Conditions: Borderline Resectable Pancreatic Cancer
Keywords: Borderline Resectable Pancreatic Cancer Neoadjuvant Chemotheraphy Gemcitabine Nab-Paclitaxel mFOFIRINOX Sterotatic Body Radiation Therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
This is a prospective, randomized phase II trial. Patients diagnosed with borderline resectable pancreatic adenocarcinoma will be randomly assigned to one of two treatment arms, either mFOLFIRINOX or gemcitabine and nab-paclitaxel. After three cycles of treatment in the gemcitabine/nab-paclitaxel arm and 6 cycles in the mFOLFIRINOX arm, patients will be restaged with CT scans and if they remain borderline resectable or have improvement of their disease They will then proceed to SBRT followed by surgical resection.

Detailed description:

Arms:
arm 1: three cycles of treatment in the gemcitabine/nab-paclitaxel arm 2: 6 cycles in the mFOLFIRINOX

Interventions: intervention 1: gemcitabine/nab-paclitaxel intervention 2: mFOLFIRINOX
Intervention descriptions: intervention 1: three cycles of treatment in the gemcitabine/nab-paclitaxel intervention 2: 6 cycles in the mFOLFIRINOX

Protocol document:
Prot_SAP_000.pdf: 
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Title: Randomized Phase II Study of Neoadjuvant Chemotheraphy (Gemcitabine and Nab-Paclitaxel 
vs. mFOFIRINOX) and Sterotatic Body Radiation Therapy for Borderline Resectable Pancreatic 
Cancer 
 
 Principal Investigator 
Nathan Bahary, MD 
Associate Professor of Surgery 
UPMC Cancer Pavilion, 5th Floor 
5150 Center Ave 
Pittsburgh, PA 15101 
 
Pathology 
Aatur Singhi, MD, PhD 
 
Biostatistics 
Daniel Normolle, PhD 
 
Radiation Oncology 
Dwight Heron, MD, FACRO, FACR 
David Clump, MD PhD 
Steve Burton, MD 
 
 
 
 


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 Table of Contents 
Section                                                                                                                                                       Page 
 
Research Protocol Abstract ........................................................................................................................... 5 
 
1.0. Primary Objective(s) ............................................................................................................................ 9 
  
 
2.0. Secondary Objectives(s) ...................................................................................................................... 9 
 
 
3.0. Primary endpoint(s) ............................................................................................................................. 9 
 
 
4.0. Secondary endpoint(s) ......................................................................................................................... 9 
  
 
5.0. Background .......................................................................................................................................... 9 
 
 
6.0. Locally Advanced Disease and Borderline Resectable Disease ........................................................ 10 
 
 
6.1. Chemotherapy for Metastatic Disease. ....................................................................................... 10 
 
6.2. Neoadjuvant Chemotherapy for LAD......................................................................................... 11 
         6.3. Tumour Markers in Pancreatic Cancer – Role of CA-19.9 ........................................................ 12 
 
 
6.4. Role of Radiation Therapy in Pancreatic Cancer........................................................................ 13 
 
6.4.1. Radiation Therapy Locally-advanced Pancreatic Adenocarcinoma. ................................... 13 
 
6.4.2. Stereotactic Body Radiotherapy (SBRT). ............................................................................ 13 
 
6.4.3. Experience with SBRT at the University of Pittsburgh Cancer Institute ............................. 14 
 
7.0. Rationale ............................................................................................................................................ 15 
  
 
8.0. Patient Selection and Eligibility ........................................................................................................ 15 
 
 
8.1. Selection of Subjects ................................................................................................................... 15 
 
 
8.2. Number of Subjects. ................................................................................................................... 16 
 
8.3. Inclusion Criteria. ....................................................................................................................... 16 
 
8.4. Exclusion Criteria ....................................................................................................................... 17 
 
 
9.0. Investigational Plan and Study Evaluations ...................................................................................... 17 
 
 
9.1. Overall Design ............................................................................................................................ 17 
 
 
9.2. Pre-treatment Evaluation. ........................................................................................................... 17 
 
9.3. Day 0. .......................................................................................................................................... 18 
     9.4. During Study Evaluation. ............................................................................................................ 18 
     9.5. Disease Response Evaluation (MDC Evaluation). ...................................................................... 19 
     9.6. SBRT. .......................................................................................................................................... 19 
     9.7. Pre-Op. ........................................................................................................................................ 20 
     9.8. Surgery. ....................................................................................................................................... 20 
     9.9. Post treatment Assessment/Follow Up.. ...................................................................................... 20 
     9.10. Treatment .................................................................................................................................. 20 
        9.10. 1. Study Drug and Doses ........................................................................................................ 20 
10.0. Treatment Plan ................................................................................................................................... 22 
 
 
10.1. Gemcitabine / nab-Paclitaxel .................................................................................................... 22 
 
10.2. mFOLFIRINOX........................................................................................................................ 24 


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11.0. Chemotherapeutic Agents .................................................................................................................. 26 
  
 
11.1. Gemcitabine Hydrochloride (Gemzar®) .................................................................................. 26 
 
         11.1.1. Description. ........................................................................................................................ 26 
 
11.1.2. Toxicology ......................................................................................................................... 26 
 
11.1.3. Pharmacology. .................................................................................................................... 26 
 
11.2. nab-Paclitaxel (Abraxane™). ................................................................................................... 27 
 
11.2.1. nab-paclitaxel Packaging, Labelling, and Storage. ............................................................ 27 
 
11.2.2. nab-paclitaxel (Abraxane™) Administration ..................................................................... 28 
 
11.2.3. Reconstitution and Use of nab-paclitaxel (Abraxane™). .................................................. 28 
 
11.3. modified FOLFIRINOX. .......................................................................................................... 29 
 
11.3.1. Rounding Drug Doses. ....................................................................................................... 29 
 
11.3.2. Fluorouracil (5-FU). ........................................................................................................... 29 
 
11.3.2.1. Clinical Pharmacology ................................................................................................ 29 
 
11.3.2.2. Precautions: General.................................................................................................... 30 
 
11.3.2.3. Dosage and Administration ......................................................................................... 30 
 
11.3.2.4. Handling and Disposal ................................................................................................ 31 
 
 
11.3.3. Irinotecan. .............................................................................................................................. 31 
 
11.3.3.1. Pharmacology .............................................................................................................. 32 
 
11.3.3.2. Pharmacokinetics......................................................................................................... 32 
 
11.3.3.3. Metabolism and Excretion........................................................................................... 33 
 
 
11.3.3.4. Administration ............................................................................................................. 33 
 
11.3.4. Oxaliplatin ............................................................................................................................. 33 
 
 
11.3.4.1. Dosage and Administration  ............................................................................................ 33 
 
 
11.3.4.2. Dosage ............................................................................................................................. 33 
 
11.3.4.2.1 Preparations of Infusion Solution .............................................................................. 33 
 
11.4.4.4. Warnings and Precautions ............................................................................................... 34 
 
11.3.4. Gemcitabine .......................................................................................................................... 35 
 
 
11.3.4.1. Premedication for Gemcitabine ................................................................................... 35 
 
 
11.3.4.2. Toxicity and Dose Modifications for Gemcitabine ......................................................... 35 
11.3.6. nab-Paclitaxel (Abraxane™) ................................................................................................... 36 
 
 
11.3.6.1. nab-Paclitaxel (Abraxane™) ........................................................................................... 36 
 
 
12.0. Dose Modifications for Chemotherapy.............................................................................................. 37 
 
 
12.1. mFOLFIRINOX........................................................................................................................ 37 
 
12.2. nab-Paclitaxel (Abraxane™) and Gemcitabine (Gemzar®) ..................................................... 39 
 
13.2.1. Dose Modifications for Gemcitabine and/or Nab-paclitaxel. ....................................... 39 
 
 
13.0. Supportive Care ................................................................................................................................. 45 
 
 
13.1. Both chemotherapy Regimen.................................................................................................... 45 
 
13.2. mFOLFIRINOX........................................................................................................................ 46 
 
13.2.1. Antidiarrheal Medications .................................................................................................. 46 
 
13.2.2. Irinotecan-related Cholinergic Syndrome .......................................................................... 46 
 
 
13.2.3. Antiemetic Therapy ............................................................................................................ 46 
 
13.2.4. Growth Factor Support ....................................................................................................... 46 
 
13.2.5. Fever ................................................................................................................................... 46 
 
13.2.6. Management of Laryngopharyngeal Dysesthesias ............................................................. 47 
 
13.3. SBRT Guidelines ...................................................................................................................... 47 
 
13.3.1. Tissue Constraints .............................................................................................................. 47 
 
13.3.2. Dose Specification, Homogeneity Considerations & Plan Evaluation .............................. 47 
 
13.4. On-Treatment Assessment and Post-treatment Toxicity Evaluation ........................................ 47 
 
13.4.1. Stereotactic Body Radiotherapy Risks ............................................................................... 48 


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13.4.2. Fiducial Placement Risks ................................................................................................... 48 
 
13.4.3. CT Risks ............................................................................................................................. 48 
 
 
14.0. Statistics ............................................................................................................................................. 48 
 
 
15.0. Report of Adverse Reactions ............................................................................................................. 50 
 
 
15.1. Adverse Event Definitions ........................................................................................................ 50 
. 
 
15.2. Reporting of Suspected Adverse Events. .................................................................................. 52 
 
 
16.0. Data and Safety Monitoring ........................................................................................................... 52 
 
16.1. Subject Removal Criteria ...................................................................................................... 53 
 
17.0. Bibliography ................................................................................................................................... 54 
 
 
 
 
 


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Abstract 
Recent reports indicate that while overall cancer related mortality is decreasing, the incidence of pancreatic 
cancer continues to rise. In particular, pancreatic cancer is the 4th leading cause of cancer death in the USA 
with approximately 44,000 new diagnoses in the United States. At the time of presentation, at least 80% of 
patients are either inoperable due to locally advanced or metastatic disease. Surgery still offers the only 
chance at ‘cure’, however only 10-20% of patients are candidates for resection at the time of presentation. 
Defining the population who should receive resection is perhaps the most important step in treating 
pancreatic cancer. The Society of Surgical Oncology has established guidelines for the management of 
unresectable disease, separating the two groups into locally advanced and borderline resectable disease 
(Calleryet al.2009). In general, locally advanced disease (LAD) demonstrates vascular 
encasement/encroachment but no distant metastases.  The subgroup of borderline resectable (BR) disease 
demonstratestumor abutment of the visceral vasculature without encasement thereby allowing for the 
possibility of resection but with added morbidity and a significantly higher rate of relapse compared with 
resectable patients. With neoadjuvant therapy, it now appears that up to one third of patients who initially 
present with locally advanced unresectable disease can now proceed to resection (Gillen et al. 2010) 
 
In the metastatic setting, effective therapeutic options are limited. Historically, median survival time range 
from 4 to 6 months with gemcitabine alone to 11 months with newer regimens such as FOLFIRINOX. Until 
recently, gemcitabine was the standard sole chemotherapeutic agent for treatment of patients with advanced 
pancreatic cancer following the demonstration that gemcitabine produced improvement in disease-related 
symptoms and overall survival when compared with 5-FU. Since the establishment of gemcitabine as 
standard chemotherapy, multiple trials have evaluated the addition of alternate chemotherapeutic agents to 
gemcitabine with minimal improvement. Recently, data from the MPACT trial has shown a significant 
increase in one and two year survival for the combination of gemcitabine and nab-paclitaxel (paclitaxel 
bound protein bound particles (Abraxanetm) in the metastatic setting with an overall response rate of 23% in 
the combination arm (Von Hoff et al. 2013). In treatment-naïve patients with metastatic pancreatic cancer, 
combination therapy demonstrated a statistically significant improvement in overall survival compared to 
patients receiving gemcitabine alone [(median of 8.5 vs. 6.7 months) (HR 0.72, P=0.000015)] (Von Hoff 
2013). 
 
In the metastatic setting, FOLFIRINOX was compared to standard gemcitabine monotherapy in 342 patients 
with an ECOG PS0 or 1. The primary endpoint was (OS), with a median OS of 11.1 months in the 
FOLFIRINOX group vs. 6.8 months in the gemcitabine group (HR for death, 0.57; 95% confidence interval 
[CI], 0.45 to 0.73; P<0.001). Median progression-free survival (PFS) was 6.4 months in the FOLFIRINOX 
group and 3.3 months in the gemcitabine group (HR for disease progression, 0.47; 95% CI, 0.37 to 0.59; 
P<0.001). The objective RR was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group 
(P<0.001) (Conroy et al. 2011) 
 
In the neoadjuvant setting a recent retrospective review of 18 LAD patients treated with FOLFIRINOX 
demonstrated a 44% R0 (margin negative) resection rate (Hosein etal. 2012). Acknowledging the limits of a 
small retrospective trial, this trial suggests that a neoadjuvant approach utilizing FOLFIRINOX is feasible. 
In a recent study performed at our institution,25 patients with LAD, 13 (52%) unresectable and 12 (48%) 
BR were treated with FOLFIRINOX. Following treatment with FOLFIRINOX, 11 underwent surgical 
resection, of which 4 (31%) were initially unresectable.  36% of resected patients (4 of 11 patients) received 
additional chemotherapy and/or radiation therapy prior to surgery. The R0 resection rate for borderline 
resectable patients was 6/8 (75%). Of the 10 initially unresectable patients, 3 (33%) underwent surgical 
resection, with 2 (20%) R0 resections. The overall R0 resection rate was 38%. A total of 6 patients (55%) 
demonstrated a significant pathologic response (data to be published). Definition of pCR has been well 
established and recently retrospective analysis has been done to evaluate pCR that have demonstrated 
varying results from 2-35% (Evans et al 1992, White et al, 2009). Given the variability that we have with 


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pCR and the high rate of pCR we have seen in our feasibility trial, we hope to see a 12% improvement in 
pCR.   
 
Gemcitabine and nab-paclitaxel have been evaluated in the neoadjuvant resectable setting. Our Institution 
has participated in multi-center feasibility trial of preoperative gemcitabine/nab-paclitaxel. Subjects meeting 
NCCN criteria for potentially-resectable pancreatic cancer received 3 cycles of gemcitabine and nab-
paclitaxel (1000mg/m2& 125mg/m2 – day 1, 8, and 15) followed by surgical resection. The primary endpoint 
was grade III/IV pathological response in> 30% of resected tumor specimens. Of 15 patients that completed 
all 3 cycles, 6 required dose reduction. 5 patients were unable to complete all 3 cycles of therapy due to 
serious adverse events (Grade 3 or 4 toxicities).  To date, 10 patients have undergone surgical resection. All 
10 achieved negative surgical margins (R0 100%) and CA19-9 decrease from baseline (mean 181.7 U/ml) to 
end of therapy (mean 44.2 U/ml) was also noted (response measured after three cycles). There were no 
unexpected postoperative complications. A >90% tumor necrosis (Grade III/IV) was seen in 3 patients, with 
4 Grade 2, 1 Grade I, and 2 without effect (obtained from communication with the trial investigators).The 
data available suggests that gemcitabine/nab-paclitaxel is a safe and well tolerated regimen in this 
population that is highly effective as demonstrated by the data above.  
 
SBRT, modelled after intracranial stereotactic surgery, is technique that combines highly conformal 
radiotherapy with real-time imaging to deliver high doses of radiation in a small number of fractions. 
Because of the precise targeting, SBRT has the potential to improve upon the local control achieved with 
conventional EBRT while minimizing the dose to normal tissue. Most prospective randomized trials of 
conventionally fractionated EBRT for the treatment of locally-advanced pancreatic cancer have reported 
local control rates of 35%-55% (39)(40). Koong, et al established the feasibility of using SBRT for locally-
advanced pancreatic cancer in a phase I dose escalation study which achieved 100% local control with no 
treatment limiting toxicities at 25 Gy in a single fraction (41). A follow-up study combined conventionally 
fractionated 5-FU chemoradiotherapy with an SBRT boost resulting in 94% local control but no 
improvement in overall survival and an increase in toxicity compared to SBRT alone (42). A recent study 
combining full dose gemcitabine with single fraction SBRT reported 81% local control and 100% 1-year 
freedom from local progression. While acute toxicities were minimal, a significant number of subjects 
(47%) experienced Grade 2 or greater late toxicities, primarily duodenal ulcers (43). It is possible that these 
late toxicities may be reduced by increasing the degree of conformance of the radiation dose cloud and 
increasing the number of fractions, as studies comparing conventionally fractionated RT with 
hypofractionated RT have found increase incidence of late GI toxicities in the hypofractionated group (38). 
 
A retrospective review from our institution evaluated the outcome in 71 subjects with pancreatic cancer 
treated with SBRT (46). With a median follow-up of 12.7 months the freedom from local progression at 6 
months and 1 year was 72% and 49%, respectively. Median overall survival for the entire group was 10.3 
months. Treatment-related toxicity was minimal with only 3 patients experiencing acute grade 3 toxicity 
(4%). There was no recorded late toxicity. Another study from our institution examined outcomes in 24 
patients treated post-operatively with SBRT (47).  Sixty-six percent of the patients had positive margins and 
the remainder had close margins of 1-2.5mm. The median follow-up was 1 year. The freedom from local 
progression at 6 months and 1 year was 95% and 66%. There was no acute or late grade 3-4 toxicity, and 
two patients (8%) had late grade 1-2 toxicity, again demonstrating that when done properly, SBRT has a low 
potential for toxicity. 
 
It would appear that both gemcitabine/nab-paclitaxel and FOLFIRINOX are effective in the neoadjuvant 
setting. In our own institution, we demonstrated that patients who initially fail to respond to FOLFIRINOX, 
when treated with gemcitabine/nab-paclitaxel had responses and successfully underwent resection (data to 
be published, presented at GI ASCO). There are currently no direct comparisons of Gemcitabine/nab-
paclitaxel vs. FOLFIRINOX in the setting of either the metastatic, LAD or BR pancreatic adenocarcinoma. 
The preliminary data thus far from utilization of FOLFIRINOX in the locally advanced setting and more 


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recently Gemcitabine/nab-paclitaxel as neoadjuvant treatment for resectable disease have demonstrated 
promising response rates in the realm of 30-44%. We now wish to formally study the pathological response 
and ability to obtain R0 resections in this group of patients. The current study seeks to further investigate the 
impact of up-front systemic therapy in combination with fractionated SBRT for potentially resectable, 
locally-advanced pancreatic adenocarcinoma 
 
Primary Objective(s) 
Characterize the safety and efficacy of neo-adjuvant gemcitabine plus nab-paclitaxel in patients receiving 
SBRT and surgery for borderline resectable pancreatic cancer, using neo-adjuvant mFOLFIRINOX as a 
control. 
 
