A Randomized Phase II/Genomic Trial of Two Chemotherapy Regimens in Patients With Resected Pancreatic Adenocarcinoma
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma
Sponsor: Abramson Cancer Center at Penn Medicine

 
 
 
 
 
 
 
 
 
A Randomized Phase II/Genomic Trial of two chemotherapy 
regimens in patients with resected pancreatic adenocarcinoma 
 
Principal Investigators: 
Peter J. O’Dwyer, M.D. 
16 Penn Tower  
3400 Spruce Street 
Philadelphia, PA  19104 
215-662 7606 
peter.odwyer@uphs.upenn.edu 
 
 
 
 
 
 
Co-Investigators: 
 
Jeff Drebin, MD 
Charles Vollmer, MD 
Bruce Giantonio, M.D. 
Ursina Teitelbaum, MD 
Arturo Loaiza-Bonilla, MD 
Michael Feldman, MD 
Emma Furth, MD 
James Metz, MD 
Edgar Ben-Josef, MD 
John Plastaras, MD 
Grant Apisarnthanarax, MD 
Km Reiss Binder, MD 
Mark O'Hara, MD 
 
All at: The Hospital of the University of Pennsylvania 
34th and Spruce Streets 
Philadelphia, PA  19104 
 
Funding Sponsor: 
 
Statistician 
Daniel F. Heitjan, Ph.D. 
University of Pennsylvania Perelman School of Medicine 
Center for Clinical Epidemiology & Biostatistics 
622 Blockley Hall 
423 Guardian Drive 
Philadelphia, PA  19104-6021 
 
 
Protocol #: UPCC 03213 
 
Initial Version Date: 2.15.2013 
Amended: 
 
2.18.2016

 
 
page 1 
 
Schema  
Patients with operable resected adenocarcinoma of the pancreas: 
Randomized: 
 
Arm A: FOLFIRINOX 
Irinotecan 180 mg/m2 Day 1 
Oxaliplatin 85 mg/m2  Day 1 
5-FU 400 mg/m2 bolus with  
Leucovorin 200 mg/m2 over 2h, Day 1, then  
5-FU 2400 mg/m2 over 46h.   
 
Four cycles over 8 weeks 
 
Chemoradiation:  
Radiation to begin no sooner than 28 days from last day of chemotherapy.   
On Day 1(+ 2days to accommodate scheduling difficulties): 
Infusional 5-FU (225 mg/m2 continuous infusion during radiation) and radiation therapy as defined.   
 
 
FOLFIRINOX 
Irinotecan 180 mg/m2 Day 1 
Oxaliplatin 85 mg/m2  Day 1 
5-FU 400 mg/m2 bolus with  
Leucovorin 200 mg/m2 over 2h, Day 1, then  
5-FU 2400 mg/m2 over 46h.   
 
Four cycles, if tolerated 
 
Arm B: Gemcitabine / Abraxane 
Gemcitabine 1000 mg/m2 Days 1, 8, 15 
Abraxane 125 mg/m2  Days 1, 8, 15 
 
Two cycles over 8 weeks 
 
Chemoradiation:  
Radiation to begin no sooner than 28 days from last day of chemotherapy.   
On Day 1 (+ 2days to accommodate scheduling difficulties) 
Infusional 5-FU (225 mg/m2 continuous infusion during radiation) and radiation therapy as defined.   
 
Gemcitabine / Abraxane 
Gemcitabine 1000 mg/m2 Days 1, 8, 15 
Abraxane 125 mg/m2  Days 1, 8, 15   
 
Two cycles, if tolerated  
 
 

 
 
Page 2 
 
R 
XRT/5-FU 
FOLFIRINOX X 4 
Gemcitabine/ 
Abraxane X 2  
FOLFIRINOX X 4 
Gemcitabine/ 
Abraxane X 2 
Note the cycle duration for FOLFIRINOX is 2 weeks, and for Gemcitabine/ abraxane 4 weeks 

 
 
Page 3 
Study Summary 
Title 
A Randomized Phase II/Genomic Trial of two chemotherapy regimens 
in patients with resected pancreatic adenocarcinoma 
Short Title 
same 
Protocol Number 
UPCC  
Phase 
Phase II 
Methodology 
Randomized 
Study Duration 
2 years 
Study Center(s) 
Single Institution to start 
Objectives 
Primary Objective: 
1.  Determine the relapse-free survival of resected pancreatic cancer 
patients following two novel regimens  
 
                 Secondary Objectives 
1) 
 To assess the toxicity of each of these regimens in this 
setting 
 
2) 
To perform exploratory genomic analyses as a means of 
assessing molecular characteristics potentially associated with risk of relapse 
with one or both of the regimens 
 
3) 
To determine the relationship between known mutations 
and metabolic activity as measured by FDG-PET, and risk of relapse 
 
 
Number of Subjects 
50 

 
 
Page 4 
Diagnosis and Main 
Inclusion/Exclusion 
Criteria 
1.1 Inclusion Criteria 
3.1.1 Patients must have histologically or cytologically confirmed 
evidence of pancreatic adenocarcinoma or poorly-differentiated 
carcinoma.  Neuroendocrine tumors are not eligible. 
3.1.2 Patients must have had all gross disease resected (R0 or R1 
resection). 
3.1.3 Patients who underwent an R2 resection are not eligible. 
3.1.4 Patients must have had no prior chemotherapy or radiation therapy 
for pancreatic cancer. 
3.1.5 Age > 18 years.  
3.1.6 Patient must have ECOG performance status of 0-2 unless surgical 
morbidity is responsible – in such an event he must be a suitable 
candidate for adjuvant therapy in the opinion of the PI. 
3.1.7 Patients must have normal organ and marrow function measured 
within 2 weeks 
prior to registration as follows: 
ANC > 1,500/μL  
Platelets > 100,000/μL  
Total bilirubin less than 3-fold ULN 
AST (SGOT)/ALT(SGPT) < 5 X institutional upper limit of 
normal 
Creatinine clearance > 60 mL/min for patients with creatinine 
levels above institutional normal 
3.1.8 Patients must be > 4 weeks and < 16 weeks post-surgery at time of 
study registration 
3.1.9 Women of childbearing potential and sexually active males are 
strongly advised to use effective contraceptive measures. 
3.1.10 Women must not be pregnant or breast-feeding. All agents used in 
this study as well as radiation therapy to the abdomen have the 
potential for teratogenic or abortifacient effects. All females of 
childbearing potential must have a blood test or urine study within 
2 weeks prior to registration to rule out pregnancy. 
3.1.11 Patients must not be receiving any other investigational 
agents.3.1.12 Patients with known metastases are not eligible. 
3.1.14 Patients with wounds that have not fully healed are not eligible. 
3.1.15 Patients must have no known HIV infection. 

 
 
Page 5 
Study Product, Dose, 
Route, Regimen 
As detailed above.   
 
  
Statistical 
Methodology 
Randomized Phase II  
 

 
 
Page 6 
Objectives 
1.1 Primary Objectives 
   Determine the relapse-free survival of resected pancreatic cancer patients following two novel 
regimens with activity in advanced disease. 
                  
  
1.2 Secondary Objectives 
1.21  To assess the toxicity of each of these regimens in this setting 
 
1.22  To perform exploratory genomic analyses as a means of assessing molecular characteristics potentially 
associated with risk of relapse with one or both of the regimens 
 
1.23   To determine the relationship between known mutations and metabolic activity as measured by 
FDG-PET, and risk of relapse 
 
 
2 Background 
2.1 Resectable Pancreatic Cancer 
Pancreas cancer is the fourth leading cause of cancer death in the United States, with the poorest 
prognosis of the more common cancers (1). Fewer than 5% of patients survive 5 years, and of these, 
almost all have had complete resection of their primary tumor. However, despite continuing 
improvements in surgical technique that have yielded low perioperative mortality, survival among 
resected patients remains low (2). The first adjuvant trial was conducted by the Gastrointestinal Tumor 
Study Group (GITSG), and randomized 43 patients over 8 years.  Though flawed by the long duration of 
accrual and small number of patients, there was a survival advantage for the chemoradiation plus 
surgery arm compared to surgery alone (3).  A subsequent EORTC study randomized patients to 
chemoradiation plus surgery versus surgery alone: survival for both treatment groups was similar (4). 
However, this trial included both periampullary cancers and pancreatic cancers, and when subsets were 
analyzed, there was a trend to improved overall survival in patients with pancreatic cancer. A trial 
conducted in the UK, ESPAC-1, randomized patients to chemotherapy versus no chemotherapy, and to 
chemoradiation versus no chemoradiation (5). Unfortunately, in this study problems included 
incomplete participation in the 2 x 2 design, and a significant number of patients received different 
therapy than assigned. This trial did not demonstrate a benefit to chemoradiation, but suggested that 
adjuvant chemotherapy may be of benefit. A subsequent trial from this group, ESPAC-3, showed no 
difference between 5-FU and gemcitabine as chemotherapy regimens (6).  In the United States, adjuvant 
chemotherapy with chemoradiation has become standard of care. The intergroup trial, RTOG 9741, 
studied gemcitabine before and after continuous infusion (CI) 5-FU plus radiation versus 5-FU before 
and after CI 5-FU plus radiation. The initial report favored the contribution of gemcitabine over 5-FU 
for head of pancreas lesions (7), but that relationship was not maintained in a 5-year follow-up report, 
and the differences were not significant (8).  The controversy surrounding the conflicting results of 
previous trials led Oettle and colleagues (9) to perform a trial of gemcitabine as a single agent versus 
surgery only control, and demonstrated a significant benefit from therapy.   While chemoradiation 
remains the standard of care in the US, these results point to the value of systemic chemotherapy as part 

 
 
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of adjuvant therapy for patients with pancreatic cancer. They also point to the need to enhance the 
efficacy of systemic chemotherapy to improve outcomes in this disease.   
 
