 
                   Fax: 847 570-2918 
 
e-mail address: kwroblewski@health.bsd.uchicago.edu        e-mail address: mbritto@northshore.org 
 
Responsible Research Nurse: 
                       Responsible Data Manager: 
 
Name: Michele Britto                                                              Name: Michele Britto                                           
     Address: Kellogg Cancer Center                                            Address: Kellogg Cancer Center 
                   2650 Ridge Avenue                                                                 2650 Ridge Avenue                                  
                   Evanston Il 60201                                                                   Evanston Il 60201 
                  Telephone; 847-570-2109                                                      Telephone: 847-570-2109 
                 Fax: 847-570-2918                                                                  Fax: 847-570-2918 
 
 
      
 
 
 
 
 
 

 
4
A Pilot study of neoadjuvant and adjuvant mFOLFIRINOX 
in localized, resectable pancreatic adenocarcinoma. 
 
Patient eligibility: 
 
1. Histological or cytological diagnosis of adenocarcinoma of the head, body or tail 
of the pancreas – no variants such as squamous cell, acinar cell, spindle cell or 
neuroendocrine tumors permitted. 
2.  A patent superior mesenteric (SMV)-portal vein (PV) confluence (assuming the 
technical ability to resect and reconstruct this venous confluence if needed), and a  
definable tissue plane between the tumor and regional arterial structures including 
the celiac axis, common hepatic artery, and SMA. 
3. Confirmation of localized, resectable status by surgical oncology, per criteria in 
#2  and after presentation at a multidisciplinary conference.  
4. No previous therapy for pancreatic cancer. 
5. Karnofsky Performance status > 80. 
6. Age > 21 years.  
7. No currently active second malignancy. 
8. No CVA within 6 months, no MI within 6 months. 
9. Patients of reproductive age must agree to birth control methods. 
10. Negative pregnancy test in females of reproductive potential. 
                 10.  Required Lab Values: Granulocytes: ≥ 1,500/μL  
                                       Platelets: ≥ 100,000/μL  
                                       Total bilirubin: < 1.5 X ULN 
                                       SGOT/SGPT: ≤ 2.5 x ULN  
            Serum creatinine: ≤ 1.5 mg/dL, or creatinine clearance ≥                   
60ml/min by Cockroft-Gault  
                                        
 
 
 
 
  Schema: 
                                                        Confirmation of Eligibility 
                                                 
 
                ↓ 
 
 
 
 
 
 
 
 
              mFOLFIRINOX x 4 cycles  
 
 
 
 
 
 
 
 
 
 
                ↓   
                                     CT evaluation for reconfirmation of resectability. 
 
 
 
 
 
 
 
                ↓                                 ↓ 
                 Resectable, proceed to surgery          Unresectable, treat at MD discretion  
 
                             within 4-6 weeks  
 
 
 
 
                    
                                    ↓                        ↓ 
                      Successful resection      Unresectable →  treat at MD discretion 
 
 
 
            ↓ 
                      mFOLFIRINOX x 4 cycles starting 4-10 weeks after surgery 
 
 
 
 

 
5
                                                TABLE OF CONTENTS 
 
Section 
Page 
 
SCHEMA ........................................................................................................................................4  
 
1. OBJECTIVES 
 
1.1  
Primary Objectives ......................................................................................................7 
 
1.2  
Secondary Objectives ..................................................................................................7 
 
2. BACKGROUND ......................................................................................................................7 
 
2.1  
Study Disease .......................................................................................................... 7-10 
 
3. PATIENT SELECTION.................................................................................................. 11-13 
 
3.1  
Eligibility Criteria  .....................................................................................................11 
 
3.2  
Exclusion Criteria ......................................................................................................12 
 
3.3  
Inclusion of Women and Minorities .........................................................................13 
 
4. REGISTRATION PROCEDURES ................................................................................ 13-15 
 
4.1 
General Guidelines ....................................................................................................13 
 
4.2 
Registration Process ..................................................................................................14 
      4.3       Data and Safety Monitoring………………………………………………………..14 
 
5. CHEMOTHERAPY TREATMENT PLAN .................................................................. 14-20 
 
5.1  
Agent Administration………………………………………………………………14 
      5.2       General Concomitant Medication and Supportive Care Guidelines ....................15 
 
5.3        Dosing delays/dose modifications………………………………………………16-20 
 
5.4  
Duration of Therapy ..................................................................................................20 
 
5.5  
Duration of Follow Up ...............................................................................................20 
5.6 
Criteria for Removal from Study .............................................................................20 
 
 
6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................20 
 
6.1 
Adverse Events for all agents ....................................................................................21 
 
6.2 
Adverse Event Characteristics..................................................................................21 
 
6.3 
Routine Adverse Event Reporting ............................................................................21 
      6.4 
Serious or Unexpected adverse Events Reporting.................................................. 21 
 
6.5 
Secondary AML/MDS ...............................................................................................22 
 
 
 
7. PHARMACEUTICAL INFORMATION ............................................................................22 
 
7.1 Fluorouracil ........................................................................................................................22 
      7.2 Irinotecan ...........................................................................................................................23 
      7.3 Oxaliplatin ……………………………………………………………………………….26 
      7.4 Leucovorin……………………………………………………………………………….30 
 
 
8. 9MEASUREMENT OF EFFECT ........................................................................................38 

 
6
9.1 
Antitumor Effect  .......................................................................................................33 
 
 
10. DATA REPORTING / REGULATORY REQUIREMENTS ...........................................35 
 
10.1 
Data Reporting ...........................................................................................................36 
 
 
11. STATISTICAL CONSIDERATIONS .................................................................................36 
 
11.1 
Study Design/Endpoints ............................................................................................36 
 
11.2 
Stratification Factors .................................................................................................37 
 
11.3 
Sample Size with power justification .......................................................................42 
 
11.4 
Plans for analysis including plans for formal interim analysis..............................42 
      11.6     Reporting and Exclusions………………………………………………………….43 
 
REFERENCES .............................................................................................................................45 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria ..........................................................................................49 
 
APPENDIX B 
      Data and Safety Monitoring Plan..................................................................................50 
 
INFORMED CONSENT .............................................................................................................51 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
7
1. OBJECTIVES 
 
1.1  
Primary Objective 
To evaluate the percentage of patients able to complete the full course of preoperative 
chemotherapy and undergo a resection. This will be the primary determinant of 
success for this pilot study. 
 
 
1.2. 
Secondary Objectives 
 
1.2.1 To evaluate the percentage of patients able to complete all scheduled therapy, 
including preoperative chemotherapy, surgical resection and postoperative 
chemotherapy. 
  
1.2.2 To assess treatment related toxicity and other adverse events (AE’s) during 
preoperative, operative and postoperative therapy.  
 
1.2.3 To assess the R0 resection rate. 
 
1.2.4 To determine progression free survival and overall survival from the start of 
study treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
2. BACKGROUND 
 
 
 2.1 Study Disease 
 
      Pancreatic ductal adenocarcinoma is a highly lethal disease. It is estimated that in 2010 
there were approximately 43,140 new cases in the United States and 36,800 deaths which 
ranks fourth among cancer related deaths1. At diagnosis, roughly 17,000 of the initial 43,000 
patients have disease which appears to be localized to the pancreatic bed, but unfortunately, 
only a minority of these patients (15-20%) are immediately operable (on imaging studies 
their disease appears to be both localized to the pancreas and technically resectable with 
clear margins, and at surgery no unexpected findings preclude an R0 resection2). It should be 
noted that of those patients deemed immediately operable on clinical grounds, between 20 
and 57% are found to have inoperable disease on exploration depending on the series and on 
the extent and nature of preoperative staging3,4,5,6,7,8. The majority of patients have locally 
advanced, borderline resectable or unresectable disease owing to involvement of critical 

 
8
structures, most particularly sentinel blood vessels such as the SMA, celiac axis, hepatic 
artery, SMV, or portal vein. Furthermore, despite recent advances in systemic therapy, even 
those fortunate few able to undergo immediate surgery remain largely incurable, with a five 
year survival of slightly less than 20%9,10. 
 
The current standard of care for adjuvant therapy in resectable pancreatic cancer is 
based on the CONKO-001 study which randomized patients to 6 cycles of postoperative 
adjuvant therapy with gemcitabine versus observation alone11. Results favored adjuvant 
gemcitabine in both disease free survival (13.4 vs 6.9 months, p<0.001) and overall survival 
(24.2 months vs 20.5 months p=0.02) strongly supporting the use of adjuvant gemcitabine in 
the setting of both R0 and R1 resections. An RTOG study – 97-04 – concluded that 
gemcitabine was probably superior to 5FU when used pre and postoperatively in 
combination with 5FU/RT, with a HR of 0.8212. The role of radiation therapy in this setting 
remains controversial, with studies such as the GITSG trial (pro) and ESPAC 1 (con) 
criticized either for questionable design, outdated chemotherapy or unconventional radiation 
therapy13,14. Current studies in progress examining postoperative therapy include RTOG 
0848 (phase III looking at adjuvant gemcitabine versus gemcitabine plus erlotinib 
plus/minus chemo/RT using fluorouracil), ACOSOG Z5041 evaluating gemcitabine plus 
erlotinib in the pre and postoperative setting and ESPAC 4 evaluating gemcitabine versus 
gemcitabine plus capecitabine. 
 
