Conditions: Pancreatic Cancer
Keywords: Pancreatic Cancer Adenocarcinoma of the Pancreas High Risk Resectable Borderline Resectable Chemotherapy Chemoradiation therapy Oxaliplatin Eloxatin Irinotecan CPT-11 Camptosar 5-FU 5-Fluorouracil Adrucil Efudex Gemcitabine Gemcitabine Hydrochloride Gemzar Radiation Therapy XRT RT External Beam Radiation Therapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 34
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if a chemotherapy combination called modified Folfirinox (or mFolfirinox), followed by a combination of gemcitabine and radiation therapy, followed by surgery, can help to control pancreatic cancer. The safety of this treatment will also be studied.

mFolfirinox consists of 5-FU, oxaliplatin, and irinotecan. These 3 drugs, along with gemcitabine, are each designed to block the growth of cancer cells, which may lead to cancer cell death.

Detailed description:
Study Drug Administration:

You will receive up to 3 phases of study therapy: the systemic chemotherapy phase, the chemoradiation phase, and surgery, if possible.

During the systemic chemotherapy phase, you will receive mFolfirinox 1 time every 2 weeks (Weeks 1, 3, 5, 7, 9 and 11) for 12 weeks. You will receive oxaliplatin by vein over a 2-hour period. After receiving oxaliplatin, you will receive irinotecan by vein over a 90-minute period. After receiving irinotecan, you will then receive 5-FU through a portable pump for the next 46 hours. You will take the portable pump home with you and will receive instructions on how to use it.

You will begin receiving chemoradiation within 6 weeks after you have finished receiving the Week 11 dose of mFolfirinox. However, you will not begin receiving it until you have recovered from side effects of the chemotherapy.

During the chemoradiation phase, you will receive gemcitabine over about 35 minutes 1 time each week for 5 weeks. You will also receive radiation therapy 5 days a week (Monday through Friday) for 5 1/2 weeks (a total of 28 treatments). If you miss any of the days of radiation, they will be made up at the end of treatment so that you will receive the full amount of radiation. You will be given a separate consent form that explains the radiation procedure and the risks it may present.

After the chemoradiation phase, you will not receive any treatment for 4-6 weeks so your body can recover. If after this time the disease has not gotten worse or spread to other parts of the body, you will have surgery to try to remove the tumor. You will be given a separate consent form for the surgery that describes how it is performed and its risks.

If the disease has gotten worse or spread to other parts of the body, you will not be able to have surgery. The study doctor will discuss other therapy options with you.

Study Visits:

At Weeks 1, 3, 5, 7, 9, and 11 of the systemic chemotherapy phase:

* You will have a physical exam, including measurement of your weight and vital signs (blood pressure and heart rate).
* Blood (about 3 tablespoons) will be drawn for routine tests.

Within 4 weeks before beginning the chemoradiation phase:

* You will have CT or MRI scans to check the status of the disease.
* Blood (about 1 tablespoon) will be drawn for tumor marker testing.

At Weeks 1, 2, 3, 4, 5, and 6 of the chemoradiation phase:

* You will have a physical exam, including measurement of your weight and vital signs.
* Blood (about 2-3 tablespoons) will be collected for routine tests. At Week 6, an additional 2 teaspoons of blood will be drawn for CTC testing.

About 4 to 6 weeks after you complete the chemoradiation phase:

* Blood (about 1 tablespoon) will be drawn for tumor marker testing.
* You will have CT or MRI scans to check the status of the disease.

If you are eligible to have surgery after the chemoradiation phase, the following tests and procedures will also be performed:

* Blood (about 4 teaspoons total) will be drawn within 2 weeks before surgery for CTC testing. Blood will also be collected during surgery, if the surgeon thinks it is safe and feasible.
* Tumor tissue collected during a previous procedure will be used for biomarker testing. An additional sample of tumor tissue will be collected from the tissue removed during surgery and used for biomarker testing. Biomarkers are found in the blood/tissue and may be related to your reaction to the study drug.

Length of Study:

You will receive study treatment over the course of up to 30 weeks. You will be taken off study if the disease gets worse, the study doctor thinks it is in your best interest, or if you do not follow the study directions.

You may choose to stop receiving the study treatment at any time. If you choose to stop, you should tell the study doctor or a member of the staff right away. They will make sure that proper procedures are followed and a final visit will be scheduled for your safety.

Follow-up:

Blood (about 2 teaspoons) will be collected for CTC testing 2-3 months after your surgery, if you were one of the first 30 participants enrolled in the study.

You will have a CT or MRI scan of the abdomen and pelvis every 4 months for 2 years to check the status of the disease.

This is an investigational study. 5-FU, oxaliplatin, irinotecan, and gemcitabine are each FDA approved and commercially available to treat different types of cancer:

* 5-FU: pancreatic, gastric, breast, colon/rectum, and skin cancer (basal cell carcinoma)
* Oxaliplatin: colon and rectal cancer
* Irinotecan: colorectal cancer
* Gemcitabine: pancreatic, lung, ovarian, and breast cancer.

The use of these 4 drugs together and in combination with radiation therapy for the treatment of pancreatic cancer is investigational.

Up to 33 patients will be enrolled in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: SYSTEMIC PHASE: Chemotherapy with Oxaliplatin followed by Irinotecan followed by 5-FU. m FOLFIRINOX - oxaliplatin 75 mg/m2 d1 + irinotecan 150 mg/m2 d1 + 5-FUl 2,000 mg/m2 46h continuous infusion, every other week for 6 cycles (12 weeks).

CHEMORADIATION PHASE: This phase will start at least 2 weeks, but no more than 6 weeks after completion of the last cycle of mFOLFIRINOX. Chemoradiation with Gemcitabine: 350 mg/m2 IV over 35 minutes every week for 5 doses beginning day 1 (days 1, 8, 15, 22, 29)

Radiation: External beam radiation therapy will be delivered 5 days/week +/- 2 days over 5.5 weeks with 18-MeV photons. 3D conformal RT, a total dose of 50.4 Gy prescribed to the 95% isodose at 1.8 Gy/fraction (28 fractions) to the GTV + 1.5 cm margin.

SURGERY- At least 4-6 weeks after last dose of Gemcitabine, if no local progression or distant metastasis. Patients whose scans show unequivocal local or distant progression are not candidates for surgery.

Interventions: intervention 1: Oxaliplatin intervention 2: Irinotecan intervention 3: 5-FU intervention 4: Gemcitabine intervention 5: Radiation Therapy
Intervention descriptions: intervention 1: 75 mg/m2 by vein on Day 1 of weeks 1, 3, 5, 7, 9 and 11 for 12 weeks. intervention 2: 150 mg/m2 by vein on Day 1 of weeks 1, 3, 5, 7, 9 and 11 for 12 weeks. intervention 3: 2000 mg/m2 by vein over 46 hour continuous infusion, on Days 1 - 2 during weeks 1, 3, 5, 7, 9 and 11 for 12 weeks. intervention 4: 350 mg/m2 by vein every week for 5 doses beginning Day 1 (days 1, 8, 15, 22, 29). intervention 5: External beam radiation therapy delivered 5 days/week +/- 2 days over 5.5 weeks with 18-MeV photons. 3D conformal RT, a total dose of 50.4 Gy 1.8 Gy/fraction (28 fractions).

Protocol document:
Prot_SAP_000.pdf: 
Protocol 2011-1208 
April 27, 2017  
Page 1 of 38 
 
 
A Phase II Study of Preoperative Systemic Chemotherapy (modified FOLFIRINOX) 
followed by Radiation therapy for Patients with High Risk Resectable and Borderline 
Resectable Adenocarcinoma of the Pancreas 
 
 
Table of Contents 
1.0 
Objectives 
2 
 
2.0 
Background and Rationale  
 
 
 
 
 
2 
 
3.0 
Background Drug Information 
4 
 
4.0 
Patient Eligibility 
 
 
 
 
                                  12 
 
5.0 
Treatment Plan                    
 
 
                                  14 
 
6.0 
Pretreatment Evaluation 
 
 
 
                                  21 
 
7.0 
Evaluation During Preoperative Treatment         
                      21 
 
8.0 
Evaluation After Completion of Surgery  
 
 
          21
 
9.0 
Criteria for Discontinuing Therapy  
 
 
 
          22 
 
10.0 
Correlative Studies                                       
 
 
          22 
 
11.0 
Statistical Considerations  
 
 
 
 
          23 
            12.0     Data and Protocol Management                                                              24 
            13.0     Adverse Event Reporting Requirements                                                25               
Appendix A   Tables 8 and 9—Comparison of the Past Neoadjuvant Clinical 
Trials at University of Texas MD Anderson Cancer Center                                26 
 
Appendix B   ECOG Performance Status      
 
 
 
            29 
 
Appendix C  MD Anderson IRB Policy--Reporting Serious Adverse Events   30 
 
Appendix D  New York Health Association Classification of Heart Disease   33  
Appendix E ApoCell Lab Analysis                         
 
 
            34 
 
Appendix F 
Specimen Submission Form             
 
 
            37 
 
 
 
 
 
 
 
 
 
 
             
 
Study Chair:   
Gauri Varadhachary, MD 
Co-Chairs: 
 
Robert Wolff, MD 
Matthew H. Katz, MD 
 
 
 
Department of Surgical Oncology, Division of Surgery and Department of Gastrointestinal Medical Oncology, 
Division of Cancer Medicine, M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030. 


Protocol 2011-1208 
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A Phase II Study of Preoperative Systemic Chemotherapy (modified FOLFIRINOX) 
followed by Radiation therapy for Patients with High Risk Resectable and Borderline 
Resectable Adenocarcinoma of the Pancreas 
 
 
 
1.0 
OBJECTIVES 
 
1.1  
Primary Objective 
 
To assess resectability rate in patients treated with preoperative modified FOLFIRINOX (5-
fluorouracil, oxaliplatin and irinotecan) chemotherapy followed by gemcitabine -based 
chemoradiation therapy for borderline resectable adenocarcinoma of the pancreas. 
 
