A Phase II Study of Neoadjuvant Chemotherapy With and Without Immunotherapy to CA125 (Oregovomab) Followed by Hypofractionated Stereotactic Radiotherapy & Concurrent HIV Protease Inhibitor Nelfinavir in Locally Advanced Pancreatic Cancer
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma, Resectable Pancreatic Carcinoma, Stage I Pancreatic Cancer, Stage IA Pancreatic Cancer, Stage IB Pancreatic Cancer, Stage II Pancreatic Cancer, Stage IIA Pancreatic Cancer, Stage IIB Pancreatic Cancer, Stage III Pancreatic Cancer
Sponsor: University of Nebraska

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IRB #: 441-13  
 
A Phase II Study of Neoadjuvant Chemotherapy with and without 
Immunotherapy to CA125 (Oregovomab) followed by Hypofractionated 
Stereotactic Radiotherapy and Concurrent HIV Protease Inhibitor Nelfinavir in 
Patients with Locally Advanced Pancreatic Cancer 
 
 
*Principal Investigator: 
Chi Lin, MD, PhD  
987521 Nebraska Medical Center,  
Omaha, NE 68198-7521 
Phone: 402-552-3844 
Fax: 402-552-3926 
Email: Clin@unmc.edu 
 
Secondary Investigators: 
Jean L. Grem, MD 
Michael A. Hollingsworth, PhD 
Quan P. Ly, MD 
Aaron R. Sasson, MD  
James K. Schwarz, MD  
Sarah Thayer, MD, PhD 
Lyudmyla Berim, MD 
 
 
Statistician: 
 
 
 
 
 
 
Jane Meza, PhD 
 
 
 
 
 
 
984375 Nebraska Medical Center, 
 
 
 
Omaha, NE 68198-4375 
 
 
 
 
Phone: 402-559-8407 
 
 
 
 
 
Fax: 402-559-7259 
 
 
 
 
 
Email: Jmeza@unmc.edu 
 
 
 
 
 
Study Product:       Nelfinavir (Viracept®) 
 
                          Oregovomab (Quest Pharma Tech Inc, B43.13 to CA125 IND#7112 
 
 
                                                  

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NEO-ADJUVANT SCHEMA  
(Locally Advanced Pancreatic Cancer with CA125 results ) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
wk1 
wk2 
wk3 
wk4 
wk5 
wk6 
wk7 
wk8 
wk9 
wk10 
wk11 
wk12 
wk13 
wk14 
wk15 
wk16 
wk 
17-18 
RE 
Subject 
with 
C1D1 
C1D8 
C1D15 
C2D1 
C2D8 
C2D15 
C3D1 
C3D8 
C3D15 
 
 
 
 
C4D1 
C4D8 
C4D15 
 
CO 
CA125 > 10 
C 
C 
I 
C 
C 
I 
C 
C 
I 
NFV 
NFV 
NFV 
NFV 
NFV 
C 
C 
I 
 
VE 
 
BD 
 
 
 
 
 
BD 
 
 
CT 
MRI 
 
 
BD 
SRT 
 
 
 
 
BD  
Pre-op 
restage 
OR  
ET 
 
RY 
OR 
 
wk1 
wk2 
wk3 
wk4 
wk5 
wk6 
wk7 
wk8 
wk9 
wk10 
wk11 
wk12 
wk13 
wk14 
wk15 
wk16 
wk 
17-18 
RE 
Subject with 
C1D1 
C1D8 
C1D15 
C2D1 
C2D8 
C2D15 
C3D1 
C3D8 
C3D15 
 
 
 
 
C4D1 
C4D8 
C4D15 
 
CO 
CA125 < 10 
C 
C 
 
C 
C 
 
C 
C 
NFV 
NFV 
NFV 
NFV 
NFV 
C 
C 
 
 
VE 
 
 
 
 
 
 
 
 
CT 
MRI 
 
 
SRT 
 
 
 
 
Pre-op 
restage 
OR 
RY 
Neo-Adjuvant Therapy 
C = Chemotherapy Regimen (SOC); Gemcitabine 750 (females) or 900 mg/m2 (males) IV by fixed dose rate infusion,  leucovorin 50 mg/m² IV over 30 min, and 5-FU 2700 mg/m2  
IV over 24 hrs REPEAT weekly  for 2 of 3 weeks (day 1 and 8) x 4 Cycles (RESUME C after SRT for Cycle 4) 
I = Immunotherapy and Immunologic Assessment (Res):  Oregovomab 2 mg IV over 20 min will be given every 3 weeks on day 15 x 4 Cycles (RESUME I after SRT for Cycle 4)            
BD= Blood Draw (Res) for immunologic assessment will be done Pre-chemotherapy, Prior to second infusion for the first 6 obtainable patients, Pre-SRT, Pre-surgery  
ET=Excess tumor tissue sample (Res)  postsurgical resection for CA125 > 10 arm only 
NFV = Nelfinavir (Res) 1250 mg P.O. BID to start daily the Monday of week three of the  third cycle of chemotherapy (2 weeks prior to the initiation of SRT) CONTINUE x 5 weeks 
ending the Friday 2 weeks after the end of SRT 
SRT = Stereotactic Radiotherapy (SOC)   daily Monday-Friday x 1 week to start week 11 (SOC)  
OR= Surgery (SOC) to be performed sometime during week 17-18 
Diagnosis 
H/P, Abdominal MRI, CBC, Chemistry, CA19-9, Biopsy, PET/CT, CTc/a/p 
Staging laparoscope: no peritoneal disease 
Study Related Procedures Informed Consent 
 CA125 andBlood Draw (Res) for immunological assessment 
Based on CA125 results: 

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Subject with 
C5D1 
wk1 
C5D8 
wk2 
C5D15 
wk3 
C6D1 
wk4 
C6D8 
wk5 
C6D15 
wk6 
C7D1 
wk7 
C7D8 
wk8 
C7D15 
wk9 
 
wk10 
 
wk11 
End of Study 
wk12  
CA125 > 10 
C 
C 
I 
C 
C 
I 
C 
C 
I 
 
 
 
 
BD 
 
 
 
 
 
 
 
 
 
 
BD 
 
OR 
 
Subject with 
C5D1 
C5D8 
C5D15 
C6D1 
C6D8 
C6D15 
C7D1 
C7D8 
C7D15 
CA125 < 10 
C 
C 
 
C 
C 
 
C 
C 
 
 
 
 
 
 
 
 
 
 
 
Adjuvant Therapy 
C = Chemotherapy Regimen (SOC); Gemcitabine 750 (females) or 900 mg/m2 (males) IV by fixed dose rate infusion,  leucovorin 50 mg/m² IV over 30 min, and 5-FU 2700mg/m2  
IV over 24 hrs REPEAT weekly  for 2 of 3 weeks (day 1 and 8) x 3 Cycles (Cycles 5-7)   
CA125> 10 Subjects Resume: 
I =  Immunotherapy and Assessment (Res):  Oregovomab 2 mg  IV over 20min  will be given every  3 weeks on day 15 x 3 Cycles (Cycles 5-7)              
BD= Blood Draw (Res) for immunological assessment will be done prior to restarting chemotherapy after surgery/post restaging if not resectable and 3 weeks post 
(week 12) or end of study. 
 
NOTE: If the patient has CA 125 >= 10 who is not eligible for receiving oregovomab (e.g. allergic to the drug) but eligible for the rest of treatment, this patient 
should be accrued to the part of protocol without oregovomab.  In another word, patients who have CA 125 >=10 can also be accrued and treated on the part of 
protocol without oregovomab if they cannot receive oregovomab but no contraindications to the rest of treatment. 
 
 
 
 
 
 
 
 
 
**Post-operative RECOVERY / ** Post-restaging unresectable RESUME Adjuvant Chemotherapy: 
Three cycles of chemotherapy to start when the clinician’s determine that the patient has recovered from surgery  
OR if the patient was unresectable and the clinician’s determine that chemotherapy should be resumed.   

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TABLE OF CONTENTS 
 
 
Page 
 
SCHEMA ................................................................................................................................... ii/iii 
 
1. OBJECTIVES 
......................................................................................................................1 
 
2. BACKGROUND ......................................................................................................................1 
 
3. Eligibility Criteria ..................................................................................................................11 
 
4. REGISTRATION PROCEDURES………………………………………………………..13 
 
5. TREATMENT PLAN ............................................................................................................15 
 
6. MEASUREMENT OF EFFECT ..........................................................................................28 
 
 
7. STUDY PARAMETERS .......................................................................................................30 
 
8. DRUG FORMULATION AND PROCUREMENT............................................................33 
 
9. TOXICITY REPORTING GUIDELINES ..........................................................................47 
 
10. STATISTICAL CONSIDERATIONS .................................................................................51 
 
11. RECORDS TO BE KEPT .....................................................................................................53 
 
12. PATIENT CONSENT FORM STATEMENT…………………………………………….54  
 
 
13. REFERENCES .......................................................................................................................57 
 
14. DATA FORMS  Attached  
 
APPENDICES 
 
APPENDIX A 
Criteria defining resectability status ..................................................................................62 
APPENDIX B 
Performance Status Criteria ..............................................................................................63 
APPENDIX C 
            Eligibility Criteria CRF......................................................................................................64 
      APPENDIX D 
Specimen Requirement and Measurement of Immunological Parameters………………68 
     APPENDIX E 
            NCI Common Toxicity Criteria Version 4.0 .....................................................................71 
      APPENDIX F 
            Pain Assessment Scale .......................................................................................................72 
APPENDIX G 
     MEDWATCH ……………………………………………………………………………73 
APPENDIX H 

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  Medication Information Sheet ……………………………………………………………...74 

 
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1.0 OBJECTIVES 
1.1. Primary Objectives 
1.1.1 To evaluate the efficacy of neoadjuvant chemotherapy,  (gemcitabine, leucovorin, 5-FU) 
with or without Oregovomab, followed by hypofractionated stereotactic radiotherapy (SRT) 
concurrently with nelfinavir in patients with locally advanced pancreatic cancer that is CA125 
positive (>10) or CA125 negative ( <10).  
1.2 Secondary Objectives 
1.2.1 To assess the safety of neoadjuvant chemotherapy, (gemcitabine, leucovorin, 5-FU) with 
or without Oregovomab, followed by SRT concurrently with nelfinavir in patients with locally 
advanced pancreatic cancer that is CA125 positive (>10) or CA125 negative (<10). 
1.2.2 To assess the cellular and humoral immune responses to active immunotherapy with 
Oregovomab/ monoclonal antibody in patients with pancreas cancer with CA125 level greater than 
10 undergoing chemotherapy and radiation treatments. 
1.3 Correlative Studies 
 
1.3.1 To evaluate tumor and organ motion with 4D CT and respiratory gating system and to 
evaluate the effect of tumor/organ motion on the dosimetry, local control and survival. 
1.3.2 To evaluate inter- and intra-fractional target motion with Calypso system. 
 
2.0 BACKGROUND 
2.1 Current therapy for locally advanced pancreatic cancers 
Approximately 37,000 individual in the US develop pancreatic cancers each year and almost an equal 
number of patients will die from the disease (1).  Prognosis is directly related to the extent of tumor.  The 
patients are usually classified into those with localized, locally advanced, or metastatic disease.  The 
median survivals for patients in these groups range from 11-18 months, 10-12 months, and 5-7 months, 
respectively (2).  The overall 5-year survival is less than 5%. Surgical resection offers the best chance for 
long-term survival.  However, even in patients who undergo potentially curative surgery, 5-year survival 
has in general not exceeded 20%.    
 
Because surgery alone rarely provides long-term cures, an alternative strategy is to treat pancreatic cancer 
before or after surgery with either systemic chemotherapy or combined chemo-radiation therapy. In the 
majority of studies, adjuvant therapy is administered following pancreatic resection. A US Intergroup 
study compared gemcitabine vs. infusional 5-FU chemotherapy for one month prior to and three months 
after chemoradiation (CRT) consisting of continuous infusional 5-FU as adjuvant therapy after pancreatic 
cancer resection; outcome in those with tumor located in the pancreatic head was the primary study 
endpoint (3). The gemcitabine plus CRT arm was superior to the 5-FU plus CRT arm with a median 
survival of 20.6 months vs 16.9 months and survival at 3-yr 32% vs 21%. This survival advantage came 
at a cost of appreciable toxicity, with grade 3-4 hematologic and non-hematologic toxicities occurring in 
58% and 58% of subjects, respectively. Oettle et al compared gemcitabine given at 1000 mg/m² weekly 
for 3 of 4 weeks x 6 cycles to no additional therapy in 368 patients with resected pancreatic cancer (4). 
Adjuvant gemcitabine was associated with a significant improvement in disease-free survival (13.4 vs 6.9 
months), and a trend towards improvement in overall survival (median 22.1 vs 20.2 months); 34% of those 
receiving gemcitabine were alive at 3 yr vs 20.5% with surgery alone. Grade 3-4 hematologic and non-
hematologic toxicities occurred in fewer than 5% of subjects receiving gemcitabine.  
 

 
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While these studies indicate improvement with adjuvant therapy, there is still a need to improve upon 
these results. A disadvantage of adjuvant therapy is that as many as 25% of patients never receive adjuvant 
therapy or have their treatment delayed due to post-operative complications (5-7). In an effort to increase 
the number of patients receiving adjuvant therapy, chemotherapy and radiation therapy can be 
administered pre-operatively to potential surgical candidates. Additional potential benefits of pre-
operative therapy include the delivery of therapy to well-oxygenated tissues, the potential to downstage 
tumors (particularly when the lesion is borderline resectable or unresectable because of regional factors 
such as large tumor size or involvement of the mesenteric or portal vein), and the opportunity to observe 
patients for the development of metastatic disease during therapy. After maximal tumor shrinkage and no 
interval development of metastatic disease, surgery can be considered.   
 
Preoperative chemoradiation therapy is a fairly recent approach with a theoretical advantage of improving 
the resectability.   Single center studies from MD Anderson Cancer Center and Fox Chase Cancer Center 
have demonstrated favorable histopathologic features following neoadjuvant therapy (6, 8). In both studies 
the incidence of positive resection margins and positive lymph nodes were significantly less than in a 
cohort of patients that served as controls. Multiple studies have identified the presence of positive margins 
and positive lymph nodes as significant predictors of poor outcome (9-13).  
 
Because pancreatic cancer is characterized by early dissemination of disease, use of systemic 
chemotherapy is reasonable.  A recent meta-analysis suggests that gemcitabine plus fluoropyrimdine 
combinations are superior to gemcitabine alone in the treatment of patients with metastatic pancreatic 
cancer: hazard ratio 0.90, p = 0.03 (14). We have experience with a combination of gemcitabine given 
with leucovorin-modulated 5-FU given as a 24-hour infusion weekly for two of three weeks, which is well 
tolerated 
 
The rationale for this regimen is based on preclinical studies conducted in Dr. Grem’s laboratory that 
showed the sequential administration of gemcitabine followed by either 5-fluorodoexyuridine (FdUrd) or 
5-FU resulted in more than additive cytotoxicity in both cell growth and clonogenic assays [15]. The 
combination of gemcitabine followed by FdUrd produced greater damage to nascent DNA in an alkaline 
elution assay compared to either agent alone, and the locus of interaction was DNA-directed (15). 
 
This led to the development of a Phase I clinical trial of gemcitabine given with a 24-hour infusion of 
FdUrd weekly for three of four weeks. FdUrd was selected because it displays more selective TS inhibition 
than 5-FU. Thirty-eight patients were accrued into this trial before a nation-wide shortage of 
pharmaceutical grade FdUrd led to the trial’s premature closure (16). Analysis of the hematologic toxicity 
indicated that many patients could not receive the week 3 doses due to neutropenia or thrombocytopenia. 
Therefore, a new trial was implemented that evaluated escalating doses of gemcitabine given as a 30 
minute infusion weekly for two of three weeks followed by a 24-hour infusion of 5-FU modulated by low-
dose calcium leucovorin. 
 
This trial was conducted by Dr. Grem in three parts. In part 1, the initial dose level employed gemcitabine 
at 75% of its recommended dose as a single agent (750 mg/m²), 5-FU at about 50% of its recommended 
dose as a weekly 24 hr infusion (1150 mg/m²), and low-dose leucovorin for 2 weeks out of 3. In all stages 
of the protocol, to ensure tolerability, the patient received an initial cycle of gemcitabine alone. A 
conservative dose modification scheme for gemcitabine was used in the interests of patient safety to avoid 
untoward toxicity when 5-FU was added. If tolerated, 5-FU was added cycle 2. If the gemcitabine dose 

 
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was not tolerated, the dose of gemcitabine was decreased by one or two dose levels depending on the 
severity of toxicity, and a second cycle of gemcitabine alone was given. 5-FU was added the subsequent 
cycle. The dose of 5-FU were escalated in 25% increments in cohorts of three patients up to a planned 
dose of 2250 mg/m². Since dose-limiting toxicity was not observed at 2250 mg/m², the dose of gemcitabine 
was then escalated in 20% increments. Once the maximally tolerated dose of gemcitabine was determined 
(female patients, 900 mg/m², male patients, 1080 mg/m²), additional cohorts of patients have been treated 
with 5-FU increased in 20% increments while the gemcitabine dose has been held constant. The dose of 
fluorouracil has been escalated from 2250 mg/m² up to a maximum dose of 3888 mg/m². At the highest 
dose level, two patients experienced dose-limiting hematologic toxicity the cycle in which 5-FU was 
added and a third patient experienced ataxia.  
 
Therefore, the recommended dose of 5-FU was 3240 mg/m². Thirteen patients received one or more cycles 
with gemcitabine combined with 3240 mg/m² 5-FU, including 7 female and 6 male patients. For the 
females, the gemcitabine dose was 900 mg/m² in 5 patients, 750 mg/m² in 1, and 600 mg/m² in 1. For the 
males, the gemcitabine dose was 1080 mg/m² in 4 patients, and 900 mg/m² in 2. The hematologic toxicity 
with gemcitabine combined with 5-FU 3240 mg/m² is summarized below according to gender. 
 
gemcitabine 
mg/m² 
 
WBC  
x 1000/μL 
median (range) 
 
Hemoglobin 
g/dL 
median (range) 
 
Platelets 
x 1000/μL 
median (range) 
 
Granulocytes 
/μL 
median (range) 
 
females 
600-900 
 
4.2  
(1.7 - 4.8) 
 
9.8  
(6.9 - 10.5) 
 
130 
(82 - 268) 
 
2491 
(800 - 2632) 
 
males 
900-1080 
 
2.85 
(2.1 - 4.3) 
 
9.7 
(7.2 - 11.9) 
 
81 
(50 - 152) 
 
1771 
(832 - 2100) 
 
  
females 
900 
 
4.2 
(1.7 - 4.8) 
 
9.9 
(8.4 - 10.5) 
 
131 
(82 - 268) 
 
2491 
(800 - 2632) 
 
males 
1080 
 
3.35 
(2.3 - 4.3) 
 
10.15 
(7.2 - 11.9) 
 
81 
(50 - 152) 
 
1771 
(832 - 1935) 
 
Non-hematologic toxicities were mild-moderate in severity. One patient each experienced grade 1 diarrhea 
and mucositis; grade 1 and 2 fatigue was seen in 4 and 1 patients, respectively. Two patients had grade 2 
nausea/vomiting. Overall, this regimen is well-tolerated. 
 
Analysis of the toxicity in the first nine patients enrolled in a clinical trial evaluating gemcitabine/5-
FU/leucovorin (IRB protocol # 035-04) as a component of neoadjuvant chemoradiation therapy revealed 
that the major dose-limiting toxicities during the initial two cycles of chemotherapy with gemcitabine/5-
FU/leucovorin at the recommended doses were myelosuppression (grade 4 neutropenia, n = 3) and grade 
3 mucositis (n=1).  To reduce the toxicity, the dose of gemcitabine was decreased to 750 mg/m² in females 
and to 900 mg/m² in males, and the dose of 5-FU was decreased from 3240 to 2700 mg/m².  Only one of 
11 subsequent patients experienced dose-limiting toxicity during the initial two cycles of chemotherapy 
administered prior to initiation of chemoradiation. 
 
In this clinical trial, to improve patient convenience, a single dose of leucovorin, 50 mg/m², will be given 
prior to the start of the 5-FU infusion rather than giving two doses of leucovorin on the day prior to, and 

 
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the day of, IV chemotherapy.  
 
2.2. Rational for SRT and Dose 
The recently completed phase II trial on neoadjuvant regimen in our institution includes several months 
of chemotherapy followed by 5 – 6 weeks of radiation therapy concurrent with radiation sensitizing 
chemotherapy, followed by a 4 - 6 weeks of post chemoradiation therapy break prior to surgery. 
Preliminary data from our institution indicates patients may develop disseminated disease during this 
lengthy period and thus become ineligible for surgery. Further, the chemoradiation is fairly debilitating.  
ECOG (17) conducted a phase II trial of preoperative conventional (50.4 Gy, 1.8 Gy/fraction) 
chemoradiation.  The study showed that 51% of patients had hospital admission because of toxicities.  The 
treatment-related toxicities are proportional to the irradiated volume and radiation dose.  In M.D. 
Anderson, an accelerated radiotherapy schedule using 30 Gy in 10 fractions appeared to be more tolerable 
and equally effective (18, 19).  A recent randomized trial [20] has compared preoperative short-course 
radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer.  The results 
showed no difference in actuarial 4-year overall survival (67.2% in the short-course group vs. 66.2% in 
the chemoradiation group, P = 0.960), disease-free survival (58.4% vs. 55.6%, P = 0.820), and crude 
incidence of local recurrence (9.0% vs. 14.2%, P = 0.170).  The study also reported similar late toxicity 
(10.1% vs.7.1%, P = 0.360) and higher early radiation toxicity in the chemoradiation group (18.2% vs. 
3.2%, P < 0.001).  These data suggest the equivalence in efficacy between short course and long course 
neoadjuvant therapy Koong et al. [21] has conducted a phase I study of stereotactic radiosurgery (SRS) in 
patients with unresectable pancreatic cancer.  Fifteen patients were treated at 3 dose levels (3 patients 
received 15 Gy, 5 patients received 20 Gy, and 7 patients received 25 Gy).  No Grade 3 or higher acute 
GI toxicity was observed.  In the 6 evaluable patients who received 25 Gy, the median survival was 8 
months.  All of patients had local control until death or progressed systemically as the site of first 
progression.  This study suggests the feasibility of SRS in pancreatic cancer. 
 
