Clinical trial NCT01661088
Conditions: Pancreatic Cancer
Keywords: Neoadjuvant FOLFIRINOX FDR-Gemcitabine Concurrent IMRT Borderline Resectable Pancreatic Cancer
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2011-06-01; Completion date: 2019-08-30
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The investigators hypothesize that the combination of the FOLFIRINOX regimen (a combination of 5-fluorouracil, irinotecan and oxaliplatin chemotherapy) to provide maximal systemic disease control and FDR-gemcitabine chemotherapy with concurrent IMRT (Radiation therapy) to address local disease, will achieve a significant improvement R0 resection (Radiation oncology repeat surgeries) rate in borderline resectable (surgical) pancreatic cancer and enhance disease free and overall survival in this patient population.

Detailed description:
Gemcitabine has been the cornerstone of systemic therapy for pancreas cancer over this past decade. Recently, a combination of 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) was reported to have significant efficacy in advanced pancreatic cancer. Preclinical data suggests synergy between irinotecan and 5FU as well as between oxaliplatin and 5FU. Results of a phase II trial in advanced disease were reported in 2005 demonstrating a 26% confirmed response rate and median overall survival of 10.2 months. A follow-up phase III trial comparing FOLFIRINOX with gemcitabine for patients \<75 years of age with advanced pancreatic cancer was presented at ASCO 2010 revealing improvement in PFS (6.4 vs 3.3 months, p=\<.0001) and improved disease control rate (CR+PR+SD) (70.2% vs 50.9%, p=.0003). The most notable result was an impressive improvement in median overall survival with FOLFIRINOX compared to gemcitabine (11.1vs 6.8 months, p-value = \<.0001, HR=.57). The main toxicity was grade 3/4 neutropenia (45.7% vs 18.7%, p=.0001) and increased risk of febrile neutropenia (5.4% vs 0.6%, p=.009)31.

Arms: arm 1: Patients will receive FOLFIRINOX x 6 followed by IMRT concurrent with fixed dose rate (FDR)-gemcitabine (1g/m\^2) on days 1, 8, 22, 29.

Intensity-modulated radiotherapy (IMRT): The prescribed dose was 50.0Gy in 2.0Gy per fraction.

Patients without metastatic disease will be offered surgical exploration.
Interventions: intervention 1: FOLFIRINOX intervention 2: Intensity-modulated radiotherapy (IMRT) intervention 3: Surgical Exploration
Intervention descriptions: intervention 1: Starting dose levels as following:

Oxaliplatin 85mg/m2 intravenously over 120 minutes on day 1. Irinotecan 180mg/m2 intravenously over 90 minutes on day 1. NOTE: patients homozygous for the UGT1A1 (TA)7 promoter allele will be treated at an initial lower dose 140mg/m2 (please see Section 6.3.a) Leucovorin 400mg/m2 intravenously over 90 minutes on day 1. 5FU 400mg/m2 as bolus intravenous injection following leucovorin on day 1. 5FU 2,400mg/m2 infused intravenously as a continuous infusion over 46 hours following the bolus 5FU, beginning on day 1. intervention 2: 50.0Gy in 2.0Gy per fraction intervention 3: Patients without metastatic disease will be offered surgical exploration.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Protocol UMCC 2011.007 
 
A Phase II Study of Neoadjuvant FOLFIRINOX and FDR-Gemcitabine with 
Concurrent IMRT in Patients with Borderline Resectable Pancreatic Cancer 
 
 
 
 
Principal Investigator: 
Mark M. Zalupski, MD 
 
 
Medical Oncology 
 
 
1500 E. Medical Center Dr. 
3-219 CC / 5934 
Ann Arbor, MI 48109-5934 
Telephone: 734-615-3969 
Fax: 734-647-9647 
 
e-mail address: zalupski@umich.edu 
 
 
Co-Investigators: 
 
Vaibhav Sahai, MBBS, Medical Oncology 
 
 
Joel Greenson, MD, Pathology 
 
 
Kent Griffith, MS, Biostatistics 
 
 
Ravi Kaza, MD, Radiology 
 
 
Theodore Lawrence, MD, PhD, Radiation Oncology 
 
 
Hari Nathan, MD, Surgery 
 
 
Rebecca Minter, MD, Surgery 
 
 
Diane Simeone, MD, Surgery 
Christopher Sonnenday, MD, Surgery 
Oxana Rusher, MD, Medical Oncology 
 
 
 
 
Version:  1/6/11 
                  2/10/11 
                  9/28/11 
                  1/11/13 
                  8/27/13 
                 2/1/15 
                 10/14/16 
 
 
 
 


 
 
 
 


 
i 
 
SCHEMA 
 
                                                Borderline Resectable Pancreatic Cancer 
Pretreatment Evaluation to Determine Eligibility, CT scan, Ca19-9 
Written Informed Consent  
 
4 cycles - FOLFIRINOX (2 months) 
 
Repeat CT scan, blood draw for Ca19-9 
 
2 cycles - FOLFIRINOX (1 month) 
 
FDR-Gemcitabine/IMRT 50 Gy (5 weeks) 
 
Rest period 3 weeks 
 
Repeat CT scan, blood draw for Ca19-9 
                           
 
   
 
 
2 cycles - Gemcitabine (1 month) 
 
Repeat CT scan, blood draw for Ca19-9 
 
 
 
  
            Surgery 
 
*Note: If patient has evidence of distant disease progression at any restaging CT they will be 
removed from protocol treatment 


 
ii 
 
TABLE OF CONTENTS 
Page 
 
SCHEMA ......................................................................................................................................... i 
 
1. OBJECTIVES ............................................................................................................................1 
 
2. BACKGROUND .......................................................................................................................1 
 
3. PATIENT SELECTION ............................................................................................................4 
 
4. REGISTRATION PROCEDURES ...........................................................................................6 
 
5. TREATMENT PLAN ................................................................................................................6 
 
6. DOSING DELAYS/DOSE MODIFICATIONS ......................................................................11 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ..................................15 
 
 
8. PHARMACEUTICAL INFORMATION ................................................................................19 
 
9. STUDY CALENDAR..............................................................................................................24 
 
10. MEASUREMENT OF EFFECT ..............................................................................................25 
 
11. DATA REPORTING / REGULATORY CONSIDERATIONS .............................................26 
 
12. STATISTICAL CONSIDERATIONS .....................................................................................26 
 
REFERENCES ..............................................................................................................................30 
 


 
1
1.0 OBJECTIVES 
 
1.1 Primary Objective 
  
To determine the frequency of achieving an R0 resection using a neoadjuvant regimen of 
FOLFIRINOX followed by IMRT concurrent with fixed dose rate (FDR)-gemcitabine in 
patients with borderline resectable pancreatic cancer. 
 
1.2 Secondary Objectives 
 
 
1.2.1 To estimate progression-free survival and overall survival as a function of time 
from study enrollment.  
1.2.2 To evaluate tolerability and toxicity of the protocol treatment 
1.2.3 To determine the primary tumor response rate to neoadjuvant chemotherapy alone 
and following combined modality treatment 
 
2.0 BACKGROUND 
 
Pancreatic cancer 
 
There were an estimated 37,680 new cases of pancreatic cancer in the US in 2008 making it 
the 10th most common cancer. The estimated number of deaths, however, was 34,290 which 
places pancreas cancer 4th among causes of cancer death1.  A practical staging system for 
pancreas cancer based on the approach to treatment separates patients into four categories: 1) 
resectable, 2) locally advanced unresectable, 3) metastatic disease, and 4) borderline 
resectable. 
 
Resectable disease 
 
A small minority of patients fall into the category of resectable disease. Surgical treatment is 
most often the initial treatment and is offered with curative intent.  However, median survival 
with surgery alone is only 13-20 months.  Following resection, patients benefit from the 
addition of adjuvant radiation and/or chemotherapy2-4.  Even in this most favorable group of 
patients, however, the 5-year survival is less than 30% in single institution series5, 6.  A large 
majority of patients treated with surgery, with or without adjuvant therapy, fail with hepatic 
metastases. 
 