Secondary Objective(s) 
• To determine R0 resection rates in borderline resectable pancreatic cancer after treatment with 
gemcitabine/nab-paclitaxel or mFOLFIRINOX and SBRT 
• To determine the safety and toxicity of preoperative chemotherapy and SBRT 
• To determine radiological response rate to therapy 
• To determine CA19-9 response to neoadjuvant chemotherapy and other serologic markers of 
response including HMGB1, sRAGE, DNA by picogreen, and IL-6 
• To determine time to progression (TTP) in this population  
• To determine predictive factors of response to chemotherapy with the use of correlative factors 
including SPARC, RM1, and SMAD4 
• To assess absolute lymphocyte count at the beginning and end of therapy as potential novel markers 
of overall survival. 
• To determine patients Quality of Life effects during chemotherapy and SBRT  
 
Primary Endpoints 
Efficacy:  pathological complete response (pCR) and R0 resection.   
Safety:  Grade 4 toxicity. 
 
Secondary Endpoint(s): 
• R0 resection rates for patients with BR pancreatic cancer 
• Incidence of grade 3 and 4 toxicities according to the National Cancer Institute Common Toxicity 
Criteria for Adverse Events (NCI CTAE, v4.0) for the 2 chemotherapy regimens that occur after 
Cycle 1 Day 1. 
• Radiological improvements will be evaluated by determining changes in density of measurable 
disease on CT pre and post chemotherapy. 
• Ca19-9 response to neoadjuvant chemotherapy will be measured during every cycle 
• TTP in the group of patients who undergo resection.  TTP will be defined as time after surgery to 
time of first progression as measured on CT scan or Ca19-9 
•  Measurement of biomarkers (SPARC, RM1 and SMAD4) in tissues that are obtained at screening 
and in the resected tumour specimen. 
• To assess absolute lymphocyte count at the beginning and end of therapy as potential novel markers 
of overall survival 
• Quality of life effects of Chemotherapy on patients receiving chemotherapy and SBRT as measured 
by the FACT-HB questionnaire. 
 
Study Population 
Subjects with primary borderline resectable adenocarcinoma of the pancreas (as defined by SSO criteria; 
shown in figure 1) will be eligible to participate in this trial. 
 


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Number of Patients for Study 
The proportions of patients who attain R0 resection and pCR will be estimated for each arm.  A significant 
difference in the efficacy endpoint between arms is not expected; the proportion of patients achieving R0 
resection and pCR is expected to be between 0.10 and 0.15 in both arms. However, the proportion of 
patients encountering Grade 4 toxicity is expected to be much lower in the gemcitabine plus nab-paclitaxel 
arm than in the mFOLFIRINOX arm.  If the true probability of Grade 4 toxicity is 0.01 with gemcitabine 
plus nab-paclitaxel and 0.20 with mFOLFIRINOX, a direct comparison on 40 participants randomized 1:1 
using Fisher’s exact test at α=0.1 will have 62% power to reject the null hypothesis.  The expected width of 
95% confidence intervals around the probabilities of toxicity would be 0.17 (for π=0.01) and 0.38 (for 
π=0.20).  While a direct comparison is underpowered, the results will be necessary to motivate and design a 
definitive Phase III trial. 
 
Study Design and Methodology 
This is a prospective, randomized phase II trial. Patients diagnosed with borderline resectable pancreatic 
adenocarcinoma will be randomly assigned to one of two treatment arms, either mFOLFIRINOX or 
gemcitabine and nab-paclitaxel. After three cycles of treatment in the gemcitabine/nab-paclitaxel arm and 6 
cycles in the mFOLFIRINOX arm,  patients will be restaged with CT scans and if they remain borderline 
resectable or have improvement of their disease. They will then proceed to SBRT followed by surgical 
resection.  
 
Treatments Administered 
Chemotherapy with either gemcitabine/nab-paclitaxel 3 cycles (3weeks on/ 1 week off) or mFOLFIRINOX 
(every 14 days for 6 cycles). Upon completion of the chemotherapy they will proceed to SBRT followed by 
surgical resection.  


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1.0. Primary Objective 
Characterize the safety and efficacy of neo-adjuvant gemcitabine plus nab-paclitaxel in patients receiving 
SBRT and surgery for borderline resectable pancreatic cancer, using neo-adjuvant mFOLFIRINOX as a 
control. 
 
2.0. Secondary Objectives(s) 
• To determine R0 resection rates in borderline resectable pancreatic cancer after treatment with 
gemcitabine/nab-paclitaxel or mFOLFIRINOX and SBRT 
• To determine the safety and toxicity of preoperative chemotherapy and SBRT 
• To determine radiological response rate to therapy 
• To determine CA19-9 response to neoadjuvant chemotherapy and other serologic markers of 
response including HMGB1, sRAGE, DNA by picogreen, and IL-6 
• To determine time to progression (TTP) in this population  
• To determine predictive factors of response to chemotherapy with the use of correlative factors 
including SPARC, RM1, and SMAD4 
• To assess absolute lymphocyte count at the beginning and end of therapy as potential novel markers 
of overall survival. 
• To determine patients Quality of Life effects during chemotherapy and SBRT  
• To determine patients Quality of Life effects during chemotherapy and SBRT  
 
3.0. Primary Endpoint(s) 
Efficacy:  pathological complete response (pCR) and R0 resection.   
Safety:  Grade 4 toxicity. 
 
4.0. Secondary Endpoint(s) 
• R0 resection rates for patients with BR pancreatic cancer 
• Incidence of grade 3 and 4 toxicities according to the National Cancer Institute Common Toxicity 
Criteria for Adverse Events (NCI CTAE, v4.0) for the 2 chemotherapy regimens that occur after 
Cycle 1 Day 1. 
• Radiological improvements will be evaluated by determining changes in density of measurable 
disease on CT pre and post chemotherapy. 
• Ca19-9 response to neoadjuvant chemotherapy will be measured during every cycle 
• TTP in the group of patients who undergo resection.  TTP will be defined as time after surgery to 
time of first progression as measured on CT scan or Ca19-9 
•  Measurement of biomarkers (SPARC, RM1 and SMAD4) in tissues that are obtained at screening 
and in the resected tumour specimen. 
• To assess absolute lymphocyte count at the beginning and end of therapy as potential novel markers 
of overall survival 
• Quality of life effects of Chemotherapy on patients receiving chemotherapy and SBRT as measured 
by the FACT-HB questionnaire.  
 
5.0. Background 
Recent reports indicate that, while overall cancer related mortality is decreasing, the incidence of pancreatic 
cancer continues to rise. In particular, pancreatic cancer is the 4th leading cause of cancer death in the United 
States with approximately 44,000 new diagnoses. In 2012, approximately 38,000 patients will die from the 
disease (American Cancer Society, 2012). While there has been a decline in the overall mortality of several 
other leading cancers, pancreatic cancer survival has not changed in over 40 years and its incidence 
continues to increase (1). According to the National Cancer Institute, 94% of patient diagnosed with 


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pancreatic cancer will die within 5 years, of which 75% of patients die in the first 12 months of 
diagnosis(American Cancer Society, 2012)(SEER Database, 2010).  
 
Pancreatic cancer is rarely diagnosed early and is usually already metastatic or unresectable by the time of 
diagnosis. Only 15-20% of patients who are newly diagnosed can undergo potentially curative surgical 
resection (Varadhachary GR, 2006). Even those who are able to successfully undergo 
pancreaticoduodenectomy (Whipple’s procedure), only about 15-20% have a 5 year overall survival 
(Ferrone CA, 2008)(Pelzer U, 2011). Ferrone et al. (2008) reported that AJCC stage and negative margins 
were the only significant predictors of long term survival. 
 
6.0. Locally Advanced Disease and Borderline Resectable Disease 
At the time of presentation, at least 80% of patients are considered inoperable due to locally advanced or 
metastatic disease. Surgery still offers the only chance at ‘cure’; however only 10-20% of patients are 
candidates for resection at the time of presentation (Gillen S, 2010). Defining the population that should 
receive resection is perhaps the most important step in treating pancreatic cancer. The Society of Surgical 
Oncology has established guidelines for the management of unresectable disease, separating the two groups: 
locally advanced and borderline resectable disease (Callery MP, 2009)(NCCN , 2011 V2.2011).  Borderline 
resectable is defined in Figure 1. With neoadjuvant therapy, up to one third of patients who initially present 
with locally advanced unresectable disease can now proceed to resection (Gillen S, 2010).  
 
Figure 1: Definition of Borderline Resectable Pancreatic Cancer and Locally Advanced 
(Varadhachary et al, 2006) 
 
 
6.1. Chemotherapy for Metastatic Disease 
In the metastatic setting, effective therapeutic options are limited and optimal regimens are not clearly 
established. Historically, median survival time ranges from 4 to 6 months with gemcitabine, a nucleoside 
analogue, to 11 months with newer regimens like FOLFIRINOX (Conroy T D. F.-B.-A.-V., 2011). 
Gemcitabine became the standard chemotherapy backbone for treatment of advanced pancreatic cancer after 
it was demonstrated to produce improved overall survival and disease related symptoms when compared to 
5-FU (5.6 vs. 4.4 months, P=0.002)(Burris HA III, 1997)(DiMarco MC, 2009) Since the establishment of 
gemcitabine as a standard chemotherapy for pancreatic adenocarcinoma, multiple trials have evaluated the 
addition of alternate chemotherapeutic agents to gemcitabine. However, they have all failed to demonstrate 
improved OS. Recently, there has been evidence to suggest that over expression of epidermal growth factor 
leads to poor prognosis in pancreatic cancer. With this mind, Erlotinib (a tyrosine kinase inhibitor of 
epidermal growth factor) has been tested widely in combination with gemcitabine. Moore et al. (Moore MJ, 
2007) first demonstrated a small but statistically significant, improvement in survival with this combination 
leading to its approval. Since then, several other studies have aimed to reproduce these with variable results. 
A meta-analysis summarizing the available evidence on the efficacy and safety of gemcitabine plus erlotinib 


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showed a small but meaningful additive effect of the combination regimen compared to gemcitabine alone 
(Yang ZY, 2013).  
 
Secreted protein acidic and rich in cysteine (SPARC), an albumin-binding protein, was found to be over-
expressed in pancreatic adenocarcinomas (Neuzillet C, 2013). Nab-Paclitaxel, a 130-nm albumin-bound 
formulation of paclitaxel particles (Celgene, Summit, NJ), has shown antitumor activity in various advanced 
cancer types that over express SPARC (Neuzillet C, 2013). VonHoff et al. (Von Hoff DD E. T., 
2013)looked at dose escalation of nab-paclitaxel in combination with gemcitabine and demonstrated an 
overall response rate of 48%, with a 12.2 median months and 48% 1-year survival when 125mg/m2 of nab-
paclitaxel was used in combination with Gemcitabine 1000mg/m2 given weekly for 3 weeks every 28 days 
(Von Hoff DD R. R.-S., 2011).  Major dose limiting toxicities found were sepsis and neutropenia. In 
addition, they also showed that decreases in CA19-9 levels were correlated with increased response rate, 
progression-free survival, and OS (Von Hoff DD R. R.-S., 2011). 
 
Recently, a larger phase III study built on these phase I/II data, the MPACT trial was performed. It 
demonstrated a significant increase in one and two year survival for the combination of gemcitabine and 
nab-paclitaxel (paclitaxel bound protein bound particles (Abraxanetm) compared to gemcitabine alone, in the 
metastatic setting with an overall response rate of 23% in the combination arm (Von Hoff DD E. T., 
2013).  In treatment-naïve patients with metastatic pancreatic cancer, combination therapy demonstrated a 
statistically significant improvement in overall survival compared to patients receiving gemcitabine 
alone [(median of 8.5 vs. 6.7 months) (HR 0.72, P=0.000015)] (Von Hoff DD E. T., 2013).The safety profile 
of this combination in this study was well tolerated. This has now prompted the option of using 
gemcitabine/nab-paclitaxel in this group of patients. 
 
More recently, FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg 
per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a 
bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) was 
compared to standard gemcitabine monotherapy in 342 metastatic patients with an ECOG PS=0 or 1(Conroy 
T D. F.-B.-A.-V., 2011). The primary end point was overall survival (OS), with a median OS of 11.1 months 
in the FOLFIRINOX group vs. 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). Median progression-free survival (PFS) was 6.4 months in 
the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 
0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate (RR) was 31.6% in the FOLFIRINOX 
group versus 9.4% in the gemcitabine group (P<0.001). Despite more adverse events at 6 months in the 
FOLFIRINOX group, including a neutropenia, febrile neutropenia, diarrhea, neuropathy and LFT 
abnormalities, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of 
life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001). These results 
demonstrate clear advantages to the use of FOLFIRINOX over gemcitabine and have resulted in the 
adoption of FOLFIRINOX as the standard of care for newly diagnosed metastatic patients with an excellent 
performance status (PS). Recently, a study conducted at Emory University demonstrated in 60 patients that 
with the elimination of the 5FU bolus the overall response rate was 30%. Off the 60 patients, there were 2 
CR and 27 SD, demonstrating the efficacy of this combination despite the omission of the 5FU bolus 
without the hematological complications (Conroy T G. C., 2013). 
 
6.2. Neoadjuvant Chemotherapy for LAD 
Several other solid malignancies such as breast and rectal cancer have been treated neoadjuvant with 
chemotherapy or in combination with radiation. These neoadjuvant treatment regimens achieve improved 
margin negative resection rates, potential early treatment of micrometastatic disease and allow for 
improvement in the patient selection for which resection may offer a survival benefit. Several studies have 
been conducted in pancreatic cancer that looked at combination of external beam radiation therapy (EBRT) 
with chemotherapy; however, while these provide symptom alleviation and local pain control, survival 


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benefit and local disease control remains an issue. Two meta-analyses (Gillen S, 2010)(A Sultana, 2007) 
have been done that compared the use of chemotherapy with chemoradiotherapy. A survival benefit was 
demonstrated for the use of chemoradiation compared to radiotherapy alone; however the chemoradiation 
did not yield a survival advantage over chemotherapy alone (A Sultana, 2007).  
 
In the neoadjuvant setting a recent retrospective review of 18 locally advanced pancreatic adenocarcinoma 
patients treated with FOLFIRINOX followed by chemoradiation demonstrated a 44% R0 (margin negative) 
resection rate (Hosein PJ, 2013)(Peter J Hosein1*, 2012). Acknowledging the limits of a small retrospective 
trial and brief follow-up, this trial suggests that a neoadjuvant approach utilizing FOLFIRINOX is feasible. 
In a recent study performed at our institution (to be published and was presented at 2013 SSO meeting and 
GI ASCO 2013), of 25 patients with locally advanced pancreatic cancer, 13 (52%) unresectable and 12 
(48%) with borderline resectable disease, were treated with FOLFIRINOX. Following treatment with 
FOLFIRINOX, 11 underwent surgical resection, of which 4 (31%) were initially unresectable.  36% of 
resected patients (4 of 11 patients) received additional chemotherapy and/or radiation therapy prior to 
surgery. The R0 resection rate for borderline resectable patients was 6/8 (75%). Of the 10 initially 
unresectable patients, 3 (33%) underwent surgical resection, with 2 (20%) R0 resections. The overall R0 
resection rate was 38%. A total of 6 patients (55%) demonstrated a significant pathologic response (data to 
be published). 
Definition of pCR has been well established and recently retrospective analysis has been done to evaluate 
pCR that have demonstrated varying results from 10-35% (Evans et al 1992, White et al, 2009). 
 
Gemcitabine and nab-paclitaxel have been evaluated in the neoadjuvant resectable setting.  Our institution 
participated in a multi-center feasibility trial of preoperative gemcitabine/nab-paclitaxel. Subjects meeting 
NCCN criteria for potentially-resectable pancreatic cancer received 3 cycles of gemcitabine and nab-
paclitaxel (1000mg/m2& 125mg/m2 – day 1, 8, and 15) followed by surgical resection. The primary endpoint 
was grade III/IV pathological response in > 30% of resected tumor specimens. Off 15 patients that 
completed all 3 cycles, 6 required dose reduction. 5 patients were unable to complete all 3 cycles of therapy 
due to serious adverse events (Grade 3 or 4 toxicities).  To date, 10 patients have undergone surgical 
resection. All 10 achieved negative surgical margins (R0 100%) and a decrease in CA19-9 from baseline 
(mean 181.7 U/ml) to end of therapy (mean 44.2 U/ml) was also noted (response measured after three 
cycles). There were no unexpected postoperative complications. A > 90% tumor necrosis (Grade III/IV) was 
seen in 3 patients, with 4 Grade 2, 1 Grade I, and 2 without effect. (Obtained from communication with the 
trial investigators). The available data suggests that gemcitabine/nab-paclitaxel is a safe and well-tolerated 
regimen in this population that is highly effective as demonstrated by the data above.   
 
It would appear that both gemcitabine/nab-paclitaxel and FOLFIRINOX are effective in the metastatic 
setting where they each offer an OS advantage compared to therapy with gemcitabine alone. In our own 
institution, we have documented that a subset of patients who initially fail to respond to FOLFIRINOX, do 
demonstrate objective tumor responses when treated with gemcitabine/nab-paclitaxel and successfully 
underwent resection (data to be published, presented at GI ASCO). There are no direct comparisons of 
Gemcitabine/nab-paclitaxel vs. FOLFIRINOX in the setting of either the metastatic or LAD pancreatic 
adenocarcinoma. Given the non-overlapping responses seen in locally advanced patients treated with both 
FOLFIRINOX and gemcitabine/nab-paclitaxel, and the efficacy that both these regimens have in the 
metastatic setting, we believe that it will be critical to directly compare each regimen’s efficacy in treating 
locally advanced pancreatic cancer for both efficacy and toxicity profile at this setting. 
 
