A Randomized Phase III Study Evaluating Modified FOLFIRINOX (mFFX) With or Without Stereotactic Body Radiotherapy (SBRT) in the Treatment of Locally Advanced Pancreatic Cancer: A Pancreatic Cancer Radiotherapy Study Group (PanCRS) Trial
Phase: PHASE3
Conditions: Pancreatic Cancer
Sponsor: Stanford University

 
Page 1 of 84 
 
Pancreatic Cancer Radiotherapy Study Group (PanCRS) Trial:   
A Randomized Phase III Study Evaluating Modified FOLFIRINOX 
(mFFX) with or without Stereotactic Body Radiotherapy (SBRT) in 
the Treatment of Locally Advanced Pancreatic Cancer 
 
 
 
 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
 
Protocol Director/Principal Investigator  
Daniel Chang, MD 
Department of Radiation Oncology 
875 Blake Wilbur Drive, MC 5847 
Stanford, CA 94305-5847 
 
 
 
 
Co-Principal Investigators 
MD Anderson 
Albert Koong MD, PhD 
Chair of the Department of Radiation Oncology 
1515 Holcombe Blvd, Unit # 1422 
Houston,TX 77030 
 
Joseph M. Herman MD., M.Sc 
Director of Clinical Research 
Department of Radiation Oncology 
1515 Holcombe Blvd, Unit # 1422 
Houston,TX 77030 
 
 
 
 
 
Co-Investigators 
George Fisher, MD, PhD 
Medical Oncology 
875 Blake Wilbur Dr., MC 5151 
Stanford, CA   94305-5826 
 
 
 

 
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Pamela Kunz, MD 
Medical Oncology 
875 Blake Wilbur Dr. 
Stanford, CA 94305 
 
 
 
Jeffrey Norton, MD 
Department of Surgery 
300 Pasteur Dr., MC 5641 
Stanford, CA   94305-5641 
 
 
 
George Poultsides, MD 
Department of Surgery 
300 Pasteur Ave. 
Stanford, CA   94305 
 
 
 
 
Stephanie T. Chang, MD 
Stanford Department of Radiology 
300 Pasteur Drive, Rm H1307 MC 5105 
Stanford, CA 94305 
 
 
 
 
Biostatistician 
Rie Von Eyben, MS 
Department of Radiation Oncology 
Stanford University Medical Center  
875 Blake Wilber Drive, MC 5847 
Stanford, CA 94305 
 
 
 
 
Study Coordinators 
Stanford University Medical Center 
Rachel Freiberg, Ph.D. 
Clinical Trials Manager 
Department of Radiation Oncology 
Stanford University Medical Center 
800 Welch Rd., FC3C69 
Stanford, California 94305 
 

 
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Email: rachelf@stanford.edu 
 
Samantha Wong 
Clinical Research Coordinator 
Department of Radiation Oncology 
Stanford University Medical Center 
300 Pasteur Drive, 
Palo Alto, CA 94305-5763 
 
 
 
 
Stritch School of Medicine, Loyola University Chicago 
Tarita Thomas, MD, PhD, Principal Investigator 
Department of Radiation Oncology  
Cardinal Bernardin Cancer Center 
2160 S 1st Ave 
Maguire Center, Rm 2932 
Maywood, IL 60153 
 
 
 
William Small Jr., MD  
Department of Radiation Oncology  
Cardinal Bernardin Cancer Center 
2160 S 1st Ave 
Maguire Center, Rm 2932 
Maywood, IL 60153 
 
 
 
Sam Pappas, MD 
Department of Surgical Oncology 
2160 S First Avenue 
Chigaco, IL 60153 
 
 
 
Asha Dhanarajan, MD 
Department of Oncology and Hematology 
Cardinal Bernardin Cancer Center 
2160 S 1st Ave 
 
 
 
Janelle Meyer MD 
Department of Medicine 
Oncology and Hematology 
Cardinal Bernardin Cancer Center 

 
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2160 S 1st Ave Building 112 Room 271 
Maywood, IL 60153 
 
 
Gerard V. Aranha, MD 
Department of Surgery 
Division of Surgical Oncology 
2160 South First Avenue 
EMS Bldg. 110, Room 3236 
Maywood, IL  60153 
 