Locally advanced unresectable disease 
 
More often, patients present with disease that is localized but unresectable.  This designation 
and frequency at presentation reflects the anatomic location of the pancreas and specifically 
the proximity to major intra-abdominal blood vessels.  Median survival in this group of 
patients averages 6-11 months, with some suggestion of improvement for patients treated 
with combinations of radiation and/or chemotherapy7, 8. 
 


 
2
Advanced metastatic disease 
 
Patients presenting with evidence of distant metastasis at diagnosis are offered treatment with 
palliative chemotherapy.  Gemcitabine has defined systemic therapy for pancreas cancer for 
most of the past decade. A pivotal study randomized 126 patients with advanced, 
symptomatic pancreas cancer to either weekly gemcitabine 1000 mg/m2 over 30 minutes or 
weekly bolus 5FU 600 mg/m2 using clinical benefit response (CBR) as the primary 
endpoint9. The study found CBR more commonly in the gemcitabine treated patients (23.8% 
vs. 4.8%, P=0.002).  Gemcitabine also led to improved median survival (5.6 vs. 4.4 months) 
and 1-year survival (18% vs. 2%) as compared to 5FU. Tumor response was infrequent in 
both arms (5.4% gemcitabine vs. 0% 5FU).  While gemcitabine as a single agent in advanced 
pancreas cancer has utility, enthusiasm is muted considering the limited benefit it provides.    
 
Borderline resectable disease 
 
Patients with disease that falls somewhere between the first two categories, resectable and 
localized but unresectable, are designated as having borderline resectable disease.  While not 
clearly unresectable, if surgery is the initial treatment, there is a high likelihood of an R1 or 
R2 resection with subsequent local recurrence10-12.  Consequently, it is rational to provide 
chemotherapy and/or radiation with the intent of increasing the likelihood of a subsequent 
margin negative resection.   
 
Historically, the rate of resection in borderline resectable pancreatic cancer following 
neoadjuvant treatment is in the range of 30%13-15.  The variable reported rates of successful 
resection can attributed to the definition of borderline resectable disease, different approaches 
to combining chemotherapy with radiation, and the surgeon’s willingness and ability to 
perform vascular resection +/- reconstruction.  As compared to R0 resection rates in 
resectable disease with up front surgery (60-80%),  in recent studies investigating 
neoadjuvant therapies in resectable and borderline resectable disease, R0 resection rates have 
generally  been reported  in the range of 90%, suggesting an improvement in R0 resection 
rates following preoperative treatment 13, 14, 16, 17. Additionally, in locally advanced borderline 
or unresectable disease, down staging with chemotherapy and radiation permitting resection 
yields survival post-surgery similar to that achieved in upfront resectable disease17.  This 
suggests a significant value to neoadjuvant therapy that aides in obtaining an R0 resection in 
borderline resectable disease.   
 
There is currently no standard therapy approach for borderline resectable pancreas cancer. 
The goal of this study is to improve outcomes in patients with borderline resectable disease 
utilizing a planned course of neoadjuvant treatment designed to optimize R0 resection rate 
and local disease control using chemoradiation and control of distant disease using 
combination chemotherapy. 
 
Neoadjuvant therapy 
 
In resectable pancreatic cancer, surgery is most often the initial treatment.  The adequacy of 
that resection is questionable, however, in that a significant minority of patients have positive 
margins and some patients have incomplete resection (R2 resections)18, 19.  Median survivals 
in patients with R1 or R2 resections are no different than that observed with non-operative 


 
3
therapy.  Patients deemed to have borderline resectable disease are at even higher risk for a 
margin positive resection if treated initially with surgery.  A reasonable strategy to address 
this problem is neoadjuvant therapy to try to increase resectability12.  We have successfully 
and safely resected patients following gemcitabine based chemoradiotherapy20-22.  Compared 
with adjuvant therapy, neoadjuvant therapy has the potential advantage of an improved 
tolerance of combined modality treatment preoperatively, and a greater proportion of patients 
receiving all components of multimodality therapy completed over a shorter time interval.  
As many as 30% of resected patients fail to receive post-operative adjuvant therapy because 
of inadequate recovery from surgery or patient refusal.  Treatment delays following surgery 
may impact efficacy of adjuvant treatment.  In the ESPAC adjuvant trial, the median time to 
initiation of postoperative chemotherapy was 46 days and for combined modality treatment 
61 days4.  Neoadjuvant treatment provides a more timely systemic therapy.  Finally, patients 
that progress during neoadjuvant therapy have biologically aggressive disease and are spared 
a major operation which provides no benefit.   
 
There are barriers to neoadjuvant treatment.  These include biliary obstruction with a 
requirement for decompression of the biliary system, as well as a need to confirm diagnosis 
prior to treatment.  Practical barriers to neoadjuvant therapy in this disease also include 
emotion, a desire by the patient and caregivers to have the tumor removed “before it’s too 
late.” Data do not support the concern of disease becoming unresectable during neoadjuvant 
therapy. Reports from two consecutive neoadjuvant trials from MD Anderson describe only 
one isolated local progression in more than 150 patients13, 23.  
 
Optimization of local disease control using chemoradiation 
 
In order to optimize local control of disease in borderline pancreas cancer, chemoradiation 
can be given neoadjuvantly.  Chemoradiation for pancreas cancer has historically 
incorporated 5-fluorouracil.  Gemcitabine has greater systemic efficacy than 5-fluorouracil in 
pancreas cancer and is a potent radiosensitizer.  Therefore, gemcitabine has been evaluated in 
combination with radiation therapy using conformal radiation techniques.  Early studies 
using gemcitabine with radiation were hampered by limitations in radiation and or 
gemcitabine dose based on regional toxicity and poor distant disease control due to 
suboptimal doses of gemcitabine24, 25.  Beginning in 1997, gemcitabine-based chemoradiation 
has been developed at the University of Michigan with a fundamentally different approach.  
Full dose gemcitabine is used to capitalize on maximal systemic efficacy and laboratory data 
that demonstrate maximum radiosensitization when cytotoxic concentrations of drug are 
used26.  Locoregional toxicity has been addressed by limiting the radiation field to the 
primary tumor alone and titrating the radiation dose.  Over the subsequent decade, the advent 
of IMRT has allowed further escalation of radiation dose delivered to tumor.  We are 
currently nearing completion of a phase I/II trial in patients with localized unresectable 
disease evaluating escalating doses of radiation delivered by IMRT with fixed-dose rate 
gemcitabine 1000mg/m2.  Based on preliminary results of efficacy and tolerability, we have 
selected a radiation dose of 50Gy delivered by IMRT in combination with gemcitabine given 
by fixed-dose rate.  Among 50 patients with unresectable disease treated with this protocol, 
10 were able to undergo resection with a 90% R0 resection rate suggesting significant 
efficacy in obtaining local control with this regimen. 
 
Fixed-dose rate gemcitabine 


 
4
 
Gemcitabine has traditionally been given as a rapid infusion over 30 minutes.  However, 
accumulation of active phosphorylated metabolites of gemcitabine is dependent on infusion 
rate and can be optimized at a rate of 10mg/m2/min27.  Translation of increased active 
metabolite delivered by this fixed dose rate infusion to increased efficacy has been tested 
clinically.  A phase II trial comparison of 1500mg/m2 gemcitabine delivered by fixed dose 
rate with 2,200mg/m2 given over 30 minutes yielded a median survival of 8 months vs. 5 
months, respectively (p=.013)28.  A larger phase III trial compared gemcitabine 1500mg/m2 
given at a fixed dose rate with or without oxaliplatin (two separate arms) were compared to a 
single control arm of gemcitabine 1000mg/m2 given over 30 minutes.  Patients that received 
gemcitabine by fixed dose rate had an approximately 1-month increase in overall survival but 
this did not reach statistical significance29.   
 