1.2 
Secondary Objectives 
To assess margin resection rate (R0 vs. R1) in these patients 
To assess disease free survival (DFS) and overall survival (OS) 
To assess patterns of local and distant failure 
To evaluate correlative studies including DPC4 staining and circulating tumor cells (CTC) 
and CT based imaging biomarker  
 
 
2.0 BACKGROUND AND RATIONALE 
 
2.1   
Borderline resectable pancreatic cancer is an important, emerging entity with improvement in 
imaging techniques. Rigorous criteria that define “borderline resectable” pancreatic cancer 
allow for appropriate patient accrual to clinical trials examining the utility of chemotherapy 
and/or chemoradiation delivered prior to pancreatic resection for exocrine cancer. 
Radiographic criteria for borderline resectable pancreatic cancer are defined as follows 
(patient may have one or more of the following criteria): 
 Tumor abutment of <180degrees (< 50% of the vessel circumference) of the superior 
mesenteric artery (SMA),  
 Short segment abutment or encasement (> 50% of the vessel circumference) of the 
common hepatic artery (typically at the gastroduodenal artery origin),  
 Superior mesenteric vein (SMV) narrowing or impingement or segmental venous 
occlusion with a patent vessel above and below suitable for reconstruction. 
Additionally patients with a high CA19-9 (>500), indeterminate liver or peritoneal nodules, 
and large peripancreatic lymph nodes are considered high risk for surgery even in the 
presence of operable disease and fit the criteria for borderline resectability. 
 
2.2  
The rationale for pursuing preoperative chemotherapy and chemoradiation treatment for 
patients with borderline resectable pancreatic cancer includes: (1) potential for down staging 
in order to maximize the chances for a margin negative (R0) resection, (2) treating 
micrometastatic disease early, (3) giving “adjuvant” therapy in a “neoadjuvant” setting when 
it is better tolerated, and (4) using this approach to gauge the aggressiveness of the cancer 


Protocol 2011-1208 
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and thereby select patients for surgery who have the greatest likelihood of a favorable 
postoperative outcome especially given the morbid nature of the surgery. Data also suggests 
that preoperative chemoradiation may decrease the incidence of pancreaticojejunal 
anastomotic fistula, the most common complication following pancreaticoduodenectomy or 
distal pancreatectomy. 
 
2.3  
Patients with borderline resectable pancreatic cancer are poor candidates for upfront surgery 
because they are at a very high risk for margin positive resection with initial surgery. Patients 
with margin positive resection do poorly with a life expectancy between 8-12 months, which 
is no different from patients with locally advanced pancreatic cancer. Therefore, we favor a 
treatment schema that incorporates preoperative (neoadjuvant) therapy with systemic 
chemotherapy and chemoradiation and this notion has been embraced by several institutions 
and high volume pancreatic cancer centers. Patients whose tumors show radiographic 
stability or regression often accompanied by an improvement in serum tumor markers are 
candidates for surgery. Patients are typically treated with preoperative therapy for 4-6 months 
prior to consideration of surgery. 
 
2.4 
We have successfully completed five preoperative trials at M.D. Anderson Cancer Center 
(Appendix A, Tables 8and 9) for resectable pancreatic cancer. The current treatment schema 
for borderline resectable cancer builds upon our previous work with preoperative 
chemoradiation for resectable disease (protocols ID98-020, ID01-341).  To summarize, we 
have enrolled a total of 176 patients on the last two gem-based protocols for resectable 
pancreatic cancer and have significant experience with this regimen. The most common 
cause of patients not going to surgery was metastatic disease and only 1 out of 176 patients 
had local progression that precluded surgery. Also the overall median survival of 22.7 
months and 17.4 months as well as the survival of 34 and 31 months in resected patients is 
very encouraging and better than historical controls.  
 
2.5 
Patients with borderline resectable pancreatic cancer are candidates for a prolonged course of  
 
systemic therapy followed by chemoradiation. Given the high rate of systemic relapse, the 
“most encouraging” systemic therapy currently available would be applicable in this 
situation. In the recent phase 3 study (NEJM), Conroy and colleagues reported on 
FOLFIRINOX superiority over gemcitabine in the treatment of advanced pancreatic cancer. 
The group randomly assigned 342 patients with an Eastern Cooperative Oncology Group 
performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a 
greater severity of illness) to receive FOLFIRINOX or gemcitabine. Six months of 
chemotherapy were recommended in both groups in patients who had a response. The 
primary end point was overall survival. The median overall survival was 11.1 months in the 
FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for 
death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free 
survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine 
group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The 
objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the 
gemcitabine group (P<0.001).  
 


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2.6  
In this trial we propose systemic therapy with mFOLFIRINOX followed by chemoradiation 
for patients with upfront high risk resectable or borderline resectable pancreatic cancer to 
potentially maximize their chance of resectability and potentially improved disease free 
survival and overall survival after optimal preoperative therapy.   
We plan to start with a 20% dose reduction and no 5-FU and leucovorin bolus for this trial 
(mFOLFIRINOX). Dropping the bolus decreases the toxicity and there is a perennial national 
shortage of leucovorin which makes it a challenge as well. 
 
 
3.0 
BACKGROUND DRUG INFORMATION 
 
3.1 
5FU 
 
Fluorouracil injection, an antineoplastic antimetabolite, is a sterile, nonpyrogenic 
injectable solution for intravenous administration.  
 
3.1.1 Chemistry 
Chemically, fluorouracil, a fluorinated pyrimidine, is 5-fluoro-2,4 (1H,3H)- 
pyrimidinedione. It is a white to practically white crystalline powder which is 
sparingly soluble in water.  
 
3.1.2 Clinical Pharmacology:  
 
There is evidence that the metabolism of fluorouracil in the anabolic pathway blocks 
the methylation reaction of deoxyuridylic acid to thymidylic acid. In this manner, 
fluorouracil interferes with the synthesis of deoxyribonucleic acid (DNA) and to a 
lesser extent inhibits the formation of ribonucleic acid (RNA). Since DNA and RNA 
are essential for cell division and growth, the effect of fluorouracil may be to create 
a thymine deficiency which provokes unbalanced growth and death of the cell. The 
effects of DNA and RNA deprivation are most marked on those cells which grow 
more rapidly and which take up fluorouracil at a more rapid rate. Following intravenous 
injection, fluorouracil distributes into tumors, intestinal 
mucosa, bone marrow, liver and other tissues throughout the body. In spite of its 
limited lipid solubility, fluorouracil diffuses readily across the blood-brain barrier 
and distributes into cerebrospinal fluid and brain tissue. 
Seven percent to 20% of the parent drug is excreted unchanged in the urine in 6 
hours; of this over 90% is excreted in the first hour. The remaining percentage of 
the administered dose is metabolized, primarily in the liver. The catabolic 
metabolism of fluorouracil results in degradation products (e.g., CO2, urea and _- 
fluoro-_-alanine) which are inactive. The inactive metabolites are excreted in the 
urine over the next 3 to 4 hours.  
Following intravenous administration of fluorouracil, the meanhalf-life of elimination from 
plasma is approximately 16 minutes, with a range of 8 to 20 minutes, and is dose dependent. 
No intact drug can be detected in the plasma 3 hours after an intravenous injection. 
 
3.1.3 Human Toxicity:   
Stomatitis and esophagopharyngitis (which may lead to sloughing and ulceration), 
diarrhea, anorexia, nausea and emesis are commonly seen during therapy. 


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Leukopenia usually follows every course of adequate therapy with fluorouracil. The 
lowest white blood cell counts are commonly observed between the 9th and 14th 
days after the first course of treatment, although uncommonly the maximal 
depression may be delayed for as long as 20 days. By the 30th day the count has 
usually returned to the normal range. 
Alopecia and dermatitis may be seen in a substantial number of cases. The 
dermatitis most often seen is a pruritic maculopapular rash usually appearing on the 
extremities and less frequently on the trunk. It is generally reversible and usually 
responsive to symptomatic treatment. 
Other adverse reactions are: 
Hematologic: pancytopenia, thrombocytopenia, agranulocytosis, anemia. 
Cardiovascular: myocardial ischemia, angina. 
Gastrointestinal: gastrointestinal ulceration and bleeding. 
Allergic Reactions: anaphylaxis and generalized allergic reactions. 
Neurologic: acute cerebellar syndrome (which may persist following discontinuance 
of treatment), nystagmus, headache. 
Dermatologic: dry skin; fissuring; photosensitivity, as manifested by erythema or 
increased pigmentation of the skin; vein pigmentation; palmar-plantar 
erythrodysesthesia syndrome, as manifested by tingling of the hands and feet 
followed by pain, erythema and swelling. 
Ophthalmic: lacrimal duct stenosis, visual changes, lacrimation, photophobia. 
Psychiatric: disorientation, confusion, euphoria. 
Miscellaneous: thrombophlebitis, epistaxis, nail changes (including loss of nails). 
 
3.1.4 Pharmaceutical Data: Each 10 mL contains 500 mg fluorouracil; pH is adjusted to 
approximately 9.2 with sodium hydroxide. 
Chemically, fluorouracil, a fluorinated pyrimidine, is 5-fluoro-2,4 (1H,3H)- 
pyrimidinedione. It is a white to practically white crystalline powder which is 
sparingly soluble in water 
 
3.1.5 Storage and Stability 
 
Store at  room temperature 15° to 30°C (59° to 86°F). Protect from light.  
 
3.1.6 Route of Administration 
Intravenous continuous infusion at fixed dose rate of 2400mg/m2 over 46 hours  
 
3.1.7 Supplier 
 
Commercially available  
 
 
 
3.2     Oxaliplatin 
 
3.2.1 Chemistry:  
Oxaliplatin is an antineoplastic agent with the molecular formula C8H14N2O4Pt and the 
chemical name of cis-[(1R,2R)-1,2-cyclohexanediamine-N,N’] [oxalato(2-)-O,O’] platinum. 


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Oxaliplatin is an organoplatinum complex in which the platinum atom is complexed with 
1,2-diaminocyclohexane (DACH) and with an oxalate ligand as a leaving group.  
 
 
3.2.2 Clinical Pharmacology 
Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives 
via displacement of the labile 
 
3.2.3 Human Toxicity 
Neuropathy 
Neuropathy was graded using a study-specific neurotoxicity scale, which was different than 
the National Cancer Institute Common Toxicity Criteria, Version 2.0 (NCI CTC) (see 
below).  Oxaliplatin is associated with two types of neuropathy:  
 
• An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, 
occurring within hours or one to two days of dosing, that resolves within 14 days, and that 
frequently recurs with further dosing. The symptoms may be precipitated or exacerbated by 
exposure to cold temperature or cold objects and they usually present as transient paresthesia, 
dysesthesia, and hypoesthesia in the hands, feet, perioral area, or throat. Jaw spasm, 
abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also 
been observed. An acute syndrome of pharyngolaryngeal dysesthesia seen in 1-2% of 
patients is characterized by subjective sensations of dysphagia or dyspnea, without any 
laryngospasm or bronchospasm (no stridor or wheezing).  
 