6.3. Tumor Markers in Pancreatic Cancer – Role of CA-19.9 
 
The role of tumor biomarkers in monitoring and early diagnosis of cancer is an emerging field. However, 
pancreatic cancer lags behind other malignancies in the tumor markers available for monitoring. A variety of 
tumor markers have been investigated. Of these, Carbohydrate antigen 19-9 (CA19-9), which is an isolated 


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Lewis antigen of the MUC1 protein, has currently become the gold standard to diagnose and monitor 
treatment of pancreatic cancer (Herreros-Villanueva, 2013). 
 
There is also evidence to suggest that response to CA19-9 can be used as a surrogate marker for tumor 
progression. In 2008, Wong et al (Wong D, 2008)compared CA19-9 to radiographic objective response as a 
surrogate for clinical outcomes in patients receiving chemotherapy for metastatic pancreatic cancer. 
Significant correlations were observed between maximum CA19-9 decline and both TTP (P < 0.0001) and 
OS (P < 0.0001). Median OS was 12.2 months for patients with more than a 75% decline in CA19-9, 7.5 
months for those with 0% to 75% decline, and 3.5 months for those with no decline (Wong D, 2008). 
 
Similarly, the response of CA19-9 to fixed dose gemcitabine has also been investigated. In a cohort of 76 
patients with advanced pancreatic cancer receiving fixed-dose rate gemcitabine, it was shown that 
statistically significant correlations can be seen between CA-19-9 decline, time to treatment failure and OS 
(Ko AH, 2005). Median survival time ranged from 12.0 months for patients with the greatest degree of 
biomarker decline (> 75%) compared with 4.3 months in those whose CA19-9 did not decline during 
therapy (P < 0.001). More recently, improved OS was demonstrated in patients with locally advanced 
pancreatic cancer in whom greater than 75% decrease in CA19-9 from baseline was seen in response to neo-
adjuvant chemoradiation (gemcitabine, 5FU and radiation) (Singh, et al 2012). In this study, 88% of patients 
had LAD or borderline resectable disease. 34% of all patients had a greater than 75% reduction in Ca19-9 
from baseline with median survival in this group being 89.4 weeks compared to 41.3 weeks in patients who 
had less than 75% change in CA19-9. (Singh et al. 2012) 
 
6.4. Role of Radiation Therapy in Pancreatic Cancer 
 
6.4.1. Radiation Therapy Locally-advanced Pancreatic Adenocarcinoma 
Studies by the Gastrointestinal Tumor Study Group (GITSG) established combined chemotherapy and 
external beam radiation therapy (EBRT) as the treatment of choice for locally-advanced pancreatic 
adenocarcinoma (Group, 1979)(Moertel CG, 1981)(Group., Radiation therapy combined with Adriamycin or 
5-fluorouracil for the treatment of locally unresectable pancreatic carcinoma. , 1985)(Group., Treatment of 
locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy 
plus radiotherapy) to chemotherapy alone., 1988). Subsequent studies have confirmed a doubling in median 
survival time (from 3-6 months to 9 to 13 months) for combined chemoradiotherapy compared to 
observation, however improvements in 2-year survival have been minimal (Jr., 1979)(Gunderson LL, 
1983)(Mohiuddin M, 1988). While combined 5-fluoruracil (5-FU) and EBRT is the most frequently used 
treatment in the United States, multiple other treatment options and combinations have been explored in an 
attempt to improve outcomes while maintaining acceptable levels of toxicity. Intraoperative radiation 
therapy (IORT) has shown promise as a technique for improving local control while limiting the dose nearby 
normal tissue. Unfortunately, this improved local control has not translated into improved overall survival 
(Roldan GE, 1988). 
 
Multiple chemotherapeutics have been tried in combination with or replacement of 5-FU to improve upon its 
radiosensitizing effects. The nucleoside analog gemcitabine (2’,2’-difluoro-2’deoxycytidine) has been 
proven to be a potent radiosensitizing agent in human pancreatic cancer cell lines (Lawrence TS, 1996).  
Furthermore, in a randomized trial comparing single agent gemcitabine with 5-FU for the treatment of 
advanced or metastatic pancreatic cancer, the 1-year survival for subjects treated with gemcitabine was 18% 
versus 2% for those treated with 5-FU(Burris HA III, 1997).Based upon these results it was believed that 
concurrent full dose gemcitabine and EBRT could provide maximal systemic effects while enhancing local 
control as pre-clinical trials demonstrated maximal radiosensitization at cytotoxic levels. While the 
combination has demonstrated promising results in maintaining local control, it has been associated with 
significant acute and late toxicities (Blackstock AW B. S., 1999)(Blackstock AW T. M., 2001)(McGinn CJ, 
1998)(Wolf R). Investigators have tried to address this problem by either reducing the dose of gemcitabine 


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or EBRT or by increasing the number of fractions of EBRT (Poggi MM, 2006)(Wolff RA, 2001)(Symon Z, 
2006). 
 
6.4.2. Stereotactic Body Radiotherapy (SBRT) 
SBRT is technique that combines highly conformal radiotherapy with real-time imaging to deliver high 
doses of radiation in a small number of fractions. Modeled after intracranial stereotactic radiosurgery, SBRT 
has now been studied in a variety of extra-cranial locations including the spine, lung, liver, pancreas, and 
head and neck cancers. Because of the precise targeting, SBRT has the potential to improve upon the local 
control achieved with conventional EBRT while minimizing the dose to normal tissue. Most prospective 
randomized trials of conventionally fractionated EBRT for the treatment of locally-advanced pancreatic 
cancer have reported local control rates of 35%-55% (Ben-Josef E. Shields AF, 2004)(Brade A, 2005). 
Koong, et al established the feasibility of using SBRT for locally-advanced pancreatic cancer in a phase I 
dose escalation study which achieved 100% local control with no treatment limiting toxicities at 25 Gy in a 
single fraction (Koong AC L. Q., 2004). A follow-up study combined conventionally fractionated 5-FU 
chemoradiotherapy with an SBRT boost resulting in 94% local control but no improvement in overall 
survival and an increase in toxicity compared to SBRT alone (Koong AC C. E., 2005). A recent study 
combining full dose gemcitabine with single fraction SBRT reported 81% local control and 100% 1-year 
freedom from local progression. While acute toxicities were minimal, a significant number of subjects 
(47%) experienced Grade 2 or greater late toxicities, primarily duodenal ulcers (Schellenberg D, 2008). It is 
possible that these late toxicities may be reduced by increasing the degree of conformance of the radiation 
dose cloud and increasing the number of fractions, as studies comparing conventionally fractionated RT 
with hypofractionated RT have found increase incidence of late GI toxicities in the hypofractionated group 
(Symon Z, 2006). 
 
Another advantage to SBRT is the fractionation schedule. First, the entire course of treatment is often 
completed over 1 to 7 days versus the 5 to 8 weeks required for conventionally fractionated EBRT. Second, 
the accelerated fractionation schedule could improve overall survival by allowing earlier systemic doses of 
chemotherapy. Because locally-advanced pancreatic cancer is characterized by rapid progression to 
metastatic disease, early delivery of systemic chemotherapy is imperative to address potential sites of 
microscopic disease. In fact, some studies have evaluated the delivery of systemic chemotherapy followed 
by combined chemoradiotherapy for those subjects without evidence of disease progression. This strategy 
selects those subjects most likely to benefit from the local control provided by radiotherapy and in two 
separate studies has resulted in significant increases in TTP and OS for subjects treated with 
chemoradiotherapy compared to those receiving chemotherapy alone(Huguet F, 2007)(Krishnan S, 2007). 
 
6.4.3. Experience with SBRT at the University of Pittsburgh Cancer Institute 
A retrospective review from our institution evaluated the outcome in 71 subjects with pancreatic cancer 
treated with SBRT(Rwigema JC P. S., 2010). With a median follow-up of 12.7 months the freedom from 
local progression at 6 months and 1 year was 72% and 49%, respectively. Median overall survival for the 
entire group was 10.3 months. Treatment-related toxicity was minimal with only 3 patients experiencing 
acute grade 3 toxicity (4%). There was no recorded late toxicity. Another study from our institution 
examined outcomes in 24 patients treated post-operatively with SBRT(Rwigema JC H. D., 2010).  Sixty-six 
percent of the patients had positive margins and the remainder had close margins of 1-2.5mm. The median 
follow-up was 1 year. The freedom from local progression at 6 months and 1 year was 95% and 66%. There 
was no acute or late grade 3-4 toxicity, and 2 patients (8%) had late grade 1-2 toxicity, again demonstrating 
that when done properly, SBRT has a low potential for toxicity. 
 
The current study seeks to further investigate the impact of up-front systemic therapy in combination with 
fractionated SBRT for potentially resectable, locally-advanced pancreatic adenocarcinoma. 
 


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Combination chemoradiotherapy for locally advanced pancreatic cancer has been analyzed in a number of 
trials; however any survival benefit accrued has at best been modest. One recently presented study (ECOG 
4201) of gemcitabine with or without RT, was terminated early due to poor accrual. This study showed a 
barely significant increase in OS, however at the cost of a significant increase in grade 4 toxicity (41 vs. 6 
percent). 
 
One recently utilized strategy to reduce the complication risk of chemoradiation has as its basis an attempt to 
limit chemoradiotherapy to those who would most likely benefit by offering an initial period of 
chemotherapy and limiting subsequent chemoradiation to those without evidence of disease progression. As 
part of phase II and III trials conducted by the European Groupe Cooperateur Multidisciplinary en 
Oncologie (GERCOR), a retrospective series evaluated 181 patients with locally advanced disease. 
Chemotherapy was given for three months upfront, and at the patients and physicians discretion, those who 
had not progressed were treated by chemoradiation therapy. Interestingly, of 128 patients eligible for 
chemoradiation, subsequent radiotherapy after initial chemotherapy was associated with an increase in 
median OS (15 vs. 11.7 months). A separate study from the MD Anderson (Krishan et al 2007) similarly 
showed a survival advantage of 11.9 vs. 8.5 months for those patients treated by an initial period of 
chemotherapy, and subsequently reserving radiation therapy for those who did not progress. 
 
7.0. Rationale 
As discussed above, gemcitabine in combination with nab-Paclitaxel and FOLFIRINOX appear to be 
feasible and effective treatment options in the metastatic setting. While FOLFIRINOX demonstrates a 
higher RR (31.6 vs. 23%) and OS (11.1 vs8.5 months) compared to gemcitabine/nab-paclitaxel, it is 
somewhat difficult to compare directly. FOLFIRINOX was primarily studied in academic tertiary centers in 
France and there were a paucity of pancreatic head tumors in their study population. The generalizability 
and external validity with the MPACT study of gemcitabine/nab-paclitaxel is better as it was conducted in a 
community setting with well distributed cases, including patients with KPS >70 or ECOG PS 2.In addition, 
in the phase I/II trial of gemcitabine and nab-paclitaxel, the authors showed RR and OS of 48% and 12.2 
months, respectively, in certain patient population (Von Hoff DD R. R.-S., 2010)when conducted in an 
academic tertiary setting. This certainly indicates that the true RR and OS may in fact be closer to the 
FOLFIRINOX trial.  Recently, two retrospective studies of FOLFIRINOX have demonstrated increased R0 
resection and pCR rates, both of which predict OS benefit and are consistent with historic controls.  In our 
institution, we have seen responses, by CA19-9 and in terms of resectability in a subset of patients who 
received gemcitabine and nab-paclitaxel after failing FOLFIRINOX, suggesting there are non-overlapping 
populations in terms of responses.  Plus, the toxicity profiles for these two regimens are different.  
Additionally as discussed above, there is great variability in the pCR rates. Historically it has been in realm 
of 3% with some increase to 5-7% with recent advances in SBRT. Our recent feasibility data has shown 
pCR around 55%. With the introduction of both FOLFIRINOX and gemcitabine/nab-paclitaxel for 
treatment of pancreatic cancer as well as the additional use of SBRT, it is expected that we will see an 
improvement to 20% in the pCR after surgery. In addition, concerns have been raised regarding the toxicity 
of FOLFIRINOX regimen particularly with the addition of the 5FU bolus owing to significant component of 
the hematologic toxicities seen in patients. For these reasons, we now wish to formally study the 
pathological response and ability to obtain R0 resections in this group of patients using a modified 
FOLFIRINOX (mFOLFIRINOX) regimen where the 5-FU bolus is eliminated. As stated above, recent trials 
have demonstrated similar efficacy with mFOLFIRINOX compared to FOLFIRINOX itself. By using the 
modified regimen, we can eliminate the hematologic toxicities without compromising the efficacy.  The 
current study seeks to further investigate the impact of up-front systemic therapy in combination with 
fractionated SBRT for potentially resectable, locally-advanced pancreatic adenocarcinoma. 
 
8.0. Patient Selection and Eligibility 
 
8.1. Selection of Subjects 


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Enrollment is defined as the first day of the randomization. Potential subjects will be identified from the 
Principal Investigator’s and co-investigators’ current clinic population, or will be referred to the Principal 
Investigator by their own physician. They will be approached and informed of the study by an individual 
who is involved in their care. No cold-calling will occur, and no advertising will be used. The consent 
process will be carried out as a joint effort among the subject's physician, the study coordinator, and/or co-
investigators on the study.  
 
8.2. Number of Subjects 
 
The proportions of patients who attain R0 resection and pCR will be estimated for each arm.  A significant difference 
in the efficacy endpoint between arms is not expected; the proportion of patients achieving R0 resection and pCR is 
expected to be between 0.10 and 0.15 in both arms. However, the proportion of patients encountering Grade 4 toxicity 
is expected to be much lower in the gemcitabine plus nab-paclitaxel arm than in the mFOLFIRINOX arm.  If the true 
probability of Grade 4 toxicity is 0.01 with gemcitabine plus nab-paclitaxel and 0.20 with mFOLFIRINOX, a direct 
comparison on 40 participants randomized 1:1 using Fisher’s exact test at α=0.1 will have 62% power to reject the 
null hypothesis.  The expected width of 95% confidence intervals around the probabilities of toxicity would be 0.17 
(for π=0.01) and 0.38 (for π=0.20).  While a direct comparison is underpowered, the results will be necessary to 
motivate and design a definitive Phase III trial. Patients will be replaced if they withdraw from the study.  
 
8.3. Inclusion Criteria 
All patients must meet the following criteria within 28 days of randomization (unless otherwise indicated) to 
be enrolled in the protocol: 
• Patient must have the ability to give written informed consent 
• Histologically or cytologically proven adenocarcinoma of the pancreas. If the patient has mixed 
tumor with predominant adenocarcinoma pathology, they can be enrolled. 
• Subjects will be staged according to the 2010 AJCC staging system with pathologic stage T1-4, N0 
being eligible; and have a primary tumor of the pancreas (either pancreatic head, neck, uncinate 
process, or body/tail) 
• The tumor must be deemed as being borderline resectable. Final CT confirmation of surgical staging/ 
eligibility will be at the discretion of the pancreatic surgeon of the patient. 
• Disease is confined to locoregional site as confirmed by the CT and / or diagnostic staging 
laparoscopy to avoid occult peritoneal deposits. Diagnostic laproscopy will be only if absolutely 
required 
• Measurable disease per RECIST (v1.1) on imaging studies CT  
• Screening Endoscopic ultrasound if done prior to consent but within 6 weeks of expected 
randomization date it may be used. 
• Karnofsky performance status greater than or equal to 70 or ECOG performance of 0-2.  
• Age > 18 
• Estimated life expectance > 12 weeks 
• If female patient is of child bearing potential, she must have a negative serum pregnancy test (βhCG) 
documented up to 72hrs prior to administration of first study drug 
• Patient has screening blood work performed which includes the following (should be drawn ≤ 14 
days prior to randomization) 
• ANC > 1.5 x 109/L 
• Platelet count ≥ 100000/mm3 
• Hemoglobin (HgB) ≥ 9g/dL 
• AST,ALT≤ 2.5 x upper limit of normal (ULN) Total Bilirubin ≤ ULN 
• Serum Cr within normal limits (WNL) or calculated GFR ≥ 60ml/min 
• Coagulation studies with PT/INR and PTT within normal limits (±15%). If the patient is 
on Coumadin – we would switch the patient to LMW heparin product such as 
fondaparinaux (Arixtra) or enoxaprin (Lovenox). An anti-factor Xa test should be 


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available demonstrating adequate anti-coagulation on the LMWH (therapeutic range 0.4-
0.8). However, if this is not possible then INR must be kept ≤ 3.  
• Patient has a urinalysis obtained (≤14 days prior to randomization) and the results are deemed not 
clinically significant by the investigator. 
• Patient has no evidence of jaundice at the time of enrolment. If stent is required to alleviate jaundice, 
it should be metallic. If patient has a previously placed stent and this is plastic, this should be 
changed to metallic. 
• Patient’s pain symptoms have remained stable with no adjustment to analgesics within 7 days prior 
to randomization. Patient must be able to swallow entreat medications with no requirement for a 
feeding tube. Patient’s must not have intractable nausea or vomiting which prohibits the patient from 
oral medications 
• Diabetes must be controlled prior to enrollment 
• 
Disease must be encompassed in a reasonable SBRT “portal” as defined by the treating radiation oncologist 
 
8.4. Exclusion Criteria 
Subjects meeting any of the following exclusion criteria are not to be enrolled in the study: 
• Ineligible Histology including non-adenocarcinomas, adenosquamous carcinoma, islet cell 
carcinomas, cystadenomas, cystadenocarcinomas, carcinoid tumors, duodenal carcinomas, distal bile 
duct and ampullary carcinomas  
• Evidence of distant metastasis on upright CXR, CT or other staging studies 
• Subjects with recurrent disease 
• Prior radiation therapy to the upper abdomen or liver at the discretion of the treating radiation 
oncologist could impair delivery of the prescribed radiation treatment 
• Prior chemotherapy  
• Subjects in their reproductive age who are breast feeding or have a positive pregnancy test  
• Any co-morbid condition of sufficient severity to limit full compliance with the protocol per 
assessment by the individual treating physician 
• Concurrent active infection 
• Previous or current malignancies of other histologies within the last 3 yrs prior to randomization;  
with the exception of cervical cancer in situ, adequately treated basal cell or squamous cell 
carcinoma of skin or treated low risk prostate cancer 
• Patient with known historical or active infection with HIV, Hepatitis B or Hepatitis C 
• Patient who has undergone recent major surgery, other than diagnostic surgical procedure within 4 
weeks prior to randomization.  
• Patient who has a history of allergy or hypersensitivity to any of the study drugs.  
• Patients with a history of interstitial lung disease, history of slowly progressive dyspnea and 
unproductive cough, sarcoidosis, silicosis, interstitial pulmonary fibrosis, pulmonary hypersensitivity 
pneumonitis or multiple allergies 
• Patients with greater than 2 screening  peripheral neuropathy.  
 