2.2 Metastatic Pancreatic Cancer 
The development of novel therapies in the adjuvant setting usually follows upon the demonstration of 
enhanced results in patients with advanced disease.  While this model has had its limitations, there have 
also been notable successes, especially with chemotherapy.  Two new chemotherapy regimens have now 
emerged as superior to gemcitabine alone in metastatic pancreatic cancer.  One has a published Phase III 
trial – FOLFIRINOX was shown to have higher response rates and longer survival than gemcitabine 
alone (10). Response to FOLFIRINOX was 32% (versus 9.4% for gemcitabine).   The median overall 
survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine 
group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001).   
 
Recent strategies have focused on improving the efficacy of gemcitabine either by improving the 
method of delivery, or by combining gemcitabine with other non-cross resistant agents.  A sequence of 
Phase III combination studies of gemcitabine in combination (with oxaliplatin, and with the targeted 
therapies bevacizumab and cetuximab) have been negative, though based on strikingly positive Phase II 
data generated in cancer centers.   Several studies suggest that taxanes are active in pancreatic cancer, 
but a randomized trial of gemcitabine with taxanes has not been performed, probably on the basis that 
the differences in Phase II were  insufficiently persuasive.  The development of a novel taxane conjugate 
with albumin, abraxane, with established activity in breast cancer, prompted a Phase II trial of 
gemcitabine/abraxane by Von Hoff (11).  Phase I/II data were highly promising, with response rates of 
48%, with tolerable toxicity, in an expansion cohort treated at 125 mg/m2.  Overall survival in this 
group was 12.2 months.  A phase III trial of gemcitabine versus gemcitabine/abraxane has now been 
concluded and results are expected this year, and based on these promising data the regimen has served 
as the control chemotherapy for our SU2C trials.   
 
Abraxane (nab-paclitaxel) is a cremophor-free formulation of nanoparticle paclitaxel stabilized with 
human serum albumin (130 nm particles).  The drug achieves enhanced tumor penetration through gp60 
albumin receptor-mediated endothelial transcytosis, which enables transit across the vessel endothelium, 
and makes the active paclitaxel available to the tumor.  An additional pharmacodynamic consideration is 
that the albumin scaffold also binds a tumor-related protein SPARC, which may further enhance 
localization of this molecule in the tumor tissue.  Preliminary data suggest that SPARC-expressing 
tumors may have better responses to abraxane.    
 
Both FOLFIRINOX and gemcitabine/ abraxane have neutropenia as their major adverse effect.  With 
FOLFIRINOX 46% of patients experienced grade 3 or 4 neutropenia, with fatigue, nausea/vomiting and 
diarrhea much less frequently observed.  In the gemcitabine abraxane trial, neutropenia was of a similar 
order (49% at 125mg dose), and additional toxicity included fatigue and neurotoxicity (11).   
 
2.3 Markers of Therapy Effect 
Prognostic Markers.  Substantial research has been performed in the characterization of molecular 
abnormalities associated with pancreatic cancer, and samples continue to be analyzed from our ongoing 
advanced disease studies.  The best-characterized aberrations have been mutations and/or chromosomal 
losses affecting KRAS (>95%), p16/CDKN2A (95%), TP53 (50–75%), and DPC4/SMAD4 (55%), the 4 
high-frequency pancreatic cancer driver genes (12-14). The last is of particular interest in that tumors in 
which the locus is intact may have a higher risk of local relapse (15).  A radiation dose intensification 

 
 
Page 8 
trial is in development in RTOG with smad4 genetic variability as a key correlative endpoint.  None of 
the aberrant pathways identified in this disease has been clearly associated with outcome. 
 
Predictive Markers.  Data suggest that genomic variation in drug-metabolizing genes, or in genes in 
related pathways (eg DNA damage response, DNA repair) might influence the outcome of therapy.  In 
general, little positive association has been found for particular profiles of genetic aberration and 
response in pancreatic cancer, but candidate genes have emerged recently.  There are not many trials 
with follow-up and detailed genomics in pancreatic cancer, and so we propose in this study to obtain 
sufficient materials to conduct such research.  Recognizing that numbers of patients are small, such 
studies may provide the basis for targeted analyses in larger trials going forward, and generate 
hypotheses concerning potential predictive markers. 
 
1. Mutational Analysis. All tumors will be typed using the 48-gene platform of the Center for 
Personalized Diagnostics.  DNA, miRNA, and total RNA will be prepared from microdissected tumor.  
An aliquot (1 microgram approx) will be submitted for analysis.  This analysis will provide mutation 
and copy number characteristics for genes important to pancreatic cancer including Kras, p53, and 
smad4.   
 
2.  Drug Resistance genes.  An aliquot of DNA will be obtained and stored for analysis of 
polymorphisms in drug transport genes (eg hENT1, MDR), microtubule associated proteins, DNA repair 
genes, and DNA damage response genes.    
 
3.  Isolation of nuclei (in collaboration with Dr M. Barrett, TGEN) for CNV and possible exome 
sequencing studies. 
 
4.  Metabolomics studies where feasible, and the tumor has been operated on at Penn.  
 
5.  Circulating Tumor cells as soon as the methodology has been validated. 
 
 
Complementing the tissue-based studies, we propose to obtain imaging studies pre-operatively in these 
patients.  We will begin with FDG-PET, the use of which is approved for pancreatic cancer, and we will 
study as many as possible with F-misonidazole-PET for which we now have an IND.   This is justified 
by a metabolomic profile of hypoxia in our early studies (Thompson CB, manuscript submitted, 2012).  
We will plan at later stages to introduce glutamine-PET and as these tracers become more available, and 
as funding permits.   
 
2.4 Design 
This trial will be a randomized Phase II study of FOLFIRINOX versus gemcitabine/abraxane in patients 
with completely resected pancreatic cancer (Stages I-III).  Patients will receive eight weeks of 
chemotherapy, then 5-FU/radiation, then another 8 weeks.  Most patients will have insurance coverage 
that should cover these agents at this stage of the disease; however, inevitably there will be some who 
are not covered.  For those patients, a standard gemcitabine plus 5-FU/radiation regimen will be used, 
and samples obtained and analyzed for comparative purposes.  
 

 
 
Page 9 
3 Patient Eligibility 
3.1 Inclusion Criteria 
3.1.1 Patients must have histologically or cytologically confirmed evidence of pancreatic 
carcinoma. 
3.1.2 Patients must have had all gross disease resected (R0 or R1 resection). 
3.1.3 Patients who underwent an R2 resection are not eligible. 
3.1.4 Patients must have had no prior chemotherapy or radiation therapy for pancreatic 
cancer. 
3.1.5 Age > 18 years.  
3.1.6 Patient must have ECOG performance status of 0-2. 
3.1.7 Patients must have normal organ and marrow function measured within 2 weeks 
prior to registration as follows: 
ANC > 1,500/μL  
Platelets > 100,000/μL  
Total bilirubin less than 2-fold ULN 
AST (SGOT)/ALT(SGPT) < 2.5 X institutional upper limit of normal 
Creatinine clearance > 60 mL/min for patients with creatinine levels above institutional normal 
3.1.8 Patients must be > 4 weeks and < 12 weeks post-surgery at time of study registration 
3.1.9 Women of childbearing potential and sexually active males are strongly advised to use appropriate 
contraceptive measures. 
3.1.10 Women must not be pregnant or breast-feeding. All agents used in this study as well 
as radiation therapy to the abdomen have the potential for teratogenic or 
abortifacient effects. All females of childbearing potential must have a blood test or 
urine study within 2 weeks prior to registration to rule out pregnancy. 
3.1.11 Patients must not be receiving any other investigational agents. 
3.1.12 Patients with known metastases are not eligible. 
3.1.14 Patients with wounds that have not fully healed are not eligible. 