• A persistent (>14 days), primarily peripheral, sensory neuropathy that is usually 
characterized by paresthesias, dysethesias, hypoesthesias, but may also include deficits in 
proprioception that caninterfere with daily activities (e.g. writing, buttoning, swallowing, and 
difficulty walking from impaired proprioception). Persistent neuropathy can occur without 
any prior acute neuropathy event.  
 
• Pulmonary Toxicity 
Oxaliplatin has been associated with pulmonary fibrosis (0.7% of study patients), which may 
be fatal. In case of unexplained respiratory symptoms such as non-productive cough, 
dyspnea, crackles, or radiological pulmonary infiltrates, Oxaliplatin should be discontinued 
until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.  
 
3.2.4 Potential Drug-Drug Interactions 
No pharmacokinetic interaction between 85 mg/m2 of Oxaliplatin and infusional 5-FU has 
been observed in patients treated every 2 weeks, but increases of 5-FU plasma concentrations 
by approximately 20% have been observed with doses of 130 mg/m2 of Oxaliplatin 
administered every 3 weeks. In vitro, platinum was not displaced from plasma proteins by the 
following medications: erythromycin, salicylate, sodium valproate, granisetron, and 
paclitaxel. In vitro, oxaliplatin is not metabolized by, nor does it inhibit, human cytochrome 
P450 isoenzymes. No P450-mediated drug-drug interactions are therefore anticipated in 
patients.  
 


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Since platinum-containing species are eliminated primarily through the kidney, clearance of 
these products may be decreased by co-administration of potentially nephrotoxic compounds, 
although this has not been specifically studied.  
 
3.2.5 Pharmaceutical Data  
Oxaliplatin is supplied in vials containing 50 mg or 100 mg of oxaliplatin as a sterile, 
preservative-free lyophilized powder for reconstitution. Lactose monohydrate is present as an 
inactive ingredient at 450 mg and 900 mg in the 50 mg and 100 mg dosage strengths, 
respectively.  
 
 
3.2.6 Storage and Stability 
RECONSTITUTION OR FINAL DILUTION MUST NEVER BE PERFORMED WITH A 
SODIUM CHLORIDE SOLUTION OR OTHER CHLORIDE-CONTAINING 
SOLUTIONS. 
The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for 
the 100 mg vial) of Water for Injection, USP or 5% Dextrose Injection, USP. Do not 
administer the reconstituted solution without further dilution. The reconstituted solution must 
be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP.  
After reconstitution in the original vial, the solution may be stored up to 24 hours under 
refrigeration (2-8°C [36-46°F]). After final dilution with 250-500 mL of 5% Dextrose 
Injection, USP, the shelf life is 6 hours at room temperature (20-25°C [68-77°F]) or up to 24 
hours under refrigeration (2-8°C [36-46°F]). Oxaliplatin is not light sensitive.  
 
Oxaliplatin is incompatible in solution with alkaline medications or media (such as basic 
solutions of 5-FU) and must not be mixed with these or administered simultaneously through 
the same infusion line. The infusion line should be flushed with D5W prior to administration 
of any concomitant medication. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration and discarded if present.  
 
3.2.7 Route of Administration 
The recommended dose schedule given every two weeks is as follows:  
Day 1: oxaliplatin 85 mg/m2 IV infusion in 250-500 mL D5W  
  
3.2.8 Supplier 
 
Commercially available  
 
 
3.3. 
Irinotecan 
 
3.3.1. Chemistry 
Irinotecan Injection (irinotecan hydrochloride injection) is an antineoplastic agent of the 
topoisomerase I inhibitor class.  
 
3.3.2 Clinical Pharmacology 
Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the 
enzyme topoisomerase I which relieves torsional strain in DNA by inducing reversible 


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single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-
DNA complex and prevent religation of these single-strand breaks. Current research suggests 
that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during 
DNA synthesis when replication enzymes 
interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan or 
SN-38. Mammalian cells cannot efficiently repair these double-strand breaks. 
 
Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is 
formed from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond 
between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 
1000times as potent as irinotecan as an inhibitor of topoisomeraseI purified from human and 
rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 relative 
to irinotecan varies from 2- to 2000-fold. However, the plasma area under the concentration 
versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN-38 is 95% 
bound to plasma proteins compared to approximately 50% bound to plasma proteins for 
irinotecan (see Pharmacokinetics). The precise contribution of SN-38 to the activity of 
Irinotecan  is thus unknown. Both irinotecan and SN-38 exist in an active lactone form and 
an inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the two 
forms such that an acid pH promotes the formation of the lactone, while a more basic pH 
favors the hydroxyl acid anion form.  
 
3.3.3 Human Toxicity 
 
Overview of Adverse Events 
Gastrointestinal: Nausea, vomiting, and diarrhea are common adverse events following 
treatment with CAMPTOSAR and can be severe. When observed, nausea and vomiting 
usually occur during or shortly after infusion of CAMPTOSAR. In the clinical studies testing 
the every 3-week-dosage schedule, the median time to the onset of late diarrhea was 5 days 
after irinotecan infusion. In the clinical studies evaluating the weekly dosage schedule, the 
median time to onset of late diarrhea was 11 days following administration of 
CAMPTOSAR. For patients starting treatment at the 125-mg/m2 weekly dose, the median 
duration of any grade of late diarrhea was 3 days. Among those patients treated at the 125-
mg/m2 weekly dose who experienced grade 3 or 4 late diarrhea, the median duration of the 
entire episode of diarrhea was 7 days. The frequency of grade 3 or 4 late diarrhea was 
somewhat greater in patients starting treatment at 125 mg/m2 than in patients given a 100-
mg/m2 weekly starting dose (34% [65/193] versus 23% [24/102]; p=0.08). The frequency of 
grade 3 and 4 late diarrhea by age was significantly greater in patients ≥65 years than in 
patients <65 years (40% [53/133] versus 23% [40/171]; p=0.002). In one study of the weekly 
dosage treatment, the frequency of grade 3 and 4 late diarrhea was significantly greater in 
male than in female patients (43% [25/58] versus 16% [5/32]; p=0.01), but there were no 
gender differences in the frequency of grade 3 and 4 late diarrhea in the other two studies of 
the weekly dosage treatment schedule. Colonic ulceration, sometimes with gastrointestinal 
bleeding, has been observed in association with administration of CAMPTOSAR. 
 
Hematology: CAMPTOSAR commonly causes neutropenia, leukopenia (including 
lymphocytopenia), and anemia. Serious thrombocytopenia is uncommon. When evaluated in 


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the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was 
significantly higher in patients who received previous pelvic/abdominal irradiation than in 
those who had not received such irradiation (48% [13/27] versus 24% [67/277]; p=0.04). In 
these same studies, patients with baseline serum total bilirubin levels of 1.0 mg/dL or more 
also had a significantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia 
than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% 
[47/266]; p<0.001). There were no significant differences in the frequency of grade 3 and 4 
neutropenia by age or gender. In the clinical studies evaluating the weekly dosage schedule, 
neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) 
occurred in 3% of the patients; 6% of patients received G-CSF for the treatment of 
neutropenia. NCI grade 3 or 4 anemia was noted in 7% of the patients receiving weekly 
treatment; blood transfusions were given to 10% of the patients in these trials. 
 
Body as a Whole: Asthenia, fever, and abdominal pain are generally the most common 
events of this type. Cholinergic Symptoms: Patients may have cholinergic symptoms of 
rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal 
hyperperistalsis that can cause abdominal cramping and early diarrhea. If these symptoms 
occur, they manifest during or shortly after drug infusion. They are thought to be related to 
the anticholinesterase activity of the irinotecan parent compound and are expected to occur 
more frequently with higher irinotecan doses. 
Hepatic: In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4 liver 
enzyme abnormalities were observed in fewer than 10% of patients. These events typically 
occur in patients with known hepatic metastases. 
 
Dermatologic: Alopecia has been reported during treatment with CAMPTOSAR. Rashes 
have also been reported but did not result in discontinuation of treatment.  
Respiratory: Severe pulmonary events are infrequent. In the clinical studies evaluating the 
weekly dosage schedule, NCI grade 3 or 4 dyspnea was reported in 4% of patients. Over half 
the patients with dyspnea had lung metastases; the extent to which malignant pulmonary 
involvement or other preexisting lung disease may have contributed to dyspnea in these 
patients is unknown. 
Neurologic: Insomnia and dizziness can occur, but are not usually considered to be directly 
related to the administration of CAMPTOSAR. Dizziness may sometimes represent 
symptomatic evidence of orthostatic hypotension in patients with dehydration. 
 
Cardiovascular: Vasodilation (flushing) may occur during administration of CAMPTOSAR. 
Bradycardia may also occur, but has not required intervention. These effects have been 
attributed to the cholinergic syndrome sometimes observed during or shortly after infusion of 
CAMPTOSAR. Thromboembolic events have been observed in patients receiving 
CAMPTOSAR; the specific cause of these events has not been determined. 
 
3.3.4 Potential Drug-Drug Interactions 
In a phase 1 clinical study involving irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) 
in 26 patients with solid tumors, the disposition of irinotecan was not substantially altered 
when the drugs were co-administered. Although the Cmax and AUC0-24 of SN-38, the 
active metabolite, were reduced (by 14% and 8%, respectively) when irinotecan was 


Protocol 2011-1208 
April 27, 2017  
Page 10 of 38 
 
followed by 5-FU and LV administration compared with when irinotecan was given alone, 
this sequence of administration was used in the combination trials and is recommended . 
Formal in vivo or in vitro drug interaction studies to evaluate the influence of irinotecan on 
the disposition of 5-FU and LV have not been conducted. Possible pharmacokinetic 
interactions of CAMPTOSAR with other concomitantly administered medications have not 
been formally investigated. 
 