9.0. Investigational Plan and Study Evaluations 
9.1 Overall Design 
 


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9.2. Pretreatment Evaluation 
The following tests/procedures will need to be performed up to 28 days prior registration in order to 
ascertain eligibility unless otherwise specified or at the discretion of the treating physician 
• Signed informed consent by the patient (not a surrogate) 
• Complete physical examination, body weight and height taken within 21 days prior to 
randomization. This will then be used to calculate the BSA which will be used to dose chemotherapy 
drugs (mFOLFIRINOX  or gemcitabine/nab-paclitaxel) 
• Medical history (including documented Past medical history, Social history, use of other tobacco 
products), concomitant medications, medical conditions (AEs) 
• Diagnostic endoscopic ultrasound (EUS) 
• Placement of metallic biliary stent if indicated 
• Placement of infusaport for chemotherapy 
• Pathology review or biopsy for diagnosis and correlative studies 
• Blood work (within 14 days of randomization) will include: 
• 
CBC, differential and platelets 
• 
CMP (Na, K, CL, CO2, Glucose, BUN, Creatinine, Calcium, Protein Total, Albumin, AST, 
ALT, ALK Phos, Bili T), Magnesium,  LDH, and Phosphorus  
• 
Coagulation studies including INR, PT, PTT 
• 
CA19-9 CEA 
• 
Anti-factor Xa only if on fondaparinaux (Arixtra) or enoxaprin (Lovenox) 
• 
Research blood for correlative studies 
• CT scan or Spectral CT Scan and tumor measurement 
• Urinalysis 
• QoL questionnaire (FACT-HB) 
• Women of child bearing potential will have a serum pregnancy test within 72 hours of randomization 
• EKG/ECG  
• Evaluation by the pancreatic surgeon to confirm surgical status. 
• Evaluation by a radiation oncologist to confirm SBRT candidate. 
 
9.3. Day 0 
• Randomization will be performed in a 1:1 fashion utilizing a computerized block randomization 
technique.  
• Placement of gold fiducials via EUS. 
 
9.4. During Study Evaluation  
During each active treatment visit, the patient’s evaluation will consist of: 
• Complete physical examination including performance status 
• History, concomitant medication  and adverse event evaluation 
• Blood work (days 1, 8, 15 for gemcitabine/nab-paclitaxel arm or Day 1 of mFOLFIRINOX Arm): 
Eligibility 
and
Registrati
on
Fiducial PlacementRANDOMIZE
FOLFIRINOX 4 Cycles 
(3 months) OR 
Gemcitabine/nab-
paclitaxel 3 cycles (3 
months)
CT Scan (C3, 
D29 +/- 1 
week)SD, PR, CR
SBRT  
Planning
SBRT (4 weeks after 
Chemotherapy + /- 5 
business days)
within 
4 
weeks
Surgery
Adjuvant 
chemotherapy per 
physcianPD
Off Study
Additional 
Chemotheray at the 
discretion of treating 
physician


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• 
CBC with differential, platelets 
• 
CMP (Na, K, CL, CO2, Glucose, BUN, Creatinine, Calcium, Protein Total, Albumin, AST, 
ALT, ALK Phos, Bili T), Magnesium,  LDH, and Phosphorus  
• 
Tumor markers CA 19-9 and CEA will be drawn day 1 of every cycle 
• 
 If on anti-coagulation therapy Anti- Xa level will be tested at least once during chemotherapy at 
the physician's discretion 
• 
 Research blood for correlative studies 
• QoL questionnaire (FACT-HB) 
• Administration of chemotherapy based on the randomization . Patients randomized to the 
gemcitabine/nab-paclitaxel arm will receive up to 3 cycles of chemotherapy (3 weeks on/ 1 week off 
every 28 days). Patients randomized to the mFOLFIRINOX arm will receive Oxaliplatin, Ironotecan 
and 5FU 46 hour infusion every 14 days for up to 6 cycles.  Patients will be assessed during every 
cycle of chemotherapy with appropriate dose modifications as required. Chemotherapy will be 
divided such that 3 or 6 cycles of therapy will be administered prior to restaging depending upon 
arm.  
 
9.5. Disease Response Evaluation (MDC Evaluation) 
At the completion of the assigned cycles of therapy the patient will have: 
• CT Scan or Spectral CT Scan of the chest, abdomen and pelvis (CT Scan) to re-evaluate response to 
neoadjuvant chemotherapy.  
 
NOTE:  Patients who are deemed as having SD but remains unresectable or PD after 3 months of treatment 
will be deemed off treatment.  They may then receive additional off study chemotherapy based on the 
discretion of the treating physician. These subjects will be followed for TTP and survival.   
 
9.6 SBRT within 4 weeks of completion of chemotherapy (+/- 5 business days) 
Patients who are deemed as having SD, PR or CR by imaging will be seen by the pancreatic surgeon and 
radiation oncologist to confirm resectability and SBRT planning.  
 
An SBRT plan will be created based on the disease contoured on the CT. The plan will be to deliver 
fractionated SBRT to the isodose line best encompassing the PTV:  
 
12 Gy x 3 fractions (36 Gy total). 
 
Careful evaluation of the each plan will be conducted by the radio-surgical team to ensure that normal 
tissues and critical structures tolerances are maintained. 
 
The maximum dose (in Gy) within the treatment volume (MD), prescriptions dose (PD), and the ratio of 
MD/PD (as a measure of heterogeneity within the target volume), prescription isodose volume (PIV in 
mm3), tumor volume (TV in mm3), and the ratio of PIV/TV (as a measure of dose conformity of the 
treatment relative to the target) will be recorded in the patient's medical record. This concept is illustrated in
Figure 2: Example illustrating the concept of PIV/TV 
 
 


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During the SBRT the patient will have:  
• Physical exam including PS performed by the Radiation Oncologist 
• Medical history, Con meds, AE evaluation 
• CT Scan  or Spectral CT Scan of the chest, abdomen and pelvis for radiation planning will be 
done by the treating radiation oncologist. This CT scan is planning for measurements 
• Blood work: research blood for correlative studies  
• The time from the end of last cycle of chemotherapy regardless of arm to SBRT start should 
within 4 weeks  (+/- 5 business days) 
 
9.7. Pre-Op Visit - will be done within 2 (+/-3 business days) weeks of completing SBRT 
• Physical Exam including PS 
• Medical history, Con meds, AE evaluation 
• Blood work: CMP, CBC diff and platelets, magnesium, coagulation studies if on anticoagulation 
therapy, CA19-9 CEA, anti-factor Xa, and research blood for correlative studies. 
 
9.8. Surgery within 4 weeks (+/- 5 business days) of Completing SBRT 
Surgical specimen will have SPARC and SMAD4 testing performed by pathology as standard of care. 
Margin status will be recorded in the patient’s medical record and research data base. If the subject agrees a 
tissue specimen will be collected from surgery for correlative studies. 
 
9.9. Post treatment Assessment/Follow Up 
Patients will be taken off treatment if they remain surgically unresectable at the restaging scan point. At this 
stage patients can come off study therapy and additional chemotherapy may be administered at the 
discretion of the treating oncologist. These patients will be followed for TTP and survival. 
 
Follow-up after surgery is recommended at Q3 (+/-4 weeks) months for 6 months, then every 6 (+/-4 weeks) 
months for 24 months but this will be at the discretion of treating physician. During follow up the patient 
will have CT scan or Spectral CT Scan (chest abdomen/pelvis).  
 
9.10. Treatment 
 
9.10.1. Study Drug and Doses 
Patients will be treated on an outpatient basis with mFOLFIRINOX or Gemcitabine/nab-Paclitaxel.  
 
Gemcitabine/nab-Paclitaxel: 
Patients will receive nab-paclitaxel plus gemcitabine with 125 mg/m2 nab-paclitaxel as a 30- to 40-minute 
infusion (maximum infusion time not to exceed 40 minutes) followed by 1000 mg/m2gemcitabine as a 30- to 
40-minute infusion (maximum 40 minutes) for 3 weeks followed by a week of rest. 
Supportive care and antiemetics per the  treating institution standard can be provided at the Investigator’s 
discretion 
 
mFOLFIRINOX: 
Patients will receive FOLFIRINOX consisting of oxaliplatin at a dose of 85 mg/m2, given as a 2-hour 
intravenous infusion, immediately followed by irinotecan at a dose of 180 mg/m2, given as a 90-minute 
intravenous infusion. This treatment will be immediately followed by fluorouracil as a continuous 
intravenous infusion of 2400 mg /m2 over a 46-hour (+/- 30 minutes) period every 2 weeks. As noted in the 
rationale previously, elimination of bolus 5-FU appears to offer similar response rates in locally advanced 
pancreatic cancer without the added hematologic side effects. As such, we will eliminate the 5-FU bolus and 
leucovorin throughout this study.  
 


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Supportive care and antiemetics per treating institution standard will be administered for both chemotherapy 
combinations. Suggested anti-emetics for mFOLFIRINOX  including serotonin 5HT3 receptor blocker (eg: 
ondansetron), steroids pre chemotherapy and for 5days post chemotherapy at a dose of 4 mg dexamethasone 
PO BID x 2 days, 2 mg PO BID x 2 days 2mg x 1 day 5 unless there is a contraindication due to severe 
diabetes. If patient has severe diabetes it is suggested this be controlled as best as possible prior starting 
chemotherapy. Following the chemotherapy administration, it is suggested that patients be on round-the-
clock anti-serotoninergics as antiemetics for 3 days. The addition, of a second antiemetic can be added at the 
investigator’s discretion. The antiemetic regimen for the gemcitabine/nab-paclitaxel arm will be at the 
discretion of the investigator 
 
Please see Section 13 for full details of supportive care. 
10.0. Treatment Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.1. Gemcitabine / nab-Paclitaxel 
 
 
 
Cycle 1 
Cycle 2 
Cycle 33 
 
 
 
 
Parameter 
Screening 
1 
Day 0 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day  
15 
Day 
1 
Day 
8 
Day 
15 
MDC 
evaluation 
SBRT4 
# > 
Pre -
Op13 
Follow-up 
(+/-4 
weeks)5 
Physical Exam#  PS, HT2 and Wt, BSA 
X^ 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
History, Con Meds and AE Evaluation 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
Diagnostic endoscopic ultrasound (EUS)(If not already 
completed)> 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placement of Biliary stent11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Port placement12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pathology review or Biopsy for diagnosis and correlative 
studies(if not already completed) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with diff, plt 
X% 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
CMP (Na, K, CL, CO2, Glucose, BUN, Creatinine, 
Calcium, Protein Total, Albumin, AST, ALT, ALK Phos, 
Bili T), Magnesium,  LDH, and Phosphorus 
X% 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Coagulation studies including INR, PT, PTT6 
X% 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Anti Xa level7 
X% 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Ca 19-9 and CEA 
X% 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
CT Scan or Spectral CT Scan (chest/abdomen/pelvis) and 
tumor measurement 
X 
 
 
 
 
 
 
 
 
 
 
X8 
X9 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placement of Gold Fiducials via EUS> 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life questionnaire (FACT-HB) 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X10 
 
 
Serum Pregnancy Test (can be up to 72 hrs prior) if pt is < 
60ys age 
X^ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gemcitabine/nab-paclitaxel 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Correlative studies Blood work14 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 


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EKG/ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Screening tests will be done within 28 days of randomization. 
2 Height needs to be documented once at screening 
3 Only patients who are deemed to have had a response (SD, PR or CR) will proceed to SBRT and surgery 
4 Only patients who have a response after cycle 3 of chemotherapy will proceed to SBRT (completed at UPMC Shadyside Hospital) within four weeks after completion of chemotherapy (+/- 5 
business days).  
5 Follow-up after surgery is recommended at Q3 months for 6 months, then every 6 months for 24 months but this will be at the discretion of treating physician. Additional imaging and tumor 
markers will be at the discretion of the oncologist.  
6 Patients who are on Coumadin will require their INR to be checked every cycle or according to the treating oncologist 
7 If patient is on anticoagulation with either enoxaparin or fondaparinaux, Anti Xa level should be tested at least once during chemotherapy. Additional levels can be done at the discretion of 
treating oncologist 
8 Disease measurements are based on CT after 3 cycles of chemotherapy. This CT should be performed on the patient's off week prior to MDC clinic. At the MDC clinic it will be reviewed by 
the medical oncologist, surgeon and radiation oncologist to make decision as to whether patient proceeds to SBRT and surgery. 
9 Planning CT scan for measurement only 
  
10 QOL questionnaires will be done at the end of SBRT.  
11 If patient has biliary obstruction and a stent is required, it must be a metallic stent. If a pre-existing plastic stent is present, this will need to be changed to a metallic stent prior to starting 
chemotherapy. 
12 If patient is randomized to gemcitabine/nab-paclitaxel, port placement is at the discretion of the treating physician.  
13 If patient proceeds to surgery - surgery will be done within 2 (+/- 3 business days) weeks after completion of SBRT. Pre-op visit will be organized accordingly 
14 Blood will be drawn for HMGB1, sRAGE, IL-6. This will be done at the start of every cycle, at the end of SBRT and pre-op (morning of surgery). Blood will be drawn in 2 
green top tubes (heparin), two citrate, and two red top tubes. Dr. Lotze research lab will provide lab supplies and process all research samples. 
15 If patient has an extensive cardiac history 
# MD visit during chemotherapy will be with oncologist on day 1 of every cycle. If patient proceeds to SBRT, they will be seen by radiation oncologist. Follow-up with radiation oncologist is as 
needed.  
% tests need completed within 14 days of randomization 
^Completed within 7 days of randomization 
> Must be completed at UPMC Shadyside Hospital 
 
 
 
 
 
 


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10.2.mFOLFIRINOX 
  
  
  
Cycle 
1   
Cycle 
2 
Cycle 
3  
Cycle 
4 
Cycle 
53 
Cycle 
63 
 
  
  
  
Parameter 
Screening1 
Day 
0 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
MDC 
evaluation 
SBRT4 
# > 
Pre -
Op13 
Follow-
up5 
Physical Exam#  PS, HT2 and Wt, BSA 
X^ 
  
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
History, Con Meds and AE Evaluation 
X 
  
X 
X 
X 
X 
X 
X 
 
X 
X 
  
Diagnostic endoscopic ultrasound (EUS)(If not already completed) > 
X 
  
  
  
  
  
  
  
 
  
  
  
Placement of Biliary stent11 
X 
  
  
  
  
  
  
  
 
  
  
  
Port placement12 
X 
  
  
  
  
  
  
  
 
  
  
  
Pathology review or Biopsy for diagnosis and correlative studies(if not already 
completed) 
X 
  
  
  
  
  
  
  
 
  
  
  
CBC with diff, plt  
X% 
  
X 
X 
X 
X 
X 
X 
 
  
X 
  
CMP (Na, K, CL, CO2, Glucose, BUN, Creatinine, Calcium, Protein Total, 
Albumin, AST, ALT, ALK Phos, Bili T), Magnesium,  LDH, and Phosphorus 
X% 
  
X 
X 
X 
X 
X 
X 
 
  
X 
  
Coagulation studies including INR, PT, PTT6 
X% 
  
  
  
  
  
  
  
 
  
X 
  
Anti Xa level7 
X% 
  
  
  
  
  
  
  
 
  
X 
  
Ca 19-9 and CEA 
X% 
  
X 
X 
X 
X 
X 
X 
 
  
X 
 
CT  Scan  or Spectral CT Scan (chest/abdomen/pelvis ) and tumor 
measurement 
X 
  
  
  
  
  
  
  
X8 
X9  
 
X  
Urinalysis 
X 
  
  
  
  
  
  
  
 
  
  
  
Placement of Gold Fiducials via EUS> 
  
 X 
  
  
  
  
  
  
 
  
  
  
Quality of Life questionnaire (FACT-HB) 
X 
  
X 
X 
X 
X 
X 
X 
 
X10 
  
 
Serum Pregnancy Test (can be up to 72 hrs prior) if pt is < 60ys age 
X^ 
  
  
  
  
  
  
  
 
  
  
  
mFOLFIRINOX 
  
  
X 
X 
X 
X 
X 
X 
 
  
  
  
Correlative studies Blood work14 
X 
  
X 
X 
X 
X 
X 
X 
 
X 
X 
  
EKG/ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 Screening tests will be done within 28 days of randomization. 
2 Height needs to be documented once at screening 
3 Only patients who are deemed to have had a response (SD, PR or CR) will proceed to SBRT and surgery 
4 Only patients who have a response after cycle 3 of chemotherapy will proceed to SBRT (completed at UPMC Shadyside Hospital) within four weeks after completion of chemotherapy (+/- 5 
business days).  
5 Follow-up after surgery is recommended at Q3 months for 6 months, then every 6 months for 24 months but this will be at the discretion of treating physician. Additional imaging and tumor 
markers will be at the discretion of the oncologist.  
6 Patients who are on Coumadin will require their INR to be checked every cycle or according to the treating oncologist 
7 if patient is on anticoagulation with either enoxaparin or fondaparinaux, AntiXa level should be tested at least once during chemotherapy. Additional levels can be done at the discretion of 
treating oncologist 
8 Disease measurements are based on CT after 3 cycles of chemotherapy. This CT should be performed on the patient's off week prior to MDC clinic. At the MDC clinic it will be reviewed by 
the medical oncologist, surgeon and radiation oncologist to make decision as to whether patient proceeds to SBRT and surgery. 
9 Planning CT scan for measurement only10 QOL questionnaires will be done at the end of SBRT.  
11 If patient has biliary obstruction and a stent is required, it must be a metallic stent. If a pre-existing plastic stent is present, this will need to be changed to a metallic stent prior to starting 
chemotherapy. 
12 If patient is randomized to mFOLFIRINOX arm, port placement should be done prior to starting therapy.  
13 If patient proceeds to surgery - surgery will be done within 2 (+/- 3 business days) weeks after completion of SBRT. Pre-op visit will be organized accordingly 
14 Blood will be drawn for HMGB1, sRAGE, IL-6. This will be done at the start of every cycle, at the end of SBRT and pre-op (morning of surgery). Blood will be drawn in 2 
green top tubes (heparin), two citrate, and two red top tubes. Dr. Lotze research lab will provide lab supplies and process all research samples. 
# MD visit during chemotherapy will be with oncologist on day 1 of every cycle. If patient proceeds to SBRT, they will be seen by radiation oncologist. Follow-up with radiation oncologist is as 
needed.  
% tests need completed within 14 days of randomization 
^Completed within 7 days of randomization 
> Must be completed at UPMC Shadyside Hospital 
 
 
 


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11.0. Chemotherapeutic Agents 
 
11.1. Gemcitabine Hydrochloride (Gemzar®) 
Please refer to the package insert for complete information. 
 
11.1.1. Description 
2'-Deoxy-2', 2'-difluorocytidine monohydrochloride (Gemcitabine hydrochloride or Gemcitabine®) is a white to 
off-white or translucent solid with a molecular weight of 299.66. 
 