 
 
Page 10 
3.1.15 Patients must have no known HIV infection. 
3.1.16 Patients must not have any of the following: acinar cell carcinoma, neuroendocrine carcinoma, 
cystadenocarcinoma, carcinosarcoma. 
3.1.17 Patients with psychiatric or addictive disorders or other conditions that, in the opinion of the 
investigators, would preclude them from meeting the study requirements are not eligible. 
3.1.18 Patients must have the ability to understand and the willingness to sign a written informed 
consent document. 
3.1.19 Patients must have provided consent for tissue collection for the molcecular testing through 
participation on study UPCC 22210 entitled; “PROTOCOL TO PERMIT THE ACQUISITION 
OF SAMPLES OF TUMOR AND NORMAL TISSUE FOR BIOLOGICAL ENDPOINTS IN 
PANCREATIC CANCER” 
 
3.2 
Exclusion Criteria 
3.2.1 Patients may not be receiving any other investigational agents 
 
3.2.2 Patients with T1, N0M0 disease are not eligible. 
 
 
4 Treatment Plan 
4.1 Study Design 
Randomized Phase II, FOLFIRINOX versus gemcitabine/abraxane, both with 5-FU/radiation..  All 
therapy and testing times in this protocol are approximate and depend on hospital schedules, patient 
availability, and practicality. 
 
4.2 Treatment Plan  
Arm I - FOLFIRINOX 
 
Chemotherapy: 
Irinotecan 180 mg/m2  Day 1 
Oxaliplatin 85 mg/m2  Day 1 
5-FU 400 mg/m2 bolus with  
Leucovorin 200 mg/m2 over 2h, Day 1, then  
5-FU 2400 mg/m2 over 46h.   
 
This constitutes one treatment, which will be repeated four times (at 14 day intervals) before starting 
chemoradiation, and four times (as tolerated) after its completion. 
 

 
 
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Arm II – Gemcitabine/Abraxane 
 
Gemcitabine 1000mg/m2 IV over 30 to 100 minutes, day 1, 8, 15 
Abraxane 125 mg/m2 IV over 30 minutes, day 1, 8, 15 
Repeat every 4 weeks as tolerated twice before and twice (as tolerated) after chemoradiation. 
 
Chemoradiation:  
Radiation to begin no sooner than 21 days after last day of chemotherapy.   
On Day 1 (+ 2days to accommodate scheduling difficulties): 
Infusional 5-FU (225 mg/m2 continuous infusion during radiation) and radiation therapy as 
defined.   
 
Patients will receive an appropriate anti-emetic regimen usually including dexamethasone 10-20mg IV 
and a 5-HT3 agent of choice, (i.e. ondansetron or granisetron) prior to administration of chemotherapy 
to decrease the incidence and severity of chemotherapy-associated nausea and vomiting, at the discretion 
of the investigator.  Drugs such as lorazepam may also be used if clinically indicated.   
 
4.2.2 Duration of Treatment 
Patients will receive protocol therapy as outlined, followed by observation.  Toxicities related to 
treatment will be reason for chemotherapy modification, interruption or discontinuation as deemed 
appropriate by the physician as in the best interest of the patient.  All patients in whom protocol therapy 
has been discontinued will be followed for progression of disease and survival.  A schedule of clinic 
visits quarterly, and imaging at six month intervals for 2 years and annually thereafter for 5 years is 
suggested, but not mandated, given the rapid course of recurrent pancreatic cancer.     
 
4.2.3 PET 
Patients will have a FDG-PET scan pre-operatively where feasible.  Lack of such a scan will not 
preclude entry on the study or constitute a protocol deviation. 
  
4.2.4 Tumor Analysis 
Tumor obtained at surgery will be frozen and stored for genomic analysis. Where cellularity and/or 
necrosis preclude the reliable use of fresh tissue, we will plan to sequence out of FFPE after 
microdissection.   
 
4.2.5 Circulating Tumor Cells 
In addition to standard laboratory assessments prior to administration of chemotherapy, patients will 
have blood drawn to assess circulating tumor cells.  The methods for these analyses are in development, 
and will be applied as feasible to this protocol by amendment.     
5 Dosing Delays/Dose Modifications 
Toxicity will be graded using the NCI Common Toxicity Criteria which is available on the NCI website 
www.ctep.cancer.gov.  Laboratory abnormalities on the day of treatment for second and subsequent 
courses will be considered in treatment decisions.  Values that deviate from eligibility criteria for the 
study may cause a delay of up to four weeks for recovery to occur.  If the abnormalities have not 
resolved by then, the patient should ordinarily be taken off study.  Exceptions may be made after 
discussion with the Principal Investigator.  

 
 
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5.1 Dose Modifications 
 
According to the following recommended tables, the final dose modification should be based upon the 
worst grade of toxicity experienced. If patients require dose reductions lower than level -2, a 30% 
reduction will ordinarily be used.  Any dose reduction is continued for all subsequent cycles; however, 
dose re-escalation is allowed following a dose reduction to an intermediate dose. NOTE: there are no 
dose reductions for leucovorin; the dose remains fixed at 400 mg/m2 and without modification.  
 
NOTE: The tables below are provided as quidelines and may be adjusted, as appropriate, by the 
treating physician, to ensure patient safety and comfort, as is routinely done as part of standard 
care.  The rationale for straying from the guidelines will be documented in the patient’s chart and 
will NOT constitute a protocol deviation.   
 
5.1.1 Dose Modifications for Oxaliplatin, Irinotecan, and 5-FU Toxicity 
 
NOTE: There are no dose reductions for leucovorin. The dose remains fixed at 400 mg/m2. Leucovorin 
is discontinued only when bolus 5-FU is discontinued. 
 
NOTE: Patients who require discontinuation of one drug may continue to receive the others.  
 
Dose Levels of Oxaliplatin and 5-FU 
 
Starting Dose* 
Dose Level – 1 
Dose Level – 2 
Oxaliplatin advanced 
85mg/m2 
65mg/m2 
50mg/m2 
Oxaliplatin neoadjuvant 
50 mg/m2 
40 mg/m2 
30 mg/m2 
5-FU Bolus  
400mg/m2 
320mg/m2 
200mg/m2 
5-FU Infusion  
2.4g/m2 
2gm/m2 
1.6g/m2 
 
* All patients will start cycle 1 with doses listed in ‘Starting Dose’ column 
5.1.1.1  Non-Neurologic Toxicity (Oxaliplatin, irinotecan, and 5-FU Toxicity) 
 
The following table describes the recommended, not required,  dose modifications at the start of each subsequent 
course of therapy. All dose modifications should be based on the worst preceding toxicity.   
 
Toxicity NCI Grade (Value) 
Day of Treatment  
Interval Toxicity 
 
Neutropenia (ANC) 
 
 
 
Grade 1 (ANC < LLN - 1500/mm³) 
Grade 2 (ANC <1499 - 1000/mm³) 
Grade 3 (ANC <999 - 500/mm³) 
Grade 4 (ANC < 500/mm³) 
If ANC <1000 on day of treatment, hold 
and check weekly until >1000 mm3.  Then 
treat based on interval toxicity. 
 
 
Maintain dose level 
Maintain dose level 
Maintain dose level 
Reduce all 3 1 dose level (may 
subsequently increase 5-FU and 
oxaliplatin to tolerable toxicity) 
 
Febrile neutropenia: decrease irinotecan 
and oxaliplatin one dose level 
 
 
Thrombocytopenia1 
 
 
Grade 1 (PLT < LLN - 75,000/mm3) 
If PLT <75,000 on day of treatment, hold 
and check weekly until ≥ 75,000 mm3.   
 
 
Maintain dose level 
 
 
 

 
 
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Grade 2 (PLT 74,999 – 50,000/mm3) 
Grade 3 (PLT 49,999 – 25,000/mm3) 
Grade 4 (PLT< 25,000/mm3) 
 
 
Maintain dose level 
Reduce oxaliplatin 1 dose level 
Reduce oxaliplatin 2 dose levels 
 
If reducing oxaliplatin dose does not 
ameliorate toxicity may need to decrease 
irinotecan, thern 5-FU on subsequent 
cycles 
 
Diarrhea 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Hold if any grade of diarrhea above 
baseline is present.  Reduce 5-FU and 
irinotecan 1 dose level upon resolution of 
diarrhea.  If diarrhea has not resolved 
within 2 weeks of scheduled treatment 
day, wait resolution and decrease two 
levels 
 
 
Maintain dose level 
Maintain dose level 
Reduce irinotecan and 5-FU 1 dose 
level 
Reduce irinotecan and5-FU 2 dose 
levels and oxaliplatin 1 dose level (may 
subsequently increase 5-FU and 
oxaliplatin to tolerable toxicity) 
Other nonhematologic toxicities 
(except neurologic)*2 
Grade 1 
Grade 2 
 
Grade 3 
 
 
Grade 4 
 
 
Maintain dose level 
Hold until resolved to grade ≤1 
Maintain dose level 
Hold until resolved to grade <1 
Reduce most likely culprit(s) 1 dose level 
 
Hold until resolved to grade <1 
Reduce most likely culprits(s) 1 dose level 
 
 
 
Maintain dose level 
Maintain dose level 
 
Reduce most likely culprit 1 dose level 
educe all three 1 dose level, and may 
subsequently re-escalate likely 
unrelated drugs 
 
*Exceptions: alopecia, anorexia, nausea/vomiting if can be controlled by antiemetics 
 
1 Hemolytic Uremic Syndrome (HUS)/Thrombotic Thrombocytopenic Purpura (TTP): The hemolytic uremic syndrome should be suspected in individuals 
who experience unexplained severe hemolysis, hemoglobinemia and renal failure as demonstrated by an increase in serum creatinine.  Patients suspected of 
experiencing HUS or demonstrating symptoms of TTP 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), Antithrombin 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 HUS or TTP. 
 