3.3.5 Pharmaceutical Data 
Each mL of irinotecan Injection contains 20 mg irinotecan (on the basis of the trihydrate 
salt); 45 mg sorbitol; and 0.9 mg lactic acid. When necessary, pH has been adjusted to 3.5 
(range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid.  
 
Irinotecan injection must be diluted prior to infusion. Irinotecan should be diluted in 5% 
Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final 
concentration range of 0.12 to 2.8 mg/mL. The solution is physically and chemically stable 
for up to 24 hours at room temperature (approximately 25°C) and in ambient fluorescent 
lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated 
temperatures (approximately 2° to 8°C), and protected from light are physically and 
chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride 
Injection, USP, is not recommended due to a low and sporadic incidence of visible 
particulates.  
 
3.3.6 Storage and Stability 
Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from light. It is 
recommended that the vial (and backing/plastic blister) should remain in the carton until the 
time of use. 
 
3.3.7 Route of Administration 
Intravenous administration at a dose of 180mg/m2 on day 1  
 
3.3.8 Supplier 
 
Commercially available  
 
3.4       Gemcitabine 
 
3.4.1    Chemistry 
Gemcitabine HCl is 2-deoxy-2, 2-difluorocytidine monohydrochloride (beta isomer). 
 
 
3.4.2    Clinical Pharmacology:  
Gemcitabine pharmacokinetics are linear and are 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 volume or distribution based on patient characteristics or the duration of infusion 
results in changes in half-life and plasma concentrations. 
 


Protocol 2011-1208 
April 27, 2017  
Page 11 of 38 
 
The half-life of gemcitabine for short infusions ranged from 32-94 minutes, and the value for 
long infusions varied from 245-638 minutes, depending on age and gender, reflecting a 
greatly increased volume of distribution with longer infusions.  The lower clearance in 
women and the elderly result in higher concentrations of gemcitabine for any given dose.  
The volume of distribution was increased with infusion duration.  Volume of distribution of 
gemcitabine was 50 L/m2 following infusions lasting <70 minutes, indicating that 
gemcitabine, after short infusions, is not extensively distributed into tissues.  For longer 
infusions, the volume of distribution rose to 370 L/m2, reflecting slow equilibration of 
gemcitabine within the tissue compartments.  The maximum plasma concentrations of dFdU 
(inactive metabolite) were achieved up to 30 minutes after discontinuation of infusions, and 
the metabolite was excreted in urine without undergoing 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.  The effects of significant 
renal or hepatic insufficiency on the disposition of gemcitabine have not been systematically 
assessed. 
 
3.4.3  Human Toxicity:   
Hematologic:  Myelosuppression is the dose-limiting toxicity with gemcitabine, but <1% of 
patients discontinued therapy for anemia, leukopenia, or thrombocytopenia.  Red blood cell 
transfusions were required by 19% of patients.  The incidence of sepsis was less than 1%.  
Petechiae or mild blood loss (hemorrhage), from any cause, were reported in 16% of patients; 
less than 1% of patients required platelet transfusions.  Gastrointestinal:  Nausea and 
vomiting were commonly reported (69%) but were usually mild to moderate.  Severe nausea 
and vomiting (WHO grade 3/4) occurred in <15% of patients.  Diarrhea was reported by 19% 
of patients, and stomatitis by 11% of patients.   Hepatic:   gemcitabine was associated with 
transient elevations of serum transaminases in approximately two-thirds of patients, but there 
was no evidence of increasing hepatic toxicity with either longer duration of exposure to 
gemcitabine or with greater total cumulative dose.  Renal:  Mild proteinuria and hematuria 
were commonly reported.  Clinical findings consistent with the hemolytic-uremic syndrome 
(HUS) were reported in 6/24 patients (0.25%) receiving gemcitabine in clinical trials.  Four 
patients developed HUS on gemcitabine therapy, two immediately post-therapy.  Renal 
failure may not be reversible, even with discontinuation of therapy, and dialysis may be 
required.  Fever:  The overall incidence of fever was 41%.  This is in contrast to the 
incidence of infection (16%) and indicates that gemcitabine may cause fever in the absence 
of clinical infection.  Fever was frequently associated with other flu-like symptoms and was 
usually mild and clinically manageable.  Rash: Rash was reported in 30% of patients.  The 
rash was typically a macular or finely granular maculopapular pruritic eruption of mild-to-
moderate severity, involving the trunk and extremities.  Pruritus was reported in 13% of 
patients.  Pulmonary:  Dyspnea was reported in 23% of patients, severe dyspnea in 3%.  
Dyspnea may be due to underlying disease, such as lung cancer (40% of study population) or 
pulmonary manifestations of other malignancies.  Dyspnea was occasionally accompanied by 
bronchospasm (<2% of patients).  Rare reports of parenchymal lung toxicity consistent with 
drug-induced pneumonitis have been associated with the use of gemcitabine.  Edema: 
 Edema (13%), peripheral edema (20%), and generalized edema (<1%) were reported.  Less 
than 1% of patients discontinued due to edema.  Flu-like Symptoms:   "Flu syndrome" was 
reported for 19% of patients.  Individual symptoms of fever, asthenia, anorexia, headache, 
cough, chills, and myalgia, were commonly reported.  Fever and asthenia were also reported 
frequently as isolated symptoms.  Insomnia, rhinitis, sweating, and malaise were reported 
infrequently.  Less than 1% of patients discontinued due to flu-like symptoms.  Infection:  


Protocol 2011-1208 
April 27, 2017  
Page 12 of 38 
 
Infections were reported for 16% of patients.  Sepsis was rarely reported (<1%).  Alopecia:  
Hair loss, usually minimal, was reported by 15% of patients.  Neurotoxicity:  There was a 
10% incidence of mild parasthesias and a <1% rate of severe parasthesias.  Extravasation:  
Injection-site-related events were reported for 4% of patients.  There were no reports of 
injection-site necrosis.  Gemcitabine is not a vesicant.  Allergic:   Bronchospasm was 
reported for less than 2% of patients.  Anaphylactoid reaction has been reported rarely.  
Gemcitabine should not be administered to patients with a known hypersensitivity to this 
drug.  Cardiovascular:  Two percent of patients discontinued therapy with gemcitabine due 
to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, 
and hypertension.  Many of these patients had a prior history of cardiovascular disease. 
 
3.4.4    Pharmaceutical Data:  
Gemcitabine is supplied as a lyophilized powder in sterile vials containing 200 mg or 1 g of 
gemcitabine as the hydrochloride salt (expressed as the free base), mannitol, and sodium 
acetate.  Drug vials will be reconstituted with normal saline added to the vial to make a 
solution ideally containing 10 mg/mL or less.  The concentration for 200 mg and 1 g vials 
should be nor greater than 40 mg/mL.  An appropriate amount of drug will be prepared with 
normal saline and administered as a continuous infusion at 10mg/m2/min.  Once the drug has 
been reconstituted, it should be stored at room temperature and used within 24 hours. 
 
3.4.5    Storage and Stability 
Store at controlled room temperature (20-250C), should be handled and disposed of in a 
manner consistent with other anti-cancer drugs. 
 
3.4.6  Route of Administration 
Intravenous infusion at fixed dose rate of 10mg/m2/min. 
 
3.4.7   Supplier 
Commercially available. 
 
4.0 
PATIENT ELIGIBILITY 
 
4.1 
INCLUSION CRITERIA: 
 
4.1.1 Cytologic or histologic proof of adenocarcinoma of the pancreas is required prior to 
treatment. Patients with Islet cell tumors are not eligible. 
 
4.1.2 Only untreated patients with high risk pancreatic adenocarcinomas will be eligible for 
the study. For this study, such patients are defined as those who meet one or more of 
the following radiographic or serologic criteria:  
4.1.2.1  Primary tumor that involves the superior mesenteric vein causing a vein 
deformity or segmental venous occlusion with a patent vessel above and below 
suitable for reconstruction. 
4.1.2.2  Primary tumor that involves  <180 degrees of the superior mesenteric artery 
(SMA), celiac axis or any of its branches on CT or MRI 
4.1.2.3  Primary tumor that abuts or encases (> 50% of the vessel circumference) a 
short segment of the common hepatic artery (typically at the gastroduodenal 
artery origin) 


Protocol 2011-1208 
April 27, 2017  
Page 13 of 38 
 
4.1.2.4  Patients with a high CA19-9 (500mg/dl) in the presence of a bilirubin  ≤2.0 
mg/dL. 
4.1.2.5  Radiographic findings consistent with malignant peripancreatic    
lymphadenopathy outside the planned field on CT or MRI 
 4.1.2.6 Radiographic findings of indeterminate liver or peritoneal lesions on CT 
orMRI concerning but not diagnostic of metastatic disease  
 
4.1.3 Patients cannot have known hepatic or peritoneal metastases detected by ultrasound 
(US), CT scan, MRI or laparotomy. 
 
4.1.4 There will be no upper age restriction; patients with Eastern Cooperative Oncology 
Group (ECOG) 0-1 are eligible (See Appendix B - ECOG Performance Status Scale). 
 
4.1.5 Adequate renal, and bone marrow function: 
 
· 
Leukocytes ≥3,000/uL 
 
· 
Absolute neutrophil count  ≥1,500/uL 
 
· 
Platelets ≥100,000/Ul 
 
· 
Serum creatinine ≤ 2.0 mg/dL  
 
4.1.6 Hepatic function (endoscopic or percutaneous drainage as needed) 
 
· 
Total bilirubin ≤ 2 X institutional upper limits of normal (ULN) 
 
· 
AST (SGOT)/ALT (SGPT) ≤ 5 X institutional ULN 
 
4.1.7 Patients must have no fever or evidence of infection or other coexisting medical 
condition that would preclude protocol therapy. 
 
4.1.8 Women of childbearing potential (defined as those who have not undergone a 
hysterectomy or who have not been postmenopausal for at least 24 consecutive 
months) must agree to practice adequate contraception and to refrain from breast 
feeding. 
 