     Many studies have explored the use of neoadjuvant therapy in initially resectable, 
borderline resectable and unresectable disease. The majority of these have been single arm, 
single institution phase I/II studies, and results have been mixed15,16,17,18,19. Potential benefits 
of a neoadjuvant approach include: downstaging of disease with an increased percentage of 
margin negative and lymph node negative resections; no delay in systemic therapy aimed at 
eradicating micrometastatic disease; the detection of biologically aggressive tumors, as 
evidenced by early progression/metastases during this phase of therapy, thereby avoiding 
inappropriate surgery; and the greater likelihood of completing all intended therapy as 
opposed to postoperative treatment, where fully 22 – 35% of patients do not complete their 
intended program20,21. 
    A comprehensive meta-analysis and systematic review of neoadjuvant therapy in both 
resectable and unresectable pancreatic cancer has recently been published 22. The 
conclusion reached in resectable patients was that resection frequency and survival 
following neoadjuvant therapy was similar to that in patients undergoing primary 
resection followed by adjuvant therapy. In patients with initially unresectable disease, 
fully one third had resectable tumors following neoadjuvant therapy with survival 
comparable to initially resectable patients. In aggregate, these observations indicate that a 
neoadjuvant approach is feasible and effective, and that this sequence does not 
compromise resectability or survival, even in those patients with the best prognosis. 
    With respect to specific studies in resectable disease, investigators at MD Anderson 
Cancer Center have published their most recent results23,24. In their first study, 86 patients 
with resectable disease in the head of the pancreas received radiation therapy (30 Gy in 
10 fractions over 2 weeks) plus 7 weekly infusions of gemcitabine at 400 mg/m2/week. 
85% of these patients were taken to surgery and 74% were able to undergo the intended 
pancreaticoduodenectomy. Median survival for patients whose disease was resected was 
34 months, but it was only 7 months for those whose disease could not be resected. In a 

 
9
second study of patients with resectable adenocarcinoma of the pancreatic head, 90 
patients were enrolled with the goal of administering chemotherapy alone for eight 
weeks, using gemcitabine and cisplatin, followed by combined low dose gemcitabine and 
radiation therapy (30 Gy in 10 fractions). Ultimately, 79 (88%) patients completed the 
full course of preoperative therapy and 62 of these (78%) patients were taken to surgery.  
52 (66%) had their disease resected with a median survival of 31 months for those who 
had surgery, versus 10.5 months for those who did not. They concluded that initial 
combination chemotherapy with gemcitabine and cisplatin followed by chemotherapy/RT 
did not improve on the results achieved with chemotherapy/RT alone. This result is 
perhaps not surprising as gemcitabine, both alone and in doublet combinations, has 
simply not been active enough to materially impact on the outcome of this disease. 
Interestingly, the longer preoperative interval did not result in local tumor progression. 
     These findings are similar to those of other major centers reporting studies of 
neoadjuvant gemcitabine based chemoradiation for potentially resectable disease25,26 and 
suggest that this is a valid strategy for further study in this setting.  
     Recently, investigators at the Institut Paoli-Calmettes and the Universite de la 
Mediterranee reported their results with a novel combination of docetaxel 30 mg/m2 
weekly and RT of 45 Gy in 34 patients with resectable disease27. 32% had progression, 
59% stable disease and 9% partial remission. 50% of the original cohort had 
pancreaticoduodenectomy with 100% R0 resection and a median survival of 32 months. 
The numbers are small and the overall resection rate disappointingly low, but the R0 
resection rate and median survival for those resected is equivalent to patients receiving 
gemcitabine based regimens. 
     In locally advanced, unresectable disease, results have recently been reported from 
Austria with neoadjuvant gemcitabine/oxaliplatin without RT (39% of patients 
undergoing resection of disease with 69% R0 and 22 months median survival)28,  Italy 
with neoadjuvant PEFG/PEXG (cisplatin, epirubicin, 5-fluorouracil (F)/capecitabine (X), 
gemcitabine) or PDXG (docetaxel substituting for epirubicin) followed by RT plus X, F 
or G (14% resected with median survival 16.2 months)29 and Japan with neoadjuvant 
gemcitabine 1000 mg/m2/wk and RT 50 Gy in T3 disease followed by postoperative 5FU 
liver perfusion (82% of patients with disease resected, 43% 5 year survival)30. In each of 
these studies, there is a mixture of borderline resectable and unresectable disease with the 
result that the interpretation of outcomes is problematic. However, it is clear that a 
neoadjuvant approach is feasible and active. 
     It is clear from an examination of the NCI CTEP database that the neoadjuvant 
approach has been widely embraced for future study. More than 40 active protocols are 
listed, including the following select few: a UVA study of hypofractionated RT plus 
chronomodulated capecitabine in resectable and borderline resectable disease; a UT 
Southwestern phase I study of SBRT or SBRT plus gemcitabine; an Emory phase I study 
of FOLFIRINOX and SBRT; a Fred Hutchinson study of GTX and oxaliplatin with 
IMRT and adjuvant gemcitabine; a UF phase II study of risk adapted gemcitabine plus 
abraxane; a European randomized phase II study of gemcitabine plus oxaliplatin pre and 
gemcitabine postop versus gemcitabine postop only; a Memorial Sloan Kettering pahse II 
study of gemcitabine plus oxaliplatin preop plus gemcitabine postop; and an ACOSOG 
study of gemcitabine plus erlotinib pre and postop.  

 
10
                 Looking to the future there have been a number of recent innovations in 
chemotherapy. In an ongoing effort to discover non-gemcitabine based chemotherapy for 
those who have progressed on gemcitabine, and also a new regimen with more efficacy 
than those currently used in patients with pancreatic cancer, the combination of 5FU, 
leucovorin, oxaliplatin and irinotecan has been tested. This combination was initially 
studied in colorectal cancer, in a regimen known as FOLFOXIRI31. It was established that 
this combination was both tolerable and effective in this setting.  Subsequently, the 
regimen was modified slightly to the current FOLFIRINOX  format (oxaliplatin 
85mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 , 5FU 400 mg/m2 on day 1, then 
5FU 2400 mg/m2 as a 46 hour continuous infusion) and tested in a phase II study in 
pancreatic cancer. 47 chemotherapy-naïve patients with metastatic disease were enrolled 
and 46 were treated32. Confirmed response rate was 26% with 4% complete responses. 
Median time to progression was 8.2 months and median overall survival was 10.2 
months. Grade 3/4 toxicities included neutropenia (52%), nausea (20%), vomiting (17%), 
diarrhea (15%), and neuropathy (15%). No toxic death occurred. FOLFIRINOX was then 
tested after failure of previous gemcitabine therapy in metastatic disease and was deemed 
to be promising33. 13 patients were treated, with 9 evaluable for response - 6 had stable 
disease with a mean time to progression of 6.6 months, and 3 progressed.  
      As a consequence of the previously mentioned phase II study in chemo-naïve patients, 
a randomized phase II/phase III study comparing gemcitabine (G) to FOLFIRINOX (F) 
as first line treatment of metastatic pancreatic cancer was conducted 34. This study was 
terminated prematurely by the study IDMC as it was determined that additional patient 
accrual would not add to the statistical power of the study. 342 patients were accrued with 
roughly one third of the primary disease involving the head of the pancreas. Overall 
objective response rate was 32% for F versus 9.4% for G. PFS was 6.4 months versus 3.4 
months and overall survival 11.1 months versus 6.8 months, all in favor of F.  
The overall survival rate of 11.1 months is the best result achieved thus far in a 
randomized phase III study of chemotherapy in metastatic pancreatic cancer. Notable 
toxicities of at least grade III/IV, which were all worse with F, were neutropenia (45.7 vs 
18.7%), febrile neutropenia (5.4 vs 0.6%), fatigue (23.7 vs 14.2%), vomiting (14.5 vs 
4.7%) and diarrhea (12.7 vs 1.2%). These results indicate that this is a notably active 
regimen with an encouraging response rate. However, the potential toxicities are 
significant, and it is a regimen that should be offered only to patients with ECOG 0-1 
performance status and excellent supportive care. In this regard, in an attempt to 
ameliorate these toxicities, modifications to the published regimen have already been 
proposed by the French group and others. In their forthcoming study of FOLFIRINOX in 
the adjuvant setting, the French will omit the bolus of 5FU which contributes 
significantly to the myelosuppression but which is thought to have minimal impact on the 
therapeutic efficacy. In addition, most physicians now incorporate the routine use of 
neulasta with each treatment cycle. This study will similarly incorporate these 
modifications and the regimen will be named mFOLFIRINOX. 
Thus, in the context of perioperative therapy, we have identified a regimen – 
FOLFIRINOX - with the best results to date in the treatment of metastatic disease and by 
inference, promise of improved outcome in those patients with resectable disease. If 
successful, this has the potential to improve DFS and overall survival (until now no better 
than 15-20% at 5 years) in these patients, and may establish a new paradigm for future 
studies .  

 
11
 
 
 
 
3. PATIENT SELECTION 
 
3.1     Eligibility Criteria  
 
       
 
3.1.1 Histologic or cytologic diagnosis of adenocarcinoma of the pancreas. 
 
3.1.2   Resectable primary tumor of the head, body or tail of the pancreas defined as a 
visible mass in the pancreas and: 
 
   3.1.2.1 No extrapancreatic disease 
  3.1.2.2 A patent superior mesenteric (SMV)-portal vein (PV) confluence (assuming the       
technical ability to resect and reconstruct this venous confluence if needed) 
   3.1.2.3 A definable tissue plane between the tumor and regional arterial structures    
including the celiac axis, common hepatic artery, and SMA. 
 