Optimization of distant disease control using chemotherapy 
 
Gemcitabine has been the cornerstone of systemic therapy for pancreas cancer over this past 
decade.  Recently, a combination of 5-fluorouracil, irinotecan and oxaliplatin 
(FOLFIRINOX) was reported to have significant efficacy in advanced pancreatic cancer.  
Preclinical data suggests synergy between irinotecan and 5FU as well as between oxaliplatin 
and 5FU.  Results of a phase II trial in advanced disease were reported in 2005 demonstrating 
a 26% confirmed response rate and median overall survival of 10.2 months30.  A follow-up 
phase III trial comparing FOLFIRINOX with gemcitabine for patients <75 years of age with 
advanced pancreatic cancer was presented at ASCO 2010 revealing improvement in PFS (6.4 
vs. 3.3 months, p=<.0001) and improved disease control rate (CR+PR+SD) (70.2% vs. 
50.9%, p=.0003).  The most notable result was an impressive improvement in median overall 
survival with FOLFIRINOX compared to gemcitabine (11.1vs 6.8 months, p-value = <.0001, 
HR=.57).  The main toxicity was grade 3/4 neutropenia (45.7% vs. 18.7%, p=.0001) and 
increased risk of febrile neutropenia (5.4% vs. 0.6%, p=.009)31.  
 
We hypothesize that the combination of the FOLFIRINOX regimen to provide maximal 
systemic disease control and FDR-gemcitabine with concurrent IMRT to address local 
disease, will achieve a significant improvement R0 resection rate in borderline resectable 
pancreatic cancer and enhance disease free and overall survival in this patient population. 
 
3.0 PATIENT SELECTION 
 
3.1 Eligibility Criteria 
 
 
3.1.1 
Patients must have cytologic or histologic confirmation of carcinoma  
arising in the pancreas.  Patients with neuroendocrine tumors are excluded. 
 
 
3.1.2 
 Patients must be deemed to have borderline resectable disease (as defined  
in Table 1 below, adapted from NCCN Practice Guidelines in Oncology – 
v.2.2010) with no radiologic evidence of distant metastatic disease prior to 
registration. Specifically, patients must have at least one designation of borderline 
resectable and no designation of unresectable disease. 
 
 
3.1.3 
Patients must have a life expectancy of at least 12 weeks, a  


 
5
Zubrod performance status of < 1 and be willing and medically able to undergo 
surgical resection. 
 
 
3.1.4 
Patients must have adequate organ function defined as follows: absolute  
neutrophil count of > 1500/mm3, platelets > 100,000/mm3, serum Cr < 1.5 
mg/dl, total bilirubin < 2.0 mg/dl with relief of biliary obstruction if  
present (PTC tube or endobiliary stent). 
 
 
3.1.5 
Patients must be free of other active systemic malignancy, ongoing  
infection, or any other serious uncontrolled, concomitant systemic  
disorders or psychiatric condition that would interfere with the safe  
delivery of protocol therapy. 
 
 
3.1.6 
Patients with preexisting peripheral neuropathy > grade 2 are ineligible. 
 
 
3.1.7 
Pregnant or nursing women are ineligible and patients of reproductive  
potential must agree to use an effective contraceptive method during  
participation in this trial due to the unacceptable teratogenic toxicity of  
abdominal radiation and cytotoxic chemotherapy. 
 
 
3.1.8 
Patients must be aware of the investigational nature of the therapy and 
provide written informed consent. 
 
 
3.1.9 
Patients must have no history of previous chemotherapy for pancreatic  
cancer or any abdominal radiation therapy. 
 
 
3.1.10 
Patients may not have used any investigational agent within 4 weeks prior  
 
to enrollment into the study. 
 
Table 1 
SMV/PV: no contact 
resectable 
SMV/PV: contact <180 degrees without deformity 
borderline 
SMV/PV: contact <180 degrees with deformity 
borderline 
SMV/PV: contact >180 degrees w/o encasement of nearby arteries 
borderline 
SMV/PV: vessel occlusion short segment reconstructable 
borderline 
SMV/PV: vessel occlusion not reconstructable 
unresectable 
 
 
SMA: no contact  
resectable 
SMA: contact <180 degrees 
borderline 
SMA: contact >180 degrees 
unresectable 
  
 
Celiac axis: (head): no contact 
resectable 
Celiac axis: (head): any contact 
unresectable 
   
 
Celiac axis: (body/tail): no contact 
resectable 
Celiac axis: (body/tail): contact <180 degrees 
borderline 
Celiac axis: (body/tail): contact >180 degrees 
unresectable 


 
6
  
 
Hepatic artery: no contact 
  resectable 
Hepatic artery: contact amenable to resection or reconstructable 
borderline 
GDA contact > 180 degrees up to hepatic with either short segment 
encasement or direct abutment of the hepatic artery without 
extension to celiac axis  
borderline 
Hepatic artery: contact not amenable to resection or reconstructable 
unresectable 
 
3.2  
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.  
 
4.0 REGISTRATION PROCEDURES 
 
To register a patient a copy of eligibility checklist with supporting documents and the 
signed patient consent form will be forwarded to the responsible data manager. The 
data manager will verify eligibility.  To complete the registration process, the data 
manager will assign a patient study number, register the patient on the study and 
contact the treating investigator to confirm registration. 
 
5.0 TREATMENT PLAN 
 
5.1  
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks for 5-Fluorouracil (5FU), irinotecan, oxaliplatin and gemcitabine are 
described in Section 7.  Appropriate dose modifications for 5FU, irinotecan, 
oxaliplatin and gemcitabine are described in Section 6.  No investigational or 
commercial agents or therapies other than those described below may be administered 
with the intent to treat the patient's malignancy.   
 
5.2 
m-FOLFIRINOX 
 
A cycle of treatment is 14 days. Six cycles are intended prior to combined modality 
treatment, although this may be modified or shortened based on patient tolerance and 
toxicity experienced.  
 
Starting dose levels as following: 
  
Oxaliplatin 85mg/m2 intravenously over 120 minutes on day 1. 
 
Irinotecan 180mg/m2 intravenously over 90 minutes on day 1.  
 
  
5FU 2,400mg/m2 infused intravenously as a continuous infusion over 46 hours 
following the bolus 5FU, beginning on day 1. 
 


 
7
A cycle of treatment may begin when ANC ≥ 1,000/mm3, platelets ≥ 75,000/ mm3 
and all other treatment related toxicity has resolved to ≤ grade 1.  
 
Dose adjustments for toxicities may be found in Section 6.3 
 
5.3 
Gemcitabine during Radiation Therapy 
 
Combined modality treatment will begin approximately 3 weeks after last 
FOLFIRINOX administration provided ANC ≥ 1,000/mm3, platelets ≥ 100,000/ mm3 
and all other treatment related toxicity has resolved to ≤ grade 1.   
 
Gemcitabine 1000mg/m2 infused over 100 minutes on days 1, 8, 22, and 29 during 
the 5-week course of radiation treatment. 
 
Dose adjustments for gemcitabine due to toxicity are detailed in section 6.5 and will 
be based on complete blood count the day treatment is due and non-hematologic 
toxicities experienced in the preceding week(s). If gemcitabine treatment is held for 
toxicity, radiation therapy will also be held and both treatments resumed when 
resolution of toxicity permits.  
 
5.4 
Gemcitabine following Radiation Therapy 
 
Two cycles (infusions) of gemcitabine alone are intended to be given, the first 21 to 
28 days following completion of combined modality treatment.  
A cycle of treatment is 14 days.   A cycle of treatment may begin when ANC ≥ 
1,000/mm3, platelets ≥ 100,000/ mm3 and all other treatment related toxicity has 
resolved to ≤ grade 1.  
 