2 With any suspicion of veno-occlusive disease (VOD) of the liver (hyperbilirubinemia, ascites, unexplained weight gain, hepatomegaly, splenomegaly, 
esophageal varices or other sign of portal hypertension), chemotherapy must be held. If VOD is diagnosed clinically, chemotherapy must be discontinued. 

 
 
Page 14 
5.1.1.2  Dose Modifications of Oxaliplatin for Neurologic Toxicity 
 
Neurologic Toxicity a 
Parasthesias/Dysesthesias 
1-7 day duration 
> 7 day duration 
Grade 1 – Paresthesias/dysesthesias that 
resolve and do not interfere with function 
Maintain dose 
Maintain dose 
Grade 2 – Paresthesias/dysesthesias 
interfering with function, but not activities of 
daily living 
Maintain dose b 
Decrease oxaliplatin one dose 
level b 
Grade 3 – Paresthesias/dysesthesias with pain 
or with functional impairment that also 
interfere with activities of daily living 
First episode: Decrease only oxaliplatin one 
dose level b 
Second episode: Stop oxaliplatin only 
Stop oxaliplatin only.  After 
resolution to grade 1 
oxaliplatin may be 
reintroduced at discretion of 
treating physician. 
Grade 4 – Persistent paresthesias/dysthesias 
that are disabling or life-threatening 
Stop oxaliplatin only 
Stop oxaliplatin only 
Laryngeal Dysesthesias 
(Grading at physician’s discretion) 
 
Grade 1 – Mild 
Grade 2 – Moderate 
 
Maintain dose and consider increasing 
duration of oxaliplatin infusion to 6 hours 
Maintain dose and consider 
increasing duration of 
oxaliplatin infusion to 6 hours 
Grade 3 – Severe 
 
At physician’s discretion, either stop 
oxaliplatin or increase duration of infusion 
to 6 hours 
Stop oxaliplatin only 
Pulmonary Toxicity 
Dyspnea ≥ grade 2 
Hypoxia ≥ grade 2 
Pneumonitis/pulmonary infiltrates ≥ grade 2 
Cough ≥ grade 3  
 
Hold all therapy until interstitial lung disease is ruled out. 
• 
If non-infectious interstitial lung disease is confirmed, oxaliplatin 
must be discontinued. 
• 
If non-infectious interstitial disease is ruled out and infection (if any) 
has resolved, patients with persistent Grade 2 dyspnea or hypoxia can 
resume treatment at the physician’s discretion. 
a    These toxicity descriptions should be used to determine dose modifications and delays.  Use the CTCAE v3.0 to assess   
neurologic toxicity for adverse event reporting. 
b    Treatment should be withheld in patients who experience ≥ Grade 3 peripheral neuropathy or ≥ grade 2 if intolerable to the 
patient. Gemcitabine administration can continue during this period at the discretion of the investigator.  Nab-Paclitaxel treatment 
may be resumed at the next lower dose level in subsequent cycles after the peripheral neuropathy improves to ≤ Grade 1 or re-
instituted at the same dose for a grade 2 neuropathy 
 
5.1.2 Dose Modifications for Gemcitabine and Abraxane Toxicity 
 
NOTE: Patients who require discontinuation of both gemcitabine and abraxane for toxicity will 
discontinue protocol therapy but will continue to be followed for disease progression and survival.  
 
NOTE: Patients who require discontinuation of one may continue to receive the second chemotherapy 
agent.  This is expected to be common since the cumulative neurotoxicity of abraxane often requires its 
cessation after 4-6 months. 
 
5.2 Gemcitabine and nab-Paclitaxel 
 
5.2.1  Rules for Dose Omissions and Modified Schedules 
 
Day 1 dose missed: 
If the dose held or missed was to be given on Day 1 of the next cycle, that next cycle will not be 
considered to start until the day the first dose is actually administered to the patient (i.e., 1-2-3-Rest, 
X-1-2-3-Rest, etc.) 

 
 
Page 15 
 
Day 8 dose is missed: 
Cycle continues per protocol, with one dose not given (i.e., 1-2-3-Rest, 1-X-3-Rest, 1-2-3- Rest, 
etc.). Day 15 is administered as per cycle calendar if counts and chemistries permit. 
 
Day 15 dose missed: 
That week becomes the week of rest. Next dose (if counts and chemistries permit) becomes Day 1 of 
a new cycle, and the patient is considered to have had a x2q3 (21-day) cycle (i.e., 1-2-3-Rest, 1-2-X, 
1-2-3-Rest, etc). 
 
Doses will be reduced for hematologic and other non-hematologic toxicities. Dose adjustments 
should be made according to the system showing the greatest degree of toxicity. Toxicities will be 
graded using the NCI CTCAE Version 4.0.   
 
Table 3.  Dose Levels of Gemcitabine and Abraxane 
 
Dose Level 
 
nab- Paclitaxel 
(mg/m2) 
 
Gemcitabine 
(mg/m2)a 
 
 
 
 
 
Study Dose 
125 
 
1000 
-1 
100 
 
800 
- 2 b 
75 
 
600 
aDose reductions may or may not be concomitant. Please refer to Tables 4-6 for specific 
recommendations regarding dose reductions 
bAdditional 25% dose modifications are permissible to establish the tolerable dose for an individual 
patient 
 
Patients who experience study drug-related toxicities that require a delay in scheduled nab-paclitaxel 
and gemcitabine dosing for ≥ 28 days will be discontinued from further participation in this study. 
When a dose reduction is required for Day 1 of any cycle, no dose re-escalation will be permitted for 
the duration of study treatment. 
 
DOSE MODIFICATIONS AT DAY 1 
In the event dose modifications are required at the beginning of a cycle due to AEs or hematologic 
toxicities, the doses and schedule of nab-paclitaxel and/or gemcitabine may be adjusted as detailed 
in Tables 4 and 5 below: 
 
Table 4. Dose Modifications for Hematologic Toxicities (Day 1 of Each Cycle) 
 
For counts on Day 1: 
 
Absolute Granulocytes 
 
Platelets 
Timing 
≥ 1.5 x 109/L  
AND 
≥ 100 x 109/L  
Treat on time 
< 1.5 x 109/L  
OR 
<100 x 109/L  
Delay by one week 
intervals until recovery 
 
 

 
 
Page 16 
 
Table 5. Dose Modifications for Non-Hematologic Toxicity (Day 1 of Each Cycle) 
 
Non-hematologic toxicity (except neuropathy, alopecia) ordinarily should have resolved to Grade 0 or 1 
before initiating the next cycle.  If such toxicity resulted in a dose hold in the previous cycle, the 
following will determine dosing for the current cycle: 
 
Non Hematologic Toxicity (except neuropathy) and/ or Dose Hold with Previous Cycle 
 
Toxicity in previous cycle causing dose to be 
held 
 
Gemcitabine + nab-paclitaxel 
dose this cycle a 
Grade 0, 1 or 2 
Same as day 1 previous cycle 
Grade 3 toxicity 
Decrease gemcitabine by one level 
Grade 4 toxicity 
Decrease gemcitabine two levelsb 
Dose held in 2 previous consecutive cycles 
Decrease gemcitabine by one level 
 
aIf the toxicity only affects neuropathy, then only nab-paclitaxel should be reduced 
bPulmonary embolism (a Grade 4 toxicity in CTCAE tables) if mild or asymptomatic, will be exempt 
from this requirement. 
 
DOSE ADJUSTMENTS WITHIN A TREATMENT CYCLE 
In the event that patients must have treatment delayed within a treatment cycle due to toxicities, 
those doses held during a cycle will not be made up. Dose modifications due to hematologic toxicity 
(as represented by the blood counts and toxicities, below) within a treatment cycle should be 
adjusted as outlined in Table 6, whenever possible. 
 