4.1.9 Patients must sign a study-specific consent form, which is attached to this protocol. 
 
4.2 
EXCLUSION CRITERIA: 
 
 
4.2.1 Patients whose tumors are defined as locally advanced cancer or metastatic cancer are  
not eligible. 
 
4.2.2 Unstable angina or New York Heart Association (NYHA) Grade II or greater 
congestive heart failure; multiple comorbidity that preclude a major abdominal 
surgery 
 
4.2.3 Known presence of metastases 
 
4.2.4 Inability to comply with study and/or follow-up procedures 


Protocol 2011-1208 
April 27, 2017  
Page 14 of 38 
 
 
4.2.5 Patients < 18 years of age. 
 
4.2.6 Pregnant women with a positive (blood B-HCG) pregnancy test are excluded from 
this study; 
 
4.2.7 Patients with an active second malignancy with the exception of non-melanoma skin 
cancer.  
 
 
 
5.0 
TREATMENT PLAN 
 
5.1  
Study Schema: We have acquired extensive experience with the mFOLFIRINOX regimen 
and believe the doses as published in ACCORD11 can be toxic with significant hematologic 
toxicities, especially in patients with pancreatic head tumors and stent in place. We plan to 
start with a 20% dose reduction from the reported doses of FOLFIRINOX and no 5-FU and 
leucovorin bolus for this trial  (mFOLFIRINOX). Dropping the bolus decreases the toxicity 
and there is a perennial national shortage of leucovorin which makes it a challenge as well. 
Treatment schema for the various phases of the study shown below: 
 
 
 
 
 
 
SYSTEMIC PHASE:  Chemotherapy with Oxaliplatin followed by Irinotecan followed by 5Fluorouracil. 
 


Protocol 2011-1208 
April 27, 2017  
Page 15 of 38 
 
m FOLFIRINOX -  oxaliplatin 75 mg/m2 d1 + irinotecan 150 mg/m2* d1 + 5-fluorouracil 
2,000 mg/m2 46h continuous infusion, every other week for 6 cycles (12 weeks). After 
calculation, doses can be ‘rounded” to a whole number for safety.  
 
Agent
Dose
Route
Schedule
Oxaliplatin 
75 mg/m2 in 
D5W 500ml
IV infused over 
2 hours.
Day 1 
Irinotecan* 
150 mg/m2 in 
D5W 500ml
IV infused over 
90 minutes
Day 1 
5fluorouracil 
2000 mg/m2  
IV 46 hour 
continuous 
infusion via an 
ambulatory 
pump
Day 1-2 
*Patients with suspected Gilbert’s syndrome may receive 25-50% of this dose of irinotecan 
based on physician discretion for all cycles. 
 
CHEMORADIATION PHASE: This phase will start no more than 6 weeks after 
completion of the last cycle of mFOLFIRINOX.  The 6 weeks may be extended at the 
discretion of the principal investigator.  Chemoradiation with  
 
Gemcitabine:  350 mg/m2 IV over 35 minutes every week for 5 doses beginning day 1 (days 
1, 8, 15, 22, 29) 
 
Radiation:  External beam radiation therapy will be delivered 5 days/week +/- 2 days over 5.5 
weeks with 18-MeV photons.  3D conformal RT, a total dose of 50.4 Gy 
prescribed to the 95% isodose at 1.8 Gy/fraction (28 fractions) to the GTV + 1.5 
cm margin. If any days of radiation are missed, these days may be made up at the 
end of treatment so that the patient will receive the full amount of radiation. 
 
 
 (CA 19-9  and Restaging scans will be performed at the end of the systemic phase and 
chemoradiation phases of the study) 
 
SURGERY– At least 4-6 weeks after the last dose of Gemcitabine if there is no local 
progression or distant metastasis. Patients whose scans show unequivocal local or distant 
progression are not candidates for surgery 
 
Postoperative Therapy:  All patients will get postoperative restaging scans after surgery as 
per institutional standard of care guidelines. No postoperative adjuvant therapy is planned in 
this study.  


Protocol 2011-1208 
April 27, 2017  
Page 16 of 38 
 
 
Schedule of Assessments 
 
 
Baseline 
- within 
6 wks 
prior to 
start of 
tx.  
Systemic Phase 
Recovery 
≤ 6 weeks 
from end of 
Systemic 
Therapy 
Chemo-radiation Phase 
Surgery     
[ 4-6 wk 
post 
Chemo-
XRT] 
2-3 
months 
post 
surgery 
 
Postop 
wk1 
wk3 
wk5 
wk7 
wk9 
wk11 
wk1 
wk2 
wk3 
wk4 
wk5 
wk6 
Physical Exam 
X 
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Imaging/Restaging 
X 
Xa
Xb
xh
Cytology/histology 
X 
CA19-9 
X 
 X j,f
  
Xa
Xb
ECOG 
Performance 
Status 
X 
Vital Signsc  
X
X
X
X
X
X
X
X
X
X
X
X
CBCd 
X 
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Chemistriese 
X 
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Serum 
pregnancy 
test for WOCBP 
X 
mFOLFIRINOX K 
  
X
X
X
X
X
X
XRT i  
  
X
X
X
X
X
X
Gemcitabinen 
X
X
X
X
X
Surgery 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X
CTCg 
X
  
  
  
  
  
  
  
  
  
  
  
  
Xl
Xm
X
Correlative–tissue 
sample  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X
a. within  4 weeks prior to start of treatment 
 
b. at least 4 weeks post chemoxrt treatment but prior to surgery 
 
c. to include height [baseline only], weight, blood pressure, pulse 
 
d. CBC and platelet count 
 
e. Chemistries include BUN, Creatinine, total bilirubin, AST, ALT, alkaline Phosphatase, phosphorus, calcium, glucose, total 
 


Protocol 2011-1208 
April 27, 2017  
Page 17 of 38 
 
protein, albumin, sodium, potassium, CO2 , chloride and magnesium 
f. up to 7 days prior to treatment for week 1 of systemic and chemoradiation phase; for the remaining weeks up to 3 days prior 
to treatment  
 
g. from the first 30 eligible and consenting patients that begin treatment 
 
h.  After completion of surgery, CT scan or MRI of the abdomen and pelvis will be done every four months (+/- 28 days) for 
two years. 
 
i.   External beam radiation therapy will be delivered 5 days/week (Monday-Friday) over 5.5 weeks.  If any days of radiation 
are missed, these days may be made up at the end of treatment so that the patient will receive the full amount of radiation. 
 
j. Optional – may be performed at the discretion of the investigator. 
k. Window,  +/- 2 days for treatment except week 1 
l. Post treatment – pre-surgery CTC collection (within 2 weeks of surgery including day of surgery) 
m. Intraoperative CTC collection is optional for the surgeon based on safety and feasibility of portal vein blood draw. 
n. Window, +/- 1 day for treatment except week 1 
 


Protocol 2011-1208 
April 27, 2017  
Page 18 of 38 
 
 
5.2 
Dose Adjustments: 
 
5.2.1 Dose adjustment for Preoperative Chemotherapy: Dose Adjustments of 
mFOLFIRINOX on Subsequent Treatment Cycles after the toxicity has 
decreased to grade 1 or less (Based on the worst toxicity due to chemotherapy on 
any day of the previous cycle, NCI- Common Toxicity Criteria v.4). 
 
  
Table 1:  Hematologic Toxicities - Dose Adjustment  
 
 
 
ANC 
(X103/L)- as 
noted in 
previous 
cycle 
Platelet (X109/L)- 
as noted in 
previous cycle 
Percent dose of 
mFOLFIRINOX1for 
subsequent cycle 
based on previous  
> 0.91
And        >75
100
0.51-0.90
Or          51-74
75
<0.5
Or          <50
50
1. Percent dosage refers to the dose of drugs on the first day of the cycle. 
2. Patients with ANC </= 0.5 will receive pegfilgrastrim (6 mg SQ on day 3 or 4 of 
chemotherapy). In all other patients, use of pegfilgrastrim is up to the discretion of the 
physician (for initial and subsequent cycles of therapy).  
 
5.2.2  Dose Adjustments for Non-Hematological Toxicity  
 
Table 2:  Non-Hematologic Toxicities - Dose Adjustment  
                
Worst toxicity during cycle
Percent dose of 
mFOLFIRINOX1
0/1
100
2
75
3-4
50
1. Percent dosage refers to the dose of drugs on the first day of the cycle 
 
Note:   
 
1.  The physician should keep reducing the doses ( 25% reduction) in subsequent cycles if      
still faced with significant hematological or non hematological toxicity 
2. Treatment between cycles may be held for up to 4 additional weeks (total 6 weeks 
between cycles) if the patient has not recovered to grade 1 or less hematologic or non 
hematologic toxicity prior to subsequent cycle.  
3.  If deemed to be in the best interest of the patient, at the investigator’s discretion, one of  
     the 3 drugs may be reduced as per table (instead of all 3 drugs) for > grade 2 non-  
     hematologic toxicity.  
 
 
5.2.3  Dose adjustment for specific toxicities 


Protocol 2011-1208 
April 27, 2017  
Page 19 of 38 
 
 
Table 3. Dose adjustment for 5FU and irinotecan for Diarrhea (despite optimal use of 
loperamide). No change in oxaliplatin dose 
 
Worst toxicity 
Dose of 5FU and Irinotecan
Grade 1
Maintain previous dose
Grade 2
75% of previous dose
Grade 3 or 4
50% of previous dose 
 
 
 
Table 4. Dose adjustment for oxaliplatin for neurotoxicity. No change in 5FU and 
irinotecan doses. 
 
Worst toxicity 
Dose of oxaliplatin
Grade 1
Maintain previous dose
Grade > 2
Reduce by one dose level ( i.e. 25% dose 
reduction from last dose/ cycle) 
 
 
 
5.2.4 Dose adjustment for Preoperative Gemcitabine and Concurrent RT 
(chemoradiation phase)  
 
Table  5 shows the dose adjustments for gemcitabine during chemoradiation and counts 
will be monitored every week during chemoradiation.  Nonhematologic toxicities will be 
assessed and doses adjusted accordingly (Table 6).  
 
Table 5:  Hematologic Toxicities - Dose Adjustment of Gemcitabine During 
Gemcitabine/XRT* 
ANC (X103/L) 
Platelets (/mL) 
Percent of Full Dose 
>1.0           and 
0.51-0.99        or 
< 0.5 or  
>100,000 
50,000-100,000 
<50,000 
100 
75 
Hold 
 
 
*Previous experience suggests myelosuppression will not require holding radiation. 
 