Treatment may be delayed for up to 2 weeks from time that a cycle is due, after which 
time that cycle of treatment will be dropped and not made up if conditions for 
treatment are not met. 
 
Gemcitabine dosing is as follows: 
 
Gemcitabine 1,000mg/m2 intravenously over 100 minutes on day 1. Note: If patient 
required treatment interruption and subsequent dose reduction of gemcitabine during 
combined modality therapy, then starting dose for gemcitabine following radiation 
therapy will be reduced per section 6.4.   
 
5.5 
Radiation Treatment 
 
5.5.1 Radiation Dose 
 
The prescribed dose will be 50.0Gy in 2.0Gy per fraction.  Heterogeneity of -5% to 
+10% is permitted provided that normal-tissue constraints are met. The minimal PTV 
dose is dictated by the normal-tissue constraints. A maximal PTV dose of up to +10% 
is permitted provided that normal-tissue constraints are met. The mean PTV dose 
should be as close as possible to 50 Gy. 


 
8
 
Intensity-modulated radiotherapy (IMRT) will be planned based on a helical CT 
obtained in the treatment position following administration of oral and double-phase 
intravenous contrast. The treatment-planning CT scan will be obtained prior to 
initiation of the run-in chemotherapy whenever possible. For patients in which IV 
contrast is contraindicated based on severe allergy or decreased renal function, an 
MRI scan of the abdomen or CT without contrast should be performed. 
 
5.5.2 Treatment Volumes 
 
The gross tumor volume (GTV) will be the primary tumor plus any involved regional 
lymph nodes identifiable on CT scan. 
 
The clinical target volume (CTV) will be defined as the GTV plus 0.5 cm. 
 
The planning target volumes (PTV) will be the CTV plus 0.5 cm. 
 
The normal structures to be contoured are: left and right kidneys, liver, stomach, 
duodenum, small intestine, spinal cord 
  
5.5.3 Breathing and target motion management 
 
Management of motion is mandatory. The use of Active Breathing Control (ABC) is 
preferred. The device should be used during acquisition of images and during 
treatment to reduce/eliminate breathing motion. Other acceptable methods include 
tracking or gating using an implanted pancreatic fiducial. If none of these methods is 
feasible, the Radiation Oncology co-investigator, Dr. Edgar Ben-Josef, should be 
contacted to discuss. Rarely, other methods may be deemed reasonable and would be 
allowed. 
 
5.5.4 Normal-tissue dose-volume constraints 
 
 
 
 
 
 
 
 
 
 
 
5.5.5 Beam Arrangement 
 
The following beam arrangement is recommended.  In our experience, this 
arrangement results in excellent dose distributions that are hard to supersede. 
However, modifications are allowed if they result in a more favorable dose 
distribution. 
Structure 
Constraints 
Kidney(L & R) 
Max dose ≤18Gy; not more than 10% of the volume can 
be between 16 and 18Gy 
Liver 
Mean dose≤30 Gy; Minimize mean dose or NTCP 
Stomach 
Small intestine 
Max dose ≤50Gy; 25% of the volume can be between 45 
and 50Gy 
Spinal cord 
Max dose ≤45Gy 
Duodenum 
Max dose ≤50Gy; not more than 33% of the volume can 
be between 45 and 50Gy 


 
9
 
 
 
 
 
 
 
 
 
 
 
 
 
5.6   
Duration of Therapy 
 
Protocol treatment is defined as six cycles of FOLFIRINOX followed by gemcitabine 
and IMRT, then two further cycles of gemcitabine. Surgical exploration and an 
attempt at resection will be offered to all patients unless there is evidence of distant 
metastatic disease.   
 
 
 
 
 
      Patients will remain on protocol therapy until completion unless; 
 
 
      Intercurrent illness that prevents further administration of treatment 
 
Unacceptable adverse events(s) despite protocol therapy interruption and dose 
modifications  
 
Patient decision to withdraw from the study 
 
General or specific changes in the patient's condition rendering the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
Development of distant metastatic prior to surgical treatment 
 
5.7 
Re-evaluation following 4 cycles of folfirinox chemotherapy 
                  Patients will undergo repeat imaging including CT scan (or MRI) to evaluate for 
response/disease progression. It is anticipated that the large majority of patients will 
proceed to two additional cycles of chemotherapy, followed by combined radiation 
and chemotherapy after cycle 6, or if development of distant metastatic disease, 
patient will be off protocol therapy per Section 5.6.    
 
5.8 
Re-evaluation following combined chemotherapy and radiation 
Patients will undergo repeat imaging including CT scan (or MRI) 3-4 weeks 
following completion of radiation to evaluate for response/disease progression. 
Patients without evidence of distant progression will continue with two more cycles 
of gemcitabine alone.  If distant metastatic disease is demonstrated, patients will be 
Couch Angle 
Gantry Angle 
0 
350 
0 
90 
0 
30 
0 
310 
90 
20 
90 
330 


 
10
off protocol per section 5.6.   
 
5.9 
Re-evaluation following 2 additional cycles of chemotherapy 
 
 Patients will undergo repeat imaging including CT scan (or MRI) scan for final 
response  evaluation and resectability.  Patients will be discussed at the multi-
disciplinary tumor conference.  Patients without evidence of distant disease will be 
offered surgical exploration.  Patients not offered surgery or with distant metastatic 
progressive disease will be off protocol treatment per section 5.6. 
 
      5.10 
Surgical Therapy 
 
The surgical procedure performed will be that required for complete resection as per 
the judgment of the operating surgeon.  Generally, surgery should take place 
approximately 4-6 weeks following last chemotherapy administration. If surgery is 
delayed, imaging within 28 days of the surgery date will be available as clinically 
indicated, to confirm no distant disease precluding curative intent resection.  
Information regarding any surgical therapy will be recorded including the operation 
performed, whether vascular resection and reconstruction was required, completeness 
of the resection (R0, R1 or R2), duration of the operation, blood loss, the length of stay 
and the need for re-admission within 30 days of surgery.  
 
5.11 
Duration of Follow Up 
 
Following completion of protocol therapy and surgery, resected patients will undergo 
surveillance multi-slice spiral CT scans of abdomen at approximately 12, 18 and 24 
months from protocol entry and/or as clinically indicated.  Patients will be evaluated 
with interval history and physical examinations as well as CA 19-9 measurements at 
3 month intervals to the 24 month assessment.  Follow-up beyond two years will not 
be protocol directed but survival and disease free survival information will be 
collected.  All evaluable patients will be followed until death.  Patients removed from 
study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events).  Version 4.0 for toxicity and Serious Adverse Event reporting. A copy of the 
CTCAEVersion 4.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov). 
 
6.1 General Considerations – m-FOLFIRINOX treatment 
 
a. A new cycle of treatment may begin when the ANC is ≥ 1,000/mcl, the platelet 
count is ≥ 75,000/mcl, and any treatment-related GI toxicity is resolved to ≤ 
Grade 1. 
 


 
11
b.  If the initiation of a new cycle of treatment is delayed for > 4 weeks from date 
due secondary to toxicity, the patient will be removed from protocol treatment. 
 
c. Doses will not be modified for cholangitis attributable to biliary obstruction/stent 
occlusion unless this occurs in the setting of > grade 3 neutropenia.  
 
d. Dose reductions for the  agents in the m-FOLFIRINOX combination are as 
follows: 
 
 
AGENT 
INITIAL 
DOSE 
Level -1 
Level -2 
Level -3 
Irinotecan 
180 mg/m2 
140 mg/m2 
110 mg/m2 
90 mg/m2 
Oxaliplatin 
85 mg/m2 
70 mg/m2 
60 mg/m2 
50 mg/m2
5-FU infusion         2400 mg/m2     2000 mg/m2     1600 mg/m2  
1200 mg/m2  
 
 
 
Note: laboratory abnormalities that are not directly attributable to treatment (i.e., 
hyperglycemia) or not clinically relevant (i.e., lymphopenia) do not require 
modification of dosing.  
 