Table 6. Dose Modifications for Hematologic Toxicity within a Cycle (days 8, 15) 
 
ANC 
 
 
Platelets 
 
Nab- paclitaxel 
 
Gemcitabine 
 
≥1500  
AND 
≥100,000  
100% 
100% 
1000-1499  
OR 
75,000-99,000  
100% 
100% 
500-999  
OR 
50,000-74,000  
Decrease one dose 
level a 
Decrease one dose level 
<500  
OR 
<50,000  
hold 
hold 
Febrile 
Neutropenia 
(Grade 3 or 4) 
 
 
 
Hold. Upon resuming 
dosing, decrease to 
next lower level and 
do not re-escalate 
throughout the rest of 
treatment  
 
Hold. Upon resuming 
dosing, decrease to next 
lower level and do not 
re-escalate throughout 
the rest of treatment  
Recurrent 
Febrile 
neutropenia 
(Grade 3 or 4)  
 
 
 
Decrease to next 
lower dose level and 
do not  re- escalate 
throughout the rest of 
treatment  
Decrease 2 dose levels 
and continue throughout 
the rest of treatment 
 
 
aGCSF may be used (at dose and schedule per institutional guidelines) at the discretion of the 
investigator to maintain ‘nab-paclitaxel dose intensity 

 
 
Page 17 
5.2.2  Provisions for Fever/Infection 
 
Because of significant risk of non-neutropenic sepsis, at the first occurrence of fever > 38.5°C, 
regardless of the neutrophil count, either ciprofloxacin (500mg orally bid) or amoxicillin/clavulinate 
(Augmentin, 500mg orally bid or tid) should be instituted.  At initiation of the study treatment, patients 
should be provided prescriptions for one or other antibiotic, and instructed to begin treatment at the first 
observation of a fever or 35.5C or more, or if they feel they are developing a fever and a thermometer is 
not available.  They should follow a clear plan for blood count evaluation, and clinical assessment for 
infection, and/or the need for hospitalization.   
 
Febrile patients will have their treatment interrupted until recovery (temperature below 100°F for >3 
days), and will be managed according to standard practice for this disorder.  Upon resolution of this 
condition, abraxane and gemcitabine therapy can resume at the next lowest dose.  Dose modifications 
may also be made for non-hematological toxicity within a cycle as specified in Table 7. 
 
 
Table 7. Dose Modifications for Non-Hematological Toxicity within a Cycle 
CTC Grade 
 
 
CTC Grade 
 
Percent of Day 1  
 
0-2   (and Grade 3 nausea/ vomiting and alopecia) 
100% 
3      (except nausea/vomiting and alopecia) 
50% or Holda 
4 
Holda 
a  This decision as to which drug should be modified will depend upon the type of non-hematologic toxicity seen and 
which course is medically most sound in the judgment of the physician/investigator. Treatment may be reinstated on 
Day 1 of the next cycle. 
 
 
5.2.3  Peripheral Neuropathy 
 
Nab-Paclitaxel treatment should be withheld in patients who experience ≥ Grade 3 peripheral 
neuropathy or ≥ grade 2 if intolerable to the patient. Gemcitabine administration can continue during 
this period at the discretion of the investigator.  Nab-Paclitaxel treatment may be resumed at the next 
lower dose level in subsequent cycles after the peripheral neuropathy improves to ≤ Grade 1 or re-
instituted at the same dose for a grade 2 neuropathy. Patients experiencing peripheral neuropathy 
may require an extended delay in scheduled nab-Paclitaxel dosing, but can remain on gemcitabine, 
and have ‘nab-paclitaxel reintroduced at a subsequent cycle should the neuropathy improve as 
above. Patients receiving a reduced dose of nab-Paclitaxel who experience ≥ Grade 3 peripheral 
neuropathy at that dose level requiring a dose delay ≥ 21 days without resolving to < Grade 1 should 
have ‘nab-paclitaxel discontinued. 
 
As observed in other clinical trials, ≥ Grade 3 neuropathy related to nab-Paclitaxel is usually seen in 
later phases of the treatment (cycle 6 and beyond). If ≥ Grade 3 neuropathy occurs in early treatment 
cycles, other factors predisposing the patient to neuropathy might be present (eg. diabetes, alcohol 
consumption, concomitant medications). To maintain dose intensity during the first 6 treatment 
cycles, careful consideration should be exercised when these predisposing factors are present.  
 

 
 
Page 18 
 
5.2.4  Cutaneous Toxicity 
 
Patients who develop Grade 2 or 3 cutaneous toxicity should have their dose reduced to the next 
lower dose level of both drugs. If the patient continues to experience these reactions, treatment 
should be discontinued. Patients who develop Grade 4 cutaneous toxicity should have treatment 
discontinued.  
 
5.2.5  Gastrointestinal Toxicity 
 
If Grade 3 mucositis or diarrhea occurs, study drug should be withheld until resolution to ≤ Grade 1, 
then reinstituted at the next lower dose level of both drugs. Patients who develop Grade 4 mucositis 
or diarrhea should have treatment discontinued 
 
5.2.6  G-CSF 
The use of growth factors to support neutrophil counts is permissible after cycle 1 if neutropenia would 
otherwise require a dose reduction to less than 100 mg/m2 of abraxane.  GCSF may also be considered 
for therapeutic administration in the event of febrile neutropenia as noted above, according to 
institutional practice.   
 
5.3  Supportive Care 
All supportive measures consistent with optimal patient care will be given throughout treatment. 
 
5.4 Duration of Therapy 
Patients will receive protocol therapy unless the constraints of this therapy are detrimental to the 
patient’s health.  In this event, the protocol should be discontinued.  Furthermore, the protocol will be 
discontinued should the patient withdraw consent. 
 
5.5 Duration of Follow-up 
For this protocol, all patients, including those who discontinue protocol therapy early, will be followed 
for recurrence and for survival. All patients must also be followed through completion of all protocol 
therapy. 
 
6 Pharmacologic Data  
6.1 Oxaliplatin 
For complete instruction regarding preparation, handling, dosing and storage, please refer to the FDA-
approved package insert. 
 
6.1.1 Other Names 
Eloxatin, trans-l-diaminocyclohexane oxalatoplatinum, cis-[oxalato(trans-l-1,2-
diaminocyclohexane)platinum(II)]. 
 

 
 
Page 19 
6.1.2 Classification 
Platinating agent. 
 
6.1.3 Mode of Action 
The mechanism of action of oxaliplatin is similar to cisplatin. The main site of action is intrastrand 
cross-linking, therefore inhibiting DNA replication and transcription. 
 
6.1.4 Storage and Stability 
Oxaliplatin vials are stored at room temperature between 20° and 25°C protected from light. 
Reconstituted solution in sterile water or 5% dextrose may be stored for 24 to 48 hours at 2° to 8°C. 
After further dilution in 5% dextrose, the solution is stable for 24 hours at room temperature. 
 
 
6.2.5 Dose Specifics 
85 mg/m² IV in 500 ml D5W. 
 
6.1.5 Preparation 
The freeze-dried powder is reconstituted by adding 10mL (for the 50 mg vials) or 20mL (for the 100mg 
vials) of Water for Injection or Dextrose 5% in Water to yield a 5mg/mL solution. The reconstituted 
solution must be further diluted in an infusion solution of 250mL Dextrose 5% in Water. The 
reconstitution or final dilution must never be performed with a sodium chloride solution. 
 
6.1.6 Administration 
The diluted solution of oxaliplatin in 500mL D5W is administered intravenously over 2 hours 
concurrent with leucovorin. Separate infusion bags and lines must be used with Y-line tubing connecting 
the two lines before the single injection site. 
 
6.1.7 Incompatibilities 
When oxaliplatin is administered with 5-fluorouracil, the oxaliplatin infusion should precede that of 5-
fluorouracil. Ensure the infusion lines are adequately flushed with 5% Dextrose between administration 
of the two drugs. 
Do not mix or administer with saline or other chloride containing solutions. 
Oxaliplatin is unstable in the presence of chloride. 
Do not simultaneously administer other drugs by the same infusion line. 
Do not mix with alkaline solutions. Oxaliplatin is unstable under alkaline conditions. 
Do not use components containing aluminum for the preparation of oxaliplatin administration. There is a 
risk of drug degradation when in contact with aluminum. 
 
6.1.8 Reported Adverse Events and Potential Risks 
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. 

 
 
Page 20 
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 (HUS) 
should be suspected in individuals who experience the following: unexplained severe hemolysis, 
hemoglobinemia and renal failure as demonstrated by an increase in serumcreatinine.  Patients suspected 
of experiencing HUS should be carefully evaluated. 
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, 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 l09/L 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. 

 
 
Page 21 
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 
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. 
 
6.1.9 Nursing/Patient Implications 
• Premedicate with antiemetics (5 HT3 antagonist and steroid) to prevent severe nausea and 
vomiting. 
• Monitor for diarrhea and treat symptomatically. 
• Monitor for neuropathies (parasthesias of hands, feet and toes, pharynx; occasionally cramps). If 
they occur, they tend to be brief (less than one week) during the first course but longer with 
subsequent courses. Advise patients to avoid cold exposure and against touching cold objects. 
Sensory neuropathies develop with continued treatment. Ask patient if changes in ambulation, 
swallowing, breathing or fine motor activity have been noted. 
• Prolonging the oxaliplatin infusion time to 6 hours may alleviate acute neurologic toxicities. 
• Monitor for respiratory changes, such as shortness of breath. 
 