3.1.3 Confirmation of resectability by surgical oncology consultation. 
 
3.1.4 Presentation at a multidisciplinary conference at either University of Chicago or 
NorthShore University  
 
3.1.5  No previous therapy for pancreatic cancer  
 
3.1.6  Short removable metal stents rather than plastic stents are preferred but not required 
for palliation of initial obstructive jaundice 
 
3.1.7   Karnofsky performance status 80 or better 
 
3.1.8  Age > 21 years  
 
3.1.9  No currently active second malignancy 
 
3.1.10  No CVA within 6 months, no MI within 6 months 
 
3.1.11   The effects of mFOLFIRINOX on the developing human fetus are unknown.  For 
this reason and because chemotherapy agents as well as other therapeutic agents used in 
this trial are known to be teratogenic, women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation.  Should a 
woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately. 
 
3.1.12  Negative pregnancy test in females of reproductive age    
 

 
12
3.1.13 Life expectancy of greater than 3 months. 
 
3.1.14 Anticoagulation is permitted but patients may only be on lovenox for this purpose. 
 
3.1.15 Patients must have normal organ and marrow function as defined below: 
 
 absolute neutrophil count  
>1,500/mcL 
 platelets  
 
 
 
 
 
>100,000/mcL 
 total bilirubin 
 
 
 
 
< 1.5X upper limits of normal 
 AST(SGOT)/ALT(SGPT)  
<2.5 X institutional upper limit of normal 
 creatinine 
 
 
 
 
 
within normal institutional limits 
 
OR 
 creatinine clearance  
 
 
>60 mL/min/ per Cockroft-Gault equation 
for patients with creatinine levels above 
institutional normal. 
          
3.1.16 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2  
Exclusion Criteria 
 
3.2.1 Patients who have had previous chemotherapy or radiotherapy for pancreatic 
adenocarcinoma prior to entering the study. 
 
3.2.2    Pathologic subtypes other than pure adenocarcinoma; acinar cell carcinoma, 
squamous cell carcinoma, spindle cell carcinoma, neuroendocrine cancer, and 
mixed types are not eligible. 
 
3.2.3 Patients who are receiving any investigational agents. 
 
3.2.4 Patients with borderline resectable, locally advanced or metastastatic disease. 
 
3.2.5 History of allergic reactions attributed to 5FU, leucovorin, irinotecan or 
oxaliplatin or to compounds of similar chemical or biologic composition.  
 
3.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, active liver disease including viral or non-viral 
hepatitis and cirrhosis, chronic diarrhea or inflammatory disease of the colon 
or rectum, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
3.2.7 Pregnant women are excluded from this study. mFOLFIRINOX is a regimen 
containing more than one chemotherapy agent with the potential for 
teratogenic or abortifacient effects.  Because there is an unknown but potential 
risk for adverse events in nursing infants secondary to treatment of the mother 
with FOLFIRINOX, breastfeeding should be discontinued if the mother is 
treated with these agents.  These potential risks may also apply to other agents 

 
13
used in this study. 
 
3.2.8 HIV-positive patients on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with 
mFOLFIRINOX.  In addition, these patients are at increased risk of lethal 
infections when treated with marrow-suppressive therapy.  Appropriate 
studies will be undertaken in patients receiving combination antiretroviral 
therapy when indicated. 
 
3.2.9 Currently active second malignancy other than non-melanoma skin cancer or 
carcinoma in-situ of the cervix. Patients are not considered to have a “currently 
active” malignancy if they have completed therapy and have no evidence of 
recurrence for at least 5 years. 
 
3.2.10  Pre-existing neuropathy greater than grade 1. 
 
3.2.11  Anticoagulants other than low molecular weight heparin. 
 
 
3.3  
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
 
4. 
REGISTRATION PROCEDURES 
 
 
4.1 
General Guidelines 
 
Eligible patients will be entered on study at both the University of Chicago and at 
NorthShore University by the Study Coordinator. Confirm all selection criteria listed 
in section 3.0 and then call the registrar (Michele Britto) at 847-570-2109 with the 
following information: 
 
Provider of information 
Study # and Institution 
Treating Physician 
Patient name and hospital ID number 
Patient’s zip code of residence 
Date of signed informed consent 
Race, gender, date of birth of patient 
Diagnosis and date of initial diagnosis 
 
Following registration, a copy of all pertinent records should be forwarded to Michelle 
Britto in order that patients begin protocol treatment within 14 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the 
study may be canceled.  The Study Coordinator should be notified of cancellations as soon 

 
14
as possible. These patients should still be kept in the database so that this may be tabulated 
and reported and the reasons for not receiving protocol therapy analyzed. 
 
 
 
4.2 
Registration Process 
 
To register a patient, the following documents should be completed by the research 
nurse or data manager and faxed _ 847-570-2918   or e-mailed 
_mbritto@northshore.org)_ to the Study Coordinator (phone 847-570-2109): 
 Copy of required laboratory tests/pathology report/surgical oncology 
consultation 
 Signed patient consent form 
 HIPAA authorization form 
 Eligibility Screening Worksheet, Registration Form 
 All documents that support eligibility  
 
The research nurse or data manager at the participating site will then call _(847-
5702109)_ or e-mail (mbritto@northshore.org) the Study Coordinator within 2 
working days to verify eligibility.  To complete the registration process, the 
Coordinator will 
 assign a patient study number 
 register the patient on the study 
 fax or e-mail the patient study number to the participating site 
 
4.3 
Data and Safety Monitoring Plan 
  
Data Safety and Monitoring will occur monthly at NorthShore University protocol 
review meetings, which are led by senior level medical oncologists. At each meeting, all 
active studies are reviewed for safety and progress toward completion. Toxicities and 
adverse events will be reviewed at each meeting and a Data Safety and Monitoring form 
will be filled out for this protocol and signed by either the chairperson or by his/her 
designee if he/she is not available. Biweekly telephone calls will take place between the 
principal investigators at NorthShore University and University of Chicago to review all 
toxicity and adverse event data. Please see Appendix B for full details. 
 
 
 
5. CHEMOTHERAPY TREATMENT PLAN 
 
 
 
 
 
 
 
 
5.1       Agent administration 
 
Treatment will be administered on outpatient basis.  Appropriate dose modifications 
are described in Section 6. Reported adverse events and potential risks are described 
in Section 7.  No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the patient's malignancy. 
 
5.1.1 mFOLFIRINOX will be administered for 8 cycles (4 preoperatively and 4 

 
15
postoperatively, 2 weeks per cycle) in the following fashion: 
 
 
 
  
 
Oxaliplatin 85 mg/m² IV infusion on Day 1 over 2 hours and then 
 
Leucovorin 400 mg/m² IV infusion on Day 1 over 2 hours immediately following           
oxaliplatin If there is a shortage of leucovorin,  then a reduced dose of 40mg/m2 may be 
given. If unavailable, then leucovorin may be omitted and restarted when available.  
 
Irinotecan 180 mg/m² IV  infusion on Day 1 over 90-120 minutes (infusion via a 
Y connector during the infusion of leucovorin) 
 
Fluorouracil 2.4 g/m² continuous IV infusion over 46 hours (1200 mg/m² per day 
for two days) immediately following leucovorin and irinotecan 
 
Treatment is given every 2 weeks provided that blood counts and other toxicity 
criteria are met as below in sec 5.3. 
 
 
 
 
 
 
 
Oxaliplatin 
85 mg/m² 
Leucovorin 
400 mg/m² 
Continuous 5-FU 
2400 mg/m² 
Pegfilgrastim 
6 mg  
     2 hours         
Irinotecan 
180 mg/m² 
46 hours 
 
 
 
1.5 - 2 hours 
 
 
 
 
 
 
5.2  
General Concomitant Medication and Supportive Care Guidelines 
 
 
     5.2.1 Hematopoietic growth factor support 
Due to the high incidence of neutropenia associated with the FOLFIRINOX regimen 
(42.5% in the ACCORD study), growth factor support will be mandated beginning 
with the first treatment cycle. This may consist of either pegfilgrastim (Neulasta, 
PEG-rmetHuG-CSF) 6 mg s.c. x 1 dose on discontinuation of the 5-FU pump; or 
filgrastim (Neupogen, G-CSF) 300 or 480 micrograms s.c. daily for 5 consecutive 
days, beginning 24 to 48 hours after discontinuation of the 5-FU pump (i.e., 
beginning day 4 or 5) of each 14-day cycle. The duration of G-CSF may be 
lengthened or decreased with subsequent treatment cycles, at the discretion of the 
treating physician, depending on count recovery at the start of the next treatment 
cycle. 
Erythropoiesis stimulating agents may be used at the discretion of the treating 
physician and implemented in accordance with ASCO guidelines. 
5.2.2 Anti-emetics 
Patients should be premedicated prior to each treatment cycle of FOLFIRINOX with 
an HT-3 antagonist and dexamethasone. The addition of aprepitant (Emend) is 

 
16
strongly encouraged. Other anti-emetics, such as lorazepam may also be provided as 
clinically necessary.  
5.2.3 Anti-diarrheals 
For symptoms of diarrhea (and/or abdominal cramping), patients will be instructed to 
take loperamide. This should be started at the earliest sign of loose stool, an increase 
in bowel movements by 1 to 2 episodes compared to baseline, or an increase in stool 
volume or liquidity. Dosing is as follows: 4 mg at the first onset of diarrhea, then 2 
mg every 2 hours (4 mg every 4 hours at night) until diarrhea-free for at least 12 
hours. Maximum 24-hour dose is 16 mg total. Additional antidiarrheal measures may 
be implemented at the discretion of the treating physician. Patients should also be 
instructed to increase fluid intake to help maintain fluid and electrolyte balance 
during episodes of diarrhea. 
5.2.4 Antibiotics 
Prophylactic oral antibiotic therapy will not be given at the start of study treatment. 
However, antibiotics (i.e. oral fluoroquinolones) should be initiated for patients in the 
following instances: those who have (a) endobiliary stents with an ANC that falls 
below 500; (b) endobiliary stents who develop a fever above 38.5C; (c) diarrhea 
persisting for more than 48 hours despite loperamide; (d) fever with diarrhea, 
regardless of ANC. Administration of long-term prophylactic antibiotics following 
the first occurrence of any of the above scenarios may be considered only following 
discussions with the PI or one of the co-PI’s. 
5.2.5 Anticholinergics 
Prophylactic use of atropine prior to irinotecan dosing is strongly encouraged and 
should be on hand for any cholinergic reaction given the higher incidence of this 
problem in patients receiving irinotecan following oxaliplatin. 
 