Efforts to attribute toxicity experienced to a single component or some 
combination of the cytotoxic agents will be made by treating investigator and 
doses of the accountable agent(s) modified according to that judgment. Dose 
adjustments for toxicity will be described in the clinical record.  
 
Once doses are reduced for toxicity, they will not be subsequently increased.  
 
An agent(s) may be discontinued (i.e., oxaliplatin for neuropathy or 
hypersensitivity) and protocol therapy continue with remaining agents.  
 
Agent(s) or FOLFIRINOX combination therapy will be discontinued if more than 
three dose reductions for toxicity are needed.  
 
 
6.2 Supportive Care 
 
White blood cell colony stimulating factors will not be administered as primary 
prophylaxis following the first cycle of FOLFIRINOX administration.  
 
Subsequent growth factor use will be at the discretion of the treating physician. 
 
6.3 Dose Modifications 
 
a. Dose modifications for toxicities during FOLFIRINOX 
 


 
12
i. Hematologic Toxicities 
 
 
Dose Modification 
ANC <1000/mm3 
And/or 
Platelets <75,000/mm3 
Hold all chemotherapy and re-evaluate weekly. 
When toxicity permits, treatment will be continued 
with one level dose reduction of irinotecanand 
oxaliplatin. 
*Note: for platelets 75,000 – 99,000 continue FOLFIRINOX but reduce 
oxaliplatin one dose level  
 
 
 
 
Febrile Neutropenia 
If a patient experiences neutropenic fever at any 
point in the treatment cycle, chemotherapy will be 
delayed until ANC > 1,000 and antibiotic treatment 
of the event is completed. When treatment resumes,  
reduce agents one level including infusional 5FU if 
diarrhea and/or stomatitis are part of the adverse 
event profile 
 
 
 
 
*Note: no dose reductions for anemia or 
lymphopenia  
 
 
 
 
ii. Diarrhea 
 
Grade 
Dose Modification 
3-4 
Hold all chemotherapy.  When diarrhea resolves to 
<Grade 1, chemotherapy may be resumed with 
reduction in 5FU infusion and irinotecan one dose 
level.   
*Note: No dose reductions of oxaliplatin for diarrhea.   
 
 
 
 
iii. Mucositis 
 
Grade 
Dose Modification 
3-4 
Hold all chemotherapy.  If mucositis resolves to 
<Grade 1, chemotherapy may be resumed with 
reduction in 5FU infusion and irinotecan one dose 
level.   
*Note: No dose reductions of oxaliplatin for mucositis.   
 
iiii Neuropathy 
 
Grade 
Dose Modification 
3-4 
Hold oxaliplatin.  If neuropathy resolves to <Grade 
2, oxaliplatin  may be resumed with reduction  of 
two dose levels or discontinued.   
*Note: No dose reductions for 5-FU or irinotecan  for neuropathy.   
 
6.4 Other non-hematologic toxicities attributable to 5-FU, irinotecan, and/or oxaliplatin. 


 
13
 
For all other ≥ Grade 3 non-hematologic toxicities attributable to treatment and 
not described above, hold all protocol treatment and monitor toxicity at least 
weekly. If toxicity resolves to ≤ Grade 1 within 4 weeks, treatment may resume 
with 5-FU, irinotecan, and oxaliplatin at one lower dose level. 
 
6.5 Dose modifications for toxicities during combined modality therapy 
(IMRT/Gemcitabine)  
 
Agent 
Initial Dose 
Level -1 
Level -2 
Level -3 
Gemcitabine* 
1,000 mg/m2
750 mg/m2
600 mg/m2 
500 mg/m2
*Note: all infusions by fixed dose rate 10 mg/m2/minute 
Gemcitabine and IMRT may begin when the ANC is ≥ 1,000/mcl, the platelet 
count is ≥ 100,000/mcl, and any treatment-related toxicity to folfirinox is resolved 
to ≤ Grade 1. 
 
During combined modality treatment, gemcitabine will be given days 1, 8, 22 and 
29 as per UMCC 06.018.  
 
During gemcitabine/IMRT dose of gemcitabine for days 8 and 29 will be based 
on toxicities experienced as follows: 
 
i. Hematologic toxicity - dose adjustments of gemcitabine will be made 
based on the ANC and platelet counts taken on the day of therapy. 
 
For ANC ≥ 1,000 /mm3 and platelets ≥ 75,000/mm3, full dose due will be 
given 
 
For ANC of 500- 999/mm3 and/or platelets of 50,000 to 74,999/mm3, 
50% of the gemcitabine dose due will be given. 
 
For ANC < 500/mm3 or platelets < 50,000/mm3, gemcitabine treatment 
and radiation therapy will be held. Combined modality treatment will 
resume upon recovery to values permitting chemotherapy with one dose 
level reduction of gemcitabine. 
 
During combined gemcitabine/IMRT dose of gemcitabine for day 22 will be 
based on toxicities experienced as follows: 
 
ii. Hematologic toxicity - dose adjustments of gemcitabine will be made 
based on the ANC and platelet counts taken on the day of therapy. 
 
 
 
For ANC ≥ 1,000 /mm3 and platelets ≥ 75,000/mm3, full dose due will be 
given 
 
For ANC of 500- 999/mm3 and/or platelets of 50,000 to 74,999/mm3, 
75% of the gemcitabine dose due will be given. If gemcitabine is dose 
reduced on this day, this dose will be dose due on day 29 and starting dose 


 
14
of post-combined modality therapy.  
 
For ANC < 500/mm3 or platelets < 50,000/mm3, gemcitabine treatment 
and radiation therapy will be held. Combined modality treatment will 
resume upon recovery to values permitting chemotherapy with one dose 
level reduction of gemcitabine.  
 
iii. Non-hematologic toxicity- Dose adjustments of chemotherapy will be 
made following assessment of non-hematologic toxicity on the day of 
therapy. 
 
Chemotherapy will be held for ≥ Grade 3 toxicity in any organ system. If 
gemcitabine is held, radiation therapy will also be held while appropriate 
physical, laboratory, radiologic assessments are undertaken to define cause 
and direct supportive therapy. Treatment may be resumed upon recovery 
to toxicity < grade 2 at the discretion of the physician investigator. 
 
iv. If combined modality therapy is interrupted, when resumed, chemotherapy 
will be given on the first day of the next week of radiation therapy with 
Gemcitabine dose reduced one level to complete the treatment cycle. A 
maximum of four doses of chemotherapy will be given during the course 
of radiation therapy. 
 
6.6 Dose Modification for Gemcitabine following Radiation Therapy 
 
There will be no modification of doses for these two cycles (infusions). The dose 
level of gemcitabine will be that given on day 22 of combined modality treatment, 
unless treatment had to be interrupted on or before day 29 for toxicity, in which 
case the investigator may choose to further reduce gemcitabine one dose level. 
 
A cycle of treatment is 14 days.   A cycle of treatment may begin when ANC ≥ 
1,000/mm3, platelets ≥ 100,000/ mm3 and all other treatment related toxicity has 
resolved to ≤ grade 1.  
 
Treatment may be delayed for up to 2 weeks after which time that cycle of 
treatment will be dropped and not made up if conditions for treatment are not met. 
 