Following the methodology of Koong et al, one can apply the linear-quadratic formalism for radiation cell 
killing to “equate” schemes that vary the dose/fraction and number of fractions. This concept of 
biologically equivalent dose (BED) says that the total effect is given by: 





+
β
α
d
nd
1
)
(
 
where n is the # of fractions and d is the dose/fraction. The “alpha-beta ratio” characterizes the radiation 
response of a particular tissue; a higher value is indicative of a tissue that responds acutely to the effects 
of radiation. Due to their highly proliferative nature, most tumors fall into this category. Because 
prolonging the treatment time introduces a sparing (repair) effect in acutely responding tissues, there is 
significant motivation to deliver radiation in larger fractions over a shorter time.  
 
Most recently, studies have shown that SBRT with sequential gemcitabine resulted in excellent local 
control of locally advanced pancreatic cancer with acceptable side effects (20, 21). 
 
The duodenum is in closest proximity to the majority of the pancreatic head tumors, it is impossible to 
avoid treating this structure to a relatively high dose.  Koong et al.’s data suggest that it is possible to 
irradiate a small volume of duodenum to a dose of 22.5 Gy in one fraction with acceptable toxicity. 
 

 
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While the dose-fractionation scheme employed by Koong et al resulted in no significant morbidity, we 
proposed a phase I trial to test hypofractionated stereotactic radiotherapy (SRT) and concurrent HIV 
protease inhibitor Nelfinavir (radiation sensitizer) as part of a neoadjuvant regimen in patients with locally 
advanced pancreatic cancer.  We used more conservative starting dose in this study (5 Gy x 5) since a 
radiosensitizer (nelfinavir) was used to enhance the anti-tumor effect.  Dose escalation of SRT/Nelfinavir 
was as follows: 1) 5 Gy x 5/625 mg BID x 3 wk; 2) 5 Gy x 5/1250 mg BID x 3 wk; 3)6 Gy x 5/1250 mg 
BID x 3 wk; 4) 7 Gy x 5/1250 mg BID x 3 wk; 5) 7 Gy x 5/1250 mg BID x 5wk; and 6) 8 Gy x 5/1250 
mg BID x 5 wk.  Toxicity was assessed with CTCAE v3.   
 
Forty-six patients have been enrolled since October, 2008 and tolerated up to the dose level 6.  Median 
follow up is 13 months (95% CI: 3-36 months). During RT and 1.5 month post RT, ≥ grade 3 GI, 
hematologic and other toxicities were 2.6%, 2.6% and 13% respectively.  Some of the side effects during 
this period were carried over from the period of induction chemotherapy. Twelve patients had resection. 
The resection rate is 27% (12/44.) Two patients are going to be evaluated for resection in the near future.  
During postoperative period, ≥ grade 3 GI, hematologic and other toxicities were 8%, 8% and 24%, 
respectively.  The rate of ≥ grade 3 toxicity for patients at dose level 6 is (4/20) 20% which is acceptable 
per protocol. The protocol defined unacceptable toxicity is 2/3, 66% or 2/6, 33%. The median pathologic 
response scores for resected tumors were 4 (range: 0-9) with 1 complete response. The overall survival 
for patients with a resected tumor is significantly longer than the patients with an unresectable tumor (Log-
Rank p=0.03) (see figure 1 below). Among patients with unresectable tumor, the overall survival of 
patients who received ≥ 35 Gy in 5 fractions is significant longer than those who received < 35 Gy in 5 
fractions (Log-Rank p=0.002) (see figure 2 below).  We concluded that SRT dose of 40 Gy in 5 fractions 
concurrent with Nelfinavir 1250 mg BID as part of neoadjuvant regimen is safe and has survival 
advantage. It is recommended to be the dose for the phase II trial. 
 
Figure 1 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Log-Rank p=0.03 
Resected 
Unresectable
Median overall Survival: 
Resected: 20M (95% CI:12-28) 
Unresectable: 13M (95% CI:10-16) 

 
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Figure 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3 Rational for using Nelfinavir (NFV) as a radiation sensitizer 
2.3.1 Molecular Markers in pancreatic cancer and Radiosensitization  
Overexpression of EGFR and oncogenic/mutant K-Ras, and constitutive activation of the 
phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is a frequent molecular alteration in 
pancreatic cancer. Over the past decade EGFR and Ras have been shown to modulate tumor 
radiosensitivity (22-24). EGFR has a number of downstream effectors that include Ras and PI3K. EGFR- 
and Ras-associated radioresistance is mediated, at least in part, by PI3K; phosphorylated Akt (P-Akt) is a 
good marker for this effect (25). Data from University of Pennsylvania have shown that blocking PI3K-
Akt pathway enhances radiation response in vitro and in vivo (25-29).  Radiosensitization occurs in cells 
in which this pathway is constitutively activated, but does not occur in cells (such as normal tissues) in 
which this pathway is not activated (25, 26, 28).  Inhibition of this pathway, therefore, is an attractive 
approach for radiation sensitization.  
 
2.3.2 NFV as a radiation sensitizer 
Unresectable 
RT dose (7 or 8 Gy x 5) 
Unresectable 
RT dose (5 or 6 Gy x 5) 
Log-Rank p=0.0021 
Median OS: 
≥ 35 Gy: 16M (95% CI: 11-24) 
< 35 Gy: 10M (95% CI: 4-13) 

 
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Studies have shown that the HIV protease inhibitors (HPIs) interfere with PI3K-Akt signaling. These 
drugs given in combination with reverse transcriptase inhibitors are the mainstay of the current therapeutic 
regimens for HIV infected patients. The HPIs are peptidomimetics that inhibit the HIV aspartyl protease, 
a retroviral enzyme that cleaves the viral gag-pol polyprotein and is necessary for the production of 
infectious viral particles (30). It was found that Nelfinavir inhibited Akt at concentrations that are routinely 
achieved in patients. It also sensitized tumor cells both in vitro and in vivo to radiation. HPIs have been 
used continuously in patients with well-characterized pharmacokinetics. There are reports of HIV patients 
on protease inhibitors who have received radiation therapy; no increase in side effects from the radiation 
have been reported and clinical outcome may be improved (31).   
 
In summary, there is clearly strong rationale to proceed with a clinical trial of nelfinavir and radiation in 
pancreatic cancer: (a) Preclinical work demonstrates NFV results in down regulation of Akt signaling in 
cancer cells and results in radiation sensitization. (b) There is no sensitization of normal tissues to 
radiation. (c) There is a high frequency of Akt activation in pancreatic cancer. (d) NFV has been safely 
administered to HIV+ patients over the last decade with minimal side effects. 
 
2.3.3 Nelfinavir Dose Rationale and Risks  
The most common side effect with NFV is diarrhea which occurs in 40-50% of the people taking it. It is 
generally mild (WHO grade 1-2) and can be managed with over the counter anti-diarrheal agents. There 
are no reported differences in side effects in HIV patients vs. non-HIV patients (30, 32). Given that the 
risk of diarrhea is lower with the 625 mg formulation compared to the 250 mg capsules, we have chosen 
to treat patients on this protocol with the 625 mg capsules (33). The standard dose of NFV in HIV patients 
is 1250 mg BID given orally (30, 32) 
 
Other less frequently reported side effects include nausea, abdominal pain, rash, headache, fever, or 
discomfort. Patients who have been on long-term NFV (1-2 years) can have hyperlipidemia, insulin 
resistance, and fat redistribution. NFV interferes with the cytochrome p450 enzymes resulting in serum 
concentrations to be high of drugs metabolized by this pathway. These drugs include: phenytoin, 
diazepam, sildenafil, St. John’s Wort, etc. The use of these drugs will be monitored carefully.   
 
2.4 Rationale for study of  immune responses in patients with pancreas cancer  
2.4.1 CA-125 Tumor-Associated Antigen 
CA-125 is a surface glycoprotein antigen that is expressed on more than 80% of all non-mucinous 
epithelial ovarian carcinomas and occurs at elevated levels in the serum of patients with ovarian cancer 
(34).  Increased CA-125 serum levels have also been observed in patients with carcinomas of the pancreas, 
lung, colon, and other gastrointestinal tumors as well as with benign tumors. Its genetic structure has 
recently been elucidated (35) but little is known about its function. Oregovomab is an investigational drug 
previously in clinical trials as an immunotherapeutic treatment of ovarian cancer patients whose tumor 
cells express the tumor associated antigen, CA125.  The active component of Oregovomab is the activated 
murine monoclonal antibody B43.13, an IgG1κ subclass immunoglobulin that binds with high affinity 
(1.16 x 1010/M) to CA125.   
 
2.4.2 Mechanism of Action of Oregovomab 
The immune system is carefully regulated to protect the body from foreign invaders, including bacteria, 
viruses, fungi, toxins, parasites, and tumors, while avoiding autoimmune diseases and destruction of the 
unborn fetus. That the immune system confers protection against tumors is well documented, where it 

 
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functions primarily to prevent the development of tumors through a process called immune surveillance 
whereby it destroys, or rejects, tumors that have developed and express mutated or altered proteins, 
glycoproteins or glycolipids that are recognized as being foreign to the host. The fact that a patient has a 
tumor implies that the immune system has failed in this important function. 
 
A cancer continues to grow because the immune system has developed a passive relationship with the 
tumor that is referred to as “tolerance”. This state of tolerance is complex and may have one or more 
different mechanisms, including immunosuppression by the tumor, failure to recognize certain altered in 
the products produced by the tumors, or other factors. There is good scientific evidence that this state of 
tolerance can be overcome and that the immune system can be stimulated to destroy the cancer. 
Oregovomab is designed to stimulate the immune system to destroy pancreatic cancers by a unique 
mechanism. To understand how Oregovomab works, an understanding is needed of how the immune 
system is regulated and of the mechanism of tolerance. 
 
Immune responses fall into two categories, namely humoral (or antibody) responses, and cellular 
responses. Antibodies are made by B cells and are important in the protection from bacteria, viruses, and 
toxins, while cellular responses are mediated by T cells and macrophages, and are important in the 
protection from fungi, some viruses, parasites, and tumors. Both humoral and cellular immune responses 
are regulated by T cells.  
 
 
To initiate an immune response, T helper cells must be activated. This happens when the antigen is taken 
up and processed by what are referred to as antigen presenting cells. Several types of cells can function as 
antigen presenting cells, the most important of which are macrophages and dendritic cells. These cells 
take the antigen into specialized compartments within the cytoplasm; partially digest it with enzymes, and 
present small fragments of the antigen on the surface of the cell. These fragments are associated with 
specialized cell surface structures called MHC (Major Histocompatibility Complex) antigens. T cells have 
specialized receptors (T cell receptors) on them that recognize the combination of antigen fragment and 
MHC antigen. 
 
The activation of the T cell requires two types of signals. The first type of signal occurs when cell-surface 
molecules on the Antigen Processing Cell (APC) and the T cell interact physically. These interactions 
include the T cell receptor interacting with the antigen fragment-MHC antigen complex on the antigen 
presenting cell, CD8 or CD4 on the T cell interacting with the MHC Class I or Class II molecules on the 
APC, and co-stimulatory molecules (“danger signals’) such as CD28 on the T cell interacting with B7 on 
the APC, among others. The interaction of the antigen presenting cells and T cells induces the secretion 
of the second set of signals in the form of small protein molecules called a cytokines, or lymphokines, 
including IL-1, IL-12, IL-4, Tumor necrosis factor-alpha, and others.  Once this happens, the T cell is 
activated to produce a variety of additional cytokines and to undergo a number of cell divisions. Over a 
few days, the T cells mature into T helper cells which cause B cells to make IgG antibodies or cause 
macrophages and killer T cells to become activated and capable of killing cells infected with viruses or 
cancer cells. 
 
If, on the other hand, the T cell receptor interacts with antigen fragment-MHC antigen complex on an 
antigen presenting cell, but no co-stimulatory “danger signals” molecules are present, or none of the 
activating cytokines are made at the same time, then the T cell is not activated. Rather, the T cell becomes 

 
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paralyzed and may actually die. In either case, no immune response is observed because no antibody or T 
killer cells can be measured. The absence of a measurable immune response is called “tolerance”. This 
state of tolerance can occur for several reasons, including having too little or too much antigen in the 
system. Ovarian, pancreatic and other adenocarcinomas frequently make a large amount of a specialized 
antigen, CA-125, which is thought to decrease the activation of T helper cells because either there is too 
much of it in the system, it cannot be processed by antigen-presenting cells, or it does not induce co-
stimulatory danger signals.  
 
Oregovomab is a mouse monoclonal antibody that is specific for CA-125. When Oregovomab is injected 
intravenously at low doses into a patient, the antibody binds to circulating CA-125. Complexes are formed 
between the antibody and the CA-125 antigen (antigen-antibody complexes). These complexes are taken 
up by antigen presenting cells and at the same time, decrease the amount of CA-125 in the circulation. It 
is thought that the antigen-antibody complexes enhance the ability of the antigen presenting cells to 
present fragments of the CA-125 antigen on the surface of the cell and activate the antigen presenting cells 
to make co-stimulatory cell-surface molecules and cytokines. The combination of decreased amounts of 
CA-125 in the circulation and the enhanced presentation of CA-125 on activated antigen presenting cells 
results in a more efficient stimulation and activation of T helper cells. This would then result in a 
measurable immune response to CA-125 and the apparent reversal of “tolerance”.  
 
2.4.3 Rationale for giving Oregovomab concurrently with chemotherapy 
Most clinical trials with the agent have been conducted in maintenance settings when chemotherapy was 
not being administered (36, 37) and the magnitude of response in this clinical setting has proven 
inadequate to produce clinical benefit.  Several reports, however, have suggested that administration of 
Oregovomab in association with chemotherapy may result in enhanced cellular immunity relative to the 
monotherapy settings (36, 38).    
 
In 2009, Braly published a randomized phase II study in which simultaneously administered Oregovomab 
with standard chemotherapy in a first group of patients and a week after chemotherapy in the second one. 
The study showed that the arm subjected to simultaneous immuno-chemotherapy developed a better 
immune response (contrary to what was previously thought considering the immunosuppressive effects of 
chemotherapy) (39). Further studies, however, are needed to completely assess the magnitude of the 
immune response. The measure of effectiveness of an immunotherapy in the treatment of cancer has been 
fraught with the inability to successfully measure direct effect on tumor burden similar to cytotoxic 
therapies. We therefore believe in the importance of assessing the rate of positivity obtained by ELISPOT 
method against Oregovomab, disease-free survival, overall survival (up to the date fixed as the last visit 
to complete the entire population evaluation).  
 
2.4.4 Rationale for giving Oregovomab with the neoadjuvant regimen proposed in 
this study 
Since the safety profile of our neoadjuvant regimen (chemotherapy with gemcitabine and 5FU followed 
by hypofractionated stereotactic radiotherapy concurrent with Nelfinavir) has been established in our 
phase I study, it provides an ideal clinical setting to study the potential benefit of addition of Oregovomab 
into this neoadjuvant regimen.  It is possible that administration of Oregovomab with chemotherapy in 
patients with gross tumor may result in better immune responses due to more antigens being released by 
chemotherapy.  Moreover, initiation of an immune response during the neoadjuvant phase may eliminate 
distant micrometastases that are believed to exist but have not been yet detected. 

 
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2.5 Special Studies Background  
2.5.1. Rational for using real-time motion tracking during SRT 
The issue of respiratory motion has long been recognized as a major limitation in the management of 
radiotherapy patients. For patients receiving stereotactic body radiation therapy (SBRT), the dose per 
fraction is large.   Therefore, the high-dose tumor volume has to be compact.  We elect not to irradiate the 
lymphatic drainage area prophylactically since studies have shown that regional nodal failure is only 7-
10% while local and distant failure has reached 50% (40, 41). With such a compact volume, tumor position 
must be accurately assessed throughout the radiation treatment, especially for the pancreatic tumor that 
moves with respiration.   
 
Minimizing the impact of respiratory motion is essential in order to achieve further gains in the treatment 
of pancreatic disease. In this study, we will apply advanced imaging and delivery technology to provide 
added confidence in imaging and targeting. All patients will undergo a planning 4D CT. CT images will 
be reconstructed as a function of respiratory phases. End exhale images will be used for planning purposes, 
as this has been shown to be the most reproducible phase of respiration with the longest duration (42-48). 
 
The linear accelerators with SRT capabilitywill be used to deliver SRT.  For patients consented prior to 
diagnostic laparoscopy, Calypso Beacon markers will be placed during the laparoscopy.  The Calypso 
System allows for real-time tracking of tumors during cancer radiation treatment.  Calypso continuously 
tracks the position of the tumor using an innovative technology known as “GPS for the Body®.” This 
tracking technology is guided by three tiny Beacon transponders — wireless devices that each are about 
the size of a grain of rice. The transponders transmit safe radiofrequency waves that provide sub-
millimeter, real-time information about the position and movement of the tumor. 
 
For patients who consent after diagnostic laparoscopy, Calypso Beacon markers will be placed by 
Interventional Radiology. For those patients who can not use Calypso system, radio-opaque gold markers 
will be placed. The Exac Trac incorporates stereotactic x-ray capabilities for verifying target position.  For 
soft tissue targets the system is designed to be used with radio-opaque gold markers implanted near the 
target.  These markers are implanted prior to CT imaging and treatment planning, and should be placed 
close enough to the target anatomy so that they can be observed within the field of view of the x-ray 
localization system at the time of treatment. The use of implanted makers for radiotherapy localization 
has been described for a number of tumor sites, including prostate (49, 50), liver (51), lung (52, 53) and 
pancreas (54). 
 
When the Artiste and Truebeam linear accelerators are used to deliver radiation therapy, the maximum 
dimension of the tumor can be up to 10 cm.  CT on rail (Artiste) or KV cone beam CT (Truebeam) together 
with Calypso system will be used for image-guided radiation therapy. 
 
 
 
 
 
3.0  
ELIGIBILITY CRITERIA  
3.1 Inclusion Criteria  

 
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3.1.1  
Pathologically confirmed adenocarcinoma of the pancreas.  Patients have 
resectable,  borderline resectable disease, or unresectable disease with no evidence 
of distant metastases or peritoneal disease (Resectable or borderline resectable 
disease is defined in Appendix A).  The maximum dimension of the tumor must be 
≤  10 cm.  
3.1.2  
Age: Patients must be 19 years of age or older. (This is the age of consent in 
Nebraska. Pancreatic cancer does not occur in the pediatric age group.) 
3.1.3  
Karnofsky Performance Status of 60% or better. (Appendix B) 
3.1.4  
Patients who received chemotherapy > 5 years ago for malignancies other than 
pancreatic cancer are eligible, provided that chemotherapy was completed > 5 years 
ago and that there is no evidence of the second malignancy at the time of study 
entry. 
3.1.5 
Patients who received radiation therapy > 5 years ago for malignancies other than 
pancreatic cancer and whose radiation therapy field is not overlapping with the 20% 
isodose line of current radiation field are eligible, provided that radiation therapy 
was completed > 5 years ago and that there is no evidence of the second malignancy 
at the time of study entry. 
3.1.6  
All malignant disease must be able to be encompassed within a single irradiation 
field. 
3.1.7  
All patients must have radiographically assessable disease 
3.1.8 
Patients must have a ANC greater than or equal to 1500/μL and platelet count 
greater than or equal to 100,000/μL 
3.1.9 
Patients must have a serum creatinine less than or equal to 2.0 mg/dL and total 
bilirubin less than or equal to 2.0 mg/dL in the absence of biliary obstruction. If the 
patient has biliary obstruction, biliary decompression will be required. Either 
endoscopic placement of biliary stent (7 French or greater) or percutaneous 
transhepatic drainage are acceptable. Once biliary drainage has been established, 
institution of gemcitabine therapy may proceed when the total bilirubin falls to  <= 
4.0 mg/dL. Patients with biliary or gastroduodenal obstruction must have drainage 
or surgical bypass prior to starting chemoradiation. 
3.1.10 
The patient must be aware of the neoplastic nature of his/her disease and willingly 
provide written, informed consent after being informed of the procedure to be 
followed, the experimental nature of the therapy, alternatives, potential benefits, 
side-effects, risks, and discomforts. 
3.1.11 
 No prior therapy with the exception of 1 cycle of chemotherapy based on current 
diagnosis and clinical condition. 
3.1.12    
Patients must have CA125 level ≥10 to participate in the immunotherapy aspect of 
the trial and receive oregovomab. If the patient has CA125 > 10 who is not eligible 
to receive oregovomab (e.g. allergic to the drug) but is eligible for the rest of 
treatment, this patient should be accrued to the part of protocol without 
oregovomab.  
  
 
 
 

 
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3.2 
Exclusion criteria 
3.2.1 
Patients who cannot undergo staging laparoscopy. For example, this may include 
patients with a prior history of multiple abdominal operations in which laparoscopy 
may not be technically feasible or potentially harmful. The patient is eligible if they 
have a common bile duct stent adjacent to the tumor that may be used as an internal 
marker, or if the patient has already had a staging laparoscopy without marker 
implantation and the markers can be implanted (by interventional radiology) prior 
to the beginning of radiation therapy. 
3.2.2 
Patients with a known allergy to murine proteins or have had a documented 
anaphylactic reaction or allergy to any of  chemotherapy agents used in this 
protocol, oregovomab, or to antiemetics appropriate for administration in 
conjunction with protocol-directed therapy. 
3.2.3 
Uncontrolled inter-current illness including, but not limited to ongoing or active 
infection requiring intravenous antibiotics, symptomatic congestive heart failure, 
unstable angina pectoris, or serious, uncontrolled cardiac arrhythmia, that might  
jeopardize the ability of the patient to receive the therapy program outlined in this 
protocol with reasonable safety. 
3.2.4 
Pregnant and nursing women are excluded from this study because the 
chemotherapy agents, Oregovomab, Nelfinavir and abdominal radiation therapy  all 
have the potential for teratogenic or abortifacient effects. 
3.2.5 
Patients with prior malignancy will be excluded except for adequately treated basal 
cell or squamous cell skin cancer, adequately treated noninvasive carcinomas, or 
other cancers from which the patient has been disease-free for at least 5 years. 
3.2.6 
Patients with active duodenal ulcer or bleeding or history of a gastrointestinal 
fistula or perforation or other significant bowel problems (severe nausea, vomiting, 
inflammatory bowel disease and significant bowel resection). 
3.2.7 
Patients with known HIV infection, or hepatic insufficiency. 
3.2.8 
Patients who cannot take oral medications. 
3.2.9 
Patients may not be receiving or have received any other investigational agents 
during/or within 1 month prior to treatment with Oregovomab or Nelfinavir. 
3.2.10  
Patients with an active autoimmune disease (e.g., rheumatoid arthritis, systemic 
lupus erythematosus (SLE), ulcerative colitis, Crohn's Disease, multiple sclerosis 
(MS), ankylosing spondylitis). 
3.2.11 
Patients with a recognized acquired, hereditary, or congenital immunodeficiency 
disease including              cellulaimmunodeficiency’s, hypogammaglobulinemiaor 
dysgammaglobulinemia.  
3.2.12     Patients receiving the following drugs that are contraindicated with NFV 
(VIRACEPT)       will be excluded if they cannot be change or discontinued.  