5.3 
Dosing delays/dose modifications 
 
Dose Modification Guidelines for FOLFIRINOX 
These will be based on NCI Common Toxicity Criteria Version 4 
 
** The dose of leucovorin is not modified for toxicity, but may be reduced for 
shortages. 
Once a dose is decreased, re-escalation is not permitted. Patients are off study if they 
develop the same grade 4 toxicity despite a first dose reduction. 
 
 
5.3.1.  Hematologic toxicity 
Do not treat until the granulocyte count is ≥ 1.5 x 10
9/L and the platelet count is ≥ 75 x 
10
9/L.  
5.3.1a.  Doses according to the blood counts at the beginning of a cycle (Day 1)  
 

 
17
 
 
Blood counts at 
D1 of each cycle 
DELAY OF            
CYCLE 
                                 DOSE REDUCTION  
 
 
    Irinotecan  
   Oxaliplatin  
       LV5FU 
Granulocytes < 
1.5 x 109/L 
Hold treatment until 
granulocytes  1.5 x 
109/L (one or two 
weeks if necessary).  
 
 
 
In case of non 
recovery after 2 
weeks delay, stop 
treatment* 
1st occurrence: 
reduction of dose to 
150 mg/m² 
 
2nd occurrence: 
maintain the dose at 
150 mg/m² 
 
3rd occurrence: 
treatment 
discontinuation 
 
1st occurrence : no 
reduction of dose 
 
 
2nd occurrence: 
reduce the dose to 
60 mg/m2 
 
3rd occurrence: 
treatment 
discontinuation 
Any occurrence: no 
change in 5FU 
infusion 
Platelets < 75 x 
109/L 
Hold the treatment 
until recovery 
(platelets 75 x 
109/L). 
 
In case of non 
recovery after 2 
weeks delay, stop 
treatment 
1st occurrence : no 
reduction of dose 
 
 
2nd occurrence: 
reduce the dose to 
150 mg/m² 
 
 
1st occurrence: 
reduce the dose to 
60 mg/m² 
 
2nd occurrence: 
maintenance of the 
reduced dose 
 
3rd occurrence: 
treatment 
discontinuation 
 
1st occurrence: reduce 
the continuous 
infusion to 75% of 
the original dose 
 
 
 
5.3.1b  Doses according to subsequent blood counts or in case of infection 
 
ADVERSE EVENTS 
REDUCTION OF DOSE FOR SUBSEQUENT CYCLES 
Febrile neutropenia  
               or 
Grade 4 neutropenia (<500) 
for more than 7 days 
               or 
Infection with concomitant 
grade 3-4 neutropenia  
 
1st occurrence: reduce the dose of irinotecan to 150 mg/m²  
 
2nd occurrence: reduce also the dose of oxaliplatin to 60 mg/m² 
 
3rd occurrence: treatment discontinuation 
Grade 3-4 thrombocytopenia 
 
[grade 3 <50,000  
 grade 4 <25,000] 
1st occurrence: reduce the oxaliplatin dose to 60 mg/m² and the 
continuous 5-FU dose to 75 % of the original dose 
 
2nd occurrence: reduce also the dose of irinotecan to 150 mg/m2 and 
the dose of continuous 5FU an additional 25 % 
  
3rd occurrence: treatment discontinuation 
 
 

 
18
 
 
 
5.3.2. Gastrointestinal toxicities 
 
Patients must be instructed in the use of loperamide as treatment for diarrhea, and 
must have a supply of this drug upon starting mFOLFIRINOX. Patients should not be 
retreated with irinotecan until recovery from diarrhea (without loperamide for at least 
24 h) has occurred.  
 
 
 
 
 
 
5.3.3 
Mucositis or “hand-foot” syndrome 
 
In case of grade 3-4 toxicity, a reduction in dosage of 25% of continuous 5FU will be 
carried out for the subsequent cycles. 
 
5.3.4 
Cardiac toxicity 
 
In case of angina pectoris or of myocardial infarction, 5FU and leucovorin  has to be 
stopped.  
 
5.3.5 
Increase in bilirubin 
 
In case of elevation of bilirubin, it is essential to exclude an obstruction of the biliary 
stent or progressive disease and to postpone chemotherapy. If bilirubin is >1.5xULN, 
irinotecan is held and should not be given until bilirubin is < 1.5xULN.  
 
ADVERSE EVENTS 
REDUCTION OF DOSE FOR SUBSEQUENT CYCLES 
Diarrhea grade 1-2 
 
Diarrhea grade 3-4  
or 
Diarrhea + fever and/or  
neutropenia grade 3-4 
 
No change in doses 
 
 
1st occurrence: reduce the irinotecan dose to 150 mg/m2  
 
2nd occurrence: reduce also the oxaliplatin dose to 60 mg/m² 
and reduce the dose of continuous 5FU to 75 % of the 
original dose 
 
3rd occurrence: treatment discontinuation 
 
Diarrhea ≥ 48 h despite high dose 
loperamide 
 
 
No reduction of the irinotecan, oxaliplatin or 5FU doses 
after complete recovery, unless either grade 3-4 diarrhea, or 
diarrhea + fever, and/or concomitant  neutropenia grade 3-4 
has occurred 
 

 
19
5.3.6 
Other toxicities 
 
Any other toxicity  grade 2, except anemia and alopecia, may require a reduction in 
the dose of irinotecan to 150 mg/m² and/or oxaliplatin to 60mg/m² and/or 5FU of 25% 
depending on the type of adverse event. 
5.3.7 Peripheral neuropathy  
 
The dose of oxaliplatin should be adjusted according to the table below: 
 
 
 
Duration of the toxicity 
Toxicity 
 7 days 
7 days and 
14 days 
Persistent between the 
cycles 
Paraesthesia/dysesthesia without 
functional impairement (grade 1 
NCI)  
 
No change 
No change 
No change 
Paraesthesia/dysesthesia with 
functional impairment but not 
impeding the activities of the 
daily lives (grade 2 NCI) 
No change 
 
No change 
 
65 mg/m2 
Paraesthesia/dysesthesia with 
pain or functional impairment 
impeding the activities of  daily 
life (grade 3 NCI)  
 
 
65 mg/m2 
 
65 mg/m2 
 
Stop oxaliplatin 
Paraesthesia/dysesthesia 
persistent, disabling 
Not applicable Not applicable 
   Stop oxaliplatin 
 
If the oxaliplatin is stopped for neurotoxicity, irinotecan and the 5-FU will be 
continued. 
 
 
 
Once the dose of any drug has been decreased, re-escalation is not permitted. 
Patients are off study if they develop the same grade 4 toxicity despite a first dose 
reduction. 
All dose adjustments should be based on the worst preceding toxicity, graded using the 
National Cancer Institute Common Toxicity Criteria (version 4.0). 
 
 
5.4 
 
Duration of Therapy 
 
5.4.1 Including treatment delays due to adverse event(s), as specified in section 5.3, 
 initial preoperative chemotherapy treatment with FOLFIRINOX will continue for 4  
cycles or until one of the following criteria applies: 
 

 
20
 
Disease progression, 
 
 
Intercurrent illness that prevents further administration of treatment, 
 
 
Unacceptable adverse event(s), 
 
 
Patient decides to withdraw from the study, or 
 
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
5.4.2   Following successful surgery, subsequent FOLFIRINOX will be given for 4 cycles 
or until one of the aforementioned criteria for stopping applies.        
 
 
 
5.5 
Duration of Follow Up 
 
Patients will be followed every 3 months for 2 years and every 6 months for years 3-5 
after completion or removal from study or until death, whichever occurs first.  
Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
5.6   Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.4 applies.  
The reason for study removal and the date the patient was removed must be documented 
in the Case Report Form. 
 
 
 
 
 
 
6.   ADVERSE EVENTS:  LISTING AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  
The following list of AEs (Section 6.1) and the characteristics of an observed AE 
(Section 6.2) will determine whether the event requires expedited reporting to the local 
IRB (NorthShore or University of Chicago), to the data manager at NorthShore 
(Michelle Britto) and to MedWatch in addition to routine reporting.  
 