WARNING: 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. 
 
6.2 Fluorouracil 
6.2.1 Other Names 
5-Fluorouracil, 5-FU, Adrucil, Efudex. 
 
6.2.2 Classification 
Antimetabolite 
 
6.2.3 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 

 
 
Page 22 
thymidylic acid from deoxyuridylic acid, thus interfering in the synthesis of DNA. It also interferes with 
RNA synthesis. 
 
6.2.4 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. 
6.2.5 Dose Specifics 
400mg/m², then 2.4g/m². 
 
6.2.6 Administration 
5-FU will be administered at 400mg/m² IV bolus, followed by 2.4g/m² continuous infusion over 46 
hours on day 1 and day 2. 
 
6.2.7 Incompatibilities 
Incompatible with doxorubicin and other anthracyclines. When giving doxorubicin IV push or through a 
running IV, flush line before giving fluorouracil. May form precipitate with fluorouracil in some 
concentrations. 
 
6.2.8 Availability 
Commercially available in 500mg/10ml ampules and vials, and 1g/20mL, 2.5g/50mL, and 5gm/100mL 
vials. 
 
6.2.9 Side Effects 
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. 
 
6.2.10 
Nursing/Patient 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. 

 
 
Page 23 
• 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. 
 
6.3 Leucovorin 
For complete prescribing information, please refer to the approved package insert. 
 
6.3.1 Other Names 
Leucovorin Calcium, Wellcovorin‚ citrovorum factor, folinic acid, 5-formyl tetrahydrofolate, LV, LCV. 
 
6.3.2 Classification 
Tetrahydrofolic acid derivative. 
 
6.3.3 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 thymidylate synthetase, thus inhibiting pyrimidine synthesis. Leucovorin increases the folate 
pool, thereby increasing the binding of folate cofactor and active 5-FU with thymidylate synthetase. 
 
6.3.4 Storage and Stability 
All dosage forms are stored at room temperature. The reconstituted parenteral solution, 10mg/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. 
6.3.5 Dose Specifics 
400 mg/m² 
6.3.6 Dose 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. 
 
6.3.7 Administration 
Intravenous infusion over 2 hours, concurrent with oxaliplatin. 
 

 
 
Page 24 
6.3.8 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 compatible with fluorouracil and oxaliplatin. 
 
6.3.9 Availability 
Commercially available in parenteral formulations (50 mg, 100 mg and 350 mg vial). 
 
6.3.10 
Side Effects 
Hematologic: Thrombocytosis. 
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. 
 
6.3.11 
Nursing/Patient Implications 
• Observe for sensitization reactions. 
• When given with fluoropyrimidines, monitor closely for diarrhea and stomatitis. 
 
 
 
6.4 Gemcitabine 
6.4.1 Generic Name 
2'-Deoxy-2',2'-difluorocytidine monohydrochloride, Gemzar 
 
6.4.2   Classification 
 
Antimetabolite (nucleoside analog) 
 
6.4.3  Mechanism of Action 
 
Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S 
phase) and also blocking the progression of cells through the G1/S phase boundary. Gemcitabine 
is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and 
triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is attributed to a combination of 
two actions of the diphosphate and the triphosphate nucleosides, which leads to 
inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits ribonucleotide reductase, 
which is responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates 
for DNA synthesis. Inhibition of this enzyme by the diphosphate nucleoside causes a reduction in the 
concentrations of deoxynucleotides, including dCTP. Second, gemcitabine triphosphate 

 
 
Page 25 
competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of 
dCTP (by the action of the diphosphate) enhances the incorporation of gemcitabine triphosphate into 
DNA (self-potentiation). After the gemcitabine nucleotide is incorporated intoDNA, only one additional 
nucleotide is added to the growing DNA strands. After this addition, there is inhibition of further DNA 
synthesis. DNA polymerase epsilon is unable to remove the gemcitabine nucleotide and repair the 
growing DNA strands (masked chain termination). In CEM T lymphoblastoid cells, gemcitabine induces 
internucleosomal DNA fragmentation, one of the characteristics of programmed cell death. 
 
 
6.4.4  Storage and Stability 
 
Unreconstituted drug vials are stored at controlled room temperature. Reconstituted solution 
should be stored at controlled room temperature and used within 24 hours. Solutions of 
gemcitabine should not be refrigerated; crystallization may occur. The unused portion should be 
discarded. 
 
6.4.5  Dose Specifics  
 
For pancreatic cancer, a dose of 1000mg/m2 over 30 minutes once weekly for up to 7 weeks 
followed by a week of rest, then once weekly for three weeks of every four weeks is used. Other 
dosing schedules currently are being studied. 
 
 
6.4.6  Preparation   
 
Reconstitute the 200mg vial with 5ml and the 1Gm vial with 25ml preservative free normal saline to 
make a solution containing 38 mg/ml. Shake to dissolve. 
 
6.4.7  Administration 
 
The drug may be administered as prepared above or further diluted with normal saline to a 
minimum concentration of 0.1mg/ml. Gemcitabine is commonly diluted in 100 ml or 250ml of 
saline. 
 
6.4.8 Availability  
 
Gemcitabine is commercially available in 200mg and 1Gm vials. 
 
6.4.9  Side Effects 
 
1. Hematologic: Myelosuppression is usually mild to moderate and is more pronounced for 
the granulocyte count. Thrombocythemia is also commonly reported. 
2. Dermatologic: A rash is seen in about 25% of patients and is associated with pruritus in 
about 10% of patients. The rash is usually mild, not dose-limiting, and responds to local 
therapy. Desquamation, vesiculation, and ulceration have been reported rarely. Alopecia is 
reported in <1% of patients. 
3. Gastrointestinal: Nausea and vomiting are reported in about two-thirds of patients and 
requires therapy in about 20% of patients. It is rarely (<1%) dose-limiting, and is easily 
manageable with standard antiemetics. Diarrhea is reported in 8% of patients, 

 
 
Page 26 
constipation in 6%, and oral toxicity in 7%. 
4. Hepatic: Abnormalities of hepatic transaminase enzymes occur in two-thirds of patients, 
but they are usually mild, nonprogressive, and rarely necessitate stopping treatment. 
However, gemcitabine should be used with caution in patients with impaired hepatic 
function. 
5. Pulmonary: Bronchospasm after injection has been reported in less than 1% of patients 
and is usually mild and transient, but parenteral therapy may be required. Dyspnea within a 
few hours of injection is reported in 10% of patients. It is usually mild, short-lived, rarely 
dose-limiting, and usually abates without any specific therapy. Cough and rhinitis are also 
commonly reported. 
6. Neurologic: Somnolence has been reported in 10% of patients, and insomnia is common. 
7. Cardiovascular: A few cases of hypotension were reported. Some cases of myocardial 
infarction, congestive heart failure, and arrhythmia have been reported, but there is no 
clear evidence that gemcitabine causes cardiac toxicity. Peripheral edema is reported in 
about 30% of patients. Some cases of facial edema have also been reported. Edema is 
usually mild to moderate, rarely dose-limiting, sometimes painful, and reversible after 
stopping gemcitabine treatment. 
8. Other: Flu-like symptoms are reported for about 20% of patients. This includes fever, 
headache, back pain, chills, myalgia, asthenia, and anorexia. Malaise and sweating are also 
commonly reported. 
 
6.4.10  Nursing Implications 
 
 
1. Administer over 30 minutes. 
2. If the patient reports burning at the injection site, slow down rate to allow the dose to run 
in over 1 hour. 
3. Rash can be treated with topical therapy or the administration of diphenhydramine and 
dexamethasone prior to administration. 
4. Flu-like symptoms can be treated with acetaminophen. 
 
6.4.11   References 
 
1. Anon. Clinical Brochure: Gemcitabine HCl (LY188011 HCl). Lilly Research Laboratories, 
Indianapolis, IN. 
October 3, 1994. 
2. Eli Lilly & Company. Package Insert. August 26, 1998. 
 
 
6.5 nab-paclitaxel  [Abraxane] 
 
 
6.5.1 Formulation 
Nab- paclitaxel is a Cremophor EL-free, albumin-bound paclitaxel particle with a mean size of 
approximately 130 nm. Each 50 mL vial contains 100 mg of paclitaxel, and approximately 900 mg of 
human albumin, as a white to yellow sterile lyophilized powder for reconstitution with 20 mL of 0.9% 
Sodium Chloride Injection. Protocol Amendment 4, date August 16, 2010 21  
Nab- paclitaxel is a unique protein formulation of a non-crystalline, amorphous form of paclitaxel in an 
insoluble particle state. It has been developed to reduce the toxicities associated with Taxol (paclitaxel) 
Injection (in which paclitaxel - from the native crystalline form - is in solution with Cremophor 

 
 
Page 27 
EL/ethanol as the solvent) while maintaining or improving its chemotherapeutic effect. Nab- paclitaxel 
has been approved in the US, Canada, India, the EU, Korea and China (and is under review in a number 
of other countries) for the treatment of women with metastatic breast cancer (MBC). Nab- paclitaxel 
alone and in combination is being evaluated in a number of cancers including: metastatic melanoma, 
pancreatic cancer, cervical cancer and other solid tumors. Conditions which are responsive to paclitaxel 
such as non-hematological solid tumor malignancies are good clinical candidates for treatment with nab- 
paclitaxel.  
 