 
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3.2.13   
Patients receiving the following drugs will be clinically evaluated as to whether 
dosage/medication can be changed to permit patient on study:  
 
 
 
3.3 Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
 
 
4.0 REGISTRATION PROCEDURES 
All patients with pancreatic cancer or suspicious pancreatic masses referred to the Nebraska Medical 
Center (NMC) / UNMC are evaluated in a multidisciplinary team conference. On initial presentation, a 
history and physical examination are performed, laboratory data obtained, and performance status is 
assessed. Imaging studies obtained include a high-resolution multi-detector computed tomography (CT) 
of the abdomen and pelvis as well as a chest radiograph (two views). Further imaging studies will be 
obtained as clinically indicated. Any pathologic specimens obtained at referring institutions are reviewed 
for accuracy. Patients with suspicious pancreatic masses will require pancreatic biopsy for confirmation 
of malignancy. Biopsy techniques available include percutaneous, endoscopic ultrasound guidance, and 

 
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laparoscopic. Patients without evidence of metastatic disease on imaging studies will be evaluated for 
potential resectability (NCCN Guidelines- Appendix A).   
 
Imaging studies available for use in defining resectability include CT scan (MRI scan will be done if CT 
scan is not sufficient for evaluating the resectability), endoscopic ultrasound, and laparoscopic ultrasound. 
The CT scan obtained is an imaging protocol specifically designed to evaluate the pancreas using a triple 
phase contrast scan with thin (3 mm) cross-sectional images with 3-dimensional reconstruction 
availability. CT mesenteric angiography will be obtained when clinically indicated. Endoscopic 
ultrasound and laparoscopic ultrasound will be utilized when additional information regarding tumor 
relationship with surrounding vascular structures, or when diagnostic tissue samples are required. 
 
Patients with resectable or borderline resectable pancreatic adenocarcinoma who meet the eligibility 
criteria will be offered participation in the treatment portion of this trial. More subjects will participate in 
this pre-therapy evaluation phase than will ultimately be found to be suitable candidates for the 
chemotherapy/radiation therapy.  
 
Patients without evidence of metastatic disease on imaging studies will then undergo laparoscopy to 
exclude the presence of occult metastatic disease. Routine inspection of the liver, peritoneal surfaces and 
serosa of abdominal viscera will be performed. Biopsy will be performed of suspicious lesions for 
histologic examination.  Patients without peritoneal disease will have Calypso Beacons placed around the 
pancreatic cancer during laparoscopy.  Patients who undergo a laparoscopy at an outside facility or have 
laparoscopy done prior to consent will have Beacons placed by Interventional Radiology prior to 
Radiation Therapy. When Beacons are not available, gold markers will be placed. 
 
The standard of care outside clinical trials setting for patients with localized or locally advanced pancreatic 
cancer with resectable disease is surgery followed by adjuvant therapy. In patients with locally advanced 
pancreatic cancer that is potentially resectable (provided an antitumor response is obtained) or 
unresectable, palliative chemotherapy alone or in combination with palliative radiation therapy is 
considered the standard of care.   
 
NOTE: Before patients are enrolled into the treatment portion of the study, an eligibility checklist 
(Appendix C) must be completed to verify the subject meets the eligibility and may be used as source 
documentation if it has been reviewed, signed, and dated prior to registration by the treating physician. 
 
Some insurance carrier’s may decline to cover the costs of usual medical care if the patient is participating 
in a clinical trial.  The patient will be provided assistance by the research nurse coordinator in determining 
if the insurance carrier will decline coverage.  Insurance carriers may or may not pay for study related 
expenses. The patient can then decide if they wish to participate.   
 
4.1 Eligibility Verification/Registration 
Before patients are enrolled into the study, an eligibility checklist (Appendix C) must be completed to 
verify the subject meets the eligibility criteria. Date of enrollment is defined as the date of the start of 
study treatment / first protocol related intervention. The eligibility check list will be maintained in the 
study file. 
 
Study personnel will provide the UNMC Fred & Pamela Buffett  Cancer Center PRMS office (ZIP 6805) 

 
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a copy of the signed and dated consent form for each UNMC subject registered to the protocol within 7 
days that includes the following information:  
• 
Protocol Number 
• 
Patient Identification: Patient’s name NMC medical record number 
• 
Patient demographics: gender, birth date (mm/dd/yyyy), race, ethnicity 
 
5.0 TREATMENT PLAN  
 
5.1 Draw Baseline CA125 level for research purposes Research(Res) 
Patients with a CA125 level ≥10 will participate in the immunotherapy aspect of the trial (see Section 5.5) 
and receive oregovomab. If the patient has CA125 > 10 who is not eligible to receive oregovomab (e.g. 
allergic to the drug) but is eligible for the rest of treatment, this patient should be accrued to the part of 
protocol without oregovomab.   
 
5.2 Biospecimen Samples for research purposes only (Res) 
Patients who have CA125 level ≥10 will participate in the immunotherapy and immunologic assessment 
aspect of the trial and receive Oregovomab. A Blood Draw for immunological assessment of 
Oregovomab will be done Pre-chemotherapy, Prior to second infusion for the first 6 obtainable patients, 
Pre-SRT, Pre-surgery, and then prior to restarting chemotherapy after surgery/post restaging if not 
resectable and 3 weeks post cycle 7 chemotherapy (week 12) or end of study. An excess tumor tissue 
sample for immunological assessment of Oregovomab will be obtained s after the surgical resection.  
SEE APPENDIX D for instructions. 
 
5.3 Staging laparoscopy and marker implantation Standard of Care (SOC) (day -3 to day -30) 
 
As stated above in Section 3.0, patients without evidence of metastatic disease on imaging studies will 
undergo laparoscopy to exclude the presence of occult metastatic disease. Routine inspection of the liver, 
peritoneal surfaces and serosa of abdominal viscera will be performed. Biopsy will be performed of 
suspicious lesions for histologic examination.  Patients without peritoneal disease will have placement of 
Beacons around the pancreatic cancer during the procedure if they have already consented to participate 
in the study.  The staging laparoscopy must be done within 30 days of treatment start. 
 
 
All patients CA125 positive (>10) or CA125 negative (<10) who have no peritoneal metastasis will 
undergo 4 cycles of neo-adjuvant therapy.  The CA125 must be drawn within 10 days of treatment start. 
 
Patients who undergo a laparoscopy at an outside facility or have a laparoscopy done prior to consent, will 
have Beacons placed by Interventional Radiology prior to Radiation Therapy. The Beacons will be placed 
by Interventional Radiology during chemotherapy cycles. Prophylactic antibiotics will be given as 
necessary to prevent infection.  Beacon position and geometry will be documented on a post-
chemotherapy restaging CT scan.   When Beacons are not available, gold markers will be placed. 
 
5.4 Chemotherapy (SOC)  
ASSESSMENT REMINDERS: Patients will be assessed and asked to complete a pain scale assessment 
tool (Appendix F) prior to the start of each chemotherapy cycle, 3-4 weeks post radiation, and 2-4 weeks 

 
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post-surgery. 
 
Week 1-9, Cycles 1-3 / Week 14-16, Cycle 4 / then resume Post-op/ post restaging, Cycles 5-7: 
Gemcitabine 750 mg/m² (females) or 900 mg/m² (males) IV as fixed dose rate infusion on days 1, 8 
Calcium Leucovorin 50 mg/m² IV over 30 minutes on days 1, 8 
5-Fluorouracil 2700 mg/m² IV over 24 hours starting on days 1, 8 
 
 
Post-operative RECOVERY /  Post-restaging unresectable: An additional three cycles (Cycles 5-7) of 
adjuvant chemotherapy to start when the clinician’s determine that the patient has recovered from surgery  
OR if the patient was unresectable and the clinician’s determine that chemotherapy should be resumed. 
 
 
A window of -2 up to +7 days will be allowed to start planned cycles of therapy provided all other criteria 
to restart the new cycle have been met. Appropriate dose modifications are described in Section 5.10.   
 
Week 8: Cycle 3 day 8 prior to NFV:  CT scan of the chest will be performed for restaging; an MRI 
scan of the abdomen will be done for restaging and SRT planning.  Patients with no metastasis will 
proceed with SRT. 
 
5.5 
Administration of Immunotherapy (Oregovomab) and Immunologic Assessment (Res)  
ASSESSMENT REMINDERS: If the patient has CA125 > 10 who is not eligible to receive oregovomab 
(e.g. allergic to the drug) but is eligible for the rest of treatment, this patient should be accrued to the part 
of protocol without oregovomab.  Immunologic Assessment, patients who have CA125 level ≥10 will 
participate in the immunotherapy and immunologic assessment aspect of the trial and receive 
Oregovomab. A Blood Draw (appendix D) for immunological assessment of Oregovomab will be done 
Pre-chemotherapy, Prior to second infusion for the first 6 obtainable patients, Pre-SRT, Pre-surgery, and 
then prior to restarting chemotherapy after surgery/post restaging if not resectable and 3 weeks post cycle 
7 chemotherapy (week 12) or end of study 
 
Week 1-9, Cycles 1-3 / Week 14-16, Cycle 4 / then resume Post-op/ post restaging, Cycles 5-7: 
Oregovomab 2 mg IV over 20 min (in any case no less than 15 minutes and no greater than 30 minutes) 
on day 15 x 4 Cycles. Repeat at 3 week intervals x 3 Cycles (weeks 3, 6, 9) and then post SRT Cycle 4, 
week 16. 
 
 Post-operative RECOVERY /  Post-restaging unresectable: An additional three cycles (Cycles 5-7) of 
adjuvant chemotherapy to start when the clinician’s determine that the patient has recovered from surgery  
OR if the patient was unresectable and the clinician’s determine that chemotherapy should be resumed.   
 
We will try to minimize the use of corticosteroids. Appropriate dose modifications are described in Section 
5.10.  No investigational or commercial agents or therapies other than those described in this protocol may 
be administered with the intent to treat the patient's malignancy. 
 
5.6 
Administration of Nelfinavir (NFV) (Res)  

 
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Week 9-13: Start Nelfivavir (NFV) 1250 mg orally twice daily starting the Monday of Cycle 3 day 
15(week 9), (2 weeks prior to the initiation of SRT) CONTINUE for 5 weeks to discontinue the Friday 2 
weeks after SRT has completed (day 57-91). 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential risks are 
described in Section 8.Appropriate dose modifications are described in Section 5.10.  No investigational 
or commercial agents or therapies other than those described in this protocol may be administered with 
the intent to treat the patient's malignancy. 
 
The patient will be given a “medication information sheet” at the beginning of their Nelfinavir treatment. 
The patient will also be asked to maintain documentation of medication adherence by filling out a calendar 
of when and how many tablets of Nelfinavir were taken.  The patient will be asked to bring the calendar 
back along with any leftover medication at their convenience at the end of treatment.  
 
 
Week 9-10: 
Treatment planning for Stereotactic Radiotherapy (SRT). 
 
5.7 
Stereotactic Radiotherapy (SRT) (SOC) 
Week 11: 
Start Stereotactic Radiotherapy (SRT) the total dose of 40 Gy will be delivered in 5 
Fractions over 5 consecutive days for 1 week (details of SRT are provided in Section 5.9). Continue 
Nelfinavir. 
 
Week 12: 
Stop SRT and continue Nelfinavir for 14 more days (week 12-13) 
 
5.8 
Surgery (SOC) 
Week 16-17: Restaging, a CT scan of the chest and abdomen will be performed for restaging 5-6weeks 
after completing SRT (week 16-17) to assess disease response.  An MRI scan may be performed if CT 
scan is not sufficient for assessing the resectability. 
 
If surgical resection is not possible and the clinician determines that chemotherapy should be resumed, 
patients will receive an additional three cycles of chemotherapy to start when the clinician determine that 
chemotherapy should be resumed.  
 
Week 17-18:  Surgery (if resectable or potentially resectable)  
Patients without metastasis and with resectable or borderline resectable disease will undergo definitive 
surgery. If no contraindication for surgical resection is identified, resection will be performed 6-8 weeks 
after completing SRT. At the time of surgical resection, an extensive examination of the abdomen will be 
performed to exclude the presence of metastatic disease. All operations will be performed with curative 
intent with resection of all gross tumor (ie R0 [negative margins]. Resection of adjacent involved organs 
or vascular structures will be performed as clinically indicated. Standardized histopathologic analysis of 
resected specimens will be performed. Margins to be evaluated include: common bile duct, pancreatic, 
retroperitoneal (tissue between superior mesenteric artery and duodenum), as well as tissue along the 
superior mesenteric vein and artery. Examination of regional lymphatics will be performed according to 
standard pathology techniques.  
 

 
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Upon recovery from surgery, the patients will receive three additional cycles (Cycles 5-7) of adjuvant 
chemotherapy with gemcitabine/leucovorin/5-FU.  Patients who have CA125 level ≥10 will continue to 
participate in the immunotherapy and immunologic assessment aspect of the trial and receive 
Oregovomab on day 15 of these additional 3 cycles and a Blood Draw for immunological assessment will 
be done prior to restarting chemotherapy and at the end of study (week 12 of adjuvant therapy).  
 
Patients will then be followed at 3 month intervals with a history and physical exam, CT scan of the 
chest/abdomen/pelvis, and lab work. 
 
5.9 
Details of SRT  
The SRT treatment will consist of image-guided radiotherapy. 
 
5.9.1 Patient’s positioning 
The treatment position of the patient is supine, with the arms placed above the head. The 
immobilization device (thermoplastic mask) will include total body to make sure that the 
patients’ position is the same during planning, simulation and treatment.  
 
5.9.2  Patient data acquisition. 
Treatment planning 4D CT scans are required to define tumor, clinical, and planning target 
volumes. The treatment planning 4D CT scan with IV contrast will be acquired with the 
patient in the same position and immobilization device as for treatment.  
All tissues to be irradiated will be included in the CT scan. CT scan thickness should be ≤ 
3 mm through the region that contains the primary target volumes. Conventional MRI scans 
(T1 and T2) may be included to assist in definition of target volumes.  FDG PET-CT 
information may be included in the treatment planning; no extra scans will be performed 
for study purposes.  
The GTV, CTV and PTV, and normal tissues (OAR) must be outlined on all CT slices in 
which the structures exist. 
 
5.9.3  Volumes 
Definition of volumes: 
The definition of volumes will be in accordance with the 1993 ICRU Report #50:  
 
5.9.4     Prescribing, Recording and Reporting Photon Beam Therapy.  
The Gross Tumor Volume (GTV) is defined as all known gross disease determined from 
CT, clinical information, endoscopic findings, FDG PET-CT and/or conventional MRI.  
The Integrated Tumor Volume based on CT/MRI/PET (GTVfusion) is defined as gross 
disease on the free breathing CT scan, MRI scan and FDG-PET scan.  These scans will be 
correlated by imaging fusion technique.  The volume will be delineated by the treating 
physician on the above scans separately.   The GTVCT, GTVMRI and GTVPET (if done) will 
be eventually fused together to generate GTVfusion.  Patients who have the maximal 
dimension of the GTVfusion > 8 cm will not be eligible for the study. 

 
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The Clinical Target Volume (CTV) is defined as the GTVs plus areas considered to 
contain potential microscopic disease.  In this study, we have no intension to treat the 
potential microscopic disease with SRT, therefore, the CTV is defined as GTVs (i.e. both 
the primary tumor and the lymph nodes containing clinical or radiographic evidence of 
metastases) and areas between GTVs. The integrated CTV is created with 4D CT 
information to compensate internal organ motion. 
The Planning Target Volume (PTV) will provide a margin around integrated CTV to 
compensate for the variability of treatment set-up and internal organ motion.   
5.9.5 Organs at Risk (OAR)  
The normal tissue volumes to be contoured include: 
o 
the skin surface (the tissue within the skin surface and outside all other critical 
normal structures and PTVs is designated as unspecified tissue) 
o 
spinal cord (spinal cord contours will be defined at least 5 mm larger in the 
radial dimension than the spinal cord itself, i.e. the cord diameter on any given 
slice will be 10 mm larger than the cord itself) 
o 
duodenum 
o 
stomach 
o 
liver 
o 
right kidney 
o 
left kidney 
o 
small bowels exclude duodenum 
o 
spleen  
 
5.9.6   The treatment technique. 
The linear accelerators that have SRT capability will be used to deliver SRT.  The ExacTrac 
incorporates stereotactic x-ray capabilities for verifying target position.  This consists of 
two floor mounted x-ray tubes and two opposing amorphous silicon (aSi) flat panel 
detectors mounted to the ceiling.  Each x-ray tube/detector pair is configured to image 
through the linac isocenter with a coronal field of view of approximately 18cm in both the 
superior-inferior (S-I) and left-right (L-R) directions at isocenter. For soft tissue targets the 
system is designed to be used with radio-opaque gold markers or Beacon markers 
implanted near the target.  These markers are implanted prior to CT imaging and treatment 
planning, and should be placed close enough to the target anatomy so that they can be 
observed within the field of view of the x-ray localization system at the time of treatment.  
 
Specific patient breathing characteristics is determined during 4D CT. If the breathing 
pattern is adequate, respiratory-gated delivery, which is, turning the beam on only at a 
specified phase of respiration will be determined.  This “freezes” target motion and allows 
reduction of beam margins, thereby reducing the amount of irradiated normal tissue (in this 
case, normal liver).  The Novalis system is well suited to gated delivery and has been 
evaluated extensively by Tenn et al [48].  The following is a brief procedural summary 
from that work which will be incorporated into this study: 
 
The patient is set up in the treatment room and IR reflective markers with adhesive bases 
are attached to their anterior surface so that breathing motion can be monitored. A second 

 
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set of IR reflective markers is rigidly attached to the treatment couch and used as a 
reference against which the movement of patient markers is measured. These rigidly 
mounted reflectors are also used to track couch location during the patient positioning 
process. The 3D movement of the patient’s anterior surface is tracked via the IR markers 
and the anterior-posterior (A-P) component of this trajectory is used to monitor breathing 
motion. The system plots breathing motion versus time and a reference level is specified 
on this breathing trace. This designates the point in the breathing trace at which the 
verification x-ray images will be triggered. The two images are obtained sequentially at 
the instant the breathing trace crosses this level during exhale phase. Because the patient 
is localized based on these images, the gating level is set at the same phase in the breathing 
cycle at which the planning CT data was obtained. Within each image the user locates the 
positions of the implanted markers. From these positions the system reconstructs the 3D 
geometry of the implanted markers and determines the shifts necessary to bring them into 
alignment with the planning CT. The patient is subsequently positioned according to the 
calculated shifts. Finally, a gating window (beam-on region) during which the linac beam 
will be delivered is selected about the reference level. The system can gate the beam in 
both inhale and exhale phases of the breathing cycle. Subsequent x-ray images verifying 
the location of the implanted markers locations are obtained at the gating level 
continuously during treatment. If marker positions remain within tolerance limits the target 
position may also be assumed to be correctly positioned. If they are outside the limit, the 
newly obtained images can be used to reposition the patient and maintain treatment 
accuracy. 
 
When the Artiste and Truebeam linear accelerators are used to deliver radiation therapy, 
the maximum dimension of the tumor can be up to 10 cm.  CT on rail (Artiste) or KV cone 
beam CT (Truebeam) together with Calypso system will be used for image-guided 
radiation therapy. When Beacons are not available, gold markers will be used. 
 
 
5.9.7   Dose computation. 
The treatment plan used for each patient will be based on an analysis of the volumetric 
dose, including DVH analyses of the PTV and critical normal structures. Treatment 
planning should be accomplished with multiple coplanar/noncoplanar conformal beams or 
arcs to allow for a high degree of dose conformality.  The uniformity requirement will be 
+10% -5% of the total dose at the prescription point within the tumor volume. The IMRT 
may be used if there is a benefit of decreasing tissue complications.   
 
5.9.8 
Equipment and tools.  
Beam’s Eye View techniques will be used to select the beam isocenter and direction to 
fully encompass the target volume but minimizing the inclusion of the critical organs in 
order to select the plan that minimizes the dose to normal tissues.  
 
5.9.9 
Dose specification. 
5.9.9.1 
Dose prescription. 
The prescription dose is the isodose which encompasses at least 95% of the planning target 
volume (PTV). Prescription dose to the PTVs shall be according to the following:  

 
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The gross tumor and gross lymph node metastasis will receive a total 40 Gy.  
 
DVHs must be generated for all critical normal structures (OAR): 
The dose to the kidney will require careful monitoring and kidney volumes must be defined 
on simulation fields. The percent of total kidney volume (defined as the sum of the left and 
right kidney volume) receiving 15 Gy (3 Gy per fraction) should be required to be less than 
35% of the total kidney volume.  The maximum dose to any point within the spinal cord 
should not exceed 15 Gy (3 Gy per fraction).  At least 700 ml or 35% of normal liver (entire 
liver minus cumulative GTV) should receive at total dose less than 15 Gy (3 Gy per 
fraction).  The maximum point dose to the stomach or small bowel except duodenum 
should not exceed 80% of prescription dose.  An isodose distribution of the treatment at 
the central axis indicating the position of kidneys, liver and spinal cord is required.  
 
5.9.9.2 
Dose recording. 
 
The reported doses for each PTV shall include the prescription dose as well as the 
maximum point dose, % target volume receiving > 110% and >115% of its prescribed dose 
and the % target volume receiving < 93% of the prescribed dose, and the mean dose to the 
PTV. Doses to the organs at risk will also be recorded. 
 
5.9.9.3      Dose homogeneity. 
No more than 20% of any planning target volume (PTV) will receive >110% of its 
prescribed dose. No more than 1% of any planning target volume (PTV) will receive <93% 
of its prescribed dose. No more than 1% or 1 cc of the tissue outside the PTVs will receive 
>110% of the dose prescribed to the primary PTV. 
 
5.9.10   
Fractionation schedule. 
 
The total dose of 40 Gy will be delivered in 5 Fractions over 5 consecutive days. 
 
5.9.11       Treatment Verification. 
The location of the implanted markers will be verified on daily x-rays. 
 
5.9.12       Quality Assurance Documentation 
A copy of the daily treatment record will be maintained in the radiation oncology 
department.  Isodose distribution at the central axis will be recorded. Exact track IGRT 
data will be collected. Breath gating will be used and data will be collected. 
 