Mechanism of Action: Gemcitabine, like ara-C, is an analog of deoxycitidine. This antimetabolite, a pyrimidine 
analog inhibiting both DNA and RNA viruses, is cell-cycle-specific in blocking the cells at the G1/S and is 
retained in human tumor cells for long periods. Studies suggest that gemcitabine is activated by deoxycytidine 
kinase. Deoxycytidine has been shown to reverse the growth inhibitory activity of gemcitabine. 
 
11.1.2. Toxicology 
Human Toxicology: Dose limiting toxicity is bone marrow suppression with mild to moderate 
granulocytopenia, anemia and thrombocytopenia. There has been no evidence of cumulative WBC or platelet 
toxicity. Gastrointestinal toxicities include nausea, vomiting, and diarrhea. Gemcitabine should be used with 
caution in patients with impaired liver function since abnormalities of liver transaminase enzymes have been 
reported. Mild proteinuria and hematuria have been reported but were not clinically significant and usually not 
associated with any change in serum creatinine or BUN. A few cases of renal failure of uncertain etiology have 
been reported. While on study, one patient who received prior mitomycin developed hemolytic uremic 
syndrome requiring dialysis. The relationship of this event to gemcitabine is not known. Gemcitabine should be 
used with caution in patients with impaired renal function. Toxicities associated with allergic reaction include 
rash, pruritus, desquamation, vesiculation, ulceration, and dyspnea. Bronchospasm has been reported in less 
than 1% of patients. Twenty percent (20%) of patients have also experienced flu-like symptoms such as fever, 
headache, back pain, chills, myalgia, asthenia, anorexia, cough, rhinitis, malaise and sweating. Other toxicities 
include edema in 30% of patients, alopecia, somnolence, diarrhea, constipation, and oral toxicity (soreness and 
erythema). Pulmonary edema has been a rare occurrence (less than 1%). A few cases of hypotension have been 
reported, as well as myocardial infarction, congestive heart failure and arrhythmia. However, there is no clear 
evidence that gemcitabine causes cardiac toxicity. 
 
Pregnancy and Lactation: Gemcitabine may cause fetal harm when administered to a pregnant woman. This 
agent has produced teratogenic effects in mice and rabbits when administered at a dose of < 2 mg/m2. Adverse 
effects included decreased fetal viability, weight and morphologic defects. There is no data on gemcitabine 
administration during human pregnancy, and it is not currently known if metabolites are excreted in human 
milk. However, many drugs are excreted in human milk, and there is a potential for adverse effects in nursing 
infants. Therefore, the use of gemcitabine should be avoided in pregnant or nursing women because of the 
potential hazard to the fetus or infant. 
 
11.1.3. Pharmacology 
Kinetics: Gemcitabine is metabolized intracellularly to form active gemcitabine di- and tri-phosphates. 
Additional metabolites have not been identified in either plasma or urine. The gemcitabine di- and tri-
phosphates does not appear to circulate in plasma in measurable amounts. The compound is metabolized 
principally by the liver to form an inactive uridine derivative (dFdU or 2'-deoxy- 2',2'-difluorouridine). The 
plasma protein binding of gemcitabine is negligible. Following a single 1,000 mg/m2/30 min [14C]-
gemcitabine infusion, 92% to 98% of the dose was recovered within 1 week after gemcitabine administration. 
Urinary excretion of parent and dFdU accounted for 99% of the excreted dose, and less than 1% of the dose was 


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excreted in feces. The renal clearance of gemcitabine is less than 10%; therefore, the parent drug appears to be 
almost completely metabolized to the inactive dFdU. 
 
Half-life ranged from 11 to 26 minutes for patients receiving single dose infusions (1,000 mg/m2 to 2,500 
mg/m2) of 1.1 hours or less. Following longer duration infusions (3.6 to 4.3 hours), the half-life ranged between 
18.5 and 57.1 minutes for single gemcitabine doses between 2,500 mg/m2 and 3,600 mg/m2. The increase in 
half-life may relate to the appearance of a possible third exponential phase (representing a deep compartment) 
that is not observed following the shorter infusions. 
 
The population pharmacokinetic analyses of the effect of patient specific characteristics showed that clearance 
normalized for BSA was affected by gender. The clearance obtained for the female patient for all studies was 
46.2 L/hr/m2 and the male's was 66.8 L/hr/m2. These moderate to high gemcitabine values suggest that 
gemcitabine may be metabolized by various tissues, including the liver. The renal clearance for gemcitabine is 
less than 10% of the systemic clearance. The maximum dFdU plasma concentrations were achieved from 0 to 
30 minutes after the discontinuation of the gemcitabine infusions, ranging from 0.4 to 4.75 hours. The apparent 
formation of dFdU (determined from the fraction of the gemcitabine dose excreted as dFdU) ranged from 
91.2% to 98.2% of gemcitabine clearance in a single-dose study. Based on the imputed formation rate of dFdU, 
the mean dFdU volume of distribution at steady-state was 150.4 L/m2, indicating that dFdU was extensively 
distributed into tissues. The metabolite was excreted in urine without undergoing further biotransformation. The 
mean apparent clearance of dFdU was 2.5 L/hr/m2. 
 
Formulation: Gemcitabine is supplied as a lyophilized powder in sterile vials containing 200 mg or 1,000 mg (1 
gram) of gemcitabine as the hydrochloride salt (expressed as the free base), mannitol, and sodium acetate. 
 
Storage and Stability: The lyophilized compound should be stored at controlled room temperature, 59° to 86°F 
(15° to 30°C). Reconstituted solution should be stored at controlled room temperature and used within 24 hours; 
any unused portion should be discarded. 
 
Reconstitution:  Normal saline without preservatives is the only diluent approved. Do not use other diluents. 
 
Administration: Intravenous over 30 minutes 
 
Handling Precautions: Gemcitabine is a toxic material which could cause skin and eye irritation. Ingestion or 
inhalation exposure of sufficient quantities could result in decreased white and red blood cells, 
hypospermatogenesis, gastrointestinal disturbances, and other signs of toxicity. The compound was positive in 
one of three tests for mutagenicity. Laboratory animal studies indicate that compounds in this therapeutic class 
may be reproductive toxins and may induce fetal malformations. Contact or inhalation should be avoided. 
 
11.2. nab-Paclitaxel (Abraxane™) 
 
11.2.1. nab-paclitaxel Packaging, Labeling, and Storage  
nab-paclitaxel (Abraxane) - each single-use 50-mL vial will contain 100 mg paclitaxel and human albumin 
(HA) as a stabilizer. Each vial will be labeled according to country-specific regulatory requirements for labeling 
of investigational products. Unreconstituted nab-paclitaxel (Abraxane) should be stored at controlled room 
temperature (20 to 25C or 68F to 77F) and reconstituted nab-paclitaxel (Abraxane) must be refrigerated at 2 to 
8C (36 to 46F) and used within 8 hours. Both forms of Nab-paclitaxel (Abraxane) should be stored in an area 
free of environmental extremes and must be accessible only to study personnel.  
 


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11.2.2. nab-paclitaxel (Abraxane™) Administration 
 
NOTE: It is not a requirement to use filter needles in the preparation of, or in-line filters during the 
administration of Nab-paclitaxel (Abraxane). In any event, filters of pore size less than 15 microns (15 μm) 
must not be used.  
 
The Investigator or designee will calculate the body surface area (BSA) of the patient in order to determine the 
total amount of Nab-paclitaxel (Abraxane) to be administered. 
 
11.2.3. Reconstitution and Use of Nab-paclitaxel (Abraxane™)  
Calculate the patient’s BSA according to standard institutional methods. BSA will be calculated on Cycle 1 Day 
1 and recalculated per the site’s standard of care, or if body weight changes by more than 10%. Actual heights 
and weights should be used to calculate surface areas (no downward adjustment to "ideal" weight). This 
principle applies to individuals whose calculated surface area is 2.2 m2or less. In those rare cases where a 
patient's surface area is greater than 2.2 m2, the actual surface area or 2.2 may be used. Dosing BSA may be 
capped if the treating physician believes it is in the best interest of an obese patient.  
 
Calculate the total dose (in mg) to be administered by:  
Total Dose (mg) = BSA (study dose mg/m2)  
Calculate the total number of vials required by:  
Total Number of Vials = Total dose (mg) 100 (mg/vial)  
Round up the number of vials to be reconstituted to the next higher whole number when a fractional 
number of vials is obtained by the above formula (e.g., if the total number of vials = 4.05 or 4.5, then 
5 vials would be reconstituted).  
 
Using sterile technique, prepare the vials for reconstitution.  
Swab the rubber stoppers with alcohol.  
Reconstitute each Nab-paclitaxel (Abraxane) vial by using a 50-cc or 60-cc sterile syringe. (Note: Change 
the syringes after reconstituting every 3 vials).  
Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute, using the 
sterile syringe directing the solution flow onto the inside wall of the vial.  
DO NOT INJECT the 0.9% Sodium Chloride Injection, USP solution directly onto the lyophilized cake as 
this will result in foaming.  
Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of 
the lyophilized cake/powder.  
Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any 
cake/powder occurs. Avoid generation of foam. Each mL of reconstituted product will contain 5 mg of 
Abraxane.  
Calculate the exact total dosing volume (to the nearest mL) of 5 mg/mL suspension required for the patient:  
Dosing volume (mL) = Total dose (mg)/5 (mg/mL)  
The reconstituted sample should be milky and homogeneous without visible particulates. If unsuspended 
powder is visible, the vial should be gently inverted again to ensure complete resuspension, prior to use.  
Use immediately following reconstitution. If not used immediately, replace the reconstituted vial in the 
carton and store reconstituted Abraxane in a refrigerator for not more than 8 hours.  
 Using a new, sterile 50-cc or 60-cc syringe, withdraw the reconstituted Abraxane solution. Do not remove 
the rubber stopper from the Abraxane vials as this can compromise the sterility of the drug preparation.  
Inject the calculated dosing volume of reconstituted Abraxane suspension into an empty sterile, standard 
PVC IV bag using an injection port. Inject perpendicularly into the center of the injection port to avoid 


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dislodging plastic material into the IV bag. Repeat until the patient’s entire required dose is injected into the 
IV bag.  
Remove the injection port.  
Once the exact volume of reconstituted Abraxane has been withdrawn from the vials, discard any excess 
solution left over in accordance with standard operating procedures for cytotoxic drugs.  
Administer the calculated dosing volume of reconstituted Abraxane suspension by IV infusion over 30 
minutes.  
 
11.3. modified FOLFIRINOX 
 
(pronounced full-fear-o-knocks)is made up of the following drugs: 
• FOL – Folinic acid (Leucovorin), a vitamin B derivative that helps fluorouracil function better within the 
cell; - eliminated from this protocol 
• F – Fluorouracil (5-FU), gets into the DNA cancer molecule and stops synthesis; 
• IRIN – Irinotecan (Camptosar), prevents DNA cancer cell from uncoiling and duplicating, and;  
• OX –Oxaliplatin, inhibits DNA synthesis in cancer cells. 
 
11.3.1. Rounding Drug Doses   
• Rounding the doses of 5-FU, oxaliplatin, and irinotecan is optional.  
• If the treating physician decides to round the dose(s), follow these rules.  
(These rules also apply for dose modifications.)  
• 5-FU (2400 mg/m2 continuous infusion) 5-FU should be rounded to the nearest 50 
mg. 
• Irinotecan (180 mg/m2) Irinotecan should be rounded to the nearest 5 mg. 
Oxaliplatin (85 mg/m2) Oxaliplatin should be rounded to the nearest 5 mg. 
 
11.3.2. Fluorouracil (5-FU)  
An antineoplastic antimetabolite, is a colorless to faint yellow aqueous, sterile, nonpyrogenic injectable solution 
available in a 50 mL and 100 mL Pharmacy Bulk Package for intravenous administration. Each mL contains 50 
mg fluorouracil in water for injection, USP, pH is adjusted to 8.6 to 9.4 with sodium hydroxide. 
Chemically, fluorouracil, a fluorinated pyrimidine, is 5-fluoro-2,4 (1H,3H)-pyrimidinedione. It is a white to 
practically white crystalline powder which is sparingly soluble in water.  
 
Molecular formula: C4H3FN2O2 
Molecular weight 130.08 
 
A Pharmacy Bulk Package is a container of a sterile preparation for parenteral use that contains many single 
doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation 
of admixtures for intravenous infusion. 
 
11.3.2.1. Clinical Pharmacology 
There is evidence that the metabolism of fluorouracil in the anabolic pathway blocks the methylation reaction of 
deoxyuridylic acid to thymidylic acid. In this manner, fluorouracil interferes with the synthesis of 
deoxyribonucleic acid (DNA) and to a lesser extent inhibits the formation of ribonucleic acid (RNA). Since 
DNA and RNA are essential for cell division and growth, the effect of fluorouracil may be to create a thymine 
deficiency which provokes unbalanced growth and death of the cell. The effects of DNA and RNA deprivation 
are most marked on those cells which grow more rapidly and which take up fluorouracil at a more rapid rate. 
 


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Following intravenous injection, fluorouracil distributes into tumors, intestinal mucosa, bone marrow, liver and 
other tissues throughout the body. In spite of its limited lipid solubility, fluorouracil diffuses readily across the 
blood-brain barrier and distributes into cerebrospinal fluid and brain tissue. 
 
Seven to twenty percent of the parent drug is excreted unchanged in the urine in six hours; of this over 90% is 
excreted in the first hour. The remaining percentage of the administered dose is metabolized, primarily in the 
liver. The catabolic metabolism of fluorouracil results in degradation products (e.g., CO2, urea and α-fluoro-ß-
alanine) which are inactive. The inactive metabolites are excreted in the urine over the next 3 to 4 hours. When 
fluorouracil is labeled in the six carbon position, thus preventing the 14C metabolism to CO2, approximately 
90% of the total radioactivity is excreted in the urine. When fluorouracil is labeled in the two carbon position 
approximately 90% of the total radioactivity is excreted in expired CO2. Ninety percent of the dose is accounted 
for during the first 24 hours following intravenous administration. 
 
Following intravenous administration of fluorouracil, the mean half-life of elimination from plasma is 
approximately 16 minutes, with a range of 8 to 20 minutes, and is dose dependent. No intact drug can be 
detected in the plasma 3 hours after an intravenous injection. 
 
11.3.2.2. Precautions: General 
 
Fluorouracil is a highly toxic drug with a narrow margin of safety. Therefore, patients should be carefully 
supervised, since therapeutic response is unlikely to occur without some evidence of toxicity. Severe 
hematological toxicity, gastrointestinal hemorrhage and even death may result from the use of fluorouracil 
despite meticulous selection of patients and careful adjustment of dosage. Although severe toxicity is more 
likely in poor risk patients, fatalities may be encountered occasionally even in patients in relatively good 
condition. 
Therapy is to be discontinued promptly whenever one of the following signs of toxicity appears: 
• Stomatitis or esophagopharyngitis, at the first visible sign. 
• Leukopenia (WBC under 3500) or a rapidly falling white blood count. 
• Vomiting, intractable. 
• Diarrhea, frequent bowel movements or watery stools. 
• Gastrointestinal ulceration and bleeding. 
• Thrombocytopenia (platelets under 100,000). 
• Hemorrhage from any site. 
 
The administration of 5-fluorouracil has been associated with the occurrence of palmar-planter 
erythrodysesthesia syndrome, also known as hand-foot syndrome. This syndrome has been characterized as a 
tingling sensation of hands and feet which may progress over the next few days to pain when holding objects or 
walking. The palms and soles become symmetrically swollen and erythematous with tenderness of the distal 
phalanges, possibly accompanied by desquamation. Interruption of therapy is followed by gradual resolution 
over 5 to 7 days. Although pyroxine has been reported to ameliorate the palmar-planter erythrodysesthesia 
syndrome, its safety and effectiveness have not been established. 
 
11.3.2.3. Dosage and Administration 
 
All dosages are based on the patient's actual weight. However, the estimated lean body mass (dry weight) is 
used if the patient is obese or if there has been a spurious weight gain due to edema, ascities or other forms of 
abnormal fluid retention. 
 


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It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately 
as possible the optimum initial dosage of Adrucil. 
The administration of 5-fluorouracil in is given as 1200 mg/m2/day continuous infusion for 2 days (over 46 
hours) every 14 days in combination with irinotecan and oxaliplatin. 
 
11.3.2.4. Handling and Disposal 
 
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on 
this subject have been published. There is no general agreement that all of the procedures recommended in the 
guidelines are necessary or appropriate. 
Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to 
administration, whenever solution and container permit. If a precipitate occurs due to exposure to low 
temperatures, resolubilize by heating to 140°F and shaking vigorously; allow cooling to body temperature 
before using. 
 
Directions for proper use of pharmacy bulk package(Not for Direct Infusion): The 50 mL and 100 mL 
Pharmacy Bulk Packages are for use in a Pharmacy Admixture Service only. They should be inserted into a 
plastic hanging device and suspended as a unit in a laminar flow hood. Use only if clear and seal is intact and 
undamaged. 
 