Table 6:  Nonhematologic Toxicities - Dose Adjustment of Gemcitabine During 
Gemcitabine/XRT 
 


Protocol 2011-1208 
April 27, 2017  
Page 20 of 38 
 
Grade 
Percent of Full Dose 
0-1 
2 
3-4 
Hospitalization 
100 
75( 
Hold  
Hold 
Note:  For grade 3-4 toxicity, gemcitabine to be restarted after toxicity drops to ≤ grade 2 at 75% 
of the previous dose 
 
Gemcitabine Dose Modifications 
Missed doses of gemcitabine will be omitted rather than made up.  If multiple toxicities are 
seen, administer dose based on greatest reduction required for any single toxicity observed.  
Once reduced, no dose re-escalation of gemcitabine is allowed 
 
Two dose reductions are allowed. If a third reduction is required, patient should discontinue 
gemcitabine unless the investigator deems that continued treatment is in the best interest of the 
patient. 
 
 
5.3  
Standard hydration/antiemetic regimen 
 
 
IV hydration required at the medical or radiation oncologist's discretion.  Standard 
of care orders for premedications and hydration at the discretion of the medical 
oncologist. 
 
5.4  
Radiation Therapy 
 
 
5.4.1 Target Volume and Dose: 
External beam radiation therapy will be delivered 5 days/week +/- 2 days over 5.5 weeks 
with 18-MeV photons.  3D conformal RT, a total dose of 50.4 Gy prescribed to the 95% 
isodose at 1.8 Gy/fraction (28 fractions) to the GTV + 1.5 cm margin. If any days of 
radiation are missed, these days may be made up at the end of treatment so that the 
patient will receive the full amount of radiation. 
 
 
5.4.2    All patients will receive RT per informed consent and will receive AP/PA and lateral 
fields to the pancreas with customized blocking. Simulation should be done with the 
patient in the supine position with “arms up” position.  If any days of radiation are missed, 
these days may be made up at the end of treatment so that the patient will receive the full 
amount of radiation. 
 
 
5.4.3 A CT scan, excretory urogram, or renal nuclear medicine scan must be done before the 
start treatment to define renal function, as at least 2/3 of one kidney needs to be excluded 
from all irradiation fields. 
 
 


Protocol 2011-1208 
April 27, 2017  
Page 21 of 38 
 
5.5    Surgery 
 
5.5. l Surgery will be planned at least 4 weeks after radiation therapy.  
 
 
In the absence of metastases, tumor mobilization and surgical resection will be performed 
as necessary based on standard of care surgery guidelines. Feeding jejunostomy and 
gastrostomy tubes may be placed at the discretion of the operating surgeon and are part of 
standard of care management. 
 
 
5.6.3 5.6 Pathology 
 
Margins assessed: pancreatic, biliary, uncinate and duodenal based on surgical plan and 
standard of care.  All standard of care pathologic data will be recorded.   
 
 
6.0 
PRETREATMENT EVALUATION 
 
Within 6 weeks Prior to Study Enrollment: Patients must have appropriate lab and 
radiographic studies (CXR; CT abdomen and pelvis or MRI; CBC; platelet count; BUN; 
creatinine; bilirubin; AST, ALT, Ca19-9) conducted prior to study enrollment to meet 
eligibility criteria. Patient also must have undergone a (baseline) history and physical 
examination, evaluation of concomittant medications, weight, height, performance status 
measurement. 
 
 
 
7.0 
EVALUATION DURING PREOPERATIVE TREATMENT 
 
During the chemotherapy phase, the attending physician must see each patient every two 
weeks within 3 days prior to each dose of chemotherapy. 
 
The patient will be assessed as follows: 
 
7.1 
Complete blood count (CBC: hemoglobin, hematocrit, red blood cells [RBC], WBC, 
platelets, and differential blood cell counts (neutrophils, bands, lymphocytes, monocytes, 
eosinophils, basophils) within 3 days prior to  each dose of mFOLFIRINOX. 
 
7.2 
Blood chemistries (bilirubin, alkaline phosphatase, ALT, AST, BUN, creatinine, 
phosphorus, calcium, glucose, total protein, albumin, and electrolytes [sodium, 
potassium, CO2, chloride, and magnesium])  Within 3 days prior to each dose 
FOLFIRNOX. 
 
7.3 
Vital signs (blood pressure and pulse rate) on days of infusion treatment. 


Protocol 2011-1208 
April 27, 2017  
Page 22 of 38 
 
  
During chemoradiation phase, the attending physician must see each patient every week (1-3 
days prior to each dose of gemcitabine) with weekly CBC and chemistries .   
 
 
8.0 
EVALUATION AFTER COMPLETION OF SURGERY 
 
8.1. 
The primary endpoint in this study is resection rate. Survival will be followed as a secondary 
endpoint, as measured from the time of histologic or cytologic diagnosis of pancreatic 
adenocarcinoma. Patterns of tumor recurrence will be assessed by obtaining survelliance 
imaging based on standard of care guidelines. 
 
8.2  
After completion of surgery, CT scan or MRI of the abdomen and pelvis will be done every 
four months (+/- 28 days) for two years.  
 
 
 
9.0 
CRITERIA FOR DISCONTINUING THERAPY  
 
 Inability of patient to comply with study requirements 
 Determination by the investigator that it is no longer safe for the patient to continue 
therapy 
 Unresectable or metastatic disease after chemoradiation. 
 Subjects withdraws consent.  
 
10. 
Correlative studies  
 
10.1 Tissue based:  DPC4 (SMAD4) status determination – preoperative (on 
aspiration and biopsy) and after surgery (pathologic tissue) 
 
Background data: Recent rapid autopsy data presented by Dr. Iacobuzio-Donahue and 
colleagues suggest that pancreatic cancers can present with distinct genetic subtypes with 
different patterns of failure. In this study, patients with DPC4 intact tumors were more likely 
to die of locally destructive disease (30% of patients) and those with DPC4 mutated tumors 
with a distant widespread metastatic disease (70%). These distinct patterns of failure (locally 
destructive versus metastatic) were unrelated to clinical stage at presentation, treatment 
history, and histopathologic features.  There is significant interest in understanding if this 
data holds true in patients being treated (prospectively) and eventually use this information to 
guide therapy based on sub-groups of patients (locally destructive or wildly metastatic 
phenotypes). The feasibility of determining DPC4 status on diagnostic cytology specimens 
was tested recently at our institution in patients with locally advanced pancreatic cancer 
using immunohistochemical staining.  
 
We will collect preexisting fine needle aspiration and biopsy specimens (up to 4 unstained 
slides) when available from patients diagnosed with pancreatic cancer at MDACC 


Protocol 2011-1208 
April 27, 2017  
Page 23 of 38 
 
(preoperative) and their final pathology tissue (from pancreas tissue bank, up to 4 unstained 
slides). Immunohistochemistry for DPC4 will be performed on this tissue by Dr. Huamin 
Wang from pathology. This will not impact the therapy decision which is independent of the 
correlative studies. 
 
10.2 Circulating tumor cells measurements:  Preliminary study to evaluate the 
feasibility of measuring CTCs and the role of these cells as a prognostic and/or 
predictive marker in borderline resectable adenocarcinoma of the pancreas. 
 
There is an unmet research need to access pancreatic cancer CTCs from the blood given that 
biopsy of pancreatic cancerous tissue is a significant risk and requires invasive procedures. 
There is an urgent need to improve the diagnosis and treatment of pancreatic cancer patients 
by providing relatively painless, minimally invasive access to patients’ cancer cells from a 
blood sample. In addition, we are keen to evaluate a technology that can detect very low 
concentrations of target cellular material, with the goal of enabling clinicians to discover 
hard-to-detect cancers at a very early stage. CTCs are rare, usually less than 10 cells in one 
milliliter (ml) of blood, making their detection and analysis very difficult by current methods. 
The Veridex CellSearch® CTC IVD test which uses an immunomagnetic method has not 
been able retrieve optimal pancreatic CTCs from the blood and not proven to be a prognostic 
marker in pancreatic cancer.  
 
For isolating CTCs in the blood, we will collaborate with ApoCell, and evaluate its new 
technology (Apostream ™) that may improve the detection of pancreatic tumor cells 
circulating in the blood. Invented by scientists at The University of Texas MD Anderson 
Cancer Center's Laboratory of Diagnostic Microsystems this technology may enable the 
capture of pancreatic CTCs in a live and viable state, enabling post detection testing and 
culturing.  
 
The Apostream ™ technology is based on cell morphology and exploits the fundamental 
differences in form and structure between healthy cells and cancer cells. By exposing the 
patient’s blood sample to a low level electrical field of varying frequencies, enabling us to 
separate the cancer cells, based on their inherently different properties, from all other cells. 
This process is called dielectrophoresis field flow fractionation (DEP-FFF).   We are hopeful 
that with this technology, if we are able to capture sufficient viable pancreatic CTCs, it will 
allow for protein biomarker analysis, mutation detection and culturing of these rare cells for 
in vitro drug testing to accelerate the drug development process. 
 
Blood will be drawn at 4 time points from 30 patients:  
 pretreatment (baseline),  
 post treatment-presurgery ( within 2 weeks of surgery including day of surgery)  
 during surgery (portal vein blood) and  
 2-3 months after surgery.  
 
Patients will be consented for all the time points as shown above, although intra-operative CTC 
collection (time point # 3) is optional for the surgeon based on safety and feasibility of portal 
vein blood draw during pancreatectomy.  


Protocol 2011-1208 
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This pilot study will include a total of 30 patients to quantify CTCs by theApoStreamTM  system. 
In the first 10 patients, in addition to the ApoStreamTM methodology,quantification of CTCs will 
also be performed by the CellSearch® platform, and the two techniques will be compared.  
 
The first ten (10) consented individuals will each have two (2) blood tubes drawn:  
8 mL BD Vacutainer® CPT Citrate Blood Collection tube,  and 10 mL 
CellSave® blood tube. 
 
The subsequent twenty (20) consented individuals will each have one (1) 8 mL 
BD Vacutainer® CPT Citrate Blood Collection tube drawn.  ApoCell, Inc.will 
serve as the laboratory for analytical procedures.  
 