 
 
Gerard J. Abood, MD, MS 
Department of Surgery 
Division of Surgical Oncology 
Loyola University Medical Center 
 
 
 
Eva M. Wojick, MD 
Department of Pathology and Urology 
Loyola University Medical Center 
2160 South First Avenue 
Maywood, IL 60153 
 
 
 
Swedish Cancer Institute 
Vivek Mehta MD, Principal Investigator 
Radiation Oncology 
1221 Madison Street 
Arnold Pavilion, 1st Floor 
Seattle, WA 98104 
 
 
Somasundaram Subramaniam, MD MS 
Medical Oncology 
1221 Madison Street, Suite 200 
Seattle, WA 98104 
 
 
 
University of Texas Southwestern Medical Center 
Jeffrey Meyer, MD, MS, Principal Investigator  
Department of Radiation Oncology 
UT Southwestern Medical Center 
5801 Forest Park Road, NF3.206 
Dallas, TX 75390-9183 

 
Page 5 of 84 
 
 
 
 
Princess Margaret Cancer Center 
Laura A Dawson, MD FRCPC 
Professor, Dept. of Radiation Oncology,  
University of Toronto 
Clinician-scientist and staff radiation oncologist, 
Radiation Medicine Program, 
Princess Margaret Cancer Centre 
Toronto, Ontario, CANADA 
 
 
 
Hollings Cancer Center, MUSC 
David T. Marshall, M.D., M.S. 
Professor of Radiation Oncology 
Hollings Cancer Center - A NCI-Designated Cancer Center 
Medical University of South Carolina 
MSC 318 
169 Ashley Avenue 
Charleston, SC 29425 
 
 
 
The University of Texas MD Anderson Cancer Center 
Albert Koong, M.D. 
Chair of the Department of Radiation Oncology 
The Univ of Texas MD Anderson Cancer Center  
1515 Holcombe Blvd, Unit 1422  
Dept of Radiation Oncology Houston, TX 77030 
 
 
 
 
 
 
Stritch School of Medicine, Loyola University Chicago 
Beth Chiappetta, RN 
Research Nurse 
Loyola University Medical Center 
Radiation Oncology Department 
Maguire Center 105-2944 
2160 S. First Avenue 
Maywood, IL 60153 
 
     
 
 
 

 
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Swedish Cancer Institute 
Desiree Iriarte 
 
 
 
University of Texas Southwestern Medical Center 
Jean Wu, RN, MSN, OCN 
Clinical Research Manager 
Radiation Oncology 
University of Texas Southwestern Medical Center 
5641 Southwestern Medical Ave 
Dallas, TX 75235-8808 
 
 
 
Princess Margaret Cancer Center 
Sonca Lengoc, B. Sc. 
Clinical Research Data & Regulatory Affairs Coordinator 
Clinical Research Program (CRP) 
Radiation Medicine Program (RMP) 
Department of Radiation Oncology (DRO) 
Princess Margaret Cancer Centre 
700 University Ave., Toronto, ON M5G 1X6 
2nd Floor, Hydro Building (OPG), North Side, Workstation #78 
   
 
 
 
 
 
 
 
 
 
 
Stanford Shipping Address: 
For Blood or Tissue Samples: 
  For Materials and Documents: 
Stephanie Giaretta, CRA for Dr. Daniel Chang 
  Rachel Freiberg, Ph.D. 
Stanford University Medical Center 
  Stanford University / Freidenrich Center 
Center for Clinical Sciences Research 
  
 
 
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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IRB Version 22 -- -- (Submitted 23_May_2019) 
 

 
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TABLE OF CONTENTS  
 
 
Page 
PROTOCOL SYNOPSIS ............................................................................................................ 12 
SCHEMA ...................................................................................................................................... 15 
 
1. OBJECTIVES ........................................................................................................................ 16 
1.1 
Primary Objectives ................................................................................................... 16 
1.2 
Secondary Objectives ................................................................................................ 16 
 