Use of this product is restricted to a suitable work area, such as a laminar flow hood. Use only if clear and seal 
is intact and undamaged. Prior to entering the vial, remove the flip-off seal and cleanse the rubber closure with a 
suitable antiseptic agent. The container closure may be penetrated only one time, utilizing a suitable sterile 
transfer device or dispensing set which allows measured distribution of the contents. The date and time the vial 
was initially opened should be recorded in the space provided on the vial label. Transfer individual dose(s) to 
appropriate intravenous infusion solutions. Use of a syringe with a needle is not recommended. Multiple entries 
increase the potential of microbial and particulate contamination. 
 
The withdrawal of container contents should be accomplished without delay using aseptic technique. However, 
should this not be possible, a maximum time of 4 hours from initial closure entry is permitted to complete fluid 
transfer operations. It is recommended that the transferred fluids be used promptly. 
 
Recommended Storage Conditions after Opening: Keep under laminar flow hood at room temperature. The 
50 mL and 100 mL pharmacy bulk packages are packaged 5 vials per shelf pack. 
 
Store at room temperature 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from 
light. Retain in carton until time of use. NOTE: Although fluorouracil solution may discolor slightly during 
storage, the potency and safety are not adversely affected. 
 
11.3.3. Irinotecan 
 
Irinotecan hydrochloride injection is an antineoplastic agent of the topoisomerase I inhibitor class. Irinotecan 
hydrochloride was clinically investigated as CPT-11. 
Irinotecan hydrochloride injection is supplied as a sterile, pale yellow, clear, aqueous solution. It is available in 
two single-dose sizes: 2 mL-fill vials containing 40 mg Irinotecan hydrochloride, and 5 mL-fill vials containing 
100 mg Irinotecan hydrochloride. Each milliliter of solution contains 20 mg of Irinotecan hydrochloride (on the 
basis of the trihydrate salt), 45 mg of sorbitol NF powder, and 0.9 mg of lactic acid, USP. The pH of the 
solution has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. Irinotecan 


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hydrochloride injection is intended for dilution with 5% Dextrose Injection, USP (D5W), or 0.9% Sodium 
Chloride Injection, USP, prior to intravenous infusion. The preferred diluent is 5% Dextrose Injection, USP. 
 
Irinotecan hydrochloride is a semi-synthetic derivative of camptothecin, an alkaloid extract from plants such as 
Mappiafoetida and Camptothecaacuminata. The chemical name is (S) - 4,11 - diethyl - 3,4,12,14 - tetrahydro - 4 
- hydroxy - 3,14 - dioxo - 1H - pyrano[3',4':6,7] - indolizino[1,2 - b]quinolin - 9 - yl - [1,4'bipiperidine] - 1' - 
carboxylate, monohydrochloride, trihydrate. 
 
Irinotecan hydrochloride is a pale yellow to yellow crystalline powder, with the molecular formula 
C33H38N4O6•HCl•3H2O and a molecular weight of 677.19. It is slightly soluble in water and organic solvents. 
 
11.3.3.1. Pharmacology 
Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I 
which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its active 
metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent relegation of these single-strand 
breaks. Current research suggests that the cytotoxicity of Irinotecan is due to double-strand DNA damage 
produced during DNA synthesis when replication enzymes interact with the ternary complex formed by 
topoisomerase I, DNA, and either Irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-
strand breaks. 
 
Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from 
Irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and 
the dipiperidino side chain. SN-38 is approximately 1000 times as potent as Irinotecan as an inhibitor of 
topoisomerase I purified from human and rodent tumor cell lines. In vitro cytotoxicity assays show that the 
potency of SN-38 relative to Irinotecan varies from 2- to 2000-fold. However, the plasma area under the 
concentration versus time curve (AUC) values for SN-38 are 2% to 8% of Irinotecan and SN-38 is 95% bound 
to plasma proteins compared to approximately 50% bound to plasma proteins for Irinotecan. The precise 
contribution of SN-38 to the activity of Irinotecan is thus unknown. Both Irinotecan and SN-38 exist in an 
active lactone form and an inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the 
two forms such that an acid pH promotes the formation of the lactone, while a more basic pH favors the 
hydroxy acid anion form. 
 
Administration of Irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in 
human carcinoma xenografts of various histological types. 
 
11.3.3.2. Pharmacokinetics 
After intravenous infusion of Irinotecan in humans, Irinotecan plasma concentrations decline in a 
multiexponential manner, with a mean terminal elimination half-life of about 6 to 12 hours. The mean terminal 
elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. The half-lives of the lactone 
(active) forms of Irinotecan and SN-38 are similar to those of total Irinotecan and SN-38, as the lactone and 
hydroxy acid forms are in equilibrium. 
 
Over the recommended dose range of 50 to 350 mg/m2, the AUC of Irinotecan increases linearly with dose; the 
AUC of SN-38 increases less than proportionally with dose. Maximum concentrations of the active metabolite 
SN-38 are generally seen within 1 hour following the end of a 90-minute infusion of Irinotecan. 
Pharmacokinetic parameters for Irinotecan and SN-38 following a 90-minute infusion of Irinotecan at dose 
levels of 125 and 340 mg/m2 determined in two clinical studies in patients with solid tumors. 


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Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound to human 
plasma proteins (approximately 95% bound). The plasma protein to which Irinotecan and SN-38 predominantly 
binds is albumin. 
 
11.3.3.3. Metabolism and Excretion 
 
The metabolic conversion of Irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes 
and primarily occurs in the liver. In vitro studies indicate that Irinotecan, SN-38 and another metabolite 
aminopentane carboxylic acid (APC), do not inhibit cytochrome P-450 isozymes. SN-38 is subsequently 
conjugated predominantly by the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) to form a glucuronide 
metabolite. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme 
activity such as the UGT1A1*28 polymorphism. Approximately 10% of the North American population is 
homozygous for the UGT1A1*28 allele (also referred to as UGT1A1 7/7 genotype). In a prospective study, in 
which Irinotecan was administered as a single-agent (350 mg/m2) on a once-every-3-week schedule, patients 
with the UGT1A1 7/7 genotype had a higher exposure to SN-38 than patients with the wild-type UGT1A1 
allele (UGT1A1 6/6 genotype). SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38 in cytotoxicity 
assays using two cell lines in vitro. The disposition of Irinotecan has not been fully elucidated in humans. The 
urinary excretion of Irinotecan is 11% to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. The cumulative 
biliary and urinary excretion of Irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 
48 hours following administration of Irinotecan in two patients ranged from approximately 25% (100 mg/m2) to 
50% (300 mg/m2). 
 
11.3.3.4. Administration 
Irinotecan is administered at a dose of 180mg/m2 intravenous, diluted in 500 mL D5W and administer over 90 
minutes. Premedication with dexamethasone and a 5-HT3 blocker is recommended 30 minutes prior to 
administration; prochlorperazine may be considered for subsequent use (if needed). Consider atropine 0.25-1 
mg I.V. or Sub Q as premedication for or treatment of cholinergic symptoms (eg, increased salivation, rhinitis, 
miosis, diaphoresis, abdominal cramping) or early onset diarrhea. 
 
11.3.4. Oxaliplatin 
 
11.3.4.1. Dosage and Administration  
 
Oxaliplatin for Injection should be administered under the supervision of a qualified physician experienced in 
the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible 
only when adequate diagnostic and treatment facilities are readily available. 
 
11.3.4.2. Dosage 
Administer Oxaliplatin for Injection in combination with 5-fluorouracil every 2 weeks. Oxaliplatin for Injection 
85 mg/m2 intravenous infusion in 250-500 mL 5% Dextrose Injection, given over 120 minutes followed by 5-
fluorouracil 1200 mg/m2/day continuous infusion for 2 days (over 46 hours). 
The administration of Oxaliplatin for Injection does not require pre-hydration. Premedication with antiemetics, 
including 5-HT3 blockers with or without dexamethasone, is recommended. 
 
11.3.4.2.1. Preparation of Infusion Solution 
Reconstitution or final dilution must never be performed with a sodium chloride solution or other chloride 
containing solutions. 
 
The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for the 100 mg vial) of 
Water for Injection, USP or 5% Dextrose Injection, USP. Do not administer the reconstituted solution without 


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further dilution. The reconstituted solution must be further diluted in an infusion solution of 250-500 mL of 5% 
Dextrose Injection, USP. 
 
After reconstitution in the original vial, the solution may be stored up to 24 hours under refrigeration [2-8°C 
(36-46°F)]. After final dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at 
room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. 
 
Oxaliplatin for Injection is not light sensitive. 
 
Oxaliplatin for Injection is incompatible in solution with alkaline medications or media (such as basic solutions 
of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion 
line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any 
concomitant medication. 
 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to 
administration and discarded if present. 
 
Needles or intravenous administration sets containing aluminum parts that may come in contact with 
Oxaliplatin for Injection should not be used for the preparation or mixing of the drug. Aluminum has been 
reported to cause degradation of platinum compounds. 
 
Dosage Forms and Strengths: Oxaliplatin for Injection is supplied in single-use vials containing 50 mg or 100 
mg of Oxaliplatin as a sterile, preservative-free lyophilized powder for reconstitution. 
 
Contraindications: Oxaliplatin for Injection should not be administered to patients with a history of known 
allergy to Oxaliplatin for Injection or other platinum compounds. 
 
11.3.3.4. Warnings and Precautions 
 
Allergic Reactions: Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to Oxaliplatin 
for Injection has been observed in 2 to 3% of colon cancer patients. These allergic reactions which can be fatal, 
can occur within minutes of administration and at any cycle, and were similar in nature and severity to those 
reported with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, rarely, 
bronchospasm and hypotension. The symptoms associated with hypersensitivity reactions reported in the 
previously untreated patients were urticaria, pruritus, flushing of the face, diarrhea associated with Oxaliplatin 
infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope. 
These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and may 
require discontinuation of therapy. Drug-related deaths associated with platinum compounds from anaphylaxis 
have been reported. 
 
Neuropathy: Oxaliplatin for Injection is associated with two types of neuropathy: 
(1) An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours 
or one to two days of dosing, that resolves within 14 days, and that frequently recurs with further dosing. The 
symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually 
present as transient paresthesia, dysesthesia and hypoesthesia in the hands, feet, perioral area, or throat. Jaw 
spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed. 
The acute, reversible pattern of sensory neuropathy was observed in about 56% of study patients who received 
Oxaliplatin for Injection with 5-fluorouracil/leucovorin. In any individual cycle acute neurotoxicity was 


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observed in approximately 30% of patients. In adjuvant patients the median cycle of onset for grade 3 peripheral 
sensory neuropathy was 9 cycles in the previously treated patients the median number of cycles administered on 
the Oxaliplatin for Injection with 5–fluorouracil/leucovorin combination arm was 6. 
 
An acute syndrome of pharyngolaryngeal dysesthesia seen in 1 to 2% (grade 3/4) of patients previously 
untreated for advanced colorectal cancer, and the previously treated patients, is characterized by subjective 
sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing). Ice 
(mucositis prophylaxis) should be avoided during the infusion of Oxaliplatin for Injection because cold 
temperature can exacerbate acute neurological symptoms. 
 
(2) A persistent (> 14 days), primarily peripheral, sensory neuropathy that is usually characterized by 
paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with 
daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired proprioception). 
These forms of neuropathy occurred in 48% of the study patients receiving Oxaliplatin for Injection with 5-
fluorouracil/leucovorin. Persistent neuropathy can occur without any prior acute neuropathy event. The majority 
of the patients (80%) who developed grade 3 persistent neuropathy progressed from prior Grade 1 or 2 events. 
These symptoms may improve in some patients upon discontinuation of Oxaliplatin for injection. 
 
11.3.5. Gemcitabine 
11.3.5. 1. Premedication for Gemcitabine 
Antiemetic therapy should be administered at the physician’s discretion. A combination  of a 5-HT3 antagonist 
and dexamethasone is strongly recommended. Additionally, for delayed nausea, a combination of 
dexamethasone 4mg and ondansetron 8mg twice a day orally for three days, and prochlorperazine10 mg orally 
four times daily on as needed basis for nausea are recommended. Examples of standard antiemetics include 
ondansetron (Zofran), granisetron(Kytril), dolasetron (Anzemet), compazine, and dexamethasone. The 
dosage and route of administration will be determined by the treating oncologist based upon the given clinical 
scenario. 
 
11.3.5.2. Toxicity and Dose Modifications for Gemcitabine 
Gemcitabine dose modifications are presented in Appendix C.  
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0 for 
toxicity and Serious Adverse Event reporting (see Section 9.0). A copy of the CTCAE Version 4.0 can be 
downloaded from the CTEP home page (http://ctep.cancer.gov). All appropriate treatment areas should have 
access to a copy of the CTCAE Version 4.0. 
 
Toxicities: 
• 
Hematologic - In studies in pancreatic cancer, myelosuppression is the dose-limiting toxicity with 
gemcitabine, but <1% of patients discontinued therapy for either anemia, leukopenia, or 
thrombocytopenia.  Red blood cell transfusions were required by 19% of patients.  The incidence of 
sepsis was less than 1%.  Petechiae or mild blood loss (hemorrhage), from any cause, was reported in 
16% of patients; less than 1% of patients required platelet transfusions.  Patients should be monitored 
for myelosuppression during gemcitabine therapy and dosage modified or suspended according to the 
degree of hematologic toxicity  
• 
Gastrointestinal - Nausea and vomiting were commonly reported (69%) but were usually of mild to 
moderate severity.  Severe nausea and vomiting (World Health Organization [WHO] Grade 3/4) 
occurred in <15% of patients.  Diarrhea was reported by 19% of patients, and stomatitis by 11% of 
patients.   


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• 
Hepatic - In clinical trials, Gemcitabine was associated with transient elevations of one or both serum 
transaminases in approximately 70% of patients, but there was no evidence of increasing hepatic 
toxicity with either longer duration of exposure to gemcitabine or with greater total cumulative dose.  
Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients 
receiving gemcitabine.  Elevated transaminases are rarely of clinical significance.  
• 
Renal - In clinical trials, mild proteinuria and hematuria were commonly reported.  Hemolytic Uremic 
Syndrome (HUS) has been reported rarely (0.25%) with the use of gemcitabine.  Renal failure may not 
be reversible even with discontinuation of therapy and dialysis may be required. 
• 
Fever - The overall incidence of fever was 41%.  This is in contrast to the incidence of infection (16%) 
and indicates that gemcitabine may cause fever in the absence of clinical infection.  Fever was 
frequently associated with other flu-like symptoms and was usually mild and clinically manageable.   
• 
Rash - Rash was reported in 30% of patients.  The rash was typically a macular or finely granular 
maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities.  
Pruritus was reported for 13% of patients.   
• 
Pulmonary- In clinical trials, dyspnea, unrelated to underlying disease, has been reported in 
association with gemcitabine therapy.  Dyspnea was occasionally accompanied by bronchospasm.  
Pulmonary toxicity has been reported with the use of gemcitabine.  The etiology of these effects is 
unknown.  If such effects develop, gemcitabine should be discontinued and the patient at this stage will 
be taken off trial.  Early use of supportive care measures may help ameliorate these conditions.   
• 
Edema - Edema (13%), peripheral edema (20%), and generalized edema (<1%) were reported.  Less 
than 1% of patients discontinued due to edema.   
• 
Flu-like Symptoms - “Flu syndrome” was reported for 19% of patients.  Individual symptoms of 
fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly reported.  Fever and 
asthenia were also reported frequently as isolated symptoms.  Insomnia, rhinitis, sweating, and malaise 
were reported infrequently.  Less than 1% of patients discontinued due to flu-like symptoms.   
• 
Infection - Infections were reported for 16% of patients.  Sepsis was rarely reported.   
• 
Alopecia - Hair loss, usually minimal, was reported by 15% of patients.   
• 
Neurotoxicity - There was a 10% incidence of mild paresthesias and a <1% rate of severe 
paresthesias.   
 
11.3.6. nab-Paclitaxel 
11.3.6.1. Toxicity for nab-Paclitaxel (Abraxane™) 
Dose modifications for nab-paclitaxel are presented in Appendix C. This study will utilize the CTCAE (NCI 
Common Terminology Criteria for Adverse Events) Version 4.0 for toxicity and Serious Adverse Event 
reporting (see Section 9.0). A copy of the CTCAE Version 4.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov). All appropriate treatment areas should have access to a copy of the CTCAE 
Version 4.0. 
 
nab-Paclitaxel Toxicities 
• 
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 ABI-007 dose.  Following 
resolution of the peripheral neuropathy to acceptable levels, clinicians were able to restart ABI-007 
dosing at a lower dose level. 


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• 
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. 
• 
Sepsis  
• 
Pulmonary interstitial pneumonitis.  
 
12. Dose Modifications for Chemotherapy  
12.1. mFOLFIRINOX 
Neutrophils 
(x109/L)  
Delay of 
treatment 
Occurrence 
Dose Modifications  
 
Fluorouracil  
Irinotecan 
Oxaliplatin 
1.5 or greater  
None 
 
100% 
100% 
100% 
Less than 1.5 
on day 1 or at 
any time since 
the previous 
cycle 
 
 
 
 
Hold treatment 
for 1 week (2 
weeks if 
necessary) and 
continue at same 
doses 
1st  
100% 
150mg/m2  
100% 
2nd 
75% 
150mg/m2  
60mg/m2  
3rd 
stop treatment  
stop 
treatment  
stop 
treatment  
*Add Pegfilgrastim (Neulsata) or filgrastim at 1st incidence of ANC < 1.5 x 109/L if not already receiving it. 
If counts have not recovered after a delay of two weeks, despite appropriate supportive measures, it is 
recommended that treatment is stopped.  
 