 
6.5.2  Preclinical studies with nab- paclitaxel 
 
A range of preclinical studies in the appropriate species have been completed with nab- paclitaxel 
including single and repeat-dose toxicity studies, carcinogenicity evaluations, reproductive toxicity 
assessments, and mutagenicity and toxicity studies. A thorough discussion of these is included in the 
Investigator’s Brochure (IB).  
Preclinical studies comparing nab-paclitaxel to Taxol demonstrated lower toxicities, with a MTD 
approximately 50% higher for nab-paclitaxel compared to Taxol. At equitotoxic doses of paclitaxel, 
nab-paclitaxel was found to be markedly more efficacious in animal models than Taxol.  
 
6.5.3 Potential Risks for nab- paclitaxel based on previous clinical studies  
 
Nab- paclitaxel is not formulated in Cremophor and thus the risk of hypersensitivity reactions is much 
less than that of Taxol. The major risks of nab- paclitaxel have been assessed in clinical trials in patients 
with a variety of malignances and reflect the known toxicities of paclitaxel. See the IB for a complete 
description of all toxicities reported in conjunction with nab- paclitaxel administration.  
The most common toxicities reported in previous clinical trials included:  
• Myelosuppression, predominantly neutropenia. Grade 4 neutropenia was reported and typically 
resolved in < 7 days and did not require colony stimulating factor support.  
• Peripheral neuropathy, predominantly sensory. Grade 3 peripheral neuropathy was reported and 
typically improved to Grade 1 or 2 within 21 days of interrupting the nab-paclitaxel dose. Following 
resolution of the peripheral neuropathy to acceptable levels, clinicians were able to restart nab-paclitaxel 
dosing at a lower dose levels.  
• Nausea and vomiting. Nausea and vomiting were seen, typically at Grade 1 or 2 levels. This AE 
responded well to standard anti-emetic regimens.  
• Myalgias and arthralgias. Myalgias and arthralgias were reported and typically were Grade 1 or 2; 
these were responsive to standard acetaminophen-containing medication.  
• Mucositis. Mucositis was reported typically Grade 1 or 2. It was not dose limiting  
• Alopecia. Alopecia was reported by most patients and was similar to that seen with Taxol.  
 
 
6.5.4  Drug Supply 
 
Nab-paclitaxel is commercially available.. 
 
7.  Statistical Plan 
7.1 
Sample Size Determination and Methods and Randomization 
 
The primary goal of this study is to estimate the overall and relapse-free survival rates of the two test 
adjuvant chemotherapy/chemoradiotherapy regimens in resectable pancreatic cancer.  We will 

 
 
Page 28 
randomize n=50 patients between the two arms (n=25/arm).  Although we will not have sufficient power 
to test for differences between arms on the primary endpoints, randomization will permit unbiased 
estimation of these differences that can later be used in metanalyses if larger studies are conducted.  
 
We will create the randomization sequences at the Abramson Cancer Center Biostatistics Core Facility 
in the Department of Biostatistics & Epidemiology of the University of Pennsylvania Perelman School 
of Medicine.  Randomization will be stratified by center (Penn or Pittsburgh) and blocked in blocks of 
random sizes to prevent investigators from deducing the treatment assignments of future patients.  
Randomization sequences will be generated by pseudo-random number generator and made available to 
investigators as subjects are enrolled.  Because the treatment arms differ considerably in the type and 
timing of treatment, and moreover outcome variables are hard endpoints that are not subject to placebo 
effects or evaluation bias, randomizations will not be masked to either patients or clinical staff. 
 
The design calls for treating 25 resectable pancreatic cancer patients with each of the two regimens.  We 
do not plan formal interim analyses for futility, but we will conduct continuous interim monitoring for 
safety.  In each arm we will record serious, dose-limiting adverse events as they occur and calculate the 
Bayesian posterior probability distribution of the adverse event rate, updating after each patient.  We 
will raise a red flag for safety if the posterior probability that the event rate is greater than 30% exceeds 
60%.  Assuming a Beta (2,6) prior for the event rate, the red flag will occur as indicated in the Table 
below.  That is, if the first two serious events occur in the first n=2 patients, we will consider terminating 
the study or modifying the treatment.  Similarly, the occurrence of the third serious AE by the 5th patient 
will generate a safety signal, and so forth. 
 
Table.  Number of events/number of patients to trigger a safety signal. 
Number of events Minimum number of patients Maximum number of patients 
2 
2 
2 
3 
3 
5 
4 
6 
8 
5 
9 
11 
6 
12 
15 
7 
16 
18 
8 
19 
21 
9 
22 
24 
10 
25 
25 
 
We will tabulate rates of all adverse events.  With n=25 subjects per arm, 95% confidence intervals 
around event rates will extend no more than ±20% around observed rates.  With 25 subjects per 
treatment arm, we can identify with 90% power any unanticipated toxicity that has prevalence at least 
8.8%. 
 

 
 
Page 29 
The primary goals of the study are to obtain preliminary estimates of overall and progression-free 
survival rates.  We will estimate survival distributions by the Kaplan-Meier product-limit survival curve.   
In R9704, the median survival for patients with head lesions (the majority of the patients) was 20.5 
months in the arm that received gemcitabine and 5-FU/XRT.  In the German trial of gemcitabine 
without radiation the progression-free survival was 13.4 months.  In this small trial we will regard a 
median progression-free survival of 20 months, or a median survival of 30 months, as indicative of 
potential therapeutic benefit meriting additional study.  Under these assumed rates, expected 95% 
confidence intervals for the median will extend from 20 to 46 months for overall survival and from 14 to 
29 months for progression-free survival. 
 
The genomic analyses of the patients will be accomplished using biopsy samples obtained at the time of 
surgery.  Tissue containing >70% tumor will be stored at −70°C, and sequenced using the best available 
technology – tissues will be batched for this purpose and analyzed when approximately half the accrual 
has been accomplished, and again on completion.  Bioinformatic analyses will be descriptive. 
 
Imaging studies will be analyzed using at a minimum SUV values, and correlated with outcome.  In 
addition, these findings will be correlated with mutational profiles as obtained from the genomic studies.  
These analyses will be considered exploratory. 
 
8 
Safety and Adverse Events 
8.1 
Adverse Event Reporting and Definitions 
In the event of an adverse event the first concern will be for the safety of the subject.  Serious adverse 
events include: 
 
• Results in death  
• Is life-threatening  
• Requires or prolongs inpatient hospitalization  
• Is disabling  
• Is a congenital anomaly/birth defect  
• Is medically significant or requires medical or surgical intervention to prevent one of the 
outcomes listed above. 
 
Please note, clearly disease-related hospitalizations will be exempted from this requirement. 
8.2 
Reporting of Serious Treatment Emergent Adverse Events 
All serious adverse events should be recorded on a MedWatch 3500 Form and faxed to: 
 
Principal Investigator 
Peter J. O’Dwyer, M.D. 
12 Penn Tower, 
3400 Spruce Street, 
Philadelphia PA 19104 
Phone: 215-662-7606 
Fax: 215-243-3269 

 
 
Page 30 
 
AND: 
 
Cancer Center’s DSMC via VELOS.  Reporting to the IRB will follow the IRB’s rubric for Unexpected 
Events. 
 
Follow-up information:   
 
Additional information may be added to a previously submitted report by any of the following methods: 
 
• Adding to the original MedWatch 3500 report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500 form  
• Summarizing new information and faxing it with a cover letter including subject identifiers (i.e. 
D.O.B. initial, subject number), protocol description and number, if assigned, suspect drug, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted  (The subject identifiers are important so that the new information is added to the 
correct initial report) 
 
Assessing Causality: 
 
Investigators are required to assess whether there is a reasonable possibility that treatment caused or 
contributed to an adverse event.   
 
 
8.2.1 IRB and Cancer Center DSMC Notification  
Reports of all serious adverse events (including follow-up information) must be submitted to the IRB 
within 10 working days, according to IRB guidelines. 
Reporting Process to IRB 
 
Principal Investigators are encouraged to submit reports of unanticipated problems posing risks to 
subjects or others using the form: “Unanticipated Problems Posing Risks to Subjects or Others 
Including Reportable Adverse Events” via HS-ERA or a written report of the event (including a 
description of the event with information regarding its fulfillment of the above criteria, follow-
up/resolution and need for revision to consent form and/or other study documentation) within 10 
working days. 
Reporting Process to the DSMC 
In addition, all on-site SAEs for Penn subjects regardless of attribution or expectedness must be 
submitted to the DSMC within 10 days via VELOS. You should continue to send reports to the DSMC 
for 90 days following the last date the subject received study treatment/therapy or was exposed to an 
investigational device. Please do not send reports after the 90 day window. They will not be accepted 
or processed.  
All unexpected deaths or deaths related to the study agent(s)/device(s) must be reported within 24 
hours. All other deaths should be reported within 30 days.    