2. BACKGROUND .................................................................................................................... 16 
2.1 
Natural History and Management of Pancreatic Cancer ...................................... 16 
2.2 
Rational for SBRT for Pancreatic Cancer .............................................................. 17 
2.3 
Quality of Life Assessment ....................................................................................... 18 
2.4 
Correlative Studies Background .............................................................................. 18 
 
3. PATIENT SELECTION ....................................................................................................... 20 
3.1 
Inclusion Criteria  ..................................................................................................... 20 
3.2 
Exclusion Criteria ..................................................................................................... 21 
 
4. STUDY ENROLLMENT ...................................................................................................... 22 
5.1  
General Guidelines .................................................................................................... 22 
5.2  
Registration and Enrollment .................................................................................... 22 
 
5.3       Informed Consent ...................................................................................................... 22 
 
5. INDUCTION CHEMOTHERAPY ...................................................................................... 22 
5.1  
mFOLFIRINOX ........................................................................................................ 22 
5.2  
Restaging Following mFOLFIRINOX .................................................................... 23 
 
5.3       Randomization to +/- SBRT...................................................................................... 24 
 
 
6. RADIATION TREATMENT PLANNING AND SBRT ADMINISTRATION .............. 24 
6.1 
Pre-SBRT Tests, Procedures, and Planning ........................................................... 24 
6.1.1 
Fiducial Placement ........................................................................................ 25 
6.1.2 
Radiotherapy Simulation .............................................................................. 25 
6.1.3 
Radiation Treatment Planning ..................................................................... 26 
6.2 
SBRT Treatment Delivery ........................................................................................ 27 
6.2.1 
Use of Radioisotopes / Rad Machines .......................................................... 28 
6.2.2 
Prophylactic and Supportive Medications for SBRT ................................. 29 
6.2.3 
Other Concomitant Medications .................................................................. 30 
 
7. CHEMOTHERAPY AND FOLLOW-UP AFTER RANDOMIZATION ....................... 30 
7.1 
Chemotherapy following SBRT ............................................................................... 30 
7.2 
Follow-up  ................................................................................................................... 30 
7.3 
Duration of Study ...................................................................................................... 31 
7.4 
Duration of Follow Up ............................................................................................... 31 
7.5 
Criteria for Removal from Study ............................................................................. 31 
7.6 
Alternatives ................................................................................................................ 32 
7.7 
Compensation ............................................................................................................ 32 

 
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8. PHARMACEUTICAL INFORMATION ........................................................................... 32 
8.1 
Investigational Agent or Device ............................................................................... 32 
8.2 
Availability  ................................................................................................................ 32 
8.3 
Agent Ordering .......................................................................................................... 33 
8.4 
Agent Accountability ................................................................................................. 33 
 
9. TOXICITIES AND mFOLFIRINOX DOSING AND MODIFICATIONS ..................... 33 
9.1  
Modified Folfirinox (mFFX) Dosing ........................................................................ 33 
9.1.1 
Recommended Modifications for Toxicity .................................................. 34 
9.1.2  
Management of Diarrhea during Systemic Treatment Prior to  
 
Chemoradiation ............................................................................................. 38 
9.1.3  
SBRT Toxicities and Potential Risks ........................................................... 39   
 
10. DRUG FORMULATION, AVAILABILITY AND PREPARATION .............................. 39 
10.1 
 
Oxaliplatin ............................................................................................................ 40 
10.2 
 
Fluorouracil (5-FU) ............................................................................................. 42 
10.3 
 
Leucovorin Calcium (Folinic Acid) .................................................................... 42 
10.4 
 
Irinotecan (CPT-11, CAMPTOSAR) ................................................................. 43 
 
11. ADVERSE EVENTS, UNANTICIPATED PROBLEMS, AND DEVIATIONS ............. 44 
11.1 
 
Serious Adverse Events (SAEs) .......................................................................... 44 
11.1.1 
Reporting SAEs ............................................................................................. 45 
11.2 
Unanticipated Problems (UPs) ........................................................................... 45 
11.2.1 
Reporting UPs ................................................................................................ 46 
11.3 
Adverse Events (AEs) and AE Monitoring ....................................................... 47 
11.4 
Deviations ............................................................................................................. 48 
11.4.1 
Documenting and Reporting Deviations ..................................................... 48 
11.5 
Study and Subject Reviews ................................................................................. 49 
 