 
Platelets (x109/l)  
Occurrence  
Dose Modifications  
Fluorouracil  Irinotecan 
Oxaliplatin 
75 or greater  
N/A  
100% 
100% 
100% 
Platelets > 75 (hold the 
treatment until 
recovery)less than 75 on 
day 1 
or a NCI-CTC grade 3/4 
thrombocytopenia since the 
previous cycle  
1st  
75%  
100% 
60mg/m2 
2nd  
50%  
150mg/m2 
60mg/m2  
3rd  
stop treatment  
stop 
treatment  
stop treatment  
 
 
 
 
 


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Adverse Event 
Occurrence  
Dose Modifications 
Febrile Neutropenia 
1st 
Decrease Irinotecan to 150mg/m2 
Grade 3 or 4 Neutropenia 
lasting > 7 days 
2nd  
Decrease Oxaliplatin to 60mg/m2 in addition to 
Irinotecan dose reduction  
Infection with Grade 3 or 4 
neutropenia 
3rd  
Stop treatment 
Grade 3 -4 
thrombocytopenia 
1st 
reduce the oxaliplatin dose to 60 mg/m²  
and the continuous 5-FU dose to 75 % of the 
original dose 
 
2nd 
reduce also the dose of irinotecan to 150mg/m2 
And the dose of continuous 5FU by an 
additional 25 % (to 50%) 
 
3rd 
Stop treatment 
 
 
 
Hepatic Impairment  
Drug 
Bilirubin mg/dl 
Dose (% of original) 
5FU 
>1.5 x ULN -  
hold treatment for investigation 
 
 
 
 
 
 
Irinotecan 
> 1.5 x ULN  
hold treatment for investigation 
 
 
 
 
 
 
Oxaliplatin 
> 1.5 x ULN 
hold treatment for investigation 
 
 
 
 
 
 
 
Renal Impairment 
CrCl 
Dose (% of original) 
5FU 
N/A 
N/A 
Irinotecan 
N/A 
limited data but not thought necessary 
Oxaliplatin 
<20 
contraindicated 
 
Diarrhea: 
NCI-CTC grade 1 or 2 diarrhea occurring between cycles does not generally necessitate dose modification, 
unless accompanied by fever or neutropenia. However, diarrhea should resolve to < grade 2 before re-treatment, 
especially with irinotecan. If the diarrhea has not resolved delay treatment by seven days and reassess. 


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The Following dose modifications below should be applied to subsequent cycles where appropriate: 
At any time since the previous cycle: 
NCI-CTC grade 3/4 - accompanied by fever and / or NCI-CTC grade 3/4 neutropenia 
Occurrence 
5FU 
Irinotecan 
Oxaliplatin 
1 
Reduce by 25% 
150mg/m2 
100% 
2 
Reduce by 50% 
150mg/m2 
60 mg/m2 
3 
stop 
stop 
stop 
 
 
12.2. nab-Paclitaxel (Abraxane™) and Gemcitabine (Gemzar®) 
 
12.2.1. Dose Modifications for Gemcitabine and/or Nab-paclitaxel 
 
E.1.1  
Doses will be reduced for hematologic and other toxicities. Dose adjustments are to be made according to the 
system showing the greatest degree of toxicity.  Toxicities will be graded using the NCI CTCAE Version 4.0. 
 
E.1.2 
Two levels of dose modifications are permitted according to the criteria below. If a toxicity requiring dose 
modification occurs following the second dose reduction of either study drug, further treatment should be 
discontinued. 
Fluorouracil 
• Where a NCI-CTC Grade 3 or 4 stomatitis occurs dose reduction of infusion will be to 75% of the original dose. 
• For a NCI-CTC Grade 3 or 4 palmer-plantar erythrodysesthesia reduce the infusion dose to 75% of the original 
dose. 
• Fluorouracil MUST be stopped in any case of angina pectoris or of myocardial infarction. 
Oxaliplatin 
• If the neurosensory toxicity is NCI-CTC Grade 1 or 2 and lasts less than seven days administer the full dose of 
oxaliplatin. If the toxicity is NCI-CTC Grade 2 and persists for more than seven days reduce the oxaliplatin dose 
to 60mg/m2.  
• Oxaliplatin should be discontinued for neurosensory toxicities NCI-CTC grade 3 or above. 
• For transient cold related dysesthesia or paresthesia without pain there is no need to delay or reduce oxaliplatin. 
• For acute laryngopharygeal dysesthesia increase the infusion time to 6 hours. 
• There are rare case reports of acute interstitial lung disease or lung fibrosis in association with oxaliplatin. 
Where an unexplained respiratory symptoms occur stop treatment until pulmonary investigations have been 
conducted to exclude an interstitial cause. 


UPCI# 13-143 
Protocol Version: 4/27/2015  
 
Page 40 of 54 
 
 
 Modifications 
Dose Levela) 
Nab-paclitaxel Dose (mg/m2)b) 
Gemcitabine (mg/m2)b) 
Study Dose 
125 
1000 
-1 
100 
800 
-2 
75 
600 
 
 A maximum of 2 dose level reductions are allowed.   
b) Dose reductions may or may not be concomitant.  Please refer to Table1 and Table2 for specific recommendations regarding dose modifications for Day 1 of 
each cycle for hematologic and non-hematologic toxicity, respectively.  Please refer to Table 3and Table 4 for specific recommendations regarding dose 
modifications within a cycle for hematologic and non-hematologic toxicities, respectively. 
 
E.1.3 
Patients experiencing study drug-related toxicities that require a delay in scheduled nab-paclitaxel or 
gemcitabine dosing for 21 days will be discontinued from further treatment in this study (except for 
peripheral neuropathy;).  When a dose reduction is required, no dose re-escalation will be permitted for the 
duration of study treatment (with the exception mentioned in  
 
Table 3, namely: on Day 15, re-escalation with granulocyte-colony stimulating factor (G-CSF) support is 
permitted, after a previous dose reduction on Day 8 of the same cycle). 
 
E.1.4 Dose Modifications at Day 1 
In the event dose modifications are required at the beginning of a cycle due to AEs or hematologic 
toxicities, doses of nab-paclitaxel and gemcitabine may be adjusted as detailed in Table1andTable2 as 
presented below: 
 
Table1:  Dose Modifications for Day 1 of Each Cycle (Hematologic Toxicity) 
Treatment day counts and toxicity 
ANC 
 
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 1 week intervals until recovery 
Key: ANC = Absolute neutrophil count. 
 
Table2:  Dose Modifications for Day 1 of Each Cycle (Non-Hematologic Toxicity) 
Non Hematologic Toxicity and/or Dose Hold with Previous Cycle 
Toxicity/dose held 
Gemcitabine+nab-paclitaxel dose this cycle 
Grade 0, 1 or 2 toxicity 
Same as Day 1 of previous cycle (except for Grade 2 cutaneous toxicity where 
doses of gemcitabine and nab-paclitaxel should both be reduced to next lower 
dose level; please refer to Section F 1.5) 
Grade 3 toxicitya) 
Decrease gemcitabine and nab-paclitaxel to next lower dose level 
Grade 4 toxicityb) 
Off protocol treatment 
Dose held in 2 previous consecutive 
cycles 
Decrease gemcitabine to next lower dose level and continue throughout the 
rest of treatment 
Key: CTCAE = Common terminology criteria for adverse events.   


UPCI# 13-143 
Protocol Version: 4/27/2015  
 
Page 41 of 54 
 
a) 
If the toxicity only affects neuropathy, then only nab-paclitaxel should be reduced. 
b) 
Pulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or a symptomatic, will be exempt from this requirement.   
 
E.1.5 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  


 
Page 42 of 54 
 
 
Table3: 
Dose Modifications for Hematologic Toxicity within a Cycle 
Day 8 
Blood Counts 
Day 8 
Nab-paclitaxel 
Day 8 
Gemcitabine 
Day 15 
Blood Counts 
Day 15 
Nab-paclitaxel 
Day 15 
Gemcitabine 
Any Day 
Nab-paclitaxel 
Any Day 
Gemcitabine 
ANC >1000 
and 
Platelets ≥75,000 
100% 
100% 
ANC 
>1000 
and 
Platelets ≥75,000 
100% 
100% 
 
 
ANC 
500-1000or 
Platelets 
50,000-
74,999 
Full Dose (treat on 
time)  
+ G-CSFa 
Full Dose (treat on 
time)  
+ G-CSFa 
ANC 
<500 
or 
Platelets <50,000 
Hold + G-CSFa 
Hold + G-CSFa 
ANC 500- 1000b 
or 
Platelets 50,000-
74,999 
Decrease dose 
by 
1 
level 
(treat on time) 
Decrease dose 
by 
1 
level 
(treat on time) 
ANC 
>1000 
and 
Platelets ≥75,000 
Return 
to 
Previous 
Dose level (treat on 
time) + G-CSFa 
Return to Previous 
Dose Level (treat on 
time) + G-CSFa 
 
 
ANC 
500-1000or 
Platelets 
50,000-
74,999 
Same Dose (as Day 8, 
treat on time) + G-CSFa 
Same Dose (as Day 
8, treat on time) + 
G-CSFa 
ANC 
<500 
or 
Platelets <50,000 
Hold + G-CSFa 
Hold + G-CSFa 
ANC 
<500a 
or 
Platelets <50,000 
Hold 
Hold 
ANC 
>1000 
and 
Platelets ≥75,000 
Decrease Day 8 dose by 
1 level (treat on time) + 
G-CSFa 
Decrease 
Day 
8 
dose by 1 level (treat 
on time) + G-CSFa 
 
 


 
Page 43 of 54 
 
Table3: 
Dose Modifications for Hematologic Toxicity within a Cycle 
Day 8 
Blood Counts 
Day 8 
Nab-paclitaxel 
Day 8 
Gemcitabine 
Day 15 
Blood Counts 
Day 15 
Nab-paclitaxel 
Day 15 
Gemcitabine 
Any Day 
Nab-paclitaxel 
Any Day 
Gemcitabine 
 
 
 
ANC 
500-1000or 
Platelets 
50,000-
74,999 
Decrease Day 8 dose by 
1 level (treat on time)  
+ G-CSFa 
Decrease 
Day 
8 
dose by 1 level (treat 
on 
time)  
+ G-CSFa 
 
 
 
 
 
ANC 
<500 
or 
Platelets <50,000 
Hold + G-CSFa 
Hold + G-CSFa 
 
 
Febrile 
Neutropenia 
(Grade 3 or 4)c 
 
 
 
 
 
Hold.  Upon 
resuming 
dosing, decrease 
to next lower 
level and do not 
reescalate 
throughout the 
rest of 
treatment. 
Hold.  Upon 
resuming dosing, 
decrease to next 
lower dose level 
and do not 
reescalate 
throughout the 
rest of treatment. 
Recurrent  
Febrile 
Neutropenia 
(Grade 3 or 4)b 
 
 
 
 
 
Decrease to next 
lower dose level 
and do not 
re-escalate 
throughout the 
rest of treatment. 
Decrease 2 dose 
levels (to 
600 mg/m2) and 
do not re-escalate 
throughout the 
rest of treatment. 
 Abbreviations:  ANC = Absolute neutrophil count; G-CSF = Granulocyte colony stimulating factor. 
• 
G-CSF is optional if descent only affects platelets. 
• 
If patients do not experience resolution of neutropenia within 21 days, despite uninterrupted G-CSF treatment, study treatment will be discontinued. 
• 
Febrile patients (regardless of neutrophil count) should have their chemotherapy treatment interrupted.  A full sepsis diagnostic work-up should be performed while continuing broad spectrum antibiotics.  If 
cultures are positive, the antibiotic may or may not be changed, depending on the sensitivity profile of the isolated organism.  Patients with persisting fever after 3 weeks, despite uninterrupted antibiotic treatment, 
will discontinue study treatment.  Febrile neutropenic patients can also receive G-CSF, in addition to antibiotic treatment, to hasten the resolution of their febrile neutropenia (following current institutional 
guidelines).  In all cases, blood counts must have returned to screening levels before resuming chemotherapy treatment.


 
Page 44 of 54 
 
E.1.6 
Dose modifications may also be made for non-hematological toxicity within a cycle as specified in Table 
4 
 
Table 4: Dose Modifications for Non-Hematological Toxicity within a Cycle 
CTCAE Grade 
Percent of Day 1  
Nab-paclitaxel+Gemcitabine Dose 
0-2 (and Grade 3 nausea/vomiting and 
alopecia) 
100%a 
3 (except nausea/vomiting and alopecia) 
Hold either one or both drugs until resolution to ≤Grade 1.  Then 
resume treatment at the next lower dose level. 
4  
Hold 
 
E.1.7 Peripheral Neuropathy 
Nab-paclitaxel treatment should be withheld in patients who experience ≥Grade 3 peripheral neuropathy.  
Gemcitabine administration can continue during this period.  Nab-paclitaxel treatment may be resumed 
at the next lower dose level in subsequent cycles after the peripheral neuropathy improves to ≤Grade 1.  
Patients experiencing peripheral neuropathy that requires a delay in scheduled nab-paclitaxel dosing for 
≥21 days will discontinue study treatment.  The time to resolution to Grade ≤1 should be the adverse 
event duration used for adverse event reporting. 
 
E.1.8 Cutaneous Toxicity 
Patients who develop Grade 2 or 3 cutaneous toxicity should have their dose reduced to the next lower 
dose level for both drugs.  If the patient continues to experience these reactions, despite dose reduction, 
treatment should be discontinued.  Patients who develop Grade 4 cutaneous toxicity should have 
treatment discontinued. 
 
E.1.9 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. 
 
E.1.10 Pulmonary Embolism 
Asymptomatic or clinically mild pulmonary embolism can be treated with low-molecular-weight heparin 
without interruption of therapy.  Moderate to severe pulmonary embolism will require permanent 
discontinuation of treatment. 
 
E.1.11 Interstitial Pneumonitis 
During study participation, patients should be carefully monitored for signs and symptoms of 
pneumonitis (ie, episodes of transient or repeated dyspnea with unproductive persistent cough or fever) 
and, if observed, immediate clinical evaluation and timely institution of appropriate management 
(emphasizing the need for corticosteroids if an infectious process has been ruled out as well as 
appropriate ventilation and oxygen support when required).  Study drug administration should be 
permanently discontinued upon making a diagnosis of interstitial pneumonitis. 
 
E.1.12 Colony Stimulating Factor Administration 
Colony stimulating factors may be given according to institutional guidelines for the treatment of 
neutropenic fever or infections associated with neutropenia and for the prevention of febrile neutropenia 
in patients with an ANC <500 cells/µL (as per Table 3) 
Patients who do not experience resolution of neutropenia within 21 days, despite uninterrupted G-CSF 
treatment, will discontinue study treatment. 
 


 
Page 45 of 54 
 
E.1.13 Prophylaxis Against Sepsis 
Due to the incidences of non-neutropenic sepsis, at the first occurrence of fever ≥38.5 °C (regardless of 
neutrophil count), institution of ciprofloxacin (500 mg orally, twice daily)—or amoxicillin/clavulanate 
(Augmentin®, 500 mg orally, 2-3 times daily) in patients with allergy to fluoroquinolones—should be 
initiated.  On their first visit, patients should be provided with enough ciprofloxacin (or the alternative 
antibiotic) for use at home, and they should be instructed to begin taking it when they first record a 
temperature of ≥38.5 °C (or if they feel they are developing a fever and a thermometer is not available).  
They should also immediately contact their physician for guidance on where to go for blood counts to be 
evaluated for sepsis as soon as possible.  Hospitalization or evaluation in the emergency room may be 
required depending on the clinical presentation. 
 
E.1.14 Hypersensitivity Reactions 
Hypersensitivity reactions are not expected with either nab-paclitaxel or gemcitabine.  If they do occur, 
minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia may require 
temporary interruption of the infusion.  However, severe reactions, such as hypotension requiring 
treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate 
discontinuation of study drug administration and aggressive symptomatic therapy. 
 
Patients who develop a severe hypersensitivity reaction should not be re-challenged. 
 
13.0. Supportive care 
 
13.1. Both Chemotherapy Regimens 
• All standard of care anti-emetics, anti-diarrheals, antibiotics are permitted.  
• Use of growth factor support as primary prophylaxis to prevent neutropenia is not prohibited. An 
ANC < 1500 on day 1 of any cycle will require the use of growth factor for all remaining cycles 
unless otherwise not indicated. Choice of growth factor is at the investigator's discretion 
• Use of an erythropoiesis-stimulating agent is NOT permitted. However it is suggested that anemia 
with a Hgb<8.0 g/dl be treated by pRBC transfusion at the investigator’s discretion. 
• Because of the risk of sepsis with gemcitabine plus nab-paclitaxel, especially in those patients who 
have biliary stents due to biliary obstruction, patients must be instructed to begin taking either 
ciprofloxacin 500mg orally (or amoxicillin /clavulanate 875 orally if allergic to ciprofloxacin or 
similar drugs) for any fever > 100. 5 deg F (38.3 C). They should then call their treating physician 
and be evaluated as soon as clinically indicated. 
• Concomitant medications should be avoided with the exception of analgesics (only acetaminophen or 
narcotics may be given for pain), chronic treatments for concomitant medical conditions, or agents 
required for life threatening medical problems. 
• No additional chemotherapy, immunotherapy, or other anti-tumor therapy is permitted during the 
study. 
 
13.2. mFOLFIRINOX 
 
13.2.1. Antidiarrheal Medications  
Patients should be instructed to begin taking loperamide (2mg) at the earliest sign of poorly-formed or loose 
stools (≤ grade 1). Oral loperamide 2mg every two hours should continue until 12 hours after the last liquid 
stool.  
 
Aggressive supportive care should be provided for patients with grade 4 ANC and ≥ grade 3 diarrhea until 
neutropenia and diarrhea resolve. Hospitalization for evaluation and management of complicated diarrhea is 
strongly recommended.  
 
13.2.2. Irinotecan-related Cholinergic Syndrome  
Lacrimation, rhinorrhea, miosis, diaphoresis, hot flashes, flushing, abdominal cramping, diarrhea, or other 
symptoms of early cholinergic syndrome may occur during or shortly after receiving irinotecan. Atropine, 


 
Page 46 of 54 
 
0.25-1.0 mg IV or SC should be used to treat these symptoms and should be used prophylactically. 
Additional antidiarrheal measures may be used at the discretion of the investigator.  
 
Combination anticholinergic medications containing barbiturates or other agents (e.g., Donnatal®) should 
not be used because these may affect irinotecan metabolism. Anticholinergics should be used with caution in 
patients with potential contraindications (e.g., obstructive uropathy, glaucoma, tachycardia, etc.).  
 