5.9.13      Radiation modification for hematologic toxicity 
Blood counts will be measured once weekly. Radiation will not be started if the AGC is < 
1000/μl and platelets are < 50,000/μl, and the start of radiation will be delayed until the 
blood counts are above this level.  
 
5.10 
Dose Modifications (The NCI Common Toxicity Criteria version 4.0, APPENDIX E, 
will be used, available at http://ctep.cancer.gov/reporting/ctc_v40.html). 
 
5.10.1 Chemotherapy  

 
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For all cycles, the planned treatment dosing may be either interrupted or omitted for 
significant treatment-related toxicities occurring on the day of or in the prior 24 hr of 
planned therapy: platelet count < 25,000/μL, AGC < 500/μl, grade 2 or worse non-
hematologic toxicity (excluding nausea & vomiting on sub-optimal anti-emetic therapy, 
alopecia, elevated transaminases). 
 
At the start of each new cycle, dose adjustments may also be made based upon significant 
toxicities occurring at any time in the previous cycle. 
 
 
 
 
5.10.2 Initiation of Next Cycle of Gemcitabine/5-FU/LV 
The next treatment cycle will commence 22 days after the start of the prior cycle provided 
that the absolute granulocyte count is greater than or equal to 1500/μl, the platelet count is 
greater than or equal to 75,000/μl, and all clinically significant treatment-related non-
hematologic toxicities have resolved to no more than grade 1 in severity. If multiple 
toxicities have been seen in the preceding cycle, the dose administered should be based on 
the most severe toxicity experienced. 
 
5.10.3 Dose Reductions for Hematologic Toxicity Occurring During the Prior Cycle  
The dose-limiting toxicity of gemcitabine is myelosuppression, while grade 4 
myelosuppression with a weekly 24-hr infusion of 5-FU/LV is uncommon. Therefore, the 
dose of gemcitabine will be preferentially reduced for myelosuppression. A 1-week delay 
will be allowed to permit recovery of counts, then the patient should be treated according 
to the Dose Modification table below. The dose of LV will not be adjusted for 
myelosuppression. 
 
 
Therapy (Tx) 
delay 
 
Day 
 
AGC on Tx day  
(/μL) 
 
Plt on Tx 
day 
(x10/μL) 
 
AGC nadir 
(/μL) 
 
Plt nadir 
(x10/μL) 
 
Gemcitabine 
Dose 
 
5-FU 
Dose 
 
No 
 
22 
 
>/= 1500& 
 
 >/= 75 
 
>/= 500 & 
 
 >/= 25 
 
Same 
 
Same 
 
No 
 
22 
 
 >/=1500 
& 
 
 >/=75 
 
< 500 or 
 
< 25 
 
Decrease 20% 
 
Same 
1 week 
29 
 >/=1500 
& 
 >/=75 
 
>/= 500 & 
 
>/=25 
 
Same 
 
Same 
1 week 
29 
 >/=1500 
& 
 >/=75 
 
< 500 or 
 
< 25 
 
Decrease 20% 
 
Same 
 
1 week 
 
29 
 
1000-1499 or 
 
50-74.9 
 
>/= 500 & 
 
>/=25 
 
Decrease 20% 
 
Same 
 
1 week 
 
29 
 
1000-1499 or 
 
50-74.9 
 
< 500 or 
 
< 25 
 
Decrease 40% 
 
Same 
 
1 week 
 
29 
 
< 500 or 
 
< 50 
 
Any 
 
Any 
 
Hold* 
 
Hold* 
 
During the neoadjuvant period, if chemotherapy cannot be resumed after a one-week delay, 
then the patient should proceed to NFV and SRT once the AGC is 1000/μL or higher and 
the platelets are 50,000/μL or higher. 
 
 

 
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5.10.4 Dose Reductions for Post-Operative Cycles of Gemcitabine/5-FU/LV 
Hematologic Toxicity  
 
 
Day 
 
AGC on Tx day 
(/μL) 
 
Plt on Tx day 
 (x10/μL) 
 
AGC nadir 
(/μL) 
 
 
Plt nadir 
(x10/μL) 
 
Gemcitabine  
Dose 
 
5-FU 
Dose 
 
22 
 
  >/= 1500  & 
 
  75 
 
>/= 500 & 
 
>/= 25 
 
Same 
 
Same 
 
22 
 
  >/= 1500 & 
 
  >/= 75 
 
< 500 or 
 
< 25 
 
Decrease 20% 
 
Same 
 
 
 
Therapy delay 
 
Day 
 
AGC (/μL) 
Platelets 
(x10/μL) 
 
Gemcitabine 
 Dose  
 
 
5-FU  
Dose 
 
29 
 
<1500 or 
 
<75 
 
Delay 1 week 
 
Delay 1 week 
 
36 
 
1000-1499  or 
 
50-74.9 
 
Decrease 20% 
 
Same 
 
36 
 
< 1000 
 
< 50 
 
Hold 
 
Hold 
 
43 
 
1000-14  or 
 
50-74.9 
 
Decrease 40% 
 
Same 
 
43 
 
< 1000 or 
 
< 50 
 
Discontinue 
 
Decrease 20% 
 
5.10.5   Dose Modifications for Treatment-Related Non-Hematologic Toxicity 
Occurring the Prior Cycle of Gemcitabine/5-FU/LV 
The dose of 5-FU will be preferentially decreased for treatment-related mucositis or 
diarrhea. It will also be decreased for subjects who have recovered from treatment-related 
initial cardiotoxicity with preventive anti-angina therapy (calcium channel agonists, beta-
blockers and nitrates).  If mucositis or diarrhea recurs despite the 5-FU dose reduction, then 
the dose of Gemcitabine will also be decreased the subsequent cycle. The dose of 
Gemcitabine will be preferentially reduced for side effects that are primarily associated 
with Gemcitabine and uncommon with 5-FU (e.g., pulmonary, renal). If the patient 
develops signs of microangiopathic hemolytic anemia, Gemcitabine should be 
discontinued. Dose reduction for grade 3 nausea/vomiting will only be made if adequate 
anti-emetics were used. If anti-emetic therapy was suboptimal, adjust the antiemetic 
regimen and try the same chemotherapy doses.  
 
 
Non-Hematologic Toxicity 
 
Toxicity  
Type 
 
Toxicity 
Grade 
 
Week 2 Tx held 
for toxicity? 
 
Gemcitabine Dose  
 
5-FU Dose   
 
Diarrhea or 
 
2 
 
No 
 
 
Same 
 
Same  

 
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Mucositis 
 
2 
 
Yes 
 
Same unless toxicity 
recurs despite 5-FU 
decrease, then 
decrease 20% 
 
Decrease 20% 
 
3 
 
Either 
 
Same unless toxicity 
recurs despite 5-FU 
decrease, then 
decrease 20% 
 
Decrease 20% 
 
 
Other 
 
2 
 
No 
 
Same 
 
Same  
 
2 
 
Yes 
 
Same unless toxicity 
recurs despite 5-FU 
decrease, then 
decrease 20% 
 
Decrease 20% 
 
3 
 
Either 
 
Same unless toxicity 
recurs despite 5-FU 
decrease, then 
decrease 1 level 
 
Decrease 20% 
 
 
5.10.6  Dose Modifications for NFV 
Because the duration of nelfinavir therapy is limited, there are no planned dose 
modifications  for grade 1-2 toxicities attributed to nelfinavir. In the event of grade 3 or 
worse toxicity attributed to nelfinavir, the drug will be held until the toxicity is grade 2 or 
less in severity, then the drug will be resumed at 650mg PO BID. 
 
5.10.7  Dose Modification for SRT  
Because only 5 daily doses of SRT are planned, the radiation will be interrupted only if the 
patient experiences grade 3 or worse non-hematologic toxicity or grade 4 hematologic 
toxicity during the period in which SRT is administered. CBC and differential will be 
measured pre- and post-SRT. 
 
 
 
 
 
 
5.10.8  Treatment of Allergic Adverse Events/ Dose Modifications for Oregovomab 
The dose of Oregovomab will be administered by qualified, experienced nursing personnel 
under the supervision of a physician via a slow intravenous infusion to the patient in an 
appropriate treatment area.  
An emergency crash cart will be present in the treatment area for immediate use in case of 
a life-threatening allergic reaction such as an anaphylactic reaction. The crash cart will 
contain instruments and medications in working order and within expiration dates suitable 
for the management of medical emergencies with particular reference to anaphylactic 
reactions, which may be associated with the administration of Oregovomab.  
A physician will be immediately available for emergency treatment of the patient in the 
event of such a life-threatening reaction. The patient will then be continuously monitored 
until they are stabilized.  

 
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A physician will be present during the infusion period for patients who have previously 
experience NCI Common Toxicity Criteria Grade 2 allergic events, specifically 
bronchospasm, and subsequently receive additional doses of study medication. 
Patients who experience NCI Common Toxicity Criteria Grade 3 or 4 allergic reactions 
will receive no further infusions of the study medications but will be followed for outcome. 
5.11 
 Supportive Care Guidelines 
5.11.1 Prophylactic Anti-Emetic Premedication 
Patients must be pre-medicated for nausea & vomiting with the following antiemetic 
regimens as outlined below. These recommendations follow the ASCO guidelines for the 
use of anti-emetic therapy (55):  
 
Gemcitabine/LV/5-FU:  Dexamethasone 8 mg PO (or equivalent) 30 min prior to 
gemcitabine 
 
Radiation to upper abdomen:  ondansetron 8 mg or granisetron 2 mg PO daily (or 
equivalent) < 1 hr prior to radiation, and Prilosec 20 mg PO daily(or equivalent) < 1 hr 
prior to radiation.   
 
Alternative anti-emetic agents: 
• palonsetron 0.25 mg IV pre-therapy (or equivalent) 
• prochlorperazine 5-10 mg PO or 5-10  mg IV q 6-8  hr 
• promethazine 12.5-25 mg PO/PR/IM/IV q 4-6 hr 
• lorazepam 1-2.5 mg PO or IV given the night before and just after chemo 
• ondansetron 8 mg PO or IV  
 
5.11.2 Diarrhea 
Patients will be instructed to begin taking loperamide after the first poorly formed or loose 
stool or first episode of 2 or more bowel movements in one day. Loperamide should be 
taken in the following manner:  
 
*4 mg at the first onset of diarrhea 
*then, 2 mg every 2 hours around-the-clock until diarrhea-free for at least 
12 hours 
 
*Patients may take loperamide 4 mg every 4 hours during the night 
 
*Loperamide should not be taken prophylactically 
Patients must notify the research team as to when they initiated loperamide therapy. If 
diarrhea persists despite loperamide therapy, then the patient should be evaluated for the 
need for IV fluid & electrolyte replacement. 
 
 
Alternative anti-diarrhea agents: 
• Somatostatin analog (Octreotide7) 100 - 500 mcg SC/IV tid; maximum daily dose 
= 1500 mcg/day; alternatively, somatostatin analog may be given at 25-50 
mcg/hour as a continuous IV infusion. 

 
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• Atropine/diphenoxylate which is available as either a 0.025/2.5 tab, or 0.025/2.5 
per 5 mL liquid. Patients should take 1-2 tabs PO tid or qid or 5-10 mL PO tid/qid. 
• Atropine/difenoxin (Motofen7) 0.025/1 tab; 2 tabs PO x 1, then 1 tab PO q 2-4 hr 
(max 8 tabs per day) 
• Paregoric: (an antidiarrheal opiate): 5 - 10 mL ORALLY 1-4 times daily: maximum 
40 mL/day 
• OTC meds: bismuth subsalicylate 262 mg tabs: 2 tabs PO q 1 hr prn; maximum 
4200 mg/24 hr 
 
5.11.3 Stomatitis 
Mild symptoms will be treated with topical antiseptic & analgesic agents. Various versions 
of "magic mouthwash" exist, and represent a combination product for the topical treatment 
of mild oropharyngeal pain. Such mouthwashes usually consist of viscous lidocaine, 
diphenhydramine, aluminum and magnesium hydroxide, 70% sorbitol, and orange 
flavoring. Both viscous lidocaine and diphenhydramine have local anesthetic properties, 
while the aluminum hydroxide component of Maalox has a beneficial drying property. 
Patients with severe pain require systemic narcotic analgesics. Topical anti-fungal agents 
will be added as clinically indicated. More severe symptoms will require all of the above 
as well as stronger analgesic agents & admission to hospital for IV fluid & electrolyte 
replacement if dehydrated.  
 
5.11.4 Requirement for Venous Access 
Central venous access is required for protocol participation. A previously placed central 
venous access device that is functioning properly (free infusion of saline, unimpeded blood 
return, good condition of external appliance, no recent history of device infection or 
thrombosis) can be used. Should the patient require a central venous access, an implanted 
port central venous access device will be placed (e.g. a Medi-Port, Port-a-Cath, Power Port) 
after appropriate informed consent has been obtained. Other aspects of catheter/port  
management will be in accordance with standard nursing clinic central venous port 
procedures.  
 
5.11.5 Treatment of Fever & Neutropenia  
Subjects developing a fever of 100.5º C or higher will have a CBC with WBC differential 
obtained along with a history & physical examination to look for signs of infection.If the 
ANC is < 500/μL, the patient will be treated with empiric antibiotic therapy as an inpatient 
& undergo appropriate radiographic & laboratory investigation for sources of infection, & 
development of a specific treatment plan. Fever & neutropenia occurring during a treatment 
cycle will require interruption of chemotherapy. The patient may resume chemotherapy at 
the start of the next scheduled cycle if therapy for infection has been completed & the 
patient meets other criteria for starting a new cycle 
 
If the ANC is between 500-1000/μL, antibiotic therapy will be instituted if there is clinical 
suspicion of an infection. Daily CBCs with differentials will be obtained if the patient 
remains febrile. 
 

 
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If the ANC is > 1000/μL, & there is no clinical evidence of an infection, then therapy may 
resume. 
 
5.11.6 Use of Leukocyte Colony-Stimulating Factors and Erythropoetin 
Colony stimulating factors (CSFs) will be used as clinically indicated according to ASCO 
guidelines (56).  Use of any CSFs must be discontinued at least 24 hours prior to initiation 
of the next cycle of chemotherapy & must be documented in the patient record. Epoetin 
will be used as clinically indicated according to ASCO guidelines (57).  
 
5.11.7 Pancreatic Enzyme Replacement 
Patients with symptoms of pancreatic insufficiency should receive pancreatic enzyme 
supplement.  
 
5.11.8    Nutritional Supplementation 
Patients will be evaluated by a nutritionist to review their caloric needs and daily caloric 
intake. Patients will be encouraged to supplement their nutrition with a high-protein, low 
fat nutritional drink during the neoadjuvant therapy phase of the trial.  
 
Strong consideration should be given for early, elective placement of an enteral feeding 
tube if the patient has lost 10% or more of their body weight.  
 
5.12 Duration of Study 
We estimate that there will be about 66 patients enrolled into of this protocol treated over a 5 year 
period 
 
5.13 Duration of Follow up 
If the patient undergoes surgical resection, after completing the three planned cycles of adjuvant 
chemotherapy, the patient will then be seen every 3 months for the 1st year and every 4 months for 
2nd year, then every six months thereafter. The patients will be assessed for long term toxicity from 
combination of NFV, chemotherapy, immunotherapy and radiation. Restaging radiographic scans, 
CBC and chemistry panel will be performed at each of these visits as part of standard of care. 
 
 
Post-trial Assessments 
Patients who go off study treatment at any time during the trial will be followed for 30 days after 
the last day of treatment or until other disease-related treatment begins. For all patients, drug-
related SAEs and AEs will be followed until baseline or ≤ grade 1 levels. Patients may refuse to 
participate in the post-trial assessments.  
 
 
 
 
5.14  Criteria for Removal from Study 
5.14.1  Progression of Disease 

 
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5.14.2 If at any time the constraints of this protocol are detrimental to the patient's 
wellbeing, or if the patient is unable to comply with the requirements of the protocol, the 
patient will be removed from protocol therapy. In this event, the reason(s) for withdrawal 
will be documented. 
5.14.3 If the patient experiences an adverse reaction that, in the opinion of the investigator, 
necessitates the removal of the patient from the study, including any unresolved serious 
adverse event.   
5.14.4 Any patient who suffers a serious systemic allergic response or severe degree of 
intolerance to the study medication will be withdrawn from further study treatment but will 
be followed up for a period of three years following treatment. 
5.14.6 Development of intercurrent medical problems that would make continued protocol 
therapy detrimental to the patient’s safety. 
5.14.7 There is concurrent illness or other reasons that would, in the opinion of the 
investigator, affect assessment of clinical status or conduct of the study to a significant 
degree. 
5.14.8 The patient completes study treatment as per study schedule. 
5.14.9 The patient chooses to discontinue treatment or follow-up. In this event, the 
reason(s) for withdrawal will be documented. 
 
The reason(s) for withdrawing the patient from the treatment portion of the study will be 
documented in the case report form. Where possible and feasible, patients who received at least 
one dose of Oregovomab should be subjected to the procedures scheduled at the end of the study 
and should be submitted to the follow up to assess disease progression. If available, the following 
information will be recorded in the case report form: date of disease relapse, date of death, cause 
of death, and autopsy report. 
6.0 
Measurement of Effect 
6.1 Tumor Response   
Measurable Disease Response: CTEP’s. Criteria for Radiographic Response Evaluation (RECIST) 
guidelines will be followed: A quick reference to the RECIST guidelines can be downloaded at 
the following URL:   http://ctep.cancer.gov/guidelines/recist.html  
 
Patients enrolled in this study must have a measurable pancreatic cancer which is defined as lesions 
that can be accurately measured in at least one dimension: [longest diameter to be recorded] on the 
CT scan or MRI scan. 
 
The same method of assessment & the same technique should be used to characterize each 
identified & reported lesion at baseline & during follow-up. 
 
Parameters to Measure  
Response Outcome: 
1 
Clinical examination 
2 
Chest radiograph 
3 
 CT & MRI scans 
4 
 
 Tumor markers 

 
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5 
Cytology & histology 
 
6.2 
 Response criteria 
Taking into account the measurement of the longest diameter only for those lesions with 
size response, response criteria are defined as: 
• Complete Response (CR):  the disappearance of a lesion. 
• Partial Response (PR):  at least a 30% decrease in the longest diameter of a lesion, 
taking as reference the longest diameter recorded since the treatment started. 
• Progressive Disease (PD):  at least a 25% increase in the longest diameter of a 
lesion, taking as reference the longest diameter recorded since the treatment started. 
• Stable Disease (SD):  neither sufficient shrinkage to qualify for partial response nor 
sufficient increase to qualify for progressive disease, taking as reference the longest 
diameter since the treatment started. 
 
6.3 
Time to Treatment Failure 
The time to treatment failure will be defined as from the first date of therapy until the date the 
patient is removed from study for any reason. 
 
 
6.4 
Survival 
Survival will be defined as from the first date of therapy until the date the patient dies.  
 
6.5 
Toxicity criteria 
The NCI Common Toxicity Criteria Adverse Events version 4.0 will be used to grade toxicity; it 
is available at the following internet site:  http://ctep.cancer.gov/forms/CTCAEv4.pdf. 
 
 
6.6 
Monitoring of peri-and post-marker implantation morbidity 
The marker position and geometry will be documented on simulation CT images. Information 
regarding the development of infectious complications, bleeding, and any implantation associated 
adverse events will be recorded.  

 
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7.0 Study Parameters  
Neo-Adjuvant 
 
Screening 
Staging 
Marker 
BASELINE 
Cycle
1 
 
 
Cycle 
2 
 
 
Cycle 
3 
 
 
 
 
 
 
Cycle 
4 
 
 
 
R 
E 
C 
O 
Week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17-
18 
V
E 
Day 
-3 to-30 
1 
8 
15 
1 
8 
15 
1 
8 
15 
 
 
 
 
1 
8 
15 
 
R 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Y 
Serum Pregnancy Test 
(If Female) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Staging Laparoscopy (within 
30 days of treatment start) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CA-125 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pain assessment Appendix F 
prior to the start of each chemotherapy 
cycle, 3-4 weeks post radiation, and 2-4 
weeks post-surgery 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
2-4 
wks 
post
OR 
 
Chemotherapy Regimen 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
Subject with CA 125>10 
Immunotherapy/Oregovomab 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
Subject with CA125>10 
Blood Draw for Immunologic 
Assessment (Res) 
[HAMA/CA125, ELISPOT] 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
Nelfinavir 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 Medication info. sheet and 
med adherence form given  
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
Stereotactic Radiotherapy 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 

 
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History 
X 
Every 3 weeks 
 
 
 
 
 
Physical examination 
X 
Every 3 weeks 
 
 
 
 
 
Weight 
X 
Every 3 weeks 
 
 
 
 
 
Performance status 
(Karnofsky) 
X 
Every 3 weeks 
 
 
 
 
 
CBC, diff, Plt  
X 
Every week and pre and post SRT 
 
 
 
 
 
Comprehensive metabolic 
panel  
X 
Every 3 weeks 
 
 
 
 
 
CA19-9 
X 
Every 3 weeks 
 
 
 
 
 
CT Chest  
 
Prior to SRT week 8 
 
 
 
 
 
MRI abdomen 
optional 
Prior to SRT week 8 
Prior to Surgery if needed, PRN 
 
 
  X 
opt 
 
 
CT Chest/abdomen/pelvis 
with oral/IV contrast 
X 
Prior to Surgery 
 
 
X 
 
 
 
NOTE: If the patient has CA 125 >= 10 who is not eligible for receiving oregovomab (e.g. allergic to the drug) but eligible for the rest of treatment, this patient 
should be accrued to the part of protocol without oregovomab.  In another word, patients who have CA 125 >=10 can also be accrued and treated on the part of 
protocol without oregovomab if they cannot receive oregovomab but no contraindications to the rest of treatment. 
 