6.1. Adverse Event Lists for Commercial Agents 
 
6.1.1 Common, expected adverse events 
 
5FU/leucovorin: diarrhea, esophagopharyngitis, leukopenia, infection, ulcerative 
stomatitis, gastrointestinal ulceration, thrombocytopenia, acute cerebellar 

 
21
syndrome, myocardial ischemia, palmar-plantar erythrodysesthesia, and 
pneumopathy 
Oxaliplatin: anemia, arthralgia, chest pain, dehydration, dyspnea, edema, hand-foot 
syndrome, hypokalemia, injection site reaction, leukopenia, neutropenia, 
neuropathy, cold sensitivity,persistent cough, pulmonary fibrosis, stomatitis, 
thrombocytopenia, thromboembolism. 
Irinotecan: anemia, diarrhea with or without abdominal cramping and sweating, 
dyspnea, fever, abdominal enlargement, dehydration, edema, upper respiratory 
tract infection, neutropenic fever, stomatitis, allergic reactions, including 
anaphylactoid reactions, and thrombocytopenia 
 
6.1.2 Comprehensive list of adverse events 
 
Please refer to the professional package inserts for a comprehensive list of adverse 
events. 
 
 
6.2 
Adverse Event Characteristics  
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0.  A copy 
of the CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/   
 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 6.1 above) 
for expedited reporting purposes only.   
 
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
6.3     Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions. 
 
 6.4     Serious or Unexpected Adverse Events Reporting 
 
 
All serious (Grade 4 or 5 according to CTCAE v 4.0) or unexpected adverse events 
must immediately be reported to the local IRB at NorthShore University or the 
University of Chicago, to the data manager (Michelle Britto 847-570-2109) and to 
MedWatch (fax 1-800-FDA-0178) within 7 -10 days. 
 

 
22
6.5 Secondary AML/MDS 
 
AML/MDS events must be reported.  In CTCAE v 4.0, the event(s) may be reported as 
either: 1) Leukemia secondary to oncology chemotherapy, 2) Myelodysplastic 
syndrome, or 3) Treatment-related secondary malignancy.   
 
 
7. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the commercial agents 
administered in this study can be found in Sections 7.1 – 7.4. 
 
7.1 Fluorouracil 
 
7.1.1 Other Names: 
5-Fluorouracil, 5-FU, Adrucil, Efudex 
 
7.1.2 Classification 
Antimetabolite 
 
7.1.3 Mode of Action 
Fluorouracil is a pyrimidine antagonist that interferes with nucleic acid biosynthesis. 
The deoxyribonucleotide of the drug inhibits thymidylate synthetase, thus inhibiting 
the formation of thymidylic acid from deoxyuridylic acid, thus interfering with the 
synthesis of DNA. It also interferes with RNA synthesis. See introduction for 
elaboration. 
 
7.1.4 Storage and Stability 
Stable for prolonged periods of time at room temperature if protected from light. 
Inspect for precipitate; if apparent, agitate vial vigorously or gently heat to not 
greater than 140°F in a water bath. Do not allow to freeze. 
 
7.1.5 Dose Specifics 
Initial dose following leucovorin on day 1 of every 2 week cycle: 2400 
mg/m2 continuous infusion over 46 hours immediately following leucovorin. The 46 
hour infusion should be prepared per institution guidelines. 
 
7.1.6 Administration 
IV infusion. 
 
7.1.7 Incompatibilities 
Incompatible with doxorubicin and other anthracyclines. 
 
7.1.8 Availability 
Commercially available in 500 mg/10 mL ampules and vials, and 1 g/20 mL, 2.5 g/50 
mL, and 5 g/100 mL vials. Supply for this study will be commercial. 
 
7.1.9 Side Effects 

 
23
Hematologic: Leukopenia, thrombocytopenia, anemia; can be dose-limiting; 
less common with continuous infusion. 
Dermatologic: Dermatitis, nail changes, hyperpigmentation, Hand-Foot 
Syndrome with protracted infusions, alopecia. 
Gastrointestinal: Nausea, vomiting, anorexia; diarrhea, can be dose-limiting; 
mucositis, more common with 5-day infusion, occasionally 
dose-limiting; severe, cholera-like diarrhea which can be fatal 
when given with leucovorin. 
Neurologic: Cerebellar syndrome (headache and cerebellar ataxia). 
Cardiac: Angina, noted with continuous infusion. 
Ophthalmic: Eye irritation, nasal discharge, watering of eyes, blurred vision. 
Hepatic: Hepatitis with hepatic infusion. 
 
7.1.10 Nursing Implications 
Monitor CBC, platelet counts. 
Administer antiemetics as indicated. 
Monitor for diarrhea. Encourage fluids and treat symptomatically - may be dose 
limiting. 
Assess for stomatitis - oral care recommendations as indicated. 
Monitor for neurologic symptoms (headache, ataxia). 
Patients on continuous infusions may need instruction regarding central IV catheters 
and portable IV or IA infusion devices. 
Inform patient of potential alopecia. 
 
7.1.11 References 
Hansen R, Quebbeman E, Ausman R, et al. Continuous systemic 5-fluorouracil in 
advanced colorectal cancer: Results in 91 patients. J Surg Oncol 1989; 40:177-181. 
Freeman NJ, Costanza ME. 5-Fluorouracil-associated cardiotoxicity. Cancer 1988; 
61:36-45. 
 
7.2 Irinotecan (CPT-11) (NSC-616348) 
 
7.2.1 Other Names: 
Irinotecan hydrochloride trihydrate [CPT- 1 1, (4S)-4, 1 1- diethyl-4-hydroxy-9-[(4-
piperidinopiperidino) carbonyloxy] -IHpyroano [3',4':6, 7l indolzino [1 ,2-bl quino 
line-3,14(4H, l2H)dione hydrochloride trihydrate] is a topoisomerase I inhibitor. 
 
7.2.2 Classification 
Topoisomerase I inhibitor 
 
7.2.3 Toxicology 
Human Toxicity: Virtually all Phase I and II studies of irinotecan have reported 
neutropenia and diarrhea as the dose-limiting toxicities. It is expected that these 
toxicities will also be encountered in this trial. Other Grade 2-3 toxicities seen 
include nausea and vomiting, anorexia, abdominal cramping, cumulative asthenia, 
thrombocytopenia, renal insufficiency, increase in transaminase level and hair loss. 
Sporadic cases of pulmonary toxicity, manifested as shortness of breath and 
nonproductive cough, have also been reported. 

 
24
 
7.2.4 Mode of Action 
Causes single stranded DNA breakage by inhibition of the intranuclear enzyme 
toposisomerase-1. Leads to apoptotic cell death via defects in DNA repair. 
 
7.2.5 Pharmacology 
 
7.2.5.1 Pharmacokinetics: Several studies describing the pharmacokinetic 
characteristics of irinotecan (CPT-11) and its active metabolite, SN-38, when 
administered alone or in combination with other agents (including cisplatin) in 
patients with small cell or non-small cell lung cancer have been reported in published 
literature. CPT- 11 is converted by carboxylesterases to its more active metabolite, 
SN-38. In vitro, SN-38 is 250 to 1,000 fold more potent than CPT-11 in the inhibition 
of topoisomerase I activity. A reversible, pH-dependent hydrolysis converts the 
closed lactone E ring form of both CPT-11 and SN-38 to the open, carboxylate form 
of each compound. Only the closed ring (lactone) forms of CPT-11 and SN-38 are 
effective topoisomerase I inhibitors. The mean terminal half-life of SN-38 in plasma 
is slightly longer than that for CPT-11; 11.5 ± 3.8 hours versus 6.3 ± 2.2 hours for the 
lactone forms. Peak plasma concentrations for CPT-11 occur at the end of the 
infusion. The time to peak for SN-38 is highly inter-patient dependent occurring at 
variable times points 30 to 90 minutes after the end of infusion. Murine studies 
suggest that the liver may concentrate, convert CPT-11 to SN-38, and eliminate both 
compounds as well as the glucuronide conjugate of SN-38 (SN-38G) via biliary 
secretion. In rats, 55% of radiolabeled CPT-11 was excreted unchanged in the bile 
within 24 hours, while 21.7% was transformed to SN-38. It recently was 
demonstrated that plasma concentrations of SN-38G in patients occur 0.5 to 3 hr after 
the SN38 peak and plasma levels generally exceeded that of SN-38. Overall, 73% of 
the radioactivity could be recovered from the feces of rats and 25% from the urine. 
Bile concentrations of CPT-11 were 10 to 60 fold higher than plasma concentrations 
in one patient during the first 6 hours following administration, while bile 
concentrations of SN-38 were 2 to 9 fold higher. Renal clearance has not been 
reported to be a major route of elimination for these compounds in humans. 
 
7.2.6 Formulation 
The drug is supplied in two forms: 2 ml vials containing 40 mg of drug and 5 ml vials 
containing 100 mg of drug. The drug is supplied in brown vials and appears as a 
pale-yellow-to-yellow crystalline powder and pale yellow transparent solution when 
reconstituted. 
 
7.2.7 Storage and Stability 
Irinotecan vials must be stored in a cool, dry place, protected from light in a locked 
cabinet accessible only to authorized individuals. It is stable for at least three years 
at room temperature. Irinotecan is stable for 24 hours in glass bottles or plastic bags 
after reconstitution with D5W. 
 
7.2.8 Dose Specifics 
Irinotecan will be given at a dose of 180 mg/m2 intravenously over 90-120 minutes 
every 2 weeks. 

 
25
 
7.2.9 Preparation 
Irinotecan will be diluted with D5W to a total volume of 500 ml and infused 
intravenously over 90-120 minutes. Nothing else should be added to the bag. 
 
7.2.10 Route of Administration 
Intravenous administration only. 
 
7.2.11 Incompatibilities 
Do not mix with any other compound. 
 
7.2.12 Availability 
This drug is commercially available for purchase by a third party. This drug will not 
be supplied by the NCI. 
 