 
 
Analyses:  
First 10 patients: Blood will be subjected to CTC enrichment using CellSearch® CTC kit 
(CellSave® tube) and the ApoStream™ platform (CPT tube). CTCs isolated by CellSearch® 
will be analyzed using the CellTracks® Analyzer II, and the final CTC images will be scored by 
a Veridex, LLC certified analyst. CTC enumeration will be reported as number of EpCAM 
enriched, cytokeratin CK+, CD45- and DAPI+ cells per 7.5mL of blood.  
CTCs isolated by the CTCs isolated by ApoStream™ platform will be enumerated following 
immunofluorescent staining with antibodies against Cytokeratin (CK), CD45, and CA-19-9 
(pancreatic cell marker). The following will be analyzed and reported: 1) total number of CA-19-
9+/CD45-/DAPI+ cells, 2) total number of CK+/CD45-/DAPI+ cells, 3) total number of CK-
/CD45-/DAPI+ cells , and 4) total number of CK+/CD45+/DAPI+ cells.  
 
Remaining 20 patients: CTCs isolated on the ApoStream™ platform will be enumerated 
following immunofluorescent staining with antibodies against Cytokeratin (CK), CD45, and CA-
19-9 (pancreatic cell marker). The following will be analyzed and reported: 1) total number of 
CA-19-9+/CD45-/DAPI+ cells, 2) total number of CK+/CD45-/DAPI+ cells, 3) total number of 
CA-19-9+/CK+/CD45-/DAPI+ cells. We will also plan to evaluate for Kras mutation and 
SMAD4 deletions in the CTCs of these 20 patients and compare it to the pancreas cancerous 
tissue (preoperative specimen when available and the pathologic specimen).  
 
Any residual blood will be discarded. Slides with cells extracted from patient blood will be 
discarded.  
 
Note: If during the processing phase, any of the tubes break, we will continue to proceed with 
drawing the other time points and proceed with analyses of the intact tubes ( ones already 
drawn). Also, if the patient does not proceed with surgery (and we are able to get tubes for the 2 
time points prior to surgery, these will be analyzed). Also, if at any time point (including first), if 
blood not drawn for CTC,  CTC can still be drawn at remaining time points  
 
10.3 Imaging correlative study 


Protocol 2011-1208 
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Page 25 of 38 
 
We have previously developed quantitative imaging biomarkers from standard of care computed 
tomography (CT) scans (Koay et al, JCI 2014). We will apply these methods to the CT scans in 
this study as a correlate of response and survival outcomes. Standard statistical tests will be used 
to describe the potential correlations, including chi-squared test for associations of the imaging 
biomarkers with pathological measurements, and the log rank test for associations with survival 
outcomes such as progression free survival and overall survival. 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
This is a single-center single-arm, phase II study to assess resectability rate in patients treated 
with preoperative mFOLFIRINOX chemotherapy followed by Gemcitabine based 
chemoradiation therapy for patients with borderline resectable adenocarcinoma of the pancreas. 
Patients will receive mFOLFIRINOX chemotherapy for 6 cycles (12 weeks) followed by 
chemoradiation therapy ( 5 doses of gemcitabine and 6 weeks of radiation therapy).   Patients 
will be restaged at the end of systemic chemotherapy as well as chemoradiation therapy and may 
drop off the study due to disease progression or metastasis. At least 4-6 weeks after the last dose 
of Gemcitabine, patients may undergo surgery if no local disease progression or distant 
metastasis is detected during a final restaging scan. Patient resectability rate is defined as the 
proportion of patients who undergo surgery among all enrolled patients. A total of 33patients 
will be enrolled into the study, at a rate of 1-2 patients per month.  
 
 
 
Statistical Design 
 
We will apply the Simon’s optimum two-stage design in this study. A sample size of 33 is 
chosen to differentiate between a good resectability rate of 60% and a poor resectability rate of 
40% with 80% power and at a significance level of 0.10. The trial will stop early due to lack of 
efficacy if there are 7 or fewer patients undergo surgery among the first 16 patients. Otherwise, 
the study will continue to enroll the remaining 17 patients. By the end of the trial, lack of 
efficacy will be claimed if 16 or fewer patients undergo surgery among the total 33 enrolled 
patients. Under the null hypothesis of a poor resectability rate of 40%, the probability of early 
stopping is 71.6% and the expected sample size is 21 patients. 
 
Toxicity will be continuously monitored throughout the study, which includes grade 4 
hematological toxicity and Grade 3 or higher non-hematological toxicity.  A beta (0.4, 0.6) prior 
was assumed for the distribution of the toxicity rate. Starting from the 6th patient, we will apply 
the following toxicity monitoring rule every 3 patients.  
 
Pr (Tox >40% | data) >90% 
 
The rule implies that we will stop the trial if any time, there is more than 95% probability that the 
toxicity rate is more than 40%. The corresponding stopping boundaries are to stop the trial if [# 
patients with toxicity] / [# evaluable patients] >/= 5/6, 6/9, 8/12, 9/15, 10/18, 12/21, 13/24, 
15/27, 16/30. The operating characteristics corresponding to this toxicity monitoring rule is 
shown in Table 7.  
 
Table 7. Operating characteristics for toxicity monitoring. 
True toxicity rate 
Prob(stop the trial early)


Protocol 2011-1208 
April 27, 2017  
Page 26 of 38 
 
0.2 
0.005 
0.3 
0.048 
0.4 
0.231 
0.5 
0.588 
0.6 
0.892 
 
Statistical analysis  
The resectability rate will be estimated, along with the 95% confidence interval, using the intent-
to-treat (ITT) principle. For patients who undergo surgery, the proportion of margin positive 
resection (R1) and margin negative resection (R0) will be estimated, along with the 95% 
confidence interval. Kaplan-Meier method will be used to assess overall survival (OS), 
progression-free survival (PFS) and disease-free survival (DFS). The pattern of local and distant 
failure will be summarized through frequency and percentage. In addition, we will assess the 
status of DPC4 (positive versus negative) preoperative and after surgery and to evaluate the 
association between the DPC4 status and survival endpoints. CTCs will also be measured from 
blood drawn at baseline, post treatment-presurgery, during surgery and 2-3 months after surgery. 
Analysis of CTCs will be reported by data tabulations, descriptive statistics, and graphical 
presentations and as appropriate in relation to survival endpoints. 
 
 
 
12.0 
DATA AND PROTOCOL MANAGEMENT 
 
12.1 
After obtaining informed consent, patients will be registered on the MDACC 
computerized Clinical Oncology Research System (CORe).   
 
12.2 
The attending physician must see each patient before each dose of chemotherapy. 
12.3 
Data Collection for Enrolled patients 
Designated research personnel must enter the information required by the protocol 
onto electronic Case Report Forms (CRFs). The University of Texas M D Anderson 
Cancer Center’s Clinical oncology Research (CORE) system, and the University of 
Texas MD Anderson Cancer Center’s Protocol Data Management System(PDMS) 
CRF system will be used for this study.  PDMS is a clinical research information 
management system. The PDMS CRF is an electronic document designed to record 
all the protocol-required information to be reported on each trial subject. 
PDMS provides data entry templates as defined in the protocol. Laboratory results are 
automatically transferred from M. D. Anderson Cancer Center Laboratory Medicine’s 
server to PDMS each morning. Users must have clearance through the M. D. 
Anderson Cancer Center Information Services Security Department in order to access 
PDMS. PDMS login is password protected.  
 
Only adverse events that are grade 1, 2,3,4,5 possible, probable or definite will be 
recorded.The Investigator is responsible for verifying and providing source 
documentation for all adverse events and assigning attribution for each event for all 
subjects enrolled on the trial.     
 


Protocol 2011-1208 
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Page 27 of 38 
 
 
13.0 
 ADVERSE EVENT REPORTING REQUIREMENTS 
 
 
13.1 
Reporting of adverse events will be according to MD Anderson Guidelines for AE 
Reporting. 
 
13.2 
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0 for toxicity grading and adverse event reporting. A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  
 
 
 
APPENDIX  A 
 
 
Table 8. Comparison of the past neoadjuvant clinical trials at University of Texas, M. D. 
Anderson Cancer Center  
 
 
5-FU 
50.4 Gy 
5-FU 
30 Gy 
Paclitaxel 
30 Gy 
Gem-
XRT 
Gem-
Cis 
XRT 
No. of Patients 
28 
35 
37 
86 
90 
Overall survival (mo) 
NA 
NA 
12 
23 
17 
No. Hospitalized prior to 
restaging (%) 
9 (32) 
1 (1) 
6/35 (17) 
36(42) 
*40 (51) 
No. who completed all 
treatment including PD (%) 
17(60) 
20(57) 
20(54) 
64 (74) 
 
*52 (66) 
No. Histologic response IIB-
IV/total resected (%) 
7 (41) 
4 (20) 
4/19 (21) 
37(58) 
 
31 (60) 
No. SMA margin positive 
(%) 
3 (18) 
2 
(10) 
6/19 (32) 
4(6) 
1 (2) 
No. Death during treatment 
(%) 
1 (4) 
0 
0  
1 (1) 
**1 (1) 
Median survival of patients 
who completed all treatment 
(mo) 
NA 
25  
19 
34 
31 
Median survival of patients 
who did not complete all 
treatment (mo) 
 
NA 
7 
10 
7.1 
 
 
 
 
10.5 
No. local recurrence (%) 
NA 
1 (5) 
0 
7 (11) 
 
13 (25) 
No. Isolated local recurrence 
(%) 
NA 
1 (5) 
0 
2 (3) 
3 (6) 
 


Protocol 2011-1208 
April 27, 2017  
Page 28 of 38 
 
* Out of the 79 patients who completed preoperative therapy 
** This patient was one of the 11 patients who withdrew from treatment prior to re-staging  
 
Table 9 - Comparison of the last two neoadjuvant clinical trials 
 
Gem-XRT 
Gem-Cis-XRT 
P-value 
Total No. Patients 
86 
*79 
- 
Median Age 
65 
65 
0.85 
No. Smokers (%) 
59 (69) 
48 (61) 
0.29 
No. Previous Laparotomy (%) 
8 (9) 
4 (5)  
 
No. with biliary stent (%) 
67 (78) 
64 (81)  
0.62 
No. with Metal stent (%) 
2 (2) 
36 (46)  
<.001 
No. Hospitalized (with grade 3-4 toxicity) 
prior to restaging v 
38 (44) 
40 (51)  
0.26  
No. Grade 3 or 4 toxicity (%) 
74 (86)  
63/79 (80)  
0.28 
No. who completed all treatment to 
include PD (%) 
64 (74) 
52 (66) 
0.23 
No. N1 (%) 
24 /64 (38) 
31/52 (60) 
0.01 
No. T3 (%) 
43/64 (67) 
43/52 (83) 
0.04 
No. Vascular resection (%) 
13/64 (20)  
19/52 (36) 
0.05 
No. SMA margin positive (%) 
4/64 (6) 
1/52 (2) 
0.38 
No. Histologic response IIB-IV (%) 
37/64 (58) 
31/52 (60) 
0.75 
No. Death during treatment (%) 
1 
0 
 
Median survival of all patients (months) 
22.7  
17.4  
0.08 
Median survival of patients who 
34.0 
31.0  
0.41 


Protocol 2011-1208 
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completed all treatment (months) 
Median survival of patients who did not 
complete all treatment (months) 
7.1  
10.5 
0.12 
No. isolated local failure (%) 
2/64 (3) 
3/52 (6)  
0.66 
 
* 79 patients in the current report completed preoperative therapy. 
 