C = Chemotherapy Regimen (SOC); Gemcitabine 750 (females) or 900 mg/m2 (males) IV by fixed dose rate infusion,  leucovorin 50 mg/m² IV over 30 min, and 5-
FU 2700 mg/m2  IV over 24 hrs REPEAT weekly  for 2 of 3 weeks (day 1 and 8) x 4 cycles(RESUME C after SRT for Cycle 4) 
I = Immunotherapy and Immunologic Assessment (Res):  Oregovomab 2 mg IV over 20 min will be given every 3 weeks on day 15 x 4 Cycles (RESUME I after SRT 
for Cycle 4)          
BD= Blood Draw (Res) for immunologic assessment will be done Pre-chemotherapy, Prior to second infusion for the first 6 obtainable patients, Pre-SRT, Pre-
surgery  
NFV = Nelfinavir (Res) 1250 mg P.O. BID to start daily the Monday of week three of the  third cycle of chemotherapy (2 weeks prior to the initiation of SRT) 
CONTINUE x 5 weeks ending the Friday 2 weeks after the end of SRT 
SRT = Stereotactic Radiotherapy (SOC)   daily Monday-Friday x 1 week to start week 11 (SOC)  
OR= Surgery (SOC)  to be performed sometime during week 17-18 
 
 

 
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**Post-operative RECOVERY / ** Post-restaging unresectable RESUME Adjuvant Chemotherapy: 
Three cycles of adjuvant chemotherapy to start when the clinician’s determine that the patient has recovered from surgery  OR if the patient was unresectable 
and the clinician’s determine that chemotherapy should be resumed+(Approx. 1 mo post-op).   
 
Pre 
Therapy 
Cycle5  
 
Cycle6  
 
Cycle7  
 
End of Study (week 12) 
or Early Termination 
Follow-Up 
Day 
 
1 
8 
15 
1 
8 
15 
1 
8 
15 
 
 
Pain assessment Appendix F 
prior to the start of each chemotherapy 
cycle and end of study 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Chemotherapy Regimen 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
Subject with CA 125>10 
Immunotherapy/Oregovomab 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Subject with CA125>10 
Blood Draw for Immunologic 
Assessment (Res) 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical examination 
X 
Every 3 weeks 
X 
X 
Weight 
X 
Every 3 weeks 
X 
X 
Performance status 
(Karnofsky) 
X 
Every 3 weeks 
X 
X 
CBC, diff, Plt  
X 
Every week  
X 
X 
Comprehensive metabolic 
panel 
X 
Every 3 weeks 
X 
X 
CA19-9 
X 
Every 3 weeks 
X 
X 
MRI (optional, prn) 
X prn 
PRN 
X prn 
X prn 
CT Chest/abdomen/pelvis 
with oral/IV contrast 
X 
 
X 
Every 3 months 
C = Chemotherapy Regimen (SOC); Gemcitabine 750 (females) or 900 mg/m2 (males) IV by fixed dose rate infusion,  leucovorin 50 mg/m² IV over 30 
min, and    5-FU 2700 mg/m2  IV over 24 hrs REPEAT weekly  for 2 of 3 weeks (day 1 and 8) x 3 Cycles (Cycles 5-7)   
CA125> 10 Subjects Resume: 
 I =  Immunotherapyand Assessment (Res):  Oregovomab 2 mg IV over 20 min will be given every  3 weeks on day 15 x 3 Cycles (Cycles 5-7)              

 
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BD= Blood Draw (Res) for immunological assessment will be done prior to restarting chemotherapy and at end of study.

 
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8.0  
Drug Formulation and Procurement 
 
8.1 Nelfinavir (study drug) 
8.1.1 Description 
VIRACEPT® (mesylate) is an inhibitor of the human immunodeficiency virus (HIV) protease. 
VIRACEPT Tablets are available for oral administration as a light blue, capsule-shaped tablet with 
a clear film coating in 250 mg strength (as NFV free base) and as a white oval tablet with a clear 
film coating in 625 mg strength (as NFV free base). Each tablet contains the following common 
inactive ingredients: calcium silicate, crospovidone, magnesium stearate, hypromellose, and 
triacetin. VIRACEPT Oral Powder is available for oral administration in a 50 mg/g strength (as 
NFV free base) in bottles. The oral powder also contains the following inactive ingredients: 
microcrystalline 
cellulose, 
maltodextrin, 
dibasic 
potassium 
phosphate, 
crospovidone, 
hypromellose, aspartame, sucrose palmitate, and natural and artificial flavor. The chemical name 
for nelfinavir mesylate is [3S-[2(2S*, 3S*), 3a,4ab,8ab]]-N-(1,1-dimethylethyl)decahydro-2-[2-
hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinoline 
carboxamide mono-methanesulfonate (salt) and the molecular weight is 663.90 (567.79 as the free 
base). Nelfinavir mesylate has the following structural formula: 
 
Nelfinavir mesylate is a white to off-white amorphous powder, slightly soluble in water at pH 4 
and freely soluble in methanol, ethanol, 2-propanol and propylene glycol. 
Pharmacokinetics 
The pharmacokinetic properties of NFV were evaluated in healthy volunteers and HIV-infected 
patients; no substantial differences were observed between the two groups. 
Absorption: Pharmacokinetic parameters of NFV (area under the plasma concentration-time curve 
during a 24-hour period at steady-state [AUC24], peak plasma concentrations [Cmax], morning 
and evening trough concentrations [Ctrough]) from a pharmacokinetic study in HIV-positive 
patients after multiple dosing with 1250 mg (five 250 mg tablets) twice daily (BID) for 28 days 
(10 patients) and 750 mg (three 250 mg tablets) three times daily (TID) for 28 days (11 patients) 
are summarized in Table 1. 

 
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The difference between morning and afternoon or evening trough concentrations for the TID and 
BID regimens was also observed in healthy volunteers who were dosed at precisely 8- or 12-hour 
intervals. In healthy volunteers receiving a single 1250 mg dose, the 625 mg tablet was not 
bioequivalent to the 250 mg tablet formulation. Under fasted conditions (n=27), the AUC and 
Cmax were 34% and 24% higher, respectively, for the 625 mg tablets. In a relative bioavailability 
assessment under fed conditions (n=28), the AUC was 24% higher for the 625 mg tablet; the Cmax 
was comparable for both formulations. In healthy volunteers receiving a single 750 mg dose under 
fed conditions, NFV concentrations were similar following administration of the 250 mg tablet 
and oral powder. 
Effect of Food on Oral Absorption: Food increases NFV exposure and decreases NFV 
pharmacokinetic variability relative to the fasted state. In one study, healthy volunteers received a 
single dose of 1250 mg of VIRACEPT 250 mg tablets (5 tablets) under fasted or fed conditions 
(three different meals). In a second study, healthy volunteers received single doses of 1250 mg 
VIRACEPT (5 x 250 mg tablets) under fasted or fed conditions (two different fat content meals). 
The results from the two studies are summarized in Table 2 and Table 3, respectively. 
 
 
NFV exposure can be increased by increasing the calorie or fat content in meals taken with 
VIRACEPT. A food effect study has not been conducted with the 625 mg tablet. However, based 
on a cross-study comparison (n=26 fed vs. n=26 fasted) following single dose administration of 
NFV 1250 mg, the magnitude of the food effect for the 625 mg NFV tablet appears comparable to 
that of the 250 mg tablets. VIRACEPT should be taken with a meal. 
Distribution: The apparent volume of distribution following oral administration of NFV was 2-7 
L/kg. NFV in serum is extensively protein-bound (>98%). 

 
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Metabolism: Unchanged NFV comprised 82-86% of the total plasma radioactivity after a single 
oral 750 mg dose of 14C-NFV. In vitro, multiple cytochrome P-450 enzymes including CYP3A 
and CYP2C19 are responsible for metabolism of NFV. One major and several minor oxidative 
metabolites were found in plasma. The major oxidative metabolite has in vitro antiviral activity 
comparable to the parent drug. 
Elimination: The terminal half-life in plasma was typically 3.5 to 5 hours. The majority (87%) of 
an oral 750 mg dose containing 14C-NFV was recovered in the feces; fecal radioactivity consisted 
of numerous oxidative metabolites (78%) and unchanged NFV (22%). Only 1-2% of the dose was 
recovered in urine, of which unchanged NFV was the major component. 
Special Populations 
Hepatic Insufficiency: The multi-dose pharmacokinetics of NFV have not been studied in HIV-
positive patients with hepatic insufficiency. 
Renal Insufficiency: The pharmacokinetics of NFV have not been studied in patients with renal 
insufficiency; however, less than 2% of NFV is excreted in the urine, so the impact of renal 
impairment on NFV elimination should be minimal. 
Gender and Race: No significant pharmacokinetic differences have been detected between males 
and females. Pharmacokinetic differences due to race have not been evaluated. 
8.1.2 Treatment Regiment 
Since our phase I trial of chemotherapy followed by SRT with NFV has shown no SRT-NFV 
related DLT, 1 dose level of NFV (1250 mg BID) with SRT dose of 40Gy x 5 will be evaluated 
with the immune-chemotherapy. NFV is taken orally with food preferably high in fat because the 
bioavailability of the tablets increases under the influence of a high fat meal. NFV will begin 2 
weeks prior to starting radiation and will continue 14 days after the completion of SRT. 
 
8.1.3 Method for accruing patients 
The patients will be identified for this study in conjunction with the Department of GI Surgical 
Oncology and Medical Oncology based on their inclusion/exclusion criteria. All patients are 
treated as per protocol. 
 
8.1.4 Preparation and Administration of Study Drug 
NFV is readily available in the inpatient pharmacy of the University of Nebraska Medical Center. 
When a patient is enrolled, the drug will be dispensed in the Department of Radiation Oncology. 
It is stored at room temperature.  
 
 
8.1.6 Prior and Concomitant Therapy 
Any prior therapy is acceptable except radiation to the abdomen. The time between other 
investigational agents and enrollment on this study is at least 30 days. 
 
8.1.7 Packaging 
NFV is available from the pharmacy in bottles containing 40 caplets of 625 mg drug. The drug 
will be dispensed to the patient in these marked bottles. 

 
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8.1.8 Blinding of Study Drug 
There is no blinding of NFV 
 
8.1.9 Receiving, Storage, Dispensing and Return 
8.1.9.1 Receipt of Drug Supplies: NFV will be bought as needed from the inpatient 
pharmacy. No inventory is needed.  
8.1.9.2 Storage: NFV is bought as needed. No storage is required. 
8.1.9.3 Dispensing of Study Drug: NFV will be dispensed by a research nurse in the 
Radiation Oncology Department. 
8.1.9.4 Return or Destruction of Study Drug: Once a patient is finished with the NFV 
treatment, the un-used capsules will be brought back to the Radiation Oncology 
Department and destroyed. 
 
8.2 
Gemcitabine hydrochloride  
8.2.1 Chemistry 
Other Names: Gemzar 
Chemical name: 2'-2'-difluorodeoxycytidine monohydrochloride.  
Molecular formula is C9H12ClF2N3O4 
Molecular weight is 299.7 g/mol.  
 
8.2.2 Mechanism of Action 
Gemcitabine (dFdC) is classified as an antimetabolite. This prodrug requires intracellular 
metabolic activation to the 5'-diphosphate and -triphosphate derivatives to exert cytotoxicity. The 
diphosphate metabolite inhibits ribonucleotide reductase, thereby depleting deoxyribonucleotide 
pools. The triphosphate derivative incorporates into DNA, thereby interfering with DNA chain 
elongation and cause nucleotide mis-incorporation. 
 
8.2.3 Clinical Formulation  
Gemcitabine is commercially available as a lyophilized product containing the equivalent of 200 
mg or 1000 mg gemcitabine as the hydrochloride salt, mannitol, USP (200 mg and 1000 mg, 
respectively), and sodium acetate, USP and ACS (12.5 mg and 62.5 mg, respectively). 
 
Solution preparation: Normal Saline is the only diluent approved. To make a solution containing 
10 mg/ml final concentration, add 20 ml normal saline to the 200 mg vial or 100 ml normal saline 
to the 1000 mg vial. To make a solution containing 40 mg/ml final concentration, add 5 ml 
normal saline to the 200 mg vial or 25 ml normal saline to the 1000 mg vial. The solution may be 
diluted with up to 100 ml normal saline.  
 
Storage: The lyophilized compound should be stored at controlled room temperature (151 to 301 
C) 
 
Stability: No degradation of the drug product in the dry state has been observed after 6 months at 
401 C with 75% relative humidity or after 3 years at controlled room temperature (301 C). The 

 
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reconstituted solution should be stored at controlled room temperature or at 41 C. Since the 
solution does not contain antibacterial preservatives, it should be used within 24 hr. 
 
8.2.4 Clinical Pharmacology 
Gemcitabine is primarily cleared by metabolic conversion to the inactive metabolite, dFdU, which 
is mediated by the enzyme cytidine deaminase. Both parent drug and the metabolite are excreted 
through the kidneys. Pharmacokinetic parameters reported by Eli Lilly were derived using data 
from patients treated for varying durations of therapy given weekly with periodic rest weeks and 
using both short infusions (<70 minutes) and long infusions (70 to 285 minutes). The total Gemzar 
dose varied from 500 to 3600 mg/m5. Gemcitabine pharmacokinetics were linear and were 
described by a 2-compartment model. Population pharmacokinetic analyses of combined single 
and multiple dose studies showed that the volume of distribution of gemcitabine was significantly 
influenced by duration of infusion and gender. Clearance was affected by age and gender. 
Differences in either clearance or volume of distribution based on patient characteristics or the 
duration of infusion result in changes in half-life and plasma concentrations. The following table 
shows plasma clearance and half-life of gemcitabine following short infusions for typical patients 
by age and gender. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a terminal half-life for patients receiving a short infusion (< 70 min).  
 
The terminal gemcitabine half-life for short infusions ranged from 32 to 94 minutes, and the value 
for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a 
greatly increased volume of distribution with longer infusions. The lower clearance in women and 
the elderly results in higher concentrations of gemcitabine for any given dose. The volume of 
distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 
L/m5  following infusions lasting <70 minutes, indicating that gemcitabine, after short infusions, 
is not extensively distributed into tissues. For long infusions, the volume of distribution rose to 
370 L/m5, reflecting slow equilibration of gemcitabine within the tissue compartment. The 
maximum plasma concentrations of dFdU (inactive metabolite) were achieved up to 30 minutes 
after discontinuation of the infusions and the metabolite is excreted in urine without undergoing 
 
Age 
 
 
Clearance
: Men 
(L/hr/m²) 
 
 
Clearance: 
Women 
(L/hr/m²) 
 
 
Terminal half-
lifea: 
Men (min) 
 
 
Terminal half-lifea: 
Women (min) 
 
29 
 
92.2 
 
69.4 
 
42 
 
79 
 
 
45 
 
75.7 
 
57 
 
48 
 
57 
 
 
65 
 
55.1 
 
41.5 
 
61 
 
73 
 
 
79 
 
40.7 
 
30.7 
 
79 
 
94 

 
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further biotransformation. The metabolite did not accumulate with weekly dosing, but its 
elimination is dependent on renal excretion, and could accumulate with decreased renal function. 
 
8.2.5 Clinical toxicity 
Hematologic: leukopenia, thrombocytopenia and anemia; myelosuppression is dose-limiting. 
 
GI: transient abnormalities of liver transaminase enzymes are seen in 2/3 of patients; elevations of 
alkaline phosphatase and bilirubin are less common; nausea & vomiting occur in - 1/3 of patients; 
diarrhea is noted in - 7% of patients. 
 
Renal:  mild proteinuria and hematuria occurs in - 50% of patients. Elevations of BUN and 
creatinine are uncommon. Hemolytic uremic syndrome (HUS) or renal failure have occurred 
rarely. 
 
Pulmonary: dyspnea occurring within hours following dFdC has been reported in 10% of patients; 
the mechanism is unknown, but this symptom is usually mild and short lived, and generally abates 
spontaneously. The dyspnea is not associated with signs or symptoms of bronchospasm and 
anaphylaxis. Rarer but more serious pulmonary toxicities include pneumonitis, fibrosis. edema, 
acute respiratory distress syndrome. 
 
Mucocutaneous:  a skin rash occurs in 25% of patients, with pruritus in 10%; the rash is mild, and 
responds to local therapy. A minority of patients may note pain at the injection site, but the drug 
does not appear to be a vesicant. Minimal to moderate hair loss is seen in 13% of patients. Mouth 
soreness and erythema have been noted in 7% of patients. 
 
Neurologic: somnolence occurs in 10%; mild paresthesias occur in 4% of patients. 
 
Flu-like symptoms: an entity resembling influenza is reported by 20% of patients, characterized 
by fever, headache, back pain, chills, myalgia, asthenia, and anorexia. Cough, rhinitis, malaise, 
sweating and insomnia are also reported. Paracetamol may produce symptomatic relief. 
 
Edema: 30% of patients experience edema/peripheral edema. The mechanism of action is 
unknown, but the edema is reversible after discontinuation of drug. It is not associated with any 
evidence of cardiac, renal or hepatic failure. 
 
Miscellaneous: a few cases of hypotension have been reported, but only 0.1% of patients 
discontinued gemcitabine therapy because of this effect. Some cases of myocardial infarction, 
congestive heart failure, and arrhythmia have been reported, but the contribution of gemcitabine 
to these events is unclear. 
 
 
 
 
 

 
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8.3 Fluorouracil (5-FU) 
8.3.1  
Chemistry  
 
Chemical Name: 
5-fluoropyrimidine- 2,4(1H,3H)-dione.  
 
Chemical formula: C4H3FN2O2  
 
molecular weight: 
130.1 
 
Physical form:  
A white to almost white, practically odourless, crystalline powder 
 
Solubility: 
 
Sparingly soluble in water; slightly soluble in ethanol 
 
8.3.2 Mechanism of Action 
5-FU is an analog of uracil, & can be metabolized intracellularly to both ribonucleotides & 
deoxyribonucleotides. Fluorouridine triphosphate can be incorporated into RNA by RNA 
polymerase, & consequently interferes with RNA processing & function. Fluorodeoxyuridine 
monophosphate (FdUMP) is a potent inhibitor of thymidylate synthase, the enzyme in the de novo 
pathway of pyrimidine biosynthesis that coverts dUMP to dTMP. Depletion of dTTP interferes 
with DNA synthesis & repair. FdUTP can also be incorporated into DNA. 
 
8.3.3  Clinical Formulation 
5-FU is available in 10 ml ampules as a colorless aqueous solution containing 500 mg/10 ml. The 
pH of the solution is adjusted to approximately 9.2 with sodium hydroxide. This undiluted 
preparation is suitable for direct intravenous injection.  
 
Storage:  Unused vials may be stored at room temperature & should be protected from light. If a 
precipitate forms due to exposure to low temperatures, resolubilize by heating to 140 1F & shaking 
vigorously. Allow the solution to cool to body temperature before administering. 
 
Stability: The vials bear an expiration date. 5-FU solutions may discolor slightly during storage, 
but the potency & safety are not adversely affected. 5-FU prepared for protracted continuous 
infusion is stable for 14 - 28 days (Handbook on Injectable drugs: Lawrence A. Trissel, 9th Edition. 
American Society of Health-System Pharmacists= Product Development Office. 1996). 
 
8.3.4 Clinical Pharmacology 
5-FU is cleared predominantly by enzymatic means: catabolism of 5-FU to dihydrofluorouracil by 
dihydropyrimidine dehydrogenase is the rate-limiting step in 5-FU clearance. The half-life of 5-
FU in plasma averages 8-12 minutes. Less than 10% of the administered dose is excreted as parent 
drug in the urine.  
 
8.3.5 Clinical toxicity 
GI: nausea, vomiting, diarrhea, anorexia, enteritis, stomatitis, esophagopharyngitis, GI bleeding 
 
Cutaneous: alopecia, dermatitis, pigmentation abnormalities, palmar plantar erythrodysesthesia, 
erythema, photosensitivity, ulceration,,  
 

 
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Systemic: lethargy, malaise 
 
Ocular toxicity: conjunctivitis, lacrimation, lacrimal duct stenosis, photophobia 
 
Myelosuppression: leukopenia, thrombocytopenia, anemia 
 
Cardiac: chest pain and rhythm abnormalities 
 
CNS toxicity: acute cerebellar syndrome, confusion, headache 
 
8.3.6 Drug Interactions 
Calcium leucovorin, warfarin. Possible: zidovudine, allopurinol. Several investigational drugs are 
inhibitors of dihydropyrimidine dehydrogenase; these include the antiviral drugs brivudine and 
soruvidine. 
 
8.3.7  Route of Administration 
5-FU will be given as a 24 hr continuous IV infusion starting immediately after completion of the 
gemcitabine infusion weekly for two of three weeks each cycle using an ambulatory infusion 
pump.  
 
8.4 
Calcium Leucovorin (LV) 
8.4.1 Chemistry 
chemical name: The calcium salt of racemic folinic acid (1:1).  
Other names:  folinic acid, 5-formyl-tetrahydrofolate, citrovorum factor 
Molecular formula:  C20H21CaN7O7 
Molecular weight:  
511.5  
Physical form: A yellowish-white or yellow, odorless, powder.  
Solubility: 
Very soluble in water; practically insoluble in alcohol; Protect from light. 
 
8.4.2 Mechanism of action 
LV is a water soluble vitamin in the folate group. LV is the formyl derivative and active form of 
folic acid used to counter the hematologic and other toxicities associated with methotrexate and 
other antifolates. Upon intracellular conversion to 5,10-methylenetetrahydrofolate, it serves as the 
reduced folate cofactor involved in the de novo production of dTMP from dUMP. Pharmacologic 
concentrations of reduced folates enhance the stability of the covalent complex formed with 
FdUMP and thymidylate synthase. 
 
8.4.3   Clinical Formulation 
LV is commercially available as scored oral tablets in dosages of 5 mg, 10 mg, 15 mg, and 25 mg, 
and also as a sterile, lyophilized powder in vials containing 25 mg, 50 mg, and 100 mg. 
Reconstitution with 10 ml of Sterile Water for Injection, USP, yields a 2.5 mg/ml, 5 mg/ml or 10 
mg/mL solution of LV as the calcium salt, respectively. The final administration solution may be 
prepared by adding the proper LV dose to 100 ml of 5% Dextrose Injection, USP.  
 

 
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8.4.4 Storage: Tablets and intact vials may be stored at room temperature, protected from light. 
Constituted and further diluted solutions should be stored in the refrigerator. If Bacteriostatic 
Water for Injection, USP (benzyl alcohol preserved) is used for reconstitution, the resulting 
solution is stable for seven days. If reconstituted with  Sterile Water for Injection, USP, the 
manufacturer recommends using the solution immediately. 
 
8.4.5  Clinical Pharmacology 
Calcium folinate is well absorbed after oral and intramuscular administration and, unlike folic acid, 
is rapidly converted to biologically active folates. Folate is concentrated in the liver and CSF 
although distribution occurs to all body tissues. Folates are mainly excreted in the urine, with small 
amounts in the feces. After a single oral dose of 15 mg (7.5 mg/m5), the time to peak serum folate 
concentration is 1.7 ± 0.1 hr, and the peak serum folate concentration is 268 ±18 ng/ml (0.57 ±  
0.04 μM). The serum folate half-life was 3.5 hr. Bioavailability was 100% compared to the same 
dose given i.v., but absorption is saturable with higher doses.  
 