7.2.13 Side Effects 
Hematologic: Leukopenia, neutropenia, anemia, thrombocytopenia, neutropenic 
fever, hemorrhage 
Gastrointestinal: Diarrhea (early and late – see administration above), nausea and 
vomiting, anorexia, abdominal pain, flatulence, stomatitis, dyspepsia, dehydration 
Hepatic: Elevated transaminases. 
Cardiovascular: Vasodilation, hypotension, myocardial infarction, stroke, edema 
CNS: Dizziness, confusion, somnolence, insomnia, back pain 
Respiratory: Pulmonary embolism, 
Dermatologic: Alopecia, rash 
Other: Asthenia, thrombophlebitis, sweating, weight loss, chills 
 
7.2.14 Nursing/Patient Implications 
Premedicate with antiemetics in anticipation of mild to moderate nausea and 
vomiting. When used in combination with 5-fluroruracil and leucovorin the nausea 
and vomiting will likely be worse. 
Fatalities have been reported with thromboembolic events and neutropenic sepsis in 
patients receiving 5-fluorouracil, leucovorin and irinotecan. 
Monitor for diarrhea. Diarrhea occurring within one hour of irinotecan has been 
treated with atropine 0.25 to 1mg IV or SC. Loperamide has been effective in 
treating later diarrhea and the patient should be instructed on its immediate use at 
the first loose stool following the irinotecan (see section 5.5.2). 
Monitor CBC, platelets, and liver function tests. 
Dose modifications per the protocol should be followed for hematologic and 
gastrointestinal toxicity. 
Advise patient of likely post-treatment neutropenia and instruct in appropriate 
neutropenic precautions. 
Administration of an oral quinolone antibiotic may decrease the risk of neutropenic 
sepsis in patients receiving 5-fluorouracil/leucovorin and irinotecan 
 
 
7.3 Oxaliplatin 
 

 
26
7.3.1 Generic Name 
Oxaliplatin 
 
7.3.2 Other name 
L-OHP 
 
7.3.3 Classification: 
Platinating agent 
 
7.3.4 Mode of Action 
Oxaliplatin has properties similar to those of a bifunctional platinating 
agent,producing DNA cross-links and other damage to DNA. 
 
7.3.5 Storage and Stability 
Oxaliplatin should be stored at controlled room temperatures between 20° to 25°C in 
the light-proof packaging provided. 
Oxaliplatin injection: Store between 20°C and 25°C (68°F to 77°F) with excursion 
permissible between 15°C and 30°C (59°F to 86°F). Do not freeze. For long-term 
storage, protect product from light (keep vial in outer carton). Stable for 3 years 
under these conditions. 
Diluted Solutions 
After dilution in 250-500 mL of 5% Dextrose in Water, diluted solutions are 
stable for 6 hours at room temperature (20°C to 25°C; 68°F to 77°F) or up to 24 
hours under refrigeration (2°C to 8°C; 36°F to 46°F). 
 
7.3.6 Dose Specifics 
85 mg/m² intravenously over 2 hours every 2 weeks, for 4 cycles both pre- and 
postoperatively. 
 
7.3.7 Preparation 
Oxaliplatin injection: Withdraw the calculated dose of the 5 mg/mL solution from the 
vial(s) and then dilute with 250 mL to 500 mL Dextrose 5% in Water to give an 
oxaliplatin concentration between 0.2 mg/mL and 2.0 mg/mL. Do not reconstitute 
or dilute oxaliplatin with a sodium chloride solution. 
Do not use administration needles or intravenous infusion sets containing 
aluminum items (risk of degradation of oxaliplatin upon contact with 
aluminum) for the preparation or administration of either the oxaliplatin for 
injection or the oxaliplatin injection. 
 
7.3.8 Route of Administration 
Intravenous. 
 
7.3.9 Incompatibilities 
Do not combine with alkaline medications or media (such as basic solutions of 5-FU, 
trometamol) which cause oxaliplatin to degrade. Do not use needles or IV infusion 
sets containing aluminum items for the preparation or administration (risk of 
degradation of oxaliplatin on contact with aluminum). Since little or no compatibility 
data exist on oxaliplatin at present, it should not be mixed or combined with anything 

 
27
other than 5% dextrose injection USP. The reconstitution or final dilution must never 
be performed with a sodium chloride solution. 
 
7.3.10 Availability 
For this clinical trial, the supply of oxaliplatin will be commercial. 
 
7.3.11 Side Effects 
Allergy/Immunology: Rhinitis, Allergic/Hypersensitivity reactions (including drug 
fever). Can be fatal and occur with any cycle of therapy. Manifested by: urticaria, 
pruritus, flushing of the face, diarrhea (during infusion), shortness of breath, 
bronchospasm, diaphoresis, chest pains, hypotension, disorientation, and syncope. 
Auditory: Middle ear/hearing (ototoxicity, mild), inner ear/hearing (mild hearing 
loss). 
Blood/Bone Marrow: decreased hemoglobin, hemolysis (e.g. immune hemolytic 
anemia, drug-related hemolysis), decreased leukocytes, decreased platelets, 
neutropenia. Single-agent oxaliplatin produces only mild myelosuppression with 
minimal to severe neutropenia, anemia or thrombocytopenia. In combination, more 
grade 3/4 neutropenia or thrombocytopenia may be noted. 
Cardiovascular (Arrhythmia): Sinus tachycardia, supraventricular arrhythmias 
(SVT/atrial fibrillation/flutter), ventricular arrhythmias (PVCs/bigeminy/ 
trigeminy/ventricular tachycardia). 
Cardiovascular (General): Edema, hypertension, hypotension 
Coagulation: DIC (disseminated intravascular coagulation), thrombosis/embolism 
(including pulmonary embolism), prolonged prothrombin time, increased INR, 
thrombotic microangiopathy (thrombotic thrombocytopenic purpura, hemolytic 
uremic syndrome). The hemolytic uremic syndrome should be suspected in 
individuals who experience the following: unexplained severe hemolysis, 
hemoglobinemia and renal failure as demonstrated by an increase in serum 
creatinine. 
Patients suspected of experiencing HUS should have the following laboratory 
analyses conducted: 
• Creatinine, BUN 
• Urinalysis with microscopic evaluation 
• CBC with differential and platelets 
• PT/PTT 
• Fibrinogen, Fibrinogen Degradation Products (FDP) 
• Anti-thrombin III (ATIII) 
• Von Willebrand Factor (VWF) 
• Anti-nuclear antibodies (ANA) 
• Rheumatoid Factor (RhF) 
• C3, C4, CH50 
• Anti-platelet antibodies 
• Platelet associated IgG 
• Circulating immune complexes 
Oxaliplatin should be discontinued for any suspected occurrence of hemolytic 
uremic syndrome. 
Constitutional Symptoms: Fever (in the absence of neutropenia, where neutropenia 
is defined as AGC < 1.0 x l09L), fatigue (lethargy. malaise, asthenia), rigors/chills, 

 
28
insomnia, sweating, weight gain, weight loss. 
Dermatology/Skin: Erythema or skin eruptions, alopecia, hand-foot skin reaction, 
injection site reaction, rash/desquamation, urticaria, pruritus/itching, dry skin, nail 
changes, pigmentation changes. 
Endocrine: Hot flashes/flushes. 
Gastrointestinal: Anorexia, ascites (non-malignant), colitis, constipation, dehydration, 
diarrhea, dysphagia, enteritis, esophagitis, flatulence, gastritis, gastrointestinal reflux 
(heartburn, dyspepsia), ileus (or neuroconstipation), intestinal obstruction, nausea, 
odynophagia (painful swallowing), stomatitis /pharyngitis (oral/pharyngeal 
mucositis), taste disturbance (dysgeusia), typhilitis, ulcer, vomiting, xerostomia (dry 
mouth). 
Hemorrhage: CNS hemorrhage/bleeding, hemoptysis, hemorrhage/bleeding with 
grade 3 or 4 thrombocytopenia, melena, GI bleeding, rectal bleeding/hematochesia, 
pulmonary hemorrhage, vaginal hemorrhage, other (hemorrhage NOS). 
Hepatobiliary/Pancreas: increased alkaline phosphatase, increased bilirubin, 
increased GGT (gamma glutamyl transpeptidase), hepatic enlargement, increased 
SGOT (AST) (serum glutamic oxaloacetic transaminase), increased SGPT (ALT) 
(serum glutamic pyruvic transaminase), pancreatitis, hepatic veno-occlusive disease 
(manifested by hepatomegaly, ascites, and jaundice). 
Infection/Febrile Neutropenia: Febrile neutropenia (fever of unknown origin without 
clinically or microbiologically documented fever (ANC <1.0 x l09L fever >38.5°C), 
infection (documented clinically or microbiologically with grade 3 or 4 neutropenia 
(ANC <1.0 x l09L), infection with unknown ANC, infection without neutropenia. 
Metabolic/Laboratory: Acidosis (metabolic or respiratory), hypoalbuminemia, 
hypocalcemia, hyperuricemia, hyperglycemia, hypoglycemia, hypokalemia, 
hypophosphatemia, hyponatremia, hypomagnesemia 
Musculoskeletal: Involuntary muscle contractions, trismus. 
Neurology: Ataxia (incoordination, including abnormal gait), cerebrovascular 
ischemia, confusion, dizziness, extrapyramidal movements/restlessness, insomnia, 
mood alteration (depression, anxiety), neuropathy cranial (ptosis), vertigo, acute 
sensory neuropathy induced or exacerbated by cold (including acute 
laryngopharyngeal 
dysesthesias, Lhermitte's sign, upper extremity paresthesia), chronic 
peripheral neuropathy (paresthesias, dysesthesias, hypoesthesias), seizure, 
somnolence, speech impairment, syncope. 
Ocular/Visual: Conjunctivitis, vision abnormalities including blindness, optic 
neuritis, papilledema, hemianopsia, visual field defect, transient blindness. 
Pain: abdominal pain or cramping, athralgia (joint pain), bone pain, chest pain 
(noncardiac and non- pleuritic), headache (including migraine), myalgia (muscle pain 
including cramps and leg cramps). 
Pulmonary/Upper Respiratory: Bronchospasm/wheezing, Pulmonary fibrosis, cough, 
dyspnea (shortness of breath), hiccoughs (hiccups, singultus), 
pneumonitis/pulmonary infiltrates (including eosinophilic pneumonia, interstitial 
pneumonitis, and interstitial lung disease), laryngospasm, nasal cavity/paranasal 
sinus reactions, voice changes (hoarseness, loss or alteration in voice, laryngitis). 
Renal/Genitourinary: Increased creatinine, renal failure, urinary retention, urinary 
urgency, dysuria. Hemolytic Uremic Syndrome (HUS) – see coagulation. 
Vascular: Phlebitis, thrombosis 