12. CORRELATIVE/SPECIAL STUDIES ............................................................................... 50 
12.1 
Laboratory Correlative Studies ............................................................................... 50 
12.1.1 
Analysis of patient plasma for biomarker development ............................ 50 
 
12.2 
Collection of Pre- and Post- Treatment Scans, Treatment Planning Scans,  
 
and Treatment Plans…………………………………………......…………………51 
12.2.1 
Data and Image Collection ........................................................................... 51 
 
13. INVESTIGATOR RESOURCES ......................................................................................... 51 
 
13.1     Qualifications ............................................................................................................. 51 
 
13.2     Use of Cancer Center Facilities ................................................................................ 52 
 
13.3     Conflict of Interest ..................................................................................................... 52 
 
14. STUDY CALENDAR ............................................................................................................ 53 
15. MEASUREMENT OF EFFECT .......................................................................................... 54 
15.1 
Anti-tumor Effect ...................................................................................................... 54 
15.1.1 
Definitions ...................................................................................................... 54 
15.1.2 
Disease Parameters ........................................................................................ 54 
15.1.3 
Methods for Evaluation of Measurable Disease ......................................... 55 
15.1.4 
Duration of Response .................................................................................... 55 

 
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15.1.5 
Progression-Free Survival (or other time-to-event parameters) ............... 55 
15.1.6 
Response Review ............................................................................................ 55 
 
16. MONITORING PLAN AND DATA MANAGEMENT ..................................................... 56 
 
16.1     Monitoring Plan ......................................................................................................... 56 
 
16.2 
Study Diagram ........................................................................................................... 57 
 
16.3     Trial Monitoring ........................................................................................................ 58 
16.4 
Data Management ..................................................................................................... 58 
16.4.1 
Monitoring and Study Data Review ............................................................ 59 
 
16.5     Confidentiality ........................................................................................................... 59 
 
17. STATISTICAL CONSIDERATIONS ................................................................................. 60 
17.1     Endpoints .................................................................................................................... 60 
17.1.1 
Primary endpoints ......................................................................................... 60 
17.1.2 
Secondary endpoints ..................................................................................... 60 
 
17.2     AnalysisPopulations……………...….……………………………………………...60 
 
17.3 
Sample Size………………………………………………………………...………..60 
17.3.1 
Accrual estimates ........................................................................................... 60 
17.3.2 
Sample size justification ................................................................................ 60 
17.3.3 
Criteria for future studies ............................................................................. 61 
 
17.4 
Plan of Analysis….………………………………………………………………….61 
 
 
17.4.1  
Stratification………………………………………..……………………….62 
 
17.5 
Stopping Guidelines……………………………………………………………..….62 
17.5.1 
Toxicity monitoring ....................................................................................... 62 
17.5.2 
Interim Analysis for Efficacy of Primary Endpoint:  Progression Free  
 
Survival ........................................................................................................... 64 
 
REFERENCES ............................................................................................................................ 65 
ADDITIONAL REFERENCES ................................................................................................. 66 
 
APPENDICES…………………………………………………………………………………..68 
 
Appendix I – EORTC QLQ-C30 and QLQ-PAN26 ........................................................... 69 
 
Appendix II – ECOG Performance Status .......................................................................... 74 
 
Appendix III – Definition of Menopausal Status ................................................................ 75 
Appendix IV – Eligibility Checklist ..................................................................................... 76 
Appendix V – Case Report Forms and Patient Logs ......................................................... 79 
 
 
 

 
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PROTOCOL SYNOPSIS  
TITLE 
A Randomized Phase III Study Evaluating 
Modified FOLFIRINOX (mFFX) with or 
without Stereotactic Body Radiotherapy 
(SBRT) in the Treatment of Locally 
Advanced Pancreatic Cancer 
 