8.4.6 Clinical Toxicity 
Allergic sensitization (urticaria and anaphylactoid reactions) has been reported following both oral 
& parenteral administration of LV. The administration of LV with 5-FU augments the severity of 
toxicity typically associated with 5-FU, particularly GI tract toxicities. Pyrexia has occurred rarely 
after injections. Seizures and syncope have rarely been reported. 
 
8.4.7 Route of Administration 
Calcium leucovorin will be given IV injection over 30 minutes immediately prior to 5-FU when 
given as a 24-hr infusion. 
 
8.4.8 Drug Interactions 
Calcium leucovorin may augment the toxicity associated with 5-FU and capecitabine. Calcium 
leucovorin is used to protect against the toxicity associated with high-dose methotrexate. 
 
8.5 Oregovomab OvaRex 
8.5.1  
Chemistry  
 
Chemical Name: 
MAb-B43.135  
 
 
8.5.2 Mechanism of Action 
 
The current understanding of the mechanism of action of OvaRex MAb: 

 
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OvaRex® Foreign Antibody Binds to the “Self”-Antigen
CA125
CA125
CA125
CA125
CA125
Tumor
Y
Y
Y
Y
Shed
Blood vessel
Tumor “self”antigens (TAA)
are shed into the bloodstream
Injected low-dose foreign antibody binds
TAA and forms immunogenic complex
 
• 
The key event is the formation of a complex between intravenously administered OvaRex 
MAb-B43.13 and the circulation tumor-associated antigen CA-125. Complex formation was 
confirmed in human PK studies (Noujaim et al., Cancer Biother & Radiopharm (2001)16:187). 
 
Antigen Presenting 
Cell (APC)
Complex is taken up by antigen presenting cells,
e.g. dendritic cell
Y
TAA
Immune Complex
Receptor-
Mediated
Endocytosis
Activation of APC
OvaRex - CA125 Complex Binds
Antigen Presenting Cell
 
• 
CA-125 complexed with OvaRex MAb-B43.13 is taken up uptake by dendritic cell much 
better than the CA-125 antigen alone (Schultes et al., Proceedings AACR (2001) 42:276; AltaRex 
Report RT-PRE-011). 

 
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• 
The xenotypic nature of OvaRex MAb-B43.13 aids in triggering the release of cytokines 
(Noujaim et al., Cancer Biother. & Radiopharm (2001)16:187). 
• 
Dendritic cells are capable of presenting antigen-derived peptides from extracellular 
proteins on MHC class I and II molecules. This mechanism of ‘cross-priming’ is very effective 
when the antigen is presented in complex with a specific antibody (Regnault et al., J Exp Med 
(1999)189:371; Manca et al., J Immunol (1998)140:2893; Berlyn et al., Clin Immunol 
(2001)101:276). 
• 
Intracellular cytokine staining and in vitro antigen presenting assays have demonstrated 
that MAb-B43.13-CA-125 immune complexes are vastly superior to CA-125 alone in stimulating 
IFN-γ secreting CD4+ and CD8+ T cells (Schultes et al., Proceedings AACR (2001)42:276).  
ADCC, CDC
TH1
Cytokines
Macrophage
Activation
NK
Activation
Activation
Dendritic Cell
or other APC
Cytokines
Cytokines
IFN-γ
IL-12
IL-2
HAMA
Ab2  Anti-CA125
(multi-epitopic)
TH2
Antibodies
B Cell
Activation
Y
Cytokines
IL-4
Activation of multiple arms of the immune system
Induction of T Helper Cells and CTL
CTL
TH
TH
APC
 
• 
Injection of OvaRex MAb-B43.13 leads to the generation of human-anti-CA-125 
antibodies. These antibodies recognize several epitopes on CA-125 and are of a T cell dependent 
isotype suggesting recognition of the entire immune complex by the patients’ immune system 
(Noujaim et al., Cancer Biother & Radiopharm (2001)16:187). 

 
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• 
Human anti-CA-125 antibodies, induced by the MAb-B43.13-CA-125 immune complex, 
have been shown to mediate ADCC and kill CA-125-positive ovarian cancer cells (Schultes et al., 
Cancer Immunol Immunother  (1998) 46:201).  
• 
Injection of OvaRex MAb-B43.13 leads to the induction of CA-125-specific T cells 
(Noujaim et al., Cancer Biother & Radiopharm (2001)16:187).  
• 
CA-125-specific CTL can directly kill tumor cells. In this context, activated MHC class I 
(and II) restricted T cells have been demonstrated in patients after treatment with OvaRex MAb-
B43.13, which respond with IFN-γ production upon stimulation with CA-125 and autologous 
tumor (Schultes et al., Proceedings AACR (2001) 42:276, and Gordon et al., Gynecologic 
Oncology (2004) 94:340-351). 
• 
The magnitude and quality of induced T cell immunity to CA125 or autologous tumor is 
influenced by the timing of OvaRex MAb-B43.13 infusion relative to other cancer treatments.   
(Braly et al., J Immunother (2009) 32:54-65). 
• 
TLR stimulation in association with OvaRex MAb-B43.13 and antigen has been found 
to augment induced immunity in preclinical models (Nicodemus et al., Am J Obstet Gynecol 
2010).   
 
In summary, multiple effector arms of the immune system have been shown to be activated by 
OvaRex MAb-B43.13 injection into patients. Which one of the effector arms is the most 
important or if all arms are needed to cooperate to induce a clinically beneficial response remains 
to be determined.  
 
8.5.3   Clinical Formulation 
Oregovomab is supplied in vials containing 2 mg of the monoclonal antibody with a reducing 
agent, a buffer complex, and excipients. Preparation of the final formulation will be performed 
under aseptic conditions immediately before administration to the patient (see below).  
 
The lyophilized contents of the vial of Oregovomab should be dissolved in 2 mL of 0.9% Sodium 
Chloride Injection USP then added to 50 mL of 0.9% Sodium Chloride Injection USP in a small 
(50 mL) infusion bag.   
 
A research staff member, who is qualified to prepare and dispense medication, will provide the 
dose of each study drug.  
 
8.5.4 Clinical Toxicity 
Reported Adverse Events and Potential Risks 
Oregovomab is a murine monoclonal antibody, foreign to the patients’ immune system.  It is 
immune stimulatory but has not been associated with a pattern of toxicity in previous controlled 
and open label studies.  Reported adverse events have been seen with similar frequency in active 
and placebo treated patients.  The relatively low dose and 20-30 minute infusion rate may be 
responsible for the pattern documented to date.  Hypersensitivity responses are anticipated to occur 
infrequently, but research personnel should be prepared to treat acute allergic reactions should they 
occur and be observant for manifestations of delayed hypersensitivity. Recommendations 
regarding the management of hypersensitivity reactions can be found in Appendix D. 
 

 
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Integrated Safety Experience:   
Most Frequent Treatment-Emergent Adverse Events (Oregovomab vs. Placebo) 
 
Summary of Most Frequent (> 5%) Adverse Experiences 
 
MedDRA Preferred Term 
Frequency (% of Patients in Each 
Group) 
Oregovomab 
(n=380) 
Placebo 
(n=196) 
Abdominal discomfort 
7.1 
6.6 
Abdominal distension 
12.1 
15.8 
Abdominal pain 
19.7 
28.6 
Abdominal pain lower 
7.6 
7.7 
Abdominal pain upper 
11.3 
15.3 
Anorexia 
8.4 
2.6 
Anxiety 
6.1 
6.6 
Arthralgia 
21.8 
24.5 
Asthenia 
6.8 
9.7 
Back pain 
19.2 
19.4 
Chest discomfort 
4.2 
5.6 
Chest pain 
3.9 
5.6 
Constipation 
18.7 
15.3 
Cough 
10.0 
15.8 
Depression 
9.7 
7.7 
Diarrhea 
17.1 
28.6 
Dizziness 
10.5 
18.4 
Dyspepsia 
7.6 
9.7 
 
Summary of Most Frequent ( > 5%) Adverse Experiences (continued) 
 
MedDRA Preferred Term 
Frequency (% of Patients in Each 
Group) 
Oregovomab 
(n=380) 
Placebo 
(n=196) 
Dyspnoea 
3.7 
9.2 
Fatigue 
31.3 
31.6 
Flatulence 
4.2 
5.6 
Flushing 
4.2 
5.1 
Headache 
20.3 
35.2 
Hot flush 
6.6 
9.7 
Hypoaesthesia 
3.9 
8.2 
Influenza-like illness 
4.7 
9.7 
Insomnia 
6.8 
8.7 
Muskuloskeletal discomfort 
5.0 
5.1 

 
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Myalgia 
8.9 
13.3 
Nasal congestion 
4.7 
8.7 
Nasopharyngitis 
6.3 
11.2 
Nausea 
29.5 
39.3 
Oedema peripheral 
8.9 
9.2 
Pain 
6.8 
12.8 
Pain in extremity 
12.1 
13.8 
Pharyngolaryngeal pain 
7.1 
14.8 
Pruritus 
3.9 
5.1 
Pyrexia 
4.7 
14.3 
Rash 
8.2 
10.7 
Rigors 
6.3 
9.2 
Upper respiratory tract infection 
5.5 
5.6 
Urinary tract infection 
6.8 
4.1 
Vomiting 
12.9 
20.4 
 
8.5.5 Preparation and Route of Administration of Oregovomab 
Oregovomab infusion: 
Prepare 2 mg of Oregovomab. Dilute in 50 mL of 0.9% Sodium Chloride Injection USP in a 
minibag for intravenous infusion.   
 
Patients will receive a single dose of Oregovomab diluted in 50 mL of 0.9% Sodium Chloride 
Injection USP to be infused intravenously.  The recommended infusion time is to be 
approximately 20 minutes (not less than 15 minutes, and no greater than 30 minutes). 
• Oregovomab is not cytotoxic.  
• Oregovomab can be prepared in the parenteral area of the pharmacy 
department under aseptic technique. 
Oregovomab Preparation 
1. Remove the flip seal on the top of the vial and wipe the exposed rubber septum with an 
alcohol swab. 
2. In a suitable syringe obtain a volume of 2.0 mL of 0.9% Sodium Chloride injection 
USP (or equivalent). 
3. Add the 0.9% Sodium Chloride injection USP (or equivalent) to the labelled study drug 
vial (Oregovomab). 
4. Mix the vial contents by gentle swirling.  Do not mix vigorously as this may result in 
the formation of foam. 
5. Before using examine the vial to ensure that the solution is free of particulate matter. 
6. With a suitable syringe remove the entire contents of the vial. Inject the 2 mL study 
drug into a 50 mL 0.9% Sodium Chloride injection USP infusion bag.  
7. Milk the injection port, then to ensure the contents are thoroughly mixed invert the 
injection bag several times. 
8. The final preparation may be stored at room temperature for up to 4 hours after 
reconstitution. 
 
 

 
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9.0  
Toxicity Reporting Guidelines 
 
Reporting until 30 days after last administration of study medication.   
 
NOTE: Problems related to insurance coverage will be reported to the IRB as they are encountered. 
 
This protocol will comply with monitoring and adverse event reporting requirements of the UNMC/Fred 
& Pamela Buffett Cancer Center Data Monitoring plan. The protocol will adhere to the institutional and 
FDA guidelines for the toxicity reporting.    
 
All patients will be closely followed for toxicity from the time of informed consent until 30 days after last 
administration of study medication. Adverse event and serious adverse events will be followed until 
baseline or ≤ grade 1 levels. Toxicity will be assessed using the NCI CTCAE version 4.0 (Appendix E) 
 
All adverse events will be followed to a satisfactory conclusion.  Serious adverse events should be 
followed until resolution, death, or until no further improvement is reasonably expected. Deaths occurring 
within 30 days of study treatment regardless of relationship will be reported to the UNMC IRB and Fred 
& Pamela Buffett Cancer Center DSMC.  
 
In addition to complying with all applicable regulatory reporting laws and regulations, all serious adverse 
events and toxicities will be reported to the University of Nebraska Medical Center, Institutional Review 
Board (IRB) and Fred & Pamela Buffett Cancer Center Cancer Center Data and Safety Monitoring 
Committee (DSMC).   
 
Definitions 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment.  An adverse event can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the product.  
 
An elective surgery or procedure that is scheduled to occur during a study will not be considered an 
adverse event if the surgery or procedure is being performed for a pre-existing condition and the surgery 
or procedure has been planned before study entry.  However, if the pre-existing condition deteriorates 
unexpectedly during the study (e.g., the surgery is performed earlier than planned), then the deterioration 
of the condition for which the elective surgery or procedure is being done will be considered an adverse 
event.  
 
An adverse event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
accidental or intentional overdose, drug abuse, or drug withdrawal.  Any worsening of a pre-existing 
condition or illness is considered an adverse event.  Laboratory abnormalities and changes in vital signs 
are considered to be adverse events if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, meet protocol specific criteria (see Section 5.0, Treatment Plan) and/or if the 

 
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investigator considers them to be adverse events. In general, if a laboratory abnormality or change in vital 
sign is associated with a specific diagnosis that is being reported concurrently as an adverse event (e.g. 
elevated creatinine with renal failure or sinus tachycardia in febrile neutropenia) the findings that support 
the diagnosis do not need to be reported as separate adverse events unless the investigator feels it is 
appropriate. 
 
Treatment-emergent Adverse Event  
Treatment-emergent adverse event is defined as any adverse event with onset or worsening from the time 
that the first dose of study drug is administered until 30 days after the final dose of study drug is 
administered.  
 
Unexpected Adverse Event 
An unexpected adverse event is any adverse drug event that is not listed in the current 
labeling/Investigator’s Brochure. This includes events that may be symptomatically and 
pathophysiologically related to an event listed in the labeling, but differ from the labeled event because of 
greater severity or specificity. For example, under this definition, hepatic necrosis would be unexpected 
(by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the labeling only listed cerebral vascular accidents. “Unexpected,” as used in this definition, 
refers to an adverse drug experience that has not been previously observed (i.e., included in the labeling) 
rather than from the perspective of such experience not being anticipated from the pharmacological 
properties of the pharmaceutical product. 
 
Serious Adverse Event 
A serious adverse event is one that at any dose (including overdose) and regardless of causality that: 
 
Results in death 
 
Is life-threatening1 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability or incapacity2 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event3 
 
Pregnancy 
 1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious adverse event; it does not 
refer to a serious adverse event that hypothetically might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability to carry out 
normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in situations where 
none of the outcomes listed above occurred.  Important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above should also usually be considered serious.  Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.  A new diagnosis of cancer during the course of a 
treatment should be considered as medically important. 

 
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9.1 Adverse Event Reporting and Definitions Per University of Nebraska Medical Center, IRB and 
Fred & Pamela Buffett CancerCenter Data and Safety Monitoring Committee (DSMC) and Allos 
Therapeutics Drug Safety and Surveillance 
This protocol will adhere to all institutional guidelines for adverse event reporting. Adverse events will 
be evaluated using the NCI Common Terminology Criteria for Adverse Events (CTC-AE) version 4.0. 
(Appendix E) 
 
9.1.1 IRB REPORTING 
All internal serious adverse events (AE) must be reported to the IRB promptly through the 
electronic RSS system and in no case later than two (2) business days following PI notification 
that the event occurred if the principal investigator determines that conditions A, B, and C are met:  
a. The AE is unexpected, 
 
AND 
b. The AE is related to, or possibly related to, the drug, biologic, device, or other research 
intervention, AND 
c. The AE is more than minor in nature which is defined as requiring treatment from a health 
professional.  
 
All unexpected, internal, fatal AEs must be reported promptly to the IRB, no later than 24 hours 
through the electronic RSS system following PI notification that the event occurred. If 
documentation is still pending, the IRB office must be notified by a telephone call or e-mail. 
 
All expected, internal, fatal AEs (i.e., due to progressive disease or which reflect a risk currently 
found in the consent form) must be reported through the electronic RSS system no later than ten 
(10) business days following PI notification that the event occurred.   
 
The RSS system is accessed through a link on the UNMC IRB website (http://unmc.edu/irb). 
 
9.1.2 FRED & PAMELA BUFFETT CANCER CENTER DATA AND SAFETY 
MONITORING COMMITTEE (DSMC) REPORTING 
All serious adverse events (expected or unexpected, regardless of attribution) and toxicities > grade 
3 will be reported to the University of Nebraska Medical Center, Fred & Pamela Buffett Cancer 
Center Data and Safety Monitoring Committee (DSMC) in accordance with DSMC guidelines. 
The investigator will assign a causal relationship for all reportable AE’s, using the terminology of 
probably related (AE has strong temporal relationship to study drug or recurs on re-challenge, 
another etiology is unlikely or significantly less likely), possibly related (AE has strong temporal 
relationship to study drug, alternative etiology is equally or less likely), probably not related (AE 
has little or no temporal relationship to study drug and/or a more likely etiology exists), or not 
related (AE related to underlying or concurrent illness).  
 
AEs will be collected from the time the subject signs the consent form and ending 30 days 
following the final chemotherapy. All AEs will be followed until resolution or a cause is identified. 
Prescription medication taken to relieve symptoms of the AE will be recorded in addition to the 
outcome. AEs judged by the investigator as not related or probably not related to the treatment will 
not be followed beyond the 30 days after the final chemotherapy. Transplant related Adverse 
Experiences (AE’s) or Serious Adverse Experiences (SAE’s) will NOT be collected. 

 
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Severity of AE. The severity of events reported on the AE case report form will be determined by 
the principal investigator according the NCI Common Toxicity Criteria (CTC version 4.0).  
 
The likelihood of relationship of the AE to the study drugs will be determined by the investigator 
based on the following definitions: 
 
Not related:  The subject was not exposed to the study treatment or another cause is 
obvious. 
 
Probably not related: The AE is most likely explained by another cause, and the time of 
occurrence of the AE is not reasonably related to the study treatment. 
 
Possibly related:  Study treatment administration and AE occurrence reasonably related 
in time, and the AE is explained equally well by causes other than study treatment, or 
treatment administration and AE occurrence are not reasonably related in time, but the AE 
is not obviously a result of other causes. 
 
Probably related:  Study treatment administration and AE occurrence are reasonably 
related in time, and the AE is more likely explained by study treatment than by other 
mechanisms. 
 
Definitely related: There occurrence and timing of the AE are clearly attributable to the 
study treatment.  
 
Copies of the AE report will be submitted to the IRB (when required), the Fred & Pamela Buffett 
Cancer Center’s Data Safety and Monitoring Committee and the Fred & Pamela Buffett Cancer 
Center Clinical Trials Office. 
 
It is the responsibility of the sponsor-investigator to submit to the FDA IND Safety Reports in 
accordance with 21 CFR 312.32. In addition the sponsor-investigator must notify the Ethics 
Review Committee/Institutional Review Board (EC/IRB) of a serious adverse event in writing in 
accordance with international and local laws and regulations. SAEs not meeting expedited criteria 
will be made available to FDA by the sponsor-investigator via the annual report. The Investigator 
will utilize the FDA MedWatch Form (Appendix H) for the reporting of adverse events and follow up 
information to those events. The form can be found at the following URL: 
http://www.fda.gov/medwatch 
 
Additionally, serious adverse events will be reported to the IRB, SRC and the Data Safety 
Monitoring Committee by the Investigator. 
 
9.2 Monitoring   
The UNMC Fred & Pamela Buffett Cancer Center Scientific Review Committee will review this 
protocol on at least an annual basis. This study will undergo audit on at least a quarterly basis by 
the UNMC Fred & Pamela Buffett Cancer Center Audit Committee. All adverse events and 
toxicity reporting will be reported to the UNMC Fred & Pamela Buffett Cancer Center Data and 

 
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Safety Monitoring Committee (DSMC). The DSMC will also monitor the protocol on at least a 
quarterly basis and as per the DSMC request via the regularly scheduled DSMC review process. 
 
 
10.0 STATISTICAL CONSIDERATIONS  
Study Design:  This is an open-label, uncontrolled Simon two-stage Phase II study with an safety run-in in subjects 
with locally advanced pancreatic adenocarcinoma. 
 
Since this is an open-label trial, descriptive statistics will be employed to analyze the data.  Summary 
statistics for continuous variables will include the mean, standard deviation, median, and range (minimum, 
maximum).  Categorical variables will be presented as frequency counts and percentages and time-to-
event variables will be summarized by Kaplan-Meier plots, medians and ranges. 
 
All statistical tests will be one-sided with a type I error rate of 10%.  All confidence intervals will be 
constructed at the 90% confidence level.  All statistical analyses will be performed using SAS Version 9.2 
or later. 
 
Failure-free survival will be defined as the date of administration study drug to the date of first appearance 
of tumor lesions by imaging, or death.  Overall survival will be measured from the date of first of study 
drug to the date of death.  Patients who are lost to follow-up will be censored at the date they were last 
known to be alive.   
 
10.1 Primary End Point 
To evaluate disease progression within 4 months of follow-up. 
 
10.2 Secondary End Points  
To examine the unexpected toxicity of Oregovomab when given concurrently with 
chemotherapy. Toxicity will be graded by NCI Common Toxicity Criteria (CTC Version 4.0). 
(No more than one patient with unexpected grade 4 hematologic or non-hematologic toxicities 
not medically controlled that is possibly, probably or definitely related to Oregovomab. 
 
To evaluate failure-free survival and overall survival. 
To evaluate the surgical complete resection (negative margin) rate. 
To evaluate tumor response rate on pathology specimen (see 6.2.2 for definition of response). 
To evaluate tumor response rate on CT/MRI (see 6.2.2 for definition of response) 
To evaluate tumor and organ motion with 4D CT and respiratory gating system. 
To evaluate the effect of tumor/organ motion on the dosimetry, local control and survival. 
 
 
 
 
 
Immunological endpoints (details are described in appendix D): 
CA125 ELISPOT: the proportion of patients responding (defined relative to baseline 
according to the permutation test) will be calculated. 
Positive human anti-mouse antibody (HAMA). 
 
Correlative endpoints: 
 
 
To evaluate the value of 4DCT and respiratory gating in pancreatic cancer SRT 
 
10.3 Sample Size  

 
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We estimate that there will be about 33 patients enrolled into each of the two arms of this 
protocol (with and without Oregovomab) (66 total)treated over a 5 year period; the first six 
patients in the arm that patients receiving Oregovomab will also be evaluated for the safety of 
Oregovomab given concurrently with chemotherapy.  
 