Protocol therapy may be shortened and patient may go directly to surgery 
following combined modality therapy in a scenario where toxicities and/or 
response and resectability suggest surgery as in the best interest of the patient.  
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
7.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
7.1.1 Adverse Event Lists for Commercial Agents 
 


 
15
a. 5FU - Please refer to package insert for comprehensive list of adverse 
events.  Side effects include anorexia, nausea, vomiting, diarrhea, 
gastrointestinal ulceration and bleeding, nosebleed, stomatitis, 
esophagopharyngitis, alopecia, myelosuppression, maculopapular 
eruptions, dermatitis, fingernail changes, dry skin, hyperpigmentation, 
photosensitization, palmar-plantar erythrodysesthesia syndrome as 
manifested by tingling of the hands and feet followed by pain, erythema 
and swelling, acute cerebellar syndrome including ataxia, dizziness, and 
slurred speech; visual changes, lacrimation, uncontrolled eye movements, 
headache, myocardial ischemia, thrombophlebitis, angina, anaphylaxis, 
generalized allergic reaction, disorientation, confusion and euphoria. 
 
b. Irinotecan - Please refer to package insert for comprehensive list of 
adverse events.  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. 
 
c. Oxaliplatin - Please refer to package insert for comprehensive list of 
adverse events.  The most common toxicities associated with oxaliplatin 
include fatigue, neutropenia, nausea, vomiting, diarrhea and neuropathy.  
An acute, reversible, primarily peripheral, sensory neuropathy of early 
onset and exacerbated by cold exposure is recognized.  An acute syndrome 
of pharyngolaryngeal dysesthesia is seen in 1-2% of patients characterized 
by subjective sensation of dysphagia or dyspnea.  A persistent primarily 
peripheral, cumulative dose sensory neuropathy characterized by 
parasthesias, dysesthesias, hypoesthesias and deficits in proprioception is 
also seen.  Anaphylactic-like reactions have been reported and may occur 
within minutes of oxaliplatin administration.  Fever, pain at the site of 
infusion, dehydration and electrolyte disturbances are not uncommon.  
Much less commonly, pulmonary fibrosis, renal dysfunction, and 
hemolytic-uremic syndrome have been reported. 
 
d. Gemcitabine - Please refer to package insert for comprehensive list of 
adverse events.  Myelosuppression is the principal dose-limiting factor 
with gemcitabine therapy including leukopenia, thrombocytopenia and 
anemia.  Non-hematologic toxicities include reversible hepatic enzyme 
elevations, gastrointestinal toxicity (nausea, vomiting, diarrhea, 
stomatitis), fever in the absence of infection, flu-like syndrome, rash, and 
peripheral edema.  Rarely hemolytic-uremic syndrome, drug-induced 
pneumonitis and sepsis have been reported.   
 
e. Pregnancy and Lactation: Chemotherapy has been shown to cross the 
placenta and enter into fetal circulation in the rat. Administration of 


 
16
chemotherapy has resulted in increased resorptions and embryolethality in 
rats. Also, in monkeys, chemotherapy results in abortion of embryos 
exposed. Because chemotherapy inhibits DNA, RNA and protein 
synthesis, adverse effects on peri and postnatal development might be 
expected and mothers should not nurse while receiving these drugs. 
 
 
7.2 Reporting of Serious Adverse Events 
 
All serious, unexpected adverse events possibly related to treatment should be reported as 
soon as possible and no later than 7 calendar days of knowledge of the event. 
  
A serious adverse event is one that meets any of the following criteria: 
 
 death 
 initial or prolonged inpatient hospitalization 
 life-threatening 
 severe or permanent disability 
 congenital anomaly 
 
is significant or unexpected for other reason 
 
The following adverse events are excluded from SAE reporting: 
 
Death > 30 days beyond protocol therapy completion where death of a patient is 
due to progression of the patient's cancer 
 
 
 
Hospitalization under the following circumstances: 
 
 
 
 
 
Hospitalization is secondary to expected cancer morbidity: 
 
- 
Admission for palliative care or pain management 
- 
Admission for management of biliary obstruction, or 
cholangitis 
- 
Admission for management of deep venous thrombosis or 
pulmonary embolism. 
 
 
 
Planned hospitalizations for surgical procedures.  
 
Morbidity or mortality from surgical exploration and/or resection.  
 
Common toxicities observed secondary to therapy, progressive disease and events 
secondary to progressive disease are generally excluded from reporting. However, in 
cases where the specificity or severity of an event is not consistent with the risk 
information, the event should be reported.  
 


 
17
The University of Michigan will report unexepected, possibly, probably and definitely 
related to treatment SAEs to FDA, as appropriate.  
 
Safety 
 
US Regulations require that a sponsor reports Serious Adverse Events (SAEs) occurring with use 
of its product in a clinical trial if it is unexpected, and felt to be related to use of the drug. During 
the conduct of Investigator Initiated Trials (IITs), all SAEs that occur will be evaluated by the 
investigator for reportability to FDA. An Adverse Event should be identified, Serious Adverse 
Event and Expectedness determined and causality assessed by the investigator using the 
definitions that follow:  
 
Definitions 
 
An Adverse Event is any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
the treatment. 
 
A Serious Adverse Event is any untoward medical occurrence that at any dose:  
 Results in death, or 
 Is life-threatening, or 
 Requires in-patient hospitalization or prolongation of existing hospitalization, or 
 Results in persistent or significant disability/incapacity, or 
 Is a congenital anomaly/birth defect, or 
 Is a medically important event: 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
also usually be considered serious. 
 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias, convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
 
Note: The term "life-threatening" in the definition of "Serious Adverse Event" refers to an event 
in which the patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
An Unexpected Adverse Event is not listed in the current Clinical Investigator’s Brochure 
(CIB) / Package Insert or an event that may be mentioned in the CIB / Package Insert, but differs 
from the event because of greater severity or specificity.  
For comparative drugs, expectedness is determined by using the pertinent reference text: 
the US Package Insert. 
 
Causality is a determination of whether there is a reasonable possibility that the drug may have 


 
18
caused or contributed to an adverse event. It includes assessing temporal relationships 
dechallenge/rechallenge information, association (or lack of association) with underlying 
diseases, and the presence (or absence) or a lack of one or more likely causes. 
 
Pregnancy Guidance 
 
During the course of the trial, all female patients of childbearing potential should be instructed to 
contact the treating physician immediately if they suspect they might have conceived a child. In 
addition, a missed or late menstrual period should be reported to the treating physician. If a 
female patient, or an investigator, suspects a pregnancy prior to administration of study drugs, 
the study drugs must be withheld until the results of a pregnancy test are available. If pregnancy 
is confirmed the patient must not receive study medications and must be withdrawn from the 
study. 
 
Throughout the entire pregnancy, additional contact should be made with the patient, and in 
some cases with the healthcare provider, to identify spontaneous abortions and elective 
terminations, as well as any medical reasons for elective termination. In addition, the study 
investigator should include perinatal and neonatal outcome. Infants should be followed for a 
minimum of 8 weeks.  
 
If a male patient is suspected of having fathered a child while on study drugs, the pregnant 
female partner must be notified and counseled regarding the risk to the fetus. In addition, the 
treating physician must follow the course of the pregnancy, including prenatal and neonatal 
outcome. Infants should be followed for a minimum of 8 weeks.  
 
Upon live-birth delivery, minimum information that should be collected includes date of birth, 
length of pregnancy, sex of infant, major and minor anomalies identified at birth. Outcomes can 
be obtained via mailed questionnaires, maternal interviews, medical record abstraction, or a 
combination of these methods. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with commercial agents 
administered in this study can be found in Section 7.1. 
 
8.1 5-Fluorouracil (5-FU) 
 
Please refer to the FDA-approved package insert for additional information. 
 
a. Description – 5-FU is an antimetabolite considered to act primarily as an inhibitor of 
thymidylate synthase.  
 
b. Pharmaceutical Data –  Kinetics: After IV injection, it is distributed widely 
throughout the tissues of the body and diffuses readily across the blood-brain barrier. 
The mean half-life of elimination from plasma is 16 minutes. Drug is primarily 
metabolized by the liver.  Formulation: 5-FU is a colorless to faint yellow solution 
supplied in 10 ml single use vials. Each 10 ml contains 500 mg fluorouracil. The pH 
is adjusted to approximately 9.2 with sodium hydroxide. 
 