 
 
Page 31 
 
8.3 
Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay as a result of administration of the study drug 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of 
major clinical significance.   They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures to the end of the study treatment follow-up.  For this 
study, the study treatment follow-up is defined as 30 days following the last administration of 
study treatment.  
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the condition 
worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  
At the end of the study, any new clinically significant findings/abnormalities that meet the 
definition of an adverse event must also be recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, 
the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled 

 
 
Page 32 
visit, the investigator should instruct each subject to report any subsequent event(s) that the 
subject, or the subject’s personal physician, believes might reasonably be related to participation in 
this study.  The investigator should notify the study sponsor of any death or adverse event 
occurring at any time after a subject has discontinued or terminated study participation that may 
reasonably be related to this study.  The sponsor should also be notified if the investigator should 
become aware of the development of cancer or of a congenital anomaly in a subsequently 
conceived offspring of a subject that has participated in this study.  
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in this 
protocol.  Any condition responsible for surgery should be documented as an adverse event if the 
condition meets the criteria for an adverse event.  
 
Neither the condition, hospitalization, nor surgery are reported as an adverse event in the following 
circumstances: 
• Hospitalization for diagnostic or elective surgical procedures for a preexisting condition.  
Surgery should not be reported as an outcome of an adverse event if the purpose of the 
surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization to allow efficacy measurement for the study. 
• Hospitalization for therapy of disease that is clearly related to the target disease and not the 
treatment as judged by the clinical investigator.  
8.4 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each 
event should be followed until resolution, stabilization, or until it has been determined that the study 
treatment or participation is not the cause.  Serious adverse events that are still ongoing at the end of the 
study period must be followed up to determine the final outcome.  Any serious adverse event that occurs 
after the study period and is considered to be possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
 
 

 
 
Page 33 
9 
Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents   Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, 
and at medico-technical departments involved in the clinical trial. 
 
9.3 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. All data 
requested on the CRF must be recorded. All entries will be entered into an electronic data capture 
system (EDC) via VELOS. 
9.4 
Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated 
marketing applications in their country or at least 2 years have elapsed since the formal discontinuation 
of clinical development of the investigational product.  These documents should be retained for a longer 
period if required by an agreement with the sponsor.  In such an instance, it is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to be retained.  
 

 
 
Page 34 
10 
Study Monitoring, Auditing, and Inspecting 
10.1 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, 
government regulatory bodies, and The Cancer Center monitors of all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data etc.).  The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
 
11 
Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice 
(FDA Title 21 part 312 and International Conference on Harmonization guidelines), applicable 
government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for 
formal approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study 
will be made in writing to the investigator and a copy of this decision will be provided to the sponsor 
before commencement of this study.  The investigator should provide a list of EC/IRB members and 
their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  This 
consent form will be submitted with the protocol for review and approval by the EC/IRB for the study.  
The formal consent of a subject, using the EC/IRB-approved consent form, must be obtained before that 
subject is submitted to any study procedure.  This consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator-designated research professional obtaining the consent.  
 
12 
References 
1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 
2009;59:225–249 
2. Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C. Meta-analysis of randomized trials: 
evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic 
cancer. BMC Cancer. 2008;8:82-93 
3.  Kalser MH, Ellenberg SS. Pancreatic cancer: Adjuvant combined radiation and chemotherapy 
following curative resection. Arch Surg 120:899-903, 1985 
4.  Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after 
curative resection of cancer of the pancreatic and periampullary region. Phase III trial of the 
EORTC gastrointestinal tract cancer cooperative group. Ann Surg 230:776-84, 1999 
5.  Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, 
Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW.  A 
randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. 
N Engl J Med. 2004 Mar 18;350(12):1200-10. 

 
 
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6.  Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore 
MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini 
G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe 
CL, Büchler MW; European Study Group for Pancreatic Cancer.  Adjuvant chemotherapy with 
fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized 
controlled trial.  JAMA. 2010;304(10):1073-81. 
7.  Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, 
Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA.  Fluorouracil vs 
gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of 
pancreatic adenocarcinoma: a randomized controlled trial.  JAMA. 2008;299:1019-26. 
8.  Regine WF, Winter KA, Abrams R, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, 
Rich TA, Willett CG.  Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil 
chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U.S. 
Intergroup/RTOG 9704 phase III trial.  Ann Surg Oncol. 2011;18:1319-26. 
9.  Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, 
Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, 
Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H.  Adjuvant chemotherapy with 
gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a 
randomized controlled trial.  JAMA. 2007;297:267-77. 
10.  Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, 
Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, 
Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M.  FOLFIRINOX versus 
gemcitabine for metastatic pancreatic cancer.  N Engl J Med 2011;364:1817-1825 
11.  Von Hoff DD, Ramanathan RK, Borad MJ, et al.  Gemcitabine plus nab-paclitaxel is an active 
regimen in patients With advanced pancreatic cancer: A Phase I/II trial.  J Clin Oncol 29: 4548-54, 2011 
12.  Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al.  Core signaling pathways in 
human pancreatic cancers revealed by global genomic analyses. Science 2008;321:1801–6. 
13.  Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, et al. Frequent somatic 
mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 
1994;8:27–32. 
14.  Iacobuzio-Donahue CA, Song J, Parmiagiani G, Yeo CJ, Hruban RH, Kern SE. Missense mutations 
of MADH4: characterization of the mutational hot spot and functional consequences in human tumors. 
Clin Cancer Res 2004;10:1597–604. 
15.  Crane CH, Varadhachary GR, Yordy JS, Staerkel GA, Javle MM, Safran H, Haque W, Hobbs BD, 
Krishnan S, Fleming JB, Das P, Lee JE, Abbruzzese JL, Wolff RA.  Phase II trial of cetuximab, 
gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) 
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Page 36 
 
7.0 
Schedule of Events 
 
 
7.1 
Arm A 
 
Screening procedures are to be performed within 4 weeks of cycle 1 day 1 with laboratory results within 
14 days.  
 
Test 
Screening 
C1&2  
Day 1 
C1&2 
Day 8 
C3&4 
Day  1 
C3&4 
Day 8 
 
Informed 
Consent 
X 
 
 
 
 
 
Phys 
Assessment 
X 
X 
 
 
 
Per standard practice 
Not recorded in study 
database 
Height/Weight 
X 
 
 
 
 
 
Vital Signs/PS 
X 
X 
X 
X 
X 
Per standard practice 
Not recorded in study 
database 
 
Clinical Labs 
CBC/Chemistry/ 
Tumor Markers2  
X 
X 
X 
X 
X  
Per standard practice 
AE assessment 
X 
X 
X 
X 
X 
Until completion of 
treatment 
Disease 
Assessment 
(routine CT or 
MR) 
X 
 
 
 
 
Unless rising markers, 
perform 
at end of 
treatment, then at 4-6 
months, and annually 
thereafter 
FDG-PET 
 
X1 
 
 
 
 
 
Circulating 
Tumor cells* 
X 
 
 
 
 
Before 
start 
of 
radiation/5-FU and at 
end of treatment, and 
at 
approximately 
6 
month 
intervals 
therafter 
where 
possible 
 
1 If covered by insurance.  If not, can be omitted. 
2 Tumor markers only need to be drawn monthly 
*to be initiated when feasible 
 
 
 
 
 

 
 
Page 37 
 
 
 
 
 
 
 
7.2  Arm B 
Screening procedures are to be performed within 4 weeks of cycle 1 day 1 with labs laboratory results 
within 14 days.  
 
Test 
Screening 
C1&2 
Day 1 
C1&2 
Day  15 
C1&2 
Day 28 
 
Informed 
Consent 
X 
 
 
 
 
Phys Assessment X 
X 
 
 
Per standard practice 
Not recorded in study 
database 
Height/Weight 
X 
 
 
 
 
Vital Signs/PS 
X 
X 
X 
X 
Per standard practice 
Not recorded in study 
database 
 
Clinical Labs 
CBC/Chemistry/ 
Tumor Markers  
X 
X 
X 
X  
Per standard practice 
AE assessment 
X 
X 
X 
X 
Until completion of 
treatment 
Disease 
Assessment 
(routine CT or 
MR) 
X 
 
 
 
Unless 
rising 
markers, perform at 
end of treatment, then 
at 4-6 months, and 
annually thereafter 
FDG-PET 
 
X1 
 
 
 
 
Circulating 
Tumor cells* 
X 
 
 
 
Before 
start 
of 
radiation/5-FU and at 
end of treatment, and 
at approximately 6 
month 
intervals 
therafter 
where 
possible 
 
1  If covered by insurance.  If not, can be omitted. 
*to be initiated when feasible