With standard therapeutic approaches, about 60% of these patients would be expected to develop 
progressive disease by four months of follow-up (the approximate length of the proposed neo-
adjuvant chemotherapy).  With the neo-adjuvant approach outlined in this protocol, we would 
hope to reduce this rate to 40%.  The study design will follow a two-stage design using a 
response endpoint to determine if the neoadjuvant regimen is acceptable. The following 
monitoring rule will be applied:  This neo-adjuvant treatment of patients considered to have 
locally advanced disease at initial evaluation will be considered uninteresting if 9 or more of the 
first 16 (56%) or 17 or more of 33 (52%) of these patients have progressive disease within 4 
months of follow up from the end of neo-adjuvant therapy. This therapy would be considered 
uninteresting 10% of the time if the true rate of progression within 4 months of follow up was 
40%, but would be considered uninteresting 20% of the time if the true rate of progression within 
4 months of follow up was 60%. 
 
10.4 Interim analyses 
The first interim analysis will occur when 6 subjects have been enrolled in the arm receiving 
oregovomab.  Further enrollment will be halted if there is more than one patient with unexpected 
grade 4 hematologic or non-hematologic toxicities not medically controlled that is possibly, 
probably or definitely related to Oregovomab. 
 
The second interim analysis will occur when 16 subjects have been enrolled in each arm.   Further 
enrollment into the cohort will be halted if there are ≥ 9 patients have disease progression observed 
among the 16 subjects within 4 months of follow up from the end of neo-adjuvant therapy.  Thus, 
there must be at most 8 patients with disease progression or at least 8 patients without disease 
progression at the second interim for further enrollment to continue. Immunotherapy methods will 
be modified if ≤ 8 subjects have positive immunologic response among the 16 subjects with 
ELISOT and HAMA. 
 
The final analysis will occur when all patients have completed their study participation. 
 
10.5 Stopping Rules  
Monitoring for toxicity:  The study would be suspended if 3 or more toxic deaths 
were observed in the first 22 patients (14%) This monitoring rule would indicate 
that the treatment is too toxic about 6% of the time if the true toxic death rate was 
4%, and would be considered too toxic 66% of the time if the true toxic death rate 
was 15%. Pending a review of the toxicity experience, the protocol would either be 
terminated, or amended to specify modifications in the therapy to reduce the risk of 
toxicity. 
 
 
 
 

 
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10.6 Analysis populations 
All patients who complete at least one post-baseline assessment or discontinue 
study medication early due to disease progression will be considered evaluable for 
efficacy. 
 
All patients who received study medication will be considered evaluable for the 
safety analysis regardless of the duration of treatment. 
 
       
 
10.7  Efficacy analysis:   
Progressive disease (PD) is defined as at least a 25% increase in the longest diameter of a lesion, 
taking as reference the longest diameter recorded since the treatment started.  The number and 
proportion of patients experiencing PD will be reported.  An exact one-sided 90% confidence 
interval will be constructed round the progressive disease rate.  
 
Secondary endpoints of surgical complete resection rate, pathological response rate, tumor 
response rate on CT/MRI will be analyzed as described above for disease control.  Failure-free 
survival and overall survival will be analyzed using Kaplan-Meier plots, medians and ranges. 
 
10.8 Safety analysis 
Safety variables to be analyzed are adverse events.  Adverse events will be tallied for overall 
frequency (number and percentage of subjects), worst reported severity, and relationship to study 
drugs.  Serious adverse events will be summarized similarly.  Listings of deaths, SAEs and AEs 
leading to early termination of study treatment or premature withdrawal from study will also be 
provided. 
 
10.9 Immune response analysis:  Cellular immune response is defined as having a significant 
increase from baseline in CA125- ELISPOTs normalized for background using the permutation 
test.  The proportion of patients responding will be summarized using frequencies and percentages. 
Upon completion of Simons stage 1, an interim analysis on immune response will be performed.  
The vaccination regimen will be monitored accordingly. 
 
Similar analysis will be conducted on the secondary efficacy immunological parameter endpoints 
(HAMA assays) with multiple analysis time points where appropriate.   
 
 
11.0 
RECORDS TO BE KEPT 
 
Information regarding the actual treatments, adverse effects, radiographic and laboratory information, and 
pathology are to be recorded on appropriate forms. See attached Data forms.  Serious adverse events, 
when noted, will be recorded on site via the standard serious adverse effects form. 
 
11.1 Quality assurance: Complete records must be maintained in a research chart on each patient treated 
on the protocol. These records should include primary documentation (e.g., lab. report slips, X-ray reports, 
scan reports, pathology reports, physician notes, etc.) which confirm that: 
 

 
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- The patient met the eligibility criteria. 
- Signed informed consent was obtained prior to treatment. 
- Treatment was given according to protocol (dated notes about doses given & reasons for any 
dose modifications). 
- Toxicity was assessed according to protocol (laboratory report slips, etc.). 
- Response was assessed according to protocol (x-ray, scan, lab reports, dated notes on 
measurements & clinical assessment, as appropriate). 
 
11.2 Electronic Data Capturing (EDC) System 
 
The Fred and Pamela Buffett Cancer Center Clinical Trials Office is transitioning all clinical trial data from the Medidata Rave 
system to Forte EDC system for this study.  The transition will be will be occurring over the next several months. 
 
The UNMC Fred & Pamela BuffettCancer Center (NCI-designated cancer center) is a participant in the 
National Cancer Institute Cancer Biomedical Informatics Grid (CaBIG™) initiative.   
 
The NCI purchased software license for cancer centers use of Medidata Rave 5.6 a web-based EDC 
application for managing clinical trial data across multiple cancer clinical trials.  Data will be stored 
electronically for this study on the Rave secure server.  Data forms will not differ from the paper versions 
with the exception of an electronic format containing the UNMC Fred & Pamela Buffett Cancer Center and 
Rave logo. 
 
Medidata Rave 5.6 provides for remote data collection that meets FDA 21 CFR Part 11 requirements as well 
as HIPAA and other regulatory requirements designed to enhance data security and protect patient 
confidentiality. Authorized users log into Medidata Rave 5.6 through a secure connection and must provide 
a valid username, password, and database ID.  De-identified research data will be shared with the NCI and 
the CaBIG community.  This data may be made available to the public at large. 
 
Data Coordinator Contact Information 
University of Nebraska Medical Center 
 Fred & Pamela Buffett Cancer Center 
Att: Eugene “Gene” Sehi, M.S., CCRP 
986805 Nebraska Medical Center 
Omaha, NE 68198-6805 
FAX: (402) 559-5669 
Ph: (402) 559-8514 
Email:  esehi@unmc.edu 
 
NCI Contact Information 
Email: ncicb@pop.nci.nih.gov 
Local: 301-451-4384    Toll free: 888-478-4423 
 
12.0 
PATIENT CONSENT 
12.1 Human Subjects Research Protection Training 
All personnel involved in this research project will have completed the OHRP-approved computer based 

 
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training course on the Protection of Human Research Subjects. All clinical and correlative research included 
in this application will have approval by the institutional review board. 
 
12.2 Study Population 
Patients are from all socio-economic groups and will be entered into the study without bias with respect to 
gender or race. Attempts will be made to recruit minorities. No vulnerable subjects will be included in the 
study. 
12.3 Sources of Material 
Pathology material (frozen tissue if available, if not then 5-6 unstained slides or a block) must be reviewed, 
and the diagnosis confirmed by University Nebraska Medical Center pathology department as outlined in 
the protocol.(retrospectively) 
 
12.4 Recruitment and Informed Consent 
Patients with an initial diagnosis of locally advanced pancreatic carcinoma seen and evaluated at The 
Nebraska Medical Center (TNMC) will be available for recruitment These patients will be informed of 
the nature of this study, and will be asked to participate on a voluntary basis after informing them of the 
possible risks and benefits of the study. A number of public registries may be accessible to health care 
providers and prospective subjects as listed below. 
 
National Library of Medicine - http://clinicaltrials.gov (NCT01336933) 
National Cancer Institute - http://www.cancer.gov (NCI-2011-00254) 
12.5 Subject Competency 
Subjects will be eligible to participate in the study only if they are competent to give informed consent. A 
subject that the investigators judges to be incompetent will not be enrolled. 
12.6 Process of Informed Consent 
If the patient chooses to be a participant in this study, informed consent will be obtained by the 
investigators. The study and procedures involved including the risks will be explained in detail to each 
subject. It will be clearly explained to the subject that this is a research study and that participation is 
entirely on a voluntary basis. Subjects will be given the option to discuss the study with a family member, 
friend, counselor or, another physician. The participating investigators will be available to discuss the study 
with them. 
12.7 Subject/Representative Comprehension 
When the process of informed consent is completed, the subject will be asked to state in his/her own words, 
the purpose of the study, the procedures that will be carried out, potential risk, potential benefits to the 
subject, the alternatives and the right to withdraw from the study. If there is any indication that a given 
subject's comprehension is anything less than accurate, the points of confusion will be discussed and 
clarified. 
12.8 Information Purposely Withheld. 

 
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The results of the tests done solely for research purposes will not be disclosed to the subject. No other 
information will be purposely withheld from the subject. 
 
 
12.9 Potential Benefits of the Proposed Research to the Subjects 
It is anticipated that the use of neoadjuvant therapy in this patient population would result in greater tumor 
response and possibly prolong survival.  The neoadjuvant therapy might convert patients with locally 
advanced disease to a resectable status.  
12.10 Potential Benefits to Society. 
Information obtained from this study may help other patients by contributing to the knowledge of the 
biology of pancreatic cancer, and whether this treatment offers potential advantages over other treatments 
currently available.  
12.11 Potential Risks 
The use of cytototoxic chemotherapy, external beam radiotherapy, and surgical resection are associated 
with numerous potential risks. Combined chemotherapy/radiation is considered a valid treatment option 
for patients with locally advanced pancreatic cancer who are not surgical candidates. Adjuvant therapy 
following surgical resection for pancreatic cancer is considered a valid treatment option. It is believed the 
treatment option outlined in the study will not pose significant additional risks compared to conventional 
treatment. 
12.12 Therapeutic Alternatives 
If  patients choose not to participate in this study they may elect to receive standard therapy as per their 
primary oncologist, which may include surgery, chemotherapy, or radiation, or a combination of these 
approaches. The treatment recommendations may or may not be similar to treatment as described in this 
protocol (pre-operative chemotherapy, followed by external beam radiotherapy and nelfinavir), followed 
by tumor resection and additional chemotherapy). As yet, there is no proven benefit to the use of 
neoadjuvant chemotherapy and chemotherapy/radiation prior to surgery in this patient population, and the 
use of the SRT and nelfinavir as outlined in this protocol document is considered investigational. 
12.13 Risk/Benefit Relationship 
Although there are inherent risks involved because of the use of chemotherapy, radiotherapy in 
combination with surgical resection, we anticipate that patients who receive the treatment phase of the 
protocol will do no worse than expected with standard therapy, and may experience an improved outcome. 
The risk is considered to be acceptable in the setting of cancer. 
12.14 Consent Form Documents 
No information will be purposely withheld from the patients.  The consent document used in this study 
will include the adult consent document. See attached consent form 
 
 

 
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13.0 REFERENCES: 
 
1. 
Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J 
Clin. 2007 Jan-Feb;57(1):43-66. 
2. 
Evans DBAJ WC. Cancer of the pancreas. New York: Lippincott Williams & Wilkins; 2001. 
3. 
Regine WF, Winter KW, Abrams R, Safran H, Hoffman JP, Konski A, et al. RTOG 9704 a phase 
III study of adjuvant pre and post chemoradiation 5-FU vs. gemcitabine for resected pancreatic 
adenocarcinoma. Journal of Clinical Oncology. 2006;ASCO Proc part I 24(18S):4007. 
4. 
Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, et al. Adjuvant chemotherapy 
with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a 
randomized controlled trial. Jama. 2007 Jan 17;297(3):267-77. 
5. 
Yeo CJ, Abrams RA, Grochow LB, Sohn TA, Ord SE, Hruban RH, et al. 
Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation 
improves survival. A prospective, single-institution experience. Ann Surg. 1997 May;225(5):621-33; 
discussion 33-6. 
6. 
Spitz FR, Abbruzzese JL, Lee JE, Pisters PW, Lowy AM, Fenoglio CJ, et al. Preoperative and 
postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for 
adenocarcinoma of the pancreas. J Clin Oncol. 1997 Mar;15(3):928-37. 
7. 
Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, et al. Adjuvant 
radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary 
region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999 
Dec;230(6):776-82; discussion 82-4. 
8. 
Sasson AR WR, Hoffman JP, Ross E, Cooper H, Meropol NJ, Freedman G, Pingpank JF, 
Eisenberg BL. Neoadjuvant therapy for adenocarcinoma of the pancreas: histopathologic effect and 
analysis of outcome. Proc Am Soc Clin Oncol. 2001;20. 
9. 
Yeo CJ CJ, Sohn TA, Lillemoe KD, Pitt HA, Talamini MA, Hruban RH, Ord SE, Sauter PK, 
Coleman J, Zahurak ML, Grochow LB, Abrams RA. Six hundred fifty consecutive 
pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg 
1997;226:248-57. 
10. 
Conlon KC, Klimstra DS, Brennan MF. Long-term survival after curative resection for 
pancreatic ductal adenocarcinoma. Clinicopathologic analysis of 5-year survivors. Ann Surg. 1996 
Mar;223(3):273-9. 
11. 
Benassai G, Mastrorilli M, Quarto G, Cappiello A, Giani U, Forestieri P, et al. Factors 
influencing survival after resection for ductal adenocarcinoma of the head of the pancreas. J Surg Oncol. 
2000 Apr;73(4):212-8. 
12. 
Millikan KW, Deziel DJ, Silverstein JC, Kanjo TM, Christein JD, Doolas A, et al. Prognostic 
factors associated with resectable adenocarcinoma of the head of the pancreas. Am Surg. 1999 
Jul;65(7):618-23; discussion 23-4. 

 
Page 59 of 81 
Version/Version Date: 
4.1 09/14/18 
 
13. 
Willett CG, Lewandrowski K, Warshaw AL, Efird J, Compton CC. Resection margins in 
carcinoma of the head of the pancreas. Implications for radiation therapy. Ann Surg. 1993 
Feb;217(2):144-8. 
14. 
Heinemann V HA, Bock S, Labianca R, Louvet C. Gemcitabine-based cominations vs 
gemcitabine alone in the treatment of advanced pancreatic cance: a meta-analysis of sixteen randomized 
trials. J Clin Oncol 2007. 
15. 
Ren Q, Kao V, Grem JL. Cytotoxicity and DNA fragmentation associated with sequential 
gemcitabine and 5-fluoro-2'-deoxyuridine in HT-29 colon cancer cells. Clin Cancer Res. 1998 
Nov;4(11):2811-8. 
16. 
Grem JL, Quinn MG, Keith B, Monahan BP, Hamilton JM, Xu Y, et al. A phase I and 
pharmacologic study of weekly gemcitabine in combination with infusional 5-fluorodeoxyuridine and 
oral calcium leucovorin. Cancer Chemother Pharmacol. 2003 Dec;52(6):487-96. 
17. 
Pisters PW, Hudec WA, Lee JE, Raijman I, Lahoti S, Janjan NA, et al. Preoperative 
chemoradiation for patients with pancreatic cancer: toxicity of endobiliary stents. J Clin Oncol. 2000 
Feb;18(4):860-7. 
18. 
Breslin TM, Hess KR, Harbison DB, Jean ME, Cleary KR, Dackiw AP, et al. Neoadjuvant 
chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration. Ann 
Surg Oncol. 2001 Mar;8(2):123-32. 
19. 
Pisters PW, Abbruzzese JL, Janjan NA, Cleary KR, Charnsangavej C, Goswitz MS, et al. Rapid-
fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation 
therapy for resectable pancreatic adenocarcinoma. J Clin Oncol. 1998 Dec;16(12):3843-50. 
20. 
Schellenberg D, Goodman KA, Lee F, Chang S, Kuo T, Ford JM, et al. Gemcitabine 
chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. 
Int J Radiat Oncol Biol Phys. 2008 Nov 1;72(3):678-86. 
21. 
Mahadevan A, Jain S, Goldstein M, Miksad R, Pleskow D, Sawhney M, et al. Stereotactic body 
radiotherapy and gemcitabine for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys.  Nov 
1;78(3):735-42. 
22. 
Cengel KA, Voong KR, Chandrasekaran S, Maggiorella L, Brunner TB, Stanbridge E, et al. 
Oncogenic K-Ras signals through epidermal growth factor receptor and wild-type H-Ras to promote 
radiation survival in pancreatic and colorectal carcinoma cells. Neoplasia. 2007 Apr;9(4):341-8. 
23. 
Harari PM, Huang SM. Head and neck cancer as a clinical model for molecular targeting of 
therapy: combining EGFR blockade with radiation. Int J Radiat Oncol Biol Phys. 2001 Feb 1;49(2):427-
33. 
24. 
McKenna WG, Weiss MC, Endlich B, Ling CC, Bakanauskas VJ, Kelsten ML, et al. Synergistic 
effect of the v-myc oncogene with H-ras on radioresistance. Cancer Res. 1990 Jan 1;50(1):97-102. 
25. 
Bernhard EJ, Stanbridge EJ, Gupta S, Gupta AK, Soto D, Bakanauskas VJ, et al. Direct evidence 
for the contribution of activated N-ras and K-ras oncogenes to increased intrinsic radiation resistance in 
human tumor cell lines. Cancer Res. 2000 Dec 1;60(23):6597-600. 
26. 
Gupta AK, Bakanauskas VJ, Cerniglia GJ, Cheng Y, Bernhard EJ, Muschel RJ, et al. The Ras 
radiation resistance pathway. Cancer Res. 2001 May 15;61(10):4278-82. 
27. 
Grana TM, Rusyn EV, Zhou H, Sartor CI, Cox AD. Ras mediates radioresistance through both 
phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein 
kinase/extracellular signal-regulated kinase kinase-independent signaling pathways. Cancer Res. 2002 
Jul 15;62(14):4142-50. 
28. 
Gupta AK, Cerniglia GJ, Mick R, Ahmed MS, Bakanauskas VJ, Muschel RJ, et al. Radiation 
sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using LY294002. Int J 

 
Page 60 of 81 
Version/Version Date: 
4.1 09/14/18 
 
Radiat Oncol Biol Phys. 2003 Jul 1;56(3):846-53. 
29. 
Gupta AK, McKenna WG, Weber CN, Feldman MD, Goldsmith JD, Mick R, et al. Local 
recurrence in head and neck cancer: relationship to radiation resistance and signal transduction. Clin 
Cancer Res. 2002 Mar;8(3):885-92. 
30. 
Deeks SG, Smith M, Holodniy M, Kahn JO. HIV-1 protease inhibitors. A review for clinicians. 
Jama. 1997 Jan 8;277(2):145-53. 
31. 
Stadler RF, Gregorcyk SG, Euhus DM, Place RJ, Huber PJ, Simmang CL. Outcome of HIV-
infected patients with invasive squamous-cell carcinoma of the anal canal in the era of highly active 
antiretroviral therapy. Dis Colon Rectum. 2004 Aug;47(8):1305-9. 
32. 
https://www.pfizerpro.com/brands/viracept.jsp. 
33. 
Kaesar B AD-J, Saifulanwar A , et al. Improved gastrointestinal tolerability of Roche nelfinavir 
625 mg film-coated tablets in comparison with nelfinavir 250 mg film-coated tablets (Viracept).  4th 
International Workshop on Clinical Pharmacology of HIV Therapy, Cannes, ; March 2003; March 2003. 
34. 
Bast RC, Jr., Klug TL, St John E, Jenison E, Niloff JM, Lazarus H, et al. A radioimmunoassay 
using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med. 1983 Oct 
13;309(15):883-7. 
35. 
Yin BW, Dnistrian A, Lloyd KO. Ovarian cancer antigen CA125 is encoded by the MUC16 
mucin gene. Int J Cancer. 2002 Apr 10;98(5):737-40. 
36. 
Berek J, Taylor P, McGuire W, Smith LM, Schultes B, Nicodemus CF. Oregovomab 
maintenance monoimmunotherapy does not improve outcomes in advanced ovarian cancer. J Clin 
Oncol. 2009 Jan 20;27(3):418-25. 
37. 
Berek JS, Taylor PT, Gordon A, Cunningham MJ, Finkler N, Orr J, Jr., et al. Randomized, 
placebo-controlled study of oregovomab for consolidation of clinical remission in patients with 
advanced ovarian cancer. J Clin Oncol. 2004 Sep 1;22(17):3507-16. 
38. 
Gordon AN, Schultes BC, Gallion H, Edwards R, Whiteside TL, Cermak JM, et al. CA125- and 
tumor-specific T-cell responses correlate with prolonged survival in oregovomab-treated recurrent 
ovarian cancer patients. Gynecol Oncol. 2004 Aug;94(2):340-51. 
39. 
Braly P, Nicodemus CF, Chu C, Collins Y, Edwards R, Gordon A, et al. The Immune adjuvant 
properties of front-line carboplatin-paclitaxel: a randomized phase 2 study of alternative schedules of 
intravenous oregovomab chemoimmunotherapy in advanced ovarian cancer. J Immunother. 2009 
Jan;32(1):54-65. 
40. 
McGinn CJ, Zalupski MM, Shureiqi I, Robertson JM, Eckhauser FE, Smith DC, et al. Phase I 
trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced 
pancreatic cancer. J Clin Oncol. 2001 Nov 15;19(22):4202-8. 
41. 
Muler JH, McGinn CJ, Normolle D, Lawrence T, Brown D, Hejna G, et al. Phase I trial using a 
time-to-event continual reassessment strategy for dose escalation of cisplatin combined with 
gemcitabine and radiation therapy in pancreatic cancer. J Clin Oncol. 2004 Jan 15;22(2):238-43. 
42. 
Keall P. 4-dimensional computed tomography imaging and treatment planning. Semin Radiat 
Oncol. 2004 Jan;14(1):81-90. 
43. 
Ford EC, Mageras GS, Yorke E, Ling CC. Respiration-correlated spiral CT: a method of 
measuring respiratory-induced anatomic motion for radiation treatment planning. Med Phys. 2003 
Jan;30(1):88-97. 
44. 
Low DA, Nystrom M, Kalinin E, Parikh P, Dempsey JF, Bradley JD, et al. A method for the 
reconstruction of four-dimensional synchronized CT scans acquired during free breathing. Med Phys. 
2003 Jun;30(6):1254-63. 
45. 
Pan T, Lee TY, Rietzel E, Chen GT. 4D-CT imaging of a volume influenced by respiratory 