 
29
Also reported on oxaliplatin trials but with the relationship to oxaliplatin still 
undetermined: tongue paralysis, anemia, aphasia, abnormal hepatic function, 
hyporeflexia, anxiety, depression, dysarthria, insomnia, increased sweating, rhinitis, 
epistaxis, gout, pancreatitis, idiopathic thrombocytopenia (5 cases), 
thrombocytopenia associated with hemolytic anemia (2 cases). 
NOTE: Oxaliplatin in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either 
agent. 
 
7.3.12 Nursing Implications 
Monitor CBC, platelet counts. 
Administer antiemetics as indicated. 
Monitor for diarrhea. Encourage fluids and treat symptomatically. 
Monitor for neurological symptoms (paresthesias, dysesthesias, etc.). 
Instruct patient on the care of access devices. 
Inform patient of expected side effects. 
Respiratory problems (i.e., pulmonary fibrosis, cough, dyspnea, rales, pulmonary 
infiltrates, hypoxia, and tachypnea) have been observed in patients administered 
with oxaliplatin. In rare cases, death has occurred due to pulmonary fibrosis. Please 
monitor and instruct the patient to report any respiratory difficulties and hold 
oxaliplatin until interstitial lung disease is ruled out for cases of grade >3. 
All patients must be premedicated for nausea and vomiting (see below). 
Patients on this study should be counseled to avoid cold drinks and exposure to cold 
water or air because the neurotoxicity often seen with oxaliplatin appears to be 
exacerbated by exposure to cold. The period of time during which the patient is at 
risk for these cold-induced sensory neuropathies is not well documented. Patients 
should exercise caution regarding cold exposure during the treatment period. 
Peripheral sensory neuropathies can occur at any time after receiving oxaliplatin 
therapy. There have been deaths reported, especially in the elderly, while receiving 
Oxaliplatin/5-FU 130 mg/m², 5-FU 320 mg/m², Leucovorin 20 mg day 1-5 every 
three weeks. Patients had hypotension, weakness and diarrhea. They were not all 
neutropenic. These were thought to result from diarrhea complicated by enteric 
sepsis with dehydration and hypotension. Any patient with fever, grade 3 diarrhea, 
or grade 4 neutropenia/ANC with or without fever should be monitored closely, and 
hospitalization should be considered for fever, appropriate hydration, intravenous 
antibiotic therapy appropriate for gram positive and negative sepsis, and support for 
clinically significant deterioration. Patients should be supported aggressively until 
neutropenia and fever resolve. 
Among over 50,000 patients that have been treated with Oxaliplatin, 11 patients 
developed respiratory problems. Four deaths occurred in these 11 patients, 2 of 
which were due to pulmonary fibrosis. As the relationship of such toxicity to 
Oxaliplatin cannot be confirmed, patients must be monitored closely for unexplained 
respiratory problems (i.e., pulmonary fibrosis, cough, dyspnea, rales, pulmonary 
infiltrates, hypoxia, and tachypnea) and Oxaliplatin must be held until interstitial lung 
disease is ruled out for cases of grade > 3. 
Antiemetic premedications will be given as used for any platinum-containing 
regimen. The antiemetic regimen will be defined by the participating institution. 

 
30
Antiemetic agents for platinum-induced nausea and vomiting are also effective for 
the prevention and treatment of oxaliplatin-induced nausea and vomiting. 
 
List of warnings and cautions: 
Any patient with unexplained severe hemolysis, hemoglobulinemia, and renal failure 
with increase in creatinine should be evaluated for hemolytic uremic syndrome 
(HUS). Oxaliplatin should be held in the event of hemolysis with renal failure until 
its etiology is determined in order to exclude the potential for HUS. Oxaliplatin 
should not be restarted if there is HUS. Evaluation for HUS should include CBC, 
differential, platelets, PT, PTT, fibrinogen, FDP, AT III, VWF, ANA, C3, C4, CH50, 
anti-platelet antibody, platelet-associated IgG, and circulating immune complexes. 
Renal evaluation should include creatinine, BUN, and urinalysis. 
 
7.4 Leucovorin 
 
7.4.1 Other Names: 
Leucovorin, Wellcovorin, Citrovorum factor, folinic acid, 5formyltetrahydrofolate, 
LCV 
 
7.4.2 Classification 
Tetrahydrofolic acid derivative 
 
7.4.3 Mode of Action 
Leucovorin acts as a biochemical cofactor for 1-carbon transfer reactions in the 
synthesis of purines and pyrimidines. Leucovorin does not require the enzyme 
dihydrofolate reductase (DHFR) for conversion to tetrahydrofolic acid. The effects of 
methotrexate and other DHFR-antagonists are inhibited by leucovorin. Leucovorin 
can potentiate the cytotoxic effects of fluorinated pyrimidines (i.e., fluorouracil and 
floxuridine). After 5-FU is activated within the cell, it is accompanied by a folate 
cofactor, and inhibits the enzyme thymidilate synthetase, thus inhibiting pyrimidine 
synthesis. Leucovorin increases the folate pool, thereby increasing the binding of 
folate cofactor and active 5-FU with thymidilate synthetase. 
 
7.4.4 Storage and Stability 
All dosage forms are stored at room temperature. The reconstituted parenteral 
solution, 10 mg/mL, is stable for at least 7 days at room temperature. At 
concentrations of 0.5-0.9 mg/mL the drug is chemically stable for at least 24 hours at 
room temperature under normal laboratory light. The oral solution, 1 mg/mL, is 
stable for 14 days refrigerated and 7 days at room temperature. 
 
7.4.5 Dose Specifics 
400 mg/m2 diluted in 250 cc of D5W. Leucovorin is only compatible 
with D5W and is administered as a 2-hour infusion on day 1 of each 2 week cycle. 
 
7.4.6 Preparation 
The 50 and 100 mg vials for injection are reconstituted with 5 and 10 mL of sterile 
water or bacteriostatic water, respectively, resulting in a 10 mg/mL solution. The 350 
mg vial is reconstituted with 17 mL of sterile water resulting in a 20 mg/mL solution. 

 
31
The 60 mg bottle for oral solution is reconstituted with 60 mL of aromatic elixir 
provided, resulting in a 1 mg/mL oral solution 
 
7.4.7 Administration 
Leucovorin will be given as an intravenous infusion over 2 hours. 
 
7.4.8 Compatibilities 
Leucovorin (0.5-0.9 mg/mL) is chemically stable for at least 24 hours in normal 
saline, 5% dextrose, 10% dextrose, Ringer's injection or lactated Ringer's injection. 
Leucovorin (0.03, 0.24 and 0.96 mg/mL) is stable for 48 hours at room and 
refrigeration temperatures when admixed with floxuridine (FUDR, 1, 2 and 4 
mg/mL) 
in normal saline. Leucovorin is also compatible with fluorouracil. 
 
7.4.9 Availability 
Commercially available as a tablet (5, 10, 15, 25 mg), cryodessicated powder for 
oral solution, and in parenteral formulations (3 and 5 mg ampule; 50 mg, 100 mg 
and 350 mg vial). Supply for this clinical trial will be commercial. 
 
7.4.10 Side Effects 
Dermatologic: Skin rash. 
Gastrointestinal: Nausea, upset stomach, diarrhea. 
Allergic: Skin rash, hives, pruritus. 
Pulmonary: Wheezing (possibly allergic in origin). 
Other: Headache; may potentiate the toxic effects of fluoropyrimidine 
therapy, resulting in increased hematologic and gastrointestinal 
(diarrhea, stomatitis) adverse effects. 
 
7.4.11 Nursing Implications 
Observe for sensitization reactions. 
When given with fluoropyrimidines monitor closely for diarrhea and stomatitis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. STUDY CALENDAR 
 
60 seconds 
30 seconds 

 
32
 
Schedules shown in the Study Calendar below are provided as an example and should be 
modified as appropriate. 
 
Baseline history, physical and blood work are to be conducted within 2 weeks prior to start of 
protocol therapy.  Scans and x-rays must be done <4 weeks prior to the start of therapy.  
Laboratory evaluations should be repeated within 24 hours prior to initiation of the next cycle 
of therapy. [ Cycle 1 refers to week of first actual therapy with mFOLFIRINOX.] 
 