A PanCRS Group Trial  
PRIMARY OBJECTIVE 
To compare the median progression free 
survival for patients treated with mFFX+ SBRT 
with the median progression free survival for 
patient treated with mFFX only. 
SECONDARY OBJECTIVES 
 To compare metastasis-free survival for 
pancreatic patients following chemotherapy 
+/- SBRT. 
 To compare the one year progression free 
survival for patients treated with mFFX +/- 
SBRT.  
 To determine the overall survival for patients 
treated with mFFX +/- SBRT. 
 To determine local progression-free survival 
for patients treated with mFFX +/- SBRT. 
 To evaluate acute (within 3 months of 
treatment) grade 2 or greater gastritis, fistula, 
enteritis, or ulcer and any other grade 3-4 
gastrointestinal toxicity within 3 months of 
treatment. 
 To evaluate the utility of FDG-PET for 
treatment planning and estimation of 
progression free survival. 
 To identify new biomarkers in pancreatic 
cancer.15% 
  
 To evaluate the quality of life before and 
after therapy for patients treated with mFFX 
+/- SBRT. 
HYPOTHESES 
Systemic chemotherapy followed by 
radiotherapy improves overall survival in 
patients with locally advanced pancreatic 
cancer.  Recent clinical studies have shown that 
FOLFIRINOX chemotherapy is more effective 
than gemcitabine as first-line treatment in 
patients with metastatic disease.  Similarly, 
aggressive local radiotherapy in combination 
with systemic chemotherapy has also been 
demonstrated to improve overall survival.  We 
hypothesize that optimizing local radiotherapy 
following aggressive systemic chemotherapy 
will further improve overall survival. 

 
Page 12 of 84 
 
STUDY DESIGN 
Multi-center phase III randomized study 
anticipated to accrue approximately 172 patients 
total at all participating institutions. 

 
Page 13 of 84 
 
SUMMARY OF SUBJECT ELIGIBILITY 
CRITERIA 
Inclusion:  
 Histologically confirmed adenocarcinoma 
of the pancreas. 
 Determined unresectable by a pancreatic 
cancer surgeon or a multi-disciplinary or 
gastrointestinal oncology Tumor Board 
 Stable or better disease on re-staging scans 
following induction mFOLFIRINOX. 
 Typically, pancreatic tumors must be less 
than 8.0 cm in greatest axial dimension at 
the time of treatment planning but final 
determination of eligibility will be based 
upon satisfying the radiation normal tissue 
constraints as specified below in section 
6.1.3 Radiation Treatment Planning 
 No prior systemic therapy EXCEPT 
patients may be consented and enrolled if 
they have already started mFOLFIRINOX 
for up to four cycles. 
 ECOG 0, 1, or 2 (see Appendix II). 
 Acceptable organ and marrow function (as 
defined in protocol section 3.1).  
 Ability to understand and the willingness to 
sign an informed consent form. 
 Life expectancy >6 months. 
 
Exclusion: 
 Metastatic disease.
 Children/Age<18 (rarely occurs in this age 
group)
 Prior radiotherapy to the upper 
abdomen/liver. 
 Patients who received chemotherapy for 
pancreatic cancer other than up to 4 cycles 
of mFOLFIRINOX as noted above.
 Uncontrolled illness including, but not 
limited to, ongoing or active infection (or 
infections requiring systemic antibiotic 
treatment), symptomatic congestive heart 
failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social 
situations that would limit compliance with 
study requirements.
 Any concurrent malignancy other than non-
melanoma skin cancer, non-invasive 
bladder cancer, or carcinoma in situ of the 
cervix.  Patients with a previous malignancy 
without evidence of disease for > 5 years 
will be allowed to enter the trial.
 Pregnant and breastfeeding women are 
excluded; as well as women of child-
bearing potential who are unwilling or 
unable to use an acceptable method of birth 
control (hormonal or barrier method oSEcf

 
Page 14 of 84 
 
PROCEDURES 
Optional:  Pancreatic biopsies obtained at the 
time of fiducial placement or in a separate 
procedure, and blood collected for biomarker 
analysis pre-and post-treatment. 
STATISTICAL CONSIDERATIONS 
See statistics section. 
 
 
 
 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1. 
OBJECTIVES 
 
1.1. 
Primary Objective  
 
 To compare the median progression-free survival between arm 1 (mFOLFIRINOX) 
vs arm 2 (mFOLFIRINOX+SBRT). 
 