 
19
c.  Administration –  Intravenous. 
 
d. Storage and Stability - : Store unopened vials at room temperature and protect from 
light. 
 
e. Supplier – 5-FU is commercially available. 
 
8.2 Irinotecan (CPT-11) 
 
 
Please refer to the FDA-approved package insert for additional information. 
 
a. Description –  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. 
 
b. Pharmaceutical Data – 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. 
Formulation: The drug is supplied as 20mg/mL solution in 2, 5, 25 mL vials. 
 
c. Administration –  Irinotecan must be diluted prior to administration in D5W 
(preferred) or 0.9% sodium chloride to a final concentration of between 0.12 to 0.28 
mg/mL. When diluted in D5W, and stored refrigerated (at 2-8C) protected from light, 
the solution is physically and chemically stable for 48 hours. Irinotecan is infused 
intravenously over 90 minutes. Other drugs should not be added to the bag. 
 


 
20
d. Storage and Stability - Irinotecan vials must be stored at room temperature (15-30° C) 
protected from light. Irinotecan is stable for 24 hours in glass bottles or plastic bags 
after reconstitution with D5W. 
 
e. Supplier – Irinotecan is commercially available. 
 
 
8.3 Oxaliplatin 
 
Please refer to the FDA-approved package insert for additional information. 
 
a. Description – Oxaliplatin (cis-[(1R,2R )-1,2-cyclohexanediamine- N,N ] [oxalate(2-)- 
O,O ] is an organoplatinum complex in which the platinum atom is complexed with 
1,2-diaminocyclohexane with an oxalate ligand as a leaving group. Oxaliplatin 
undergoes nonenzymatic conversion in physiologic solutions to active derivatives by 
displacement of the labile oxalate ligand.  Several reactive species are formed 
including the monoaquo and diaquo DACH platinum which covalently bind with 
macromolecules.  Crosslinks are formed between adjacent guanine N7 positions. 
These crosslinks inhibit DNA replication, transcription and repair.  Reactive 
oxaliplatin derivatives are present as a fraction of unbound platinum in plasma 
ultrafiltrate.  The decline of platinum levels following oxaliplatin administration is 
triphasic, characterized by two short distribution phases (t1/2(alpha) 0.43 hrs, t1/2 
(beta) 16.8 hrs) and a long terminal phase (t1/2 (gamma) 391 hrs).  At the end of a 2 
hour infusion approximately 15% of the administered platinum is present in the 
systemic circulation with the remaining 85% rapidly distributed into tissues or 
eliminated in urine.  The major route of elimination is renal excretion and the renal 
clearance of ultrafilterable platinum is significantly correlated with GFR.   
 
b. Pharmaceutical Data– Oxaliplatin is supplied as a sterile, preservative free, aqueous 
solution in clear glass single-use vials containing 50 mg, 100 mg or 200 mg of 
oxaliplatin at a concentration of 5 mg/ml. The solution must be further diluted in 250-
500 ml 5% dextrose for injection and is stable up to 24 hours under refrigeration or 
for 6 hours at room temperature. Needles or IV infusion sets containing aluminum 
must not be used.  
 
c. Administration – Intravenous. 
 
d. Storage and Stability –Store aqueous solution at 25o C; excursions permitted to 15-
30oC. Do not freeze and protect from light (keep in original outer carton). 
 
e. Supplier – Oxaliplatin is commercially available 
 
 
 
8.4 Gemcitabine 
 
Please refer to the FDA-approved package insert for additional information. 
 
a. Description – Gemcitabine hydrochloride (2’,2’-difluoro-2’deoxycytidine) is a 
deoxycytidine analog with structural and metabolic similarities to cytarabine. 


 
21
Gemcitabine is metabolized intracellularly by nucleoside kinases to active di- and 
triphosphate nucleosides.  The active nucleosides interfere with ribonucleotide 
reductase and compete with dCTP for incorporation into DNA, respectively, resulting 
in inhibition of DNA synthesis. Gemcitabine pharmacokinetics are linear and are 
described by a two compartment model.  Half-life varies with age, gender, and 
infusion length; for a short infusion it is generally less than 70 minutes.  Nearly all of 
an administered dose is recovered in the urine as active drug (<10%) or inactive uracil 
metabolite.  The maximum plasma concentrations of the inactive metabolite are 
achieved 30 minutes after discontinuation of the infusions, and the metabolite is 
excreted in the urine without undergoing further biotransformation.  The metabolite 
does not accumulate with weekly dosing, but its elimination is dependent on renal 
excretion, and could accumulate with decreased renal function. 
 
b. Pharmaceutical Data – Gemcitabine is supplied as a lyophilized powder in sterile 
vials containing 200 mg or 1 g of gemcitabine as the hydrochloride salt, with 
mannitol and sodium acetate. To reconstitute, add 5 mL of sodium chloride 0.9% 
injection to the 200 mg vial or 25 mL of sodium chloride 0.9% injection to the 1 g 
vial to a concentration of 38mg/mL. The appropriate amount of drug may be 
administered as prepared or further diluted with 0.9% sodium chloride solution or 
dextrose 5% solution to concentrations as low as 0.1 mg/mL. Gemcitabine 0.1 and 10 
mg/mL solutions diluted with sodium chloride 0.9% injection or dextrose 5% 
injection are chemically stable for up to 35 days at room temperature or under 
refrigeration when stored in polyvinyl chloride bags. Because these solutions contain 
no preservative, they should be used within 24 hours of preparation.  
 
c. Administration – Intravenous infusion over 100 minutes. 
 
d. Storage and Stability – Store at controlled room temperature. 
 
 
e. Supplier – Gemcitabine is commercially available 
 


 
22
9.0 STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  
Scans and x-rays must be done within 4 weeks of start of therapy.   
    
 
Pre- 
Study 
 
Cycles 
1-4 
 
Re-Eval 
Cycles 
5-6 
Chemo 
XRT 
Re-Eval 
Cycles 
7-8 
Re-Eval 
 
Surgery 
Post 
 
Performance Status 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
History/Physical 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
CBC,diff, pltsa 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Serum Chemistryb 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Ca 19-9 
 
X 
 
 
 
X 
  
 
X 
 
X 
 
 
X 
 
Urine/serum pregnancyc  
X 
 
 
 
 
  
 
 
 
 
 
 
 
CT chest/abdomend 
 
X 
 
 
 
X 
  
X 
 
X 
 
 
X 
 
Tumor Measurement 
 
X 
 
 
 
X 
  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
 
 
 
 
 
 
 
E 
 
 
Radiation 
 
 
 
 
 
  
B 
 
 
 
 
 
 
5FU, Irinotecan, 
Oxaliplatin 
 
 
A 
 
A 
 
 
 
 
 
Gemcitabine 
 
 
 
 
 
 
C 
 
D 
 
 
 
 
Toxicity Evaluation 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
a prior to chemotherapy administration, at re-evaluation visits and per post treatment follow-up 
b comprehensive chemistry panel to include albumin, alkaline phosphatase, ALT or AST, 
glucose, total bilirubin, creatinine and electrolytes 
c in women of childbearing potential only 
d at intervals post treatment noted in section 5.11 
 
A  FOLFIRINOX section 5.2 
B  IMRT section 5.5 
C  FDR-gemcitabine section 5.3 
D  FDR-gemcitabine section 5.4 
E  Surgical exploration/resection see section 5.10 
 
Post therapy follow-up at 3-month intervals through 2 years. All times are approximate. 
 
 


 
23
10. MEASUREMENT OF EFFECT 
 
10.1Primary Tumor Response 
 
Diagnostic imaging and RECIST criteria will be used to evaluate and record response 
of the primary tumor as defined below. 
 
Complete Response (CR): Disappearance of measurable and evaluable disease 
without the appearance of any new lesions. 
 