Protocol 2011-1208 
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Appendix B:  
 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982.  
 
 


Protocol 2011-1208 
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Appendix C: 
 
 
University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy on  
Reporting Serious Adverse Events 
 
 
DEFINITIONS 
Adverse Event (AE) – Any untoward or unfavorable medical occurrence 
in a human subject, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in the research, whether or not 
considered related to the subject’s participation in the research. 
 
Expected AE - Any AE with specificity or severity that is consistent with 
the current Investigator Brochure (IB) or consistent with the risk 
information described in the Informed Consent Document (ICD) or general 
investigational plan. All clinical protocols should include a list of the 
expected and anticipated events or hospitalizations relating to the study 
treatment. 
 
Unexpected (Unanticipated) AE - Any AE, with specificity or severity 
that is not consistent with the current IB or not consistent with the risk 
information described in the ICD or general investigational plan. 
 
Serious Adverse Event (SAE) – Any AE associated with the subject’s 
participation in research that:   
 results in death;  
 is life-threatening, (places the subject at immediate risk of death 
from the event as it occurred); 
 results in inpatient hospitalization or prolongation of existing 
hospitalization; 
 results in persistent or significant disability/incapacity;  
 results in a congenital anomaly/birth defect; or 
 based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to 
prevent one of the other outcomes listed in this definition. 
 
Internal AE - An AE occurring in a subject who is enrolled in a protocol 
or study that is under the oversight of a UTMDACC IRB.   
 
Related: 
Events directly or indirectly attributed to study drug, device or procedures 
and/or study participation.  Events occurring with sufficient frequency to 
suggest that they are not random. 
 


Protocol 2011-1208 
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Unrelated: 
Events that would occur regardless of study participation, including events 
that are clearly random occurrences.  If the frequency of the event suggests 
a possible connection to the study intervention, then it should be 
considered related. 
 
AE Attribution - The determination of whether an AE is related to the 
research (medical treatment or intervention):  
Definite – It is clearly related  
Probable - It is likely related  
Possible - It may be related  
Unlikely - It is doubtfully related  
Unrelated - It is clearly NOT related  
 
AE Severity - Refers to the intensity (grading) of a specific AE.  
For the purpose of this policy, toxicity is synonymous with AE. 
 
 
 
Institutional Procedures 
 
Reporting 
Requirements for 
Internal AEs 
Serious Internal AEs (SIAEs) requiring prompt reporting to the IRB 
All internal AEs that include all of the following will require prompt 
reporting to IRB via the Office of Protocol Research (OPR):  
 
 Serious  
 Unexpected 
 Related (definitely, probably, or possibly related) to participation in 
the research. 
 
Timeline for prompt reporting: 
 
1. Within 1 working day (24 hours) from the time the research team 
becomes aware of the event = Deaths that are unexpected and 
definitely, probably or possibly related to study intervention that occur 
during and within 30 days after the last day of active study intervention. 
 
2. Within 5 working days from the time the research team becomes 
aware of the event = All other serious, unexpected and definitely, 
probably or possibly related AEs.  
 
SAEs will require prompt reporting from the time protocol specific consent 
is signed, and screening has begun, during the course of study intervention 
and within 30 days after the last day of active study intervention.  
 
Beyond 30 days of study intervention, completion of only those SAEs that, 


Protocol 2011-1208 
April 27, 2017  
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in the judgment of the investigator, are related to research will require 
prompt reporting. 
 
SIAEs Requiring Documentation on AE Log: 
 
All SIAEs that do not fall under the prompt reporting requirements should 
be reported during continuing review using the Internal SAE Log or 
database printout. 
 
Note: If a trend or recurring adverse events are seen, the PI should report 
these events using the Internal SAE report Form for prompt reporting.  
 
Individual reports submitted to IRB that do not meet the requirements 
for prompt reporting will be returned to PI.  
 
NOTE: Certain types of incidents, experiences, and outcomes that occur 
during the conduct of research are unexpected, related or possibly 
related to the research, and place the research subject at a greater risk of 
harm but are not considered adverse events.  These incidents are 
classified as unanticipated problems and will require reporting to the 
IRB.  These have different reporting forms and are discussed under the 
"Policy on Reporting Protocol Deviations, Protocol Violations, and 
Unanticipated Problems." 
 
This policy does not replace the reporting requirements to the FDA, the 
sponsor or monitoring agency. 
 


Protocol 2011-1208 
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Page 34 of 38 
 
Appendix D 
New York Heart Association Classification of Cardiac Disease 
 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease.
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease.
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease. 
 


Protocol 2011-1208 
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Appendix E—ApoCell Lab Analysis 
 
Blood will be drawn at 4 time points from 30 patients:  
- 
pretreatment (baseline),  
- 
post treatment-presurgery ( within 2 weeks of surgery including day of surgery)  
- 
during surgery (portal vein blood) and  
- 
2-3 months after surgery.  
 
 
The first ten (10) consented individuals will each have two (2) blood tubes drawn:  8 mL BD Vacutainer® CPT 
Citrate Blood Collection tube, and 10 mL CellSave® blood tube. 
 
The subsequent twenty (20) consented individuals will each have one (1) 8 mL BD Vacutainer® CPT Citrate Blood 
Collection tube drawn. Coded blood collection tubes, Blood Collection Instructions and Specimen Submission 
Instruction forms will be provided by ApoCell, Inc., who will serve as the laboratory for analytical procedures.  
 
ApoCell, Inc.  
2575 West Bellfort Street. Suite 190 
Houston, Texas 77054. 
 
Blood Collection Instructions 
 Check the expiration date on the CPT and CellSave  tube before use. 
 Do NOT collect blood on weekends. 
 Notify both Courtney Williams and Apocell Logistics team by email 24 hours prior to blood draw. 
 Contact Courtney Williams by phone as primary and if not available, Apocell Logistics as back up prior to 
and immediately after blood sample collection is completed. 
 
Primary Contact 
Courtney Williams         
713-440-6070 ext 221 
Direct Line: 832-301-3221 
cwilliams@apocell.com 
 


Protocol 2011-1208 
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Secondary Contact 
Apocell Logistics 
713-440-6070 ext 122 
receiving@apocell.com 
 
 
For the CPT Vacutainer blood tube collection: 
1. Collect 8 mL of blood into a Vacutainer CPT tube using a standard method. 
2. Note: Do not shake. Vigorous mixing can cause hemolysis. 
3. Label the tube with site #, specimen ID, time point (if applicable), ApoCell Project ID Number, and collection 
date/time. (Please see example below)   
DO NOT REFRIGERATE OR FREEZE. 
 
 
 
4. FOLLOWING BLOOD DRAW, THE SPECIMENS WILL BE STORED AT ROOM TEMPERATURE 
CONDITIONS AT ALL TIMES.  
 
For CellSave blood tube collection: 
1. Preferably, the CellSave Tube should be the second tube drawn. 
2. Collect a minimum of 8 mL of whole blood into the CellSave tube with 10 mL capacity, which is provided.  
DO NOT collect sample in EDTA, sodium heparin or ACD tubes. 
3. Label each tube with Study Protocol or ApoCell Project ID, sample ID, visit or time point, sample date/time and 
phlebotomist’s initials. 
4. Gently invert CellSave  tube 8 times and store at room temperature until it can be picked up.  DO NOT 
REFRIGERATE OR FREEZE. 


Protocol 2011-1208 
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5. FOLLOWING BLOOD DRAW, THE SPECIMENS WILL BE STORED UPRIGHT, AT ROOM 
TEMPERATURE CONDITIONS AT ALL TIMES. Prepare the "Specimen Submission" form (see Appendix 
XX). Notify ApoCell by phone immediately after the samples are collected. An ApoCell-supplied courier will 
be notified the samples are ready for pickup.  The courier will pick up blood specimens within 2 hrs after the 
blood draw at an designated agreed upon location. Blood will be transported within a secondary temperature-
controlled container provided by the courier. 
 
Any residual blood will be discarded. Slides with cells extracted from patient blood will be discarded.  
 
Note: If during the processing phase, any of the tubes break, we will continue to proceed with drawing the other time points and 
proceed with analyses of the intact tubes ( ones already drawn). Also, if the patient does not proceed with surgery (and we are able 
to get tubes for the 2 time points prior to surgery, these will be analyzed) )  
 
 


Protocol 2011-1208 
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APPENDIX F : Specimen Submission Form 
Protocol # 2011-1208 
Please fill out the information below and submit with specimens:  
Protocol: 
Apocell Project #:
AR04
Total 
Specimens:
Ship Date:
Courier:
Shipping TRK #:
Shipping Conditions: 
Ambient Temp
Subject Id            
(Site # - Patient#)
Subject 
Initials
Specimen Type
Date of Collection
Time of 
Collection
Cycle
Isolation of Circulating Tumor Cells (CTC) from Blood of Pancreatic Cancer 
Patients by Antibody-Independent ApoStreamTM Technology
Local
Comments
 
If submitting more specimens than this space allows for, please attach a roster or spread sheet of specimens. 
 
Specimen(s) prepared by____________________________________________________ 
Date: ________________ 
 
ApoCell Contact Information: 
Primary Contact:  Courtney Williams Main Phone:  713-440-6070 ext 221   Direct Line: 832-301-3221  Email:  cwilliams@apocell.comSecondary Contact:  ApoCell Logistics  
713-440-6070 ext 122  receiving@apocell.com