 
Page 61 of 81 
Version/Version Date: 
4.1 09/14/18 
 
motion on multi-slice CT. Med Phys. 2004 Feb;31(2):333-40. 
46. 
Rietzel E, Pan T, Chen GT. Four-dimensional computed tomography: image formation and 
clinical protocol. Med Phys. 2005 Apr;32(4):874-89. 
47. 
Vedam SS, Keall PJ, Kini VR, Mostafavi H, Shukla HP, Mohan R. Acquiring a four-dimensional 
computed tomography dataset using an external respiratory signal. Phys Med Biol. 2003 Jan 7;48(1):45-
62. 
48. 
Wink N, Panknin C, Solberg TD. Phase versus amplitude sorting of 4D-CT data. J Appl Clin 
Med Phys. 2006 Winter;7(1):77-85. 
49. 
Litzenberg DW, Balter JM, Lam KL, Sandler HM, Ten Haken RK. Retrospective analysis of 
prostate cancer patients with implanted gold markers using off-line and adaptive therapy protocols. Int J 
Radiat Oncol Biol Phys. 2005 Sep 1;63(1):123-33. 
50. 
Kupelian PA, Willoughby TR, Meeks SL, Forbes A, Wagner T, Maach M, et al. Intraprostatic 
fiducials for localization of the prostate gland: monitoring intermarker distances during radiation therapy 
to test for marker stability. Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1291-6. 
51. 
Kitamura K, Shirato H, Shimizu S, Shinohara N, Harabayashi T, Shimizu T, et al. Registration 
accuracy and possible migration of internal fiducial gold marker implanted in prostate and liver treated 
with real-time tumor-tracking radiation therapy (RTRT). Radiother Oncol. 2002 Mar;62(3):275-81. 
52. 
Imura M, Yamazaki K, Shirato H, Onimaru R, Fujino M, Shimizu S, et al. Insertion and fixation 
of fiducial markers for setup and tracking of lung tumors in radiotherapy. Int J Radiat Oncol Biol Phys. 
2005 Dec 1;63(5):1442-7. 
53. 
de Mey J, Van de Steene J, Vandenbroucke F, Verellen D, Trappeniers L, Meysman M, et al. 
Percutaneous placement of marking coils before stereotactic radiation therapy of malignant lung lesions. 
J Vasc Interv Radiol. 2005 Jan;16(1):51-6. 
54. 
Koong AC, Le QT, Ho A, Fong B, Fisher G, Cho C, et al. Phase I study of stereotactic 
radiosurgery in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004 
Mar 15;58(4):1017-21. 
55. 
Kris MG, Hesketh PJ, Somerfield MR, Feyer P, Clark-Snow R, Koeller JM, et al. American 
Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol. 2006 
Jun 20;24(18):2932-47. 
56. 
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 2006 update of 
recommendations for the use of white blood cell growth factors: an evidence-based clinical practice 
guideline. J Clin Oncol. 2006 Jul 1;24(19):3187-205. 
57. 
Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Bennett CL, Cella D, et al. Use of epoetin in 
patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical 
Oncology and the American Society of Hematology. J Clin Oncol. 2002 Oct 1;20(19):4083-107. 
58. 
Wu EY, Wilkinson JM, 2nd, Naret DG, Daniels VL, Williams LJ, Khalil DA, et al. High-
performance liquid chromatographic method for the determination of nelfinavir, a novel HIV-1 protease 
inhibitor, in human plasma. J Chromatogr B Biomed Sci Appl. 1997 Aug 1;695(2):373-80. 
59. 
Lamotte C, Peytavin G, Farinotti R. Determination of nelfinavir, a potent HIV protease inhibitor, 
and its active metabolite M8 in human plasma by high-performance liquid chromatography with 
photodiode-array detection. J Chromatogr B Biomed Sci Appl. 1999 Dec 10;735(2):159-70. 
60. 
Dailly E, Thomas L, Kergueris MF, Jolliet P, Bourin M. High-performance liquid 
chromatographic assay to determine the plasma levels of HIV-protease inhibitors (amprenavir, indinavir, 
nelfinavir, ritonavir and saquinavir) and the non-nucleoside reverse transcriptase inhibitor (nevirapine) 
after liquid-liquid extraction. J Chromatogr B Biomed Sci Appl. 2001 Jul 15;758(2):129-35. 
 

 
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14.0 DATA FORMS  Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX A 
Criteria Defining Resectability Status 
 
NCCN Clinical Practice Guidelines in Oncology™ Version 2.2011 
RESECTABLE 
HEAD/BODY/TAIL 
1) No distant metastases 
2) No radiographic evidence of superior mesenteric arteries (SMA) and portal vein abutment, distortion, tumor 
thrombus, or venous encasement 
3) Clear fat plane around celiac axis, hepatic artery, and SMA. 
 
BORDERLINE RESECTABLE 
1) No distant metastases 
2) Venous involvement of SMV/portal vein demonstrating tumor abutment with impringement and narrowing of 
lumen, encasement of the SMV/portal vein but without encasement of the nearby arteries, or short segment 
venous occlusion resulting from either tumor thrombus or encasement but with suitable vessel proximal and 
distal to the area of vessel involvement, allowing for safe resection and reconstruction. 
3) Gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct 
abutment of the hepatic artery, without extension to the celiac axis. 
4) Tumor abutment of the SMA not to exceed greater than 180 degrees of the circumference of the vessel wall. 
 
UNRESECTABLE 
HEAD 
1) Distant metastases  
2) Greater than 180 degrees SMA encasement, any celiac abutment 
3) Unreconstructable SMV/portal occlusion 
4) Aortic invasion or encasement 
BODY 
1) Distant metastases   
2) SMA or celiac encasement greater than 180 degrees 
3) Unreconstructable SMV/portal occlusion 
4) Aortic invasion 
TAIL 
a. Distant metastases  
b. SMA or celiac encasement greater than 180 degrees 
        NODAL STATUS 
1) Metastases to lymph nodes beyond the field of resection should be considered unresectable. 
 
 
 
 
 

 
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APPENDIX B 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

 
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APPENDIX C 
Eligibility Checklist 
Date Completed: 
 
Institution: UNMC 
Eppley Cancer Center 
Patient ID:  
Date of Birth 
IRB# 441-13   Title: A Phase II Study of Neoadjuvant 
Chemotherapy with and without Immunotherapy to CA125 
(Oregovomab) followed by Hypofractionated Stereotactic 
Radiotherapy and Concurrent HIV Protease Inhibitor Nelfinavir 
in Patients with Locally Advanced Pancreatic Cancer 
UNMC MRN:  
Last Name: 
First Name: 
Gender:  [  ] M  [  ] F 
Race:  [  ] White 
[  ] Black        [  ] Hispanic 
[  ] Asian 
[  ] Native American [  ] Other 
[  ] Unknown 
Zip Code/country (if not 
USA):  
Primary method of payment information:  
 
Inclusion Criteria:  Response should be YES 
Yes    No      N/A 
1. Pathologically confirmed adenocarcinoma of the pancreas.  Patients 
have resectable,  borderline resectable disease, or unresectable disease 
with no evidence of distant metastases or peritoneal disease (Resectable or 
borderline resectable disease is defined in Appendix A).  The maximum 
dimension of the tumor must be ≤  10 cm. 
[  ]     [  ]    [  ] 
1. 
2. Is the patient 19 years of age or older?  Enter Age:___ 
[  ]     [  ]    [  ] 
3.  Is the Karnofsky Performance Status 60% or better? Enter PS: _______ 
[  ]     [  ]    [  ] 
4. Is the patient who received chemotherapy > 5 years ago for malignancies 
other than pancreatic cancer eligible, provided that chemotherapy was 
completed > 5 years ago and that there is no evidence of the second 
malignancy at the time of study entry? 
[  ]     [  ]    [  ] 
5. Is the patient who received radiation therapy > 5 years ago for 
malignancies other than pancreatic cancer and whose radiation therapy 
field is not overlapping with the 20% isodose line of current radiation field 
eligible, provided that radiation therapy was completed > 5 years ago and 
that there is no evidence of the second malignancy at the time of study 
entry? 
[  ]     [  ]    [  ] 
6. All malignant disease must be able to be encompassed within a single 
irradiation field? 
[  ]     [  ]    [  ] 

 
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7. Is the patient disease radiographically assessable ? 
[  ]     [  ]    [  ] 
8. Is the absolute neutrophil count 1,500 per mcL or higher and the platelet 
count is 100,000 per mCL or higher?  
          Enter ANC: ______  Enter Platelet count: ________ 
[  ]     [  ]    [  ] 
9. Is the serum creatinine at or below 2 mg/dL and total bilirubin at or below 
2.0 mg per dL in the absence of biliary obstruction?(If the patient has biliary 
obstruction, biliary decompression will be required. Either endoscopic 
placement of a biliary stent or percutaneous transhepatic drainage is 
acceptable. Once biliary drainage has been established, institution of 
protocol therapy may proceed when the total bilirubin falls to 4.0 mg/dL or 
lower.)   Enter creatinine: ______  Enter bilirubin: ______ 
[  ]     [  ]    [  ] 
10. The patient is aware of the neoplastic nature of his/her disease and 
willingly provide written, informed consent after being informed of the 
procedure to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side-effects, risks, and discomforts. 
[  ]     [  ]    [  ] 
11. No prior therapy with the exception of 1 cycle of chemotherapy based 
on current diagnosis and clinical condition.  
[  ]     [  ]   [  ] 
12. Patients must have CA125 level ≥10 to participate in the 
immunotherapy aspect of the trial and receive oregovomab. If the patient 
has CA125 > 10 who is not eligible to receive oregovomab (e.g. allergic to 
the drug) but is eligible for the rest of treatment, this patient should be 
accrued to the part of protocol without oregovomab. 
[  ]     [  ]   [  ] 
 
Exclusion Criteria: Response should be NO 
 
Yes No N/A 
1. Patient cannot undergo staging laparoscopy and marker implantation 
(which may consist of a surgical clip, a gold clip or a common bile duct 
stent next to the tumor)?  For example, this may include patients with a 
prior history of multiple abdominal operations in which laparoscopy may 
not be technically feasible or potentially harmful. Markers may be 
implanted by Interventional Radiology if not implanted during staging 
laparoscopy. 
[  ] [  ] [  ] 
2. Does the patient have known allergy to murine proteins or had a 
documented anaphylactic reaction or allergy to any of chemotherapy 
agents used in this protocol, oregovomab, or to antiemetics appropriate for 
administration in conjunction with protocol-directed therapy? 
[  ] [  ] [  ] 
3. Does the patient have a history of uncontrolled inter-current illness 
including, but not limited to ongoing or active infection requiring 
intravenous antibiotics, symptomatic congestive heart failure, unstable 
angina pectoris, or serious, uncontrolled cardiac arrhythmia, that might  
jeopardize the ability of the patient to receive the chemotherapy program 
outlined in this protocol with reasonable safety? 
[  ] [  ] [  ] 
4. Is the patient pregnant or breast feeding? 
[  ] [  ] [  ] 
5. Does the patient have a history of prior malignancy except for 
adequately treated basal cell or squamous cell skin cancer, adequately 
treated noninvasive carcinomas, or other cancers from which the patient 
has been disease-free for at least 5 years? 
[  ] [  ] [  ] 

 
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6. Does the patient have active duodenal ulcer or bleeding or history of a 
gastrointestinal fistula or perforation or other significant bowel problems 
(severe nausea, vomiting, inflammatory bowel disease and significant 
bowel resection)? 
[  ] [  ] [  ] 
7. Does the patient known to have a HIV infection, or hepatic 
insufficiency?  
[  ] [  ] [  ] 
8. Is the patient unable to take oral medications? 
[  ] [  ] [  ] 
9. Is the patient may receiving or have they received any other 
investigational agents during/or within 1 month prior to treatment with 
Oregovomab or Nelfinavir? 
[  ] [  ] [  ] 
10.  Does the patient have an active autoimmune disease (e.g., 
rheumatoid arthritis, systemic lupus erythematosus (SLE), ulcerative colitis, 
Crohn's Disease, multiple sclerosis (MS), ankylosing spondylitis)? 
 
[  ] [  ] [  ] 
11. Does the patient have a history of a recognized acquired, hereditary, or 
congenital immunodeficiency disease including cellular  
immunodeficiency’s, hypogammaglobulinemia or dysgammaglobulinemia? 
[  ] [  ] [  ] 
12. Is the patient receiving the following drugs that are contraindicated with 
NFV?      
 
 
[  ] [  ] [  ] 

 
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13. Is the patient receiving the following drugs? If Yes, they will be clinically 
evaluated as to whether dosage/medication can be changed to permit 
patient on study. 
 
 
[  ] [  ] [  ] 
NOTE: All questions regarding eligibility for potential subjects should be directed to the UNMC 
Coordinator at 402-559-4726 or 402-559-5286.   
Eligibility: [  ] Patient satisfies all criteria 
     [  ] Patient not formally eligible, but admitted to this study because (state reason): 
 
_____________________________________________________________________________ 
 
_____________________________________________________________________________ 
 
 
 
 
ELIGIBILITY reviewed and confirmed.  
 
Investigator Signature _______________________Date_____________        
 
Printed Name of Investigator:  __________________________  
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX D 
SPECIMEN REQUIREMENT AND MEASUREMENT OF IMMUNOLOGICAL PARAMETERS 
Patients who have CA125 level ≥10 will participate in the immunotherapy and immunologic assessment 
aspect of the trial and receive Oregovomab. A Blood Draw for immunological assessment of Oregovomab 
will be done Pre-chemotherapy,  Prior to second infusion for the first 6 obtainable patients, Pre-SRT, Pre-
surgery, and then prior to restarting chemotherapy after surgery/post restaging if not resectable and 3 weeks 
post cycle 7 chemotherapy (week 12) or end of study. 
1. Specimen Requirement 
Two serum collection tubes will be collected at each of these time points:  Pre-chemotherapy, Prior to 
second infusion for the first 6 obtainable patients , Pre-SRT, Pre-surgery, and then prior to restarting 
chemotherapy after surgery/post restaging if not resectable and 3 weeks post cycle 7 chemotherapy (week 
12) or end of study. 
 
Five whole blood collection tubes will be collected at each of these time points: Pre-chemotherapy,  Prior to 
second infusion for the first 6 obtainable patients, Pre-SRT, Pre-surgery, and then prior to restarting 
chemotherapy after surgery/post restaging if not resectable and 3 weeks post cycle 7 chemotherapy (week 
12) or end of study. 
 
An excess tumor tissue sample for immunological assessment of Oregovomab will be obtained post 
sample after the surgical resection and delivered to Dr. Hollingsworth’s lab at UNMC.  
 
Specimen 
Requirements  
 
Collect Specimen From 
The Patient 
 
Ship Specimens  
Whole Blood  
Five- 10mL Green top 
(heparin) tubes  
              and  
Serum  
Two - 10mL Red Top 
(plain) tubes 
 
Pre-chemotherapy,  Prior to 
second infusion for the first 
6  obtainable patients, Pre-
SRT, Pre-surgery, and then 
prior to restarting 
chemotherapy after 
surgery/post restaging if 
not resectable and 3 weeks 
post cycle 7 chemotherapy 
(week 12) or end of study. 
  
 
Please give all specimens the day of 
collection to Dr. Hollingsworth’s 
lab at UNMC.  They will process 
the specimens and send the 4 Green 
top tubes and 1 red tope tube at 
room temperature to the 
Immunologic Monitoring 
Laboratory using the supplied 
shipping kits no shipments sent on 
fridays.  The rest of the sample will 
be processed by Dr. 
Hollingsworth’s lab at UNMC 
Excess tumor tissue 
sample for 
immunological 
assessment of 
Oregovomab  
post sample after the 
surgical resection 
Dr. Hollingsworth’s lab at UNMC 

 
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Blood must be collected and must be shipped the day of collection to the Immunologic Monitoring 
Laboratory do not draw specimens on Friday because the receiving lab is not able to process the specimens 
on the weekend.  It is extremely important that the specimens reach the Immunologic Monitoring 
Laboratory for processing within 24 hours of collection.    
 
Isolated peripheral blood mononuclear cells (PBMNCs) from whole blood should be cryopreserved 
according to SOP provided by the sponsor and a sample containing at least 10 x 106 PBMNCs from each 
specimen shipped to the Sponsor designated lab (University of Pittsburgh Immune Monitoring Lab).   
 
Please Contact Kamiya Mehla in Dr. Hollingsworth’s lab for specimen retrieval.   
Dr. Hollingsworth’s lab will send the specimens to the University of Pittsburgh Immune Monitoring Lab. 
 
Kamiya Mehla, PhD 
University of Nebraska Medical Center 
DRC II 4067 
Omaha, Nebraska 5950 
Tel: 402-559-4609 
Cell: 858-699-5198 
 
In her absence Tom Caffery  
Tel: 402-559-4609 
 
To obtain study blood kits: 
Sharon Semberse at the University of Pittsburgh Immune Monitoring Lab 
semberse@upmc.edu    
 
2. Serum CA-125 Human Anti-Mouse Antibodies (HAMA) Assay 
The serum CA-125 level and HAMA developed against Oregovomab will be measured in patient serum 
samples using a standardized assay at a central laboratory conducted under GLP.  
3. Cytotoxic CA125 Specific T Cell (CA125 ELISPOT) Assay  
The cytotoxic CA125 antigen specific T cell response will be measured in patient blood samples measured 
using a standardized assay at a central laboratory conducted under GLP. The laboratory will also conduct 
functional assay to evaluate the viability of PBMNCs preparations and the identification of immune cells in 
whole blood including:  central memory and effector memory CD4+ and CD8+ T cells, T regulatory cells, 
Natural Killer cells, B cells and Myeloid-derived suppressor cells. 
 
Samples of the isolated peripheral blood mononuclear cells (PBMNCs) from whole blood will also be 
shipped to the Sponsor designated lab (University of Pittsburgh Immune Monitoring Lab) for testing.   
 
 
 
 

 
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441-13 Study Blood Specimens 
 
 
Five- 10mL Green top (whole blood) tubes 
Two - 10mL Red Top (Serum) tubes 
 
Intended Time 
Date of Sample obtained 
Actual Time sample Drawn 
 
Pre- Rx 
 
 
 
Prior to the second infusion 
for the first 6 obtainable 
patients 
 
 
 
Pre-SRT 
 
 
 
Pre-Surgery 
 
 
 
Prior to resuming chemo s/p 
whipple OR post restaging  
if not resectable 
 
 
 
Week 12 or end of study 
 
 
 
 
 
 
Do NOT obtain specimens on Fridays – Pittsburgh is not able to process them on the weekend. 
 
Please Contact Kamiya Mehla in Dr. Hollingsworth’s lab for specimen retrieval.   
Dr. Hollingsworth’s lab will send the specimens to the University of Pittsburgh Immune Monitoring Lab. 
 
Kamiya Mehla, PhD 
University of Nebraska Medical Center 
DRC II 4067 
Omaha, Nebraska 5950 
Tel: 402-559-4609 
Cell: 858-699-5198 
 
In her absence Tom Caffery  
Tel: 402-559-4609 
 
 
 

 
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APPENDIX E 
 
NCI Common Toxicity Criteria Version 4.0 (CTCAE) 
Active Date: October 1, 2009 
 
Toxicity will be scored using NCI CTC Version 4.0 for toxicity and adverse event reporting.  A copy of the NCI 
CTC Version 4.0 can be downloaded from the CTEP homepage: (http://ctep.info.nih.gov).  All appropriate 
treatment areas have access to a copy of the CTC Version 4.0. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix F:  
 
 
 
 
Numerical Scale 
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
Rate your pain as it is right now (circle the appropriate number) 
 
 
Name _____________________________________ 
 
 
Date _________________________ 
 
 
 
 
Medications please list name and how often they are taken: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX G 
 
FDA MEDWATCH form 
 
Available on-line at http://www.fda.gov/medwatch/SAFETY/3500.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix H: 
 
Medication Information Sheet  
 
Patient Name:                                   Study or MR #: ___________ 
 
Title of protocol:  A Phase II Study of Neoadjuvant Chemotherapy with and without Immunotherapy to 
CA125 (Oregovomab) followed by Hypofractionated Sterotactic Radiotherapy and Concurrent HIV 
Protease Inhibitor Nelfinavir in Patients with Locally Advanced Pancreatic Cancer 
IRB# 441-13 
 
Medication: Viracept (Nelfinavir) HIV protease inhibitor, it is being studied as a radiation sensitizing agent. 
 
How to take your medication: Nelfinaivr 1250 mg should be taken by mouth twice a day until your treating 
physician tells you to stop.  Follow your Medication Calendar that is provided to you by the research nurse. 
 
Things to know about your medication:  
1. Take with food approximately 12 hours apart.  The medication is better absorbed if taken with food 
that is high in fat content. 
2. take 2 hours after or one before antiacids 
3. If you miss a dose – and it is 6 or more hours late do not take the dose. This dose will be omitted 
and you should not take a double the dose at the next time period. Please tell your study coordinator 
if you miss a dose 
4. If you vomit – and it has been less than 30 minutes since you took the dose you may retake the dose. 
Please tell your study coordinator if you take another dose so they can replace the medication.  
5. If you have trouble swallowing the tablets - you may break or crush the tablets and put in food or 
dissolve in a small amount of water. If you dissolve in water the mixture will be cloudy and should 
be consumed immediately.  The glass should be rinsed with water and the rinse swallowed to ensure 
the entire dose is consumed. Avoid using acidic foods and apple sauce for mixing as these will 
increase the bitter taste of the medication.   
Please tell your study coordinator if you break or crush your dose. 
6. If you miss a dose of your medication, it should be taken as soon as possible on the same day.  If it is 
missed for the entire day, it should not be made up.  If a dose is missed make sure to mark it on your 
Medication Calendar (Form B). 
7. Return unused medication to your research nurse for proper procedures for handling and disposal of 
chemotherapy. 
 
Your research nurse is:  ___Sarah Radniecki 
Contact information: phone __402-559-8197____pager __402-888-1957_ 
After hours, nights, weekends and holidays please call 402-559-5600 and ask for the Oncologist on call. 
 
 
 
 

 
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~            ~ 
Sun 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
1  
Nelfinavir # pills ____: 
__________AM 
__________PM 
2  
 
3  
 
4  
 
5  
 
6  
 
7  
 
8  
9  
 
10  
 
11  
 
12  
 
13  
 
14  
 
15  
16  
 
17  
 
18  
 
19  
 
20  
 
21  
 
22  
23  
 
24  
 
25  
 
26  
 
27  
 
28  
 
29  
30  
 
Notes: Daily Twice a day for 5 weeks