 
Pre- 
Study 
Cycle 
   1 
Cycle 
    2 
Cycle 
   3 
Cycle 
   4 
Week 
  +4 weeks 
after Cycle 4 
completion 
Week 
+4-6 
After Cycle 
4 
completion 
Cycle 
    5e 
Cycle 
     6 
Cycle 
    7 
Cycle 
    8 
 Week 
   +4 after 
completion 
of Cycle 8 
Off Studyd 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Toxicity Assessment 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
Physical exam 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X  
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Serum chemistrya 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Pregnancy testb  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
CA 19-9 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Radiologic evaluationc 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
Chemotherapy 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
Surgery 
 
 
 
 
 
 
Exact 
timing per 
surgeon 
 
 
 
 
 
 
a. Specific minimal lab tests required –Na, K, Mg, Phosphorus, Glucose, BUN,CO2, 
         Chloride Creatinine, Calcium, Total Protein, Albumin, Total Bilirubin, Alkaline   
         Phosphotase, SGOT, SGPT 
b. May be serum or urine. 
c. CT scan of chest/abdomen/pelvis or MRI of abdomen/pelvis plus CXR if CT scan cannot 
be done. 
d. Follow up visits and studies per usual standard of care but not less than every 3 months for 
years 1-2 and every 6 months for years 3-5. 
e. Cycle 5 starts 4-10 weeks after surgery depending on patient recovery 

 
33
9. MEASUREMENT OF EFFECT 
 
 
9.1 
Antitumor Effect  
 
For the purposes of this study,  RECIST 1.1 will be used.  Patients should initially be 
re-evaluated for response 4 weeks after completion of 4 cycles of chemotherapy. 
Response and progression will be assessed in this study by evaluation at GI tumor 
board, with the presence of a minimum of one hepatobiliary surgeon, one medical 
oncologist and one radiologist. Should this not be possible, then an ad hoc meeting of 
these individuals should be convened forthwith for the purposes of making this 
determination. 
If patients are not deemed resectable after the initial phase of chemotherapy, then the 
patient is off study and therapy will proceed at the discretion of the treating 
physicians. 
 
9.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment.  
 
Evaluable for objective response.  All patients included in the study must be 
assessed for response to treatment, even if there are major protocol treatment 
deviations or if they are ineligible.  These patients will have their response 
classified according to the definitions stated in Section 12.6.2 
 
 
9.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded)  
>10 mm with CT scan. All tumor measurements must be recorded in millimeters 
(or decimal fractions of centimeters). 
 
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. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 
mm short axis), are considered non-measurable disease and will exclude the 
patient from participation in this protocol. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 

 
34
Target lesions.  The only target lesion relevant to this study is the pancreatic 
primary and any additional disease will render the patient ineligible for this study.  
 
Non-target lesions.  These are not permissible on this study.  
 
9.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is the only permitted method for this study. 
 
Conventional CT and MRI  This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less.  If 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 as a substitute.   
 
PET-CT  At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a diagnostic 
CT (with IV and oral contrast), then the CT portion of the PET-CT can be used 
for RECIST measurements and can be used interchangeably with conventional 
CT in accurately measuring cancer lesions over time.  Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator 
if it is not routinely or serially performed. The use of PET-CT is discouraged in 
this study.  
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement.  Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next.  If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT is advised.   
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.   

 
35
 
Cytology, Histology  These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 
lesions in tumor types, such as germ cell tumors, where known residual benign 
tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
 
FDG-PET:  This test is neither required nor encouraged for this study. 
 
 
9.1.4Response Criteria  
 
This study is unique in that the response evaluation is geared towards the 
maintenance of resectable status, no evidence of locally progressive or metastatic 
disease, and ultimately undergoing a resection.   
 
9.1.4.1 Tumors considered resectable according to current NCCN guidelines include 
the following: 
a. No distant metastases. 
 b. No radiographic evidence of superior mesenteric vein (SMV) and portal vein 
abutment, distortion, tumor thrombus, or venous encasement. 
 c. Clear fat planes around the celiac axis, hepatic artery, and superior mesenteric 
artery (SMA). 
 
 
9.1.5 Progression-Free Survival (PFS) 
 
PFS is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 
 
9.1.6 Overall Survival (OS) 
 
 
OS is defined as the duration of time from start of treatment to time of death from 
any cause. 
 
 
 
10.  
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in 
Section 6.0 (Adverse Events: List and Reporting Requirements). 

 
36
 
10.1 Data Reporting 
 
  
10.1.1 Method 
 
Note:  All adverse events that have occurred on the study must be reported via the 
monitoring method identified above. 
 
11.1.2.1 Responsibility for Data Submission 
 
Study participants are responsible for submitting data and/or data forms to the 
Coordinating Center within 2 weeks of each cycle along with source 
documentation for CRFs to allow time for Coordinating Center compilation, and 
Principal Investigator review. 
 
 
 
11.0 STATISTICAL CONSIDERATIONS 
 
 
11.1    Study Design/Endpoint(s). 
12.1.1 Primary Endpoint  
 To evaluate the percentage of patients able to complete the full course of 
preoperative chemotherapy and undergo a resection. This will be the primary 
determinant of success for this pilot study. 
Early withdrawals due to toxicity, disease progression, or intercurrent illness will be 
considered failures. 
 
11.1.2 Secondary Endpoints 
 
11.1.2.1 To evaluate the percentage of patients able to complete the full course of 
therapy, including preoperative chemotherapy, surgical resection and postoperative 
chemotherapy.  
111.2.2 To assess treatment related toxicity and other adverse events (AEs) during 
preoperative and postoperative therapy and the safety of this approach. 
11.1.2.3 To assess the R0 resection rate. 
11.1.2.4 To determine progression-free survival and overall survival from the start of 
study treatment. 
 
 
 
 
 
 
 
 
 

 
37
11.2      Stratification factors. 
Not applicable. 
11.3      Sample size with power justification. 
 
This pilot study will be conducted using a minimax two-stage design to test the null 
hypothesis that the success rate is 50% or less versus the alternative that it is at 
least 75%. Nine patients are to be enrolled in the first stage. If four or fewer 
patients meet the criteria for success, the trial would be terminated. Otherwise, an 
additional twelve patients (for a total of 21) are to be enrolled, and if fourteen or 
more successes are observed then the regimen will be considered worthy of 
additional evaluation in this disease. This design yields at least 0.85 probability of a 
positive result if the true success rate is at least 75% and at least 0.90 probability of 
a negative result if the true success rate is at most 50%. 
 
11.4 
Plans for analysis including plans for formal interim analysis. 
 
The proportion of patients completing preoperative therapy and undergoing 
resection will be calculated, and a confidence interval constructed based on the 
binomial distribution. Progression-free and overall survival will be calculated by 
using the method of Kaplan and Meier. The frequency of various AEs (worst 
grade) will be tabulated. 
 
Because surgery-related deaths are of concern after administration of 
FOLFIRINOX, there will be close monitoring of this adverse event. Specifically, a 
stopping rule developed by Goldman35 will be used as a guide for early termination 
due to surgery-related deaths. The trial may be halted if there is evidence that the 
true mortality rate is increased from an acceptable level of 3% to an upper limit of 
10% assuming an alpha level of 5% and power of 80%. The stopping rule requires 
that early termination be considered if 3 deaths occur in the first 14 or fewer 
patients or four deaths in the first 31 or fewer patients. Additionally, febrile 
neutropenia, platelet counts less than 20,000, and diarrhea requiring hospitalization 
are also of concern. A stopping rule, based on an acceptable level of 10% and upper 
limit of 20%, requires that early termination be considered if 4 such adverse events  
occur in the first 4 patients, 5 such adverse events occur in the first 10 or fewer 
patients, 6 such adverse events in the first 17 or fewer patients, or 7 such adverse 
events in the first 24 or fewer patients. Delayed time to surgery and delayed wound 
healing are also of concern and will be reported and tabulated carefully. In order to 
monitor these events very closely, there will be a weekly telephone call between 
site PI’s, and any events of concern will be immediately disseminated for 
discussion by all investigators. A monthly report will be generated for distribution 
to all investigators to update the group on the status of the study and of the patients 
on the study. Any concerns will receive immediate attention by the PI’s. 
 
 
 
 
11.5Reporting and Exclusions 

 
38
 
11.6.1 Evaluation of toxicity – All patients will be evaluable for toxicity from the time 
of their first treatment with FOLFIRINOX 
 
11.6.2 Evaluation of response – All patients included in the study must be assessed for 
response to treatment, even if there are major protocol treatment deviations or if 
they are ineligible.  Each patient will be assigned one of the following 
categories:  1) completion of all preoperative therapy with a resection; 2) 
completion of all preoperative therapy but unable to undergo resection; 3) early 
progressive disease or intolerable toxicity necessitating withdrawal from study, 
4) early death from malignant disease, 5) early death from toxicity, or 6) early 
death because of other cause which results in inability to complete preoperative 
therapy; 7) unknown (not assessable, insufficient data).   
 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) should be included in the main 
analysis of the response rate.  Patients in response categories 2-7 should be 
considered to have a treatment failure.  Thus, an incorrect treatment schedule or 
drug administration does not result in exclusion from the analysis of the 
response rate.   
 
If a patient has completed all preoperative therapy, continues to have localized 
disease only, but is unable to undergo resection for technical reasons, then 
further treatment with Radiation Therapy and concomitant chemotherapy is 
encouraged as per standard of care protocols. In the event that a patient should 
become resectable following this additional treatment, postoperative adjuvant 
therapy with 4 cycles of mFOLFIRINOX is encouraged. While the patient will 
be scored as a treatment failure for the specific endpoints of this study, PFS and 
OS will be determined and tabulated on all such patients. 
 

 
39
 
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