Diarrhea developing more than 24 hours after the irinotecan dose should be managed with loperamide as 
described above.  
 
13.2.3. Antiemetic Therapy 
Antiemetic therapy should be administered at the physician’s discretion. A combination  of a 5-HT3 
antagonist and dexamethasone is strongly recommended. Additionally, for delayed nausea, a combination of 
dexamethasone 4mg and ondansetron 8mg twice a day orally for three days, and prochlorperazine10 mg 
orally four times daily on as needed basis for nausea are recommended. Examples of standard antiemetics 
include ondansetron (Zofran), granisetron(Kytril), dolasetron (Anzemet), compazine, and 
dexamethasone. The dosage and route of administration will be determined by the treating oncologist based 
upon the given clinical scenario. 
 
13.2.4. Growth Factor Support 
We suggest that all patients should receive filgrastim or pegfilgrastim with all treatment cycles to prevent 
febrile neutropenic episodes . An ANC < 1500 on day 1 of any cycle will require the use of growth factor for 
all remaining cycles unless otherwise not indicated.. 
 
Use of an erythropoiesis-stimulating agent is NOT permitted. However it is suggested that anemia with an 
Hgb<8.0 g/dl be treated by pRBC transfusion at the investigator’s discretion. 
 
13.2.5. Fever  
Because of the risk of sepsis with mFOLFIRINOX, especially in those patients who have biliary stents due 
to biliary obstruction, patients must be instructed to begin taking either ciprofloxacin 500mg orally (or 
amoxicillin /clavulanate 875 orally if allergic to ciprofloxacin or similar drugs) for any fever > 100. 5 deg F 
(38.3 C). They should then call their treating physician and be evaluated as soon as clinically indicated. 
 
 
13.2.6. Management of Laryngopharyngeal Dysesthesias 
Oxaliplatin may cause discomfort in the larynx or pharynx associated with the sensation of dyspnea, anxiety, 
and swallowing difficulty. Exposure to cold can exacerbate these symptoms.  
 
Do NOT use ice chips or other forms of oral cryotherapy to decrease stomatitis in conjunction with 
oxaliplatin.  
 
Anxiolytics may be used at the physician's discretion at any time during the study. 
 
13.3. SBRT guidelines 
 
13.3.1. Tissue constraints 
Appropriate beam “nodes” or angles shall be selected to treat the primary site and areas at risk for occult 
disease spread. Careful target definition of these areas at risk is essential for optimal outcome. Beam shaping 
for treatment delivery shall be via conical or multi-leaf collimation (MLC). Treatment shall be via linear 
accelerator (LINAC) commissioned and equipped to deliver SBRT. Normal tissues and sensitive critical 
structures (e.g. duodenum, spinal cord, stomach, bowel, kidneys, liver, spleen, etc) shall be countered and 
the dose to these organs limited. See table below. 
 
Normal Tissue Constraints 


 
Page 47 of 54 
 
Organ 
Maximum Dose in 3 fractions 
Liver (700 cm3) 
15 Gy 
1/3 of total kidney volume (left and right) 
15 Gy 
Spinal Cord 
18 Gy 
Stomach 
30 Gy 
Duodenum/small bowel 
18 Gy 
 
 
The initial clinical target volume (CTV) will include all areas of measurable disease and adjacent high risk 
areas. A 1 mm margin will be added to the CTV create the initial planning target volume (PTV).  
 
13.3.2. Dose Specification, Homogeneity Considerations & Plan Evaluation 
The treatment plan used shall be based on the assessment of the dose-volume histogram (DVH) with 
attention to coverage of the planning tumor volume (PTV) and critical normal structures.  
 
 
The prescription dose is the isodose cloud that encompasses at least 95% of the PTV.  
• No more than 20% of any PTV shall receive doses >110% its prescribed dose 
• No more than 2% of any PTV shall receive <93% of its prescribed dose 
• No more than 5% of any normal tissue shall receive doses in excess of 110%of the primary PTV 
dose. 
 
13.4. On-Treatment Assessment and Post-treatment Toxicity Evaluation 
All subjects will be seen prior to each cycle of chemotherapy and completion of SBRT with toxicity 
evaluated by physical examination. Following this, follow-up will be at the discretion of the treating 
radiation oncologist. 
 
13.4.1. Stereotactic Body Radiotherapy Risks 
Short-term side effects include but not limited to skin reaction, local hair loss, fatigue, abdominal pain, 
nausea, vomiting, diarrhea, increasing liver function abnormality, GI bleeding or perforation which may 
require surgical intervention. Long term side effects are less likely to occur but if they do occur are more 
likely to be permanent. They include local hair loss, liver function abnormality, diarrhea, small bowel 
obstruction which may require surgical intervention, spinal cord injury which could result in paralysis, and 
kidney function abnormality.  
 
13.4.2 Fiducial Placement Risks 
In addition, all patients will have fiducial markers placed for localization at time of SBRT. Three to five 
soft-tissue fiducials (markers) will be placed in and/or around the tumor, at least 1cm apart. Oftentimes, 
these are placed at the time of endoscopic ultrasound and biopsy for diagnosis. If that is not the case, 
patients will be scheduled for a repeat EUS and have the markers placed prior to CT or FDG-PET/CT 
simulation. Alternatively, fiducials may be placed at the time of staging laparoscopy. The side effects of 
fiducial implantation will be similar to the biopsy of the tumor and stent placement. These include but are 
not limited to tumor seeding, infection, bleeding, pain at local area, and dislocation of the markers. 
 
13.4.3. CT Risks 
 
The subject will be exposed to radiation associated with the CT scans performed to assess response to 
therapy. CT scans are routinely performed as standard-of-care for tumor staging and to monitor response to 
therapy, and the radiation dose associated with these diagnostic scans are felt to represent minimal risk.  
 
Adverse reactions to the administration of the FDG being used for the CT scans are not expected. However, 
as with the administration of any drug, the possibility of an adverse event cannot be totally excluded. The 
subject will be monitored for adverse events, and a physician and emergency drugs and equipment will be 
available in the scanning area should a reaction occur. 


 
Page 48 of 54 
 
 
Claustrophobia:  Possible anxiety, claustrophobia, and/or temporary discomfort may occur as a result of 
being placed in the scanning devices. Subjects will be monitored and removed from the scanner if required. 
 
14.0. Statistics 
(a) 
Definition of primary endpoints: 
• Efficacy:  pathological complete response (pCR) and R0 resection.  Safety:  Grade 4 toxicity. 
 
(b) 
Definition of secondary endpoint(s): 
• R0 resection rate in locally advanced pancreatic cancer after receiving chemotherapy 
(gemcitabine/nab-paclitaxel or mFOLFIRINOX) and SBRT 
• Safety and toxicity profile will be evaluated utilizing number of grade 3 and 4 toxicities according to 
the National Cancer Institute Common toxicity Criteria for Adverse Events (NCI CTAE, v4.0) for 
the 2 chemotherapy regimens that occur after Cycle 1 Day 1. 
•  Radiological improvements will be evaluated by determining changes in density of measurable 
disease on CT at screening and post chemotherapy when scans are performed. 
• TTP and overall survival of patients. Time to progression will be defined as disease progression after 
surgical resection.   
• Ca19-9 response to neoadjuvant chemotherapy will be measured during every cycle 
• To determine correlative factors including SPARC, RM1 and SMAD4 
 
(c) 
Analytic plan for primary objectives: 
• At enrolment, patients will be randomized to one of two regimens: (1) gemcitabine+nab-paclitaxel or 
(2) mFOLFIRINOX.  All patients who receive at least one dose of their assigned regimen will be 
considered evaluable for response.  Any patient who achieves an R0 resection and the surgical 
specimen is consistent with a pCR will be considered to have experienced R0 resection with pCR.  
Toxicity will be defined as an NCI CTCAE Grade 4 or worse adverse event probably or definitely 
related to treatment. 
 
• The proportions of patients in each arm experiencing pathologic complete response and R0 resection 
will be estimated, and 95% exact binomial confidence intervals will be calculated.  The proportions 
in the two arms will be compared by means of Fisher’s exact test at α=0.1, but no significant 
difference between arms is anticipated.  The proportions of patients experiencing Grade 4 adverse 
events at least probably related to treatment will be analysed in the same fashion (although the 
difference between arms is anticipated to be larger). 
 
(d) 
Analytic plan for secondary objectives: 
• R0 resection rate will be assessed in all patients considered evaluable for the primary outcome 
measure.  Any patient in who an R0 resection is obtained will be considered to have experienced an 
R0 resection success; all other patients will be considered to have experienced an R0 resection 
failure.  The rate of R0 resection in each group will be calculated as the number of patients who have 
an R0 resection success divided by the number of patients who are evaluable for this endpoint.  The 
R0 resection rate will be compared across randomized treatment arms in the same manner as the 
primary outcome measure. 
 
• Each patient-cycle in which a grade 3 or 4 CTC AE (‘relevant toxicity’) was observed or a patient-
cycle in which no such toxicity was observed but all protocol therapy was received will be 
considered evaluable for toxicity.  The rate of each relevant toxicity will be calculated as the number 
of patient-cycles in which that toxicity was observed divided by the number of patient cycles 
considered for evaluation.  These rates will be displayed according to cycle number and randomized 
regimen.  Formal statistical testing of the toxicity rate will not be done. 
 


 
Page 49 of 54 
 
• All patients who are considered evaluable for the primary endpoint and have surgery after the third 
cycle will be considered evaluable for the assessment of changes in density. ANCOVA will be used 
to characterize the change in density, where post-treatment density is the analysis variable and pre-
treatment density is the covariate. 
 
• Time to progression (TTP) is defined as the time from enrolment until disease progression, death or 
last patient contact, whichever comes first.  A patient who dies or has disease progression will be 
considered to have experienced an event; otherwise the patient will be considered censored at last 
patient contact.  Product-limit (Kaplan-Meier) estimates of the TTP function will be calculated, 
along with 95% confidence intervals.  The log-rank test will be used to evaluate the significance of 
the difference in TTP between arms. 
 
• Overall survival (OS) is defined as the time from enrolment until death or last patient contact, 
whichever comes first.  A patient who dies will be considered to have experienced an event; 
otherwise the patient will be considered censored at last patient contact.  The analysis plan is 
identical to that of TTP. 
 
• CA-19-9 will be assessed at the start of each chemotherapy cycle.  Patients will be segregated into 
groups according to their randomized regimen.  The mean CA-19-9 level in U/ml will be calculated 
as well as the standard deviation. CA-19-9 time profiles will be compared using mixed effects linear 
(or, non-linear) models, as appropriate. 
 
• IHC staining of SPARC, RM1 and SMAD4 (high, medium or low) will be compared between arms 
by means of cumulative logit models (appropriate specifically for ordinal outcomes). 
 
(e) 
Sample size justification:   
The proportions of patients who attain R0 resection and pCR will be estimated for each arm.  A significant 
difference in the efficacy endpoint between arms is not expected; the proportion of patients achieving R0 
resection and pCR is expected to be between 0.10 and 0.15 in both arms. However, the proportion of 
patients encountering Grade 4 toxicity is expected to be much lower in the gemcitabine plus nab-paclitaxel 
arm than in the mFOLFIRINOX arm.  If the true probability of Grade 4 toxicity is 0.01 with gemcitabine 
plus nab-paclitaxel and 0.20 with mFOLFIRINOX, a direct comparison on 40 participants randomized 1:1 
using Fisher’s exact test at α=0.1 will have 62% power to reject the null hypothesis.  The expected width of 
95% confidence intervals around the probabilities of toxicity would be 0.17 (for π=0.01) and 0.38 (for π 
=0.20).  While a direct comparison is underpowered, the results will be necessary to motivate and design a 
definitive Phase III trial. 
 
15.0. Reporting of Adverse Events 
15.1. Adverse Event Definitions 
Adverse event means any untoward medical occurrence associated with the use of the drug in humans, 
whether or not considered drug related. 
 
Adverse reaction means any adverse event caused by a drug. 
 
Serious Adverse Event: Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.   Specifically, results in death, is life-threatening, requires inpatient 
hospitalization or causes prolongation of existing hospitalization, results in persistent or significant 
disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event (defined as a 
medical event(s) that may not be immediately life-threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may jeopardize the subject or may require intervention 
[e.g., medical, surgical] to prevent one of the other serious outcomes listed in the definition above.)  Any 


 
Page 50 of 54 
 
subject death within 30 days of the last dose of study drug, regardless of the causality or a secondary 
malignancy should also be recorded as a serious adverse event. 
 
Life-threatening, suspected adverse reaction.  A suspected adverse reaction is considered “life-threatening” 
if, in the view of either the Investigator (i.e., the study site principal investigator), its occurrence places the 
patient or research subject at immediate risk of death.  It does not include a suspected adverse reaction that 
had it occurred in a more severe form, might have caused death. 
 
Unexpected, suspected adverse reaction.  A suspected adverse reaction is considered “unexpected” if it is 
not listed in the general investigational plan or clinical protocol; or is not listed at the specificity or severity 
that has been previously observed and/or specified.  If an investigator brochure is not required or available, 
suspected adverse reaction is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application, as amended. “Unexpected," as used in this definition, also refers 
to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.  Any clinically important 
increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator 
brochure can also be considered unexpected.  An aggregate analysis of specific events observed in a clinical 
trial (such as known consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates those events occur 
more frequently in the drug treatment group than in a concurrent or historical control group. 
 
Suspected adverse reaction. Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event (considered “possibly related”). For the purposes of safety reporting, "reasonable 
possibility" means there is evidence to suggest a causal relationship between the drug and the adverse event. 
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug. 
 
All observed or volunteered adverse events (serious or non-serious) and abnormal test findings, regardless of 
study group or suspected causal relationship to the study drug(s) will be recorded in the subjects’ case 
histories.  For all adverse events, sufficient information will be pursued and/or obtained so as to permit 1) an 
adequate determination of the outcome of the event (i.e., whether the event should be classified as a serious 
adverse event) and; 2)  an assessment of the casual relationship between the adverse event and the study 
drug(s).   All toxicities encountered during the study will be evaluated on an ongoing basis according to the 
NCI Common Toxicity Criteria version 4.0.  
 
Adverse events or abnormal test findings felt to be associated with the study drug(s) will be followed until 
the event (or its sequelae) or the abnormal test finding resolves or stabilizes at a level acceptable to the 
Principal Investigator. 
 
In the event of an adverse event the first concern will be for the safety of the subject.   
 
Review of safety information. The principal investigator / sponsor must promptly review all information 
relevant to the safety of the drug obtained or otherwise received from foreign or domestic sources, including 
information derived from any clinical or epidemiological investigations, animal or in vitro studies, reports in 
the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory 
authorities and reports of foreign commercial marketing experience for drugs that are not marketed in the 
United States. The study sponsor must notify all participating investigators of potential serious risks, from 
clinical trials or any other source, as soon as possible. 
 
15.2. Reporting of suspected Adverse reactions  


 
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In the event of a serious adverse event, the PI, the institutional review board (per institutional reporting 
requirements),will be notified using the FDA Form 3500 MedWatch report.   
 
All events meeting the definition of a serious adverse event should be recorded on a MedWatch 3500 Form 
(http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms/UCM082725.pdf ) and 
submitted to 
1. [PI]: Nathan Bahary, MD 
a. Phone: 412-864-7764 
b. Email: baharyn@upmc.edu 
2. Local Institutional Review Board per institutional reporting requirements 
 
In addition to completing appropriate patient demographic and suspect medication information, the report 
should include as applicable the following information that is available at the time of report within the Event 
Description (section 5) of the MedWatch 3500 form: 
 
• CTCAE term(s) and grade(s) 
• current status of study drug 
• all interventions to address the AE (testing and result, treatment and response) 
• hospitalization and/or discharge dates 
• event relationship to study drug 
 
Follow-up reports:  Additional information may be added to a previously submitted report by adding to the 
original MedWatch 3500 report and submitting it as follow-up or creating supplemental summary 
information and submitting it as follow-up with the original MedWatch 3500 form. 
 
16.0. Data Safety Monitoring Plan 
Investigator/Sub-investigators, regulatory, CRS management, clinical research coordinators, clinical 
research associates, data managers, and clinic staff meet monthly in disease center Data Safety Monitoring 
Boards (DSMB) to review and discuss study data to include, but not limited to, the following: 
 
• serious adverse events 
• subject safety issues 
• recruitment issues 
• accrual 
• protocol deviations 
• unanticipated problems 
• breaches of confidentiality 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the NCI 
Common Toxicity Criteria version 4.0. All study treatment associated adverse events that are serious, at 
least possibly related and unexpected will be reported to the IRB. Any modifications necessary to ensure 
subject safety and decisions to continue, or close the trial to accrual are also discussed during these 
meetings. If any literature becomes available which changes the risk/benefit ratio or suggests that 
conducting the trial is no longer ethical, the IRB will be notified in the form of an Unanticipated Problem 
submission and the study may be terminated.  
 
All study data reviewed and discussed during these meetings will be kept confidential. Any breach in subject 
confidentiality will be reported to the IRB in the form of an Unanticipated Problem submission. The 
summaries of these meetings are forwarded to the UPCI DSMC which also meets monthly following a 
designated format. 
 


 
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For all research protocols, there will be a commitment to comply with the IRB’s policies for reporting 
unanticipated problems involving risk to subjects or others (including adverse events). DSMC progress 
reports, to include a summary of all serious adverse events and modifications, and approval will be 
submitted to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will be reviewed 
twice a year rather than monthly. 
 
Both the UPCI DSMC as well as the individual disease center DSMB have the authority to suspend accrual 
or further investigate treatment on any trial based on information discussed at these meetings. 
 
All records related to this research study will be stored in a locked environment. Only the researchers 
affiliated with the research study and their staff will have access to the research records.  
 
16.1. Subject Removal Criteria 
 
1. Development of a serious intercurrent medical illness according to the judgment of treating physician  
2. Evidence of dose-limiting toxicity if no additional dose reductions can be made 
3. Voluntary withdrawal 
4. Discretion of the clinical investigator 
5. Development of grade ≥ 4 toxicity related to experimental therapeutic 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
 
 
 
 
 


 
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