Partial Response (PR): At least 30% decrease in the LD of the primary lesion without 
the appearance of any new lesions. 
 
Progression (PD): At least 20% increase in the LD of the primary lesion or the 
appearance of one or more new lesions 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD. 
 
10.2 
Surgical Data  
 
 
The following information regarding any surgical therapy will be recorded. 
 
Operation performed 
             
Standard Whipple (pancreaticoduodenectomy) 
            Pyloric-preserving Whipple 
             
Total Pancreatectomy 
 
 
Distal Subtotal Pancreatectomy 
Any of above with vascular resection and reconstruction 
 
 
 
Exploratory laparotomy (no resection) 
 
 
With gastric bypass 
 
 
With biliary bypass 
 
 
With both 
 
Duration of operation, Blood loss, Complete resection  
 
Pathologic findings; Tumor size, Grade, Nodal status 
 
Microscopic assessment of margins, including retroperitoneal margin  
(R0 vs. R1 vs. R2 ) 
 
Length of Stay, Need for re-admission within 30 days of discharge 
 
10.3Assessment of Pathologic Response 
 
The surgical pathology slides will be reviewed at the Department of Pathology, 
University of Michigan Hospital.  All histologic slides from surgical resections 
will be reviewed by a single pathologist and assessment of therapeutic response 


 
24
will be graded using a system previously described by Evans et al as per the table 
below. 
 
 
Grade 
Histologic Appearance 
 
 
 
 
 
      
 
 
I 
 
Characteristic cytologic changes of malignancy are present, 
but very little (<10%) or no tumor cell destruction is evident 
 
 
 
II 
 
In addition to characteristic cytologic changes of 
malignancy, 10%-90% of tumor cells are destroyed   
 
IIa  
Destruction of 10%-50% of tumor cells 
 
IIb  
Destruction of 51%-90% of tumor cells 
 
III  
Few (<10%) viable-appearing tumor cells are present   
 
IIIM 
Sizable pools of mucin are present 
 
IV  
No viable tumor cells are present   
 
IVM 
Acellular pools of mucin are present  
 
11. 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
11.1Study Monitoring 
 
a. Study Forms - University of Michigan will maintain on-study forms, eligibility 
checklists, flow sheets and off-study forms for each patient entered in the study database 
 
b. Data and Safety Monitoring Committee 
 
 
 
Composition of the Committee 
This committee will be comprised of the Principal Investigator, co-Investigators (if 
available) and data manager, the Study Coordinator and the protocol's Statistician. 
 
 
 
Scheduled Meetings  
The committee will hold monthly data and safety monitoring meetings. Participants 
will include, whenever possible, the investigator(s), data manager, and statistician. 
Minutes from these meetings will be submitted to the Cancer Center DSMB. 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1Study Design/Endpoints  
 
 
Definition of primary endpoint 
 
Any eligible patient who receives at least one dose of chemotherapy according to the 
protocol will be considered evaluable for the primary study endpoint.  R0 resection 
will be defined as gross total resection with pathology review demonstrating margins 
negative for microscopic disease.  


 
25
 
12.2Definition of secondary endpoints 
 
Progression-Free Survival: Time from date of registration to the date of documented 
progressive disease, development of distant metastatic disease, non-protocol disease 
related therapy, death, or recurrence following surgical resection whichever occurs 
first.  Patients who experience therapy related death will be considered to have 
experienced a PFS-event. Otherwise, the patient will be considered censored at last 
follow-up. 
 
Overall Survival: Time from date of registration to date of  death or last follow up 
whichever occurs first.  Death regardless of cause will be considered an event.    
Otherwise, the patient will be considered censored at last follow-up. 
 
Toxicity: Toxicity encountered during the study will be evaluated using the NCI 
Common Toxicity Criteria Version 4.0.  Patients receiving any treatment will be 
evaluable for toxicity. 
 
12.3Sample Size/Accrual Rate 
 
Thirty-one patients meeting eligibility criteria will be accrued and treated on this 
clinical trial.  The sample size is based upon the statistical testing of the primary study 
hypothesis, the R0 resection rate following the neoadjuvant treatment regimen.  
Previous clinical experience treating borderline resectable pancreatic cancer patients 
with chemotherapy and chemoradiotherapy in the neoadjuvant setting yielded a 30% 
R0 rate at time of surgery.  With the addition of the FOLFIRINOX chemotherapy 
regimen, we hope to improve the R0 rate to 55%.  Thirty-one patients are necessary 
to test that hypothesis using a two-sided test with 5% type I error and 20% type II 
error (80% power).   The University of Michigan historically sees 400 new patient 
consultations for pancreatic cancer per year.  Between 10 and 15% of those patients 
are  deemed to have borderline resectable disease. We therefore anticipate between 40 
and 60 patients per year will be eligible for this protocol.  Due to dismal survival rates 
in this lethal disease and the lack of a widely accepted standard of care, it is our 
experience that patients have strong interest in participating in clinical trials.  Given 
that we have no competing trial for this patient population, we anticipate completing 
accrual to this study in 62 months. 
 
12.4Analysis of Endpoints 
 
Analytic plan for primary objective:   Since the primary study endpoint will be 
determined in some patients only after several months, halting enrollment for formal 
interim outcome monitoring will result in significant gaps in accrual and increase 
total study duration.  We, therefore, plan to enroll in a single stage, 31 patients 
evaluable for the primary endpoint. The R0 rate and exact 90% binomial confidence 
interval will be reported.    
Analytic plan for secondary objectives: Progression-Free Survival and Overall 
Survival as a function of time since enrollment will be estimated according to the 
method of Kaplan andMeier32. 


 
26
 
Toxicity - The proportion of treated patients experiencing any clinically significant 
(Grade 3 or worse) toxicity will be determined; specific toxicities of all grades will be 
tabulated.   
 
 
12.5Interim stopping rules:  It is important for the utility of this treatment regimen, that 
neoadjuvant FOLFIRINOX be tolerated, as to not delay initiating chemoradiation and 
surgery.  Although some chemotherapy treatment related delays are expected, as outlined 
in Section 6, a high proportion of patients should complete adjuvant FOLFIRINOX 
chemotherapy on schedule.  We expect, that at least 2/3 (66.7%) of patients should begin 
cycle 3, day 1 (C3D1) of neoadjuvant FOLFIRINOX chemotherapy between days 29 
and 43 on protocol (days from C1D1).  In order to assess this expectation, we will 
conduct an interim analysis for chemotherapy delay after 15 patients (approximately 
50% of our required sample size) have been treated on trial.  If less than 7 patients have 
received D1C3 by day 43 on protocol, we will close the trial to new accrual.  If 7 or 
more patients have reached the D1C3 treatment milestone, then the trial will continue 
until 31 evaluable patients have been treated on study.  The stopping-rule is based upon 
the exact binomial confidence interval.  When 6 or fewer patients can reach this 
treatment milestone, the 90% confidence interval excludes 66.7%, our minimum 
expectation.  The following table indicates the probability the trial will stop due to this 
rule for various levels for the true probability of reaching the C3D1 treatment milestone. 
 
Probability of patients having C3D1 by day 
43 
Probability of stopping at interim analysis 
0.35 
0.75 
0.40 
0.61 
0.45 
0.45 
0.50 
0.30 
0.55 
0.18 
0.60 
0.10 
0.65 
0.04 
0.70 
0.02 
 
12.6Reporting and Exclusions 
 
Evaluation of toxicity - All patients will be evaluable for toxicity from the time of their 
first treatment with protocol therapy. 
 
Evaluation of response - Patients will be evaluable for the primary endpoint if they 
receive any protocol therapy.  Patients will remain evaluable for the primary endpoint 
regardless of any reason for discontinuation from the protocol including but not limited 
to: death, withdrawal due to toxicity, and voluntary withdrawal.   
 
 


 
27
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