1.2. 
Secondary Objectives  
 
 To compare metastasis free survival for pancreatic patients following chemotherapy 
+/- SBRT. 
 To compare the one year progression-free survival for patients treated with mFFX 
+/- SBRT. 
 To determine the overall survival for patients treated with mFFX +/- SBRT.  
 To determine local progression-free survival for patients treated with mFFX +/- 
SBRT. 
 To evaluate acute (within 3 months of treatment) grade 2 or greater gastritis, fistula, 
enteritis, or ulcer and any other grade 3-4 gastrointestinal toxicity within 3 months of 
treatment. 
 To evaluate the utility of FDG-PET for treatment planning and estimation of 
progression free survival. 
 To identify new biomarkers in pancreatic cancer. 
 To evaluate the quality of life before and after therapy for patients treated with 
mFFX +/- SBRT. 
 
2. 
BACKGROUND 
 
2.1 
Natural History and Management of Pancreatic Cancer  
 
Every year in the United States, there are more than 30,000 newly diagnosed cases of 
pancreatic cancer.  Despite aggressive combined modality treatment approaches, the five-
year survival of this disease remains less than 5%(1).  Clearly, more innovative treatments 
are needed to improve overall survival in this group of patients. 
 
 
Surgical resection is considered to be the only treatment option with curative potential(2).   
However, the majority of pancreatic cancer patients do not have resectable disease at 
presentation.  More than 85% of patients have locally advanced or metastatic disease when 
initially diagnosed.  
 

 
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Since the late 1990’s, first-line chemotherapy for locally advanced/metastatic pancreatic 
cancer has been gemcitabine, a nucleoside analog.  In the pivotal trial for which the FDA 
approved this drug, patients treated with gemcitabine had a modest improvement in survival 
compared to patients treated with 5-fluorouracil (5FU)(3).  The median survival was 
improved from 4.41 months to 5.56 months.  However, nearly 25% of patients receiving 
gemcitabine were noted to have a clinical benefit compared to 5% of patients receiving 5FU.  
In a recent meta-analysis, the addition of platinum analogs to gemcitabine demonstrated a 
survival benefit in patients with a good performance status.  However, additional studies are 
necessary to determine which therapeutics are best combined with gemcitabine(4). 
 
More recently, Conroy et al reported that a non-gemcitabine containing chemotherapy 
regimen, FOLFIRINOX (5FU, leucovorin, irinotecan, oxaliplatin), provided a significant 
survival benefit compared to gemcitabine (30) in patients with metastatic pancreatic cancer.  
Although there was increased toxicity in those patients treated with FOLFIRINOX, this was 
the first randomized study showing a clinically significant advancement in the treatment of 
patients with advanced pancreatic cancer since gemcitabine was approved by the FDA.  We 
hypothesize that more aggressive systemic chemotherapy followed by intensive local 
radiotherapy will improve overall survival in patients with locally advanced pancreatic 
cancer. 
 
In a single arm multi-center (Stanford University, Johns Hopkins University, Memorial 
Sloan Kettering) phase II study in locally advanced pancreatic cancer, we have previously 
shown that integrating stereotactic body radiotherapy (SBRT, 33 Gy in 5 fractions) with 
systemic gemcitabine chemotherapy resulted in a 1 year freedom from local progression of 
78% and a median overall survival of 13.9 months (Herman et al, Cancer 2014).  There was 
minimal toxicity associated with SBRT and the entire radiotherapy course was delivered in 
1 week.  Shortening the duration of radiotherapy from 5-6 weeks (conventional IMRT) to 1 
week (SBRT) minimizes any delay in the administration of systemic chemotherapy.   
 
Another study in locally advanced pancreatic cancer compared full-dose gemcitabine (1000 
mg/m2) alone to a lower dose of gemcitabine (600 mg/m2) combined with standard 
fractionated radiation (50.4 Gy over 5.5 weeks).  Although the study was closed prior to 
reaching its planned accrual, there was a significant improvement in survival with combined 
gemcitabine and radiation compared to gemcitabine alone(5), suggesting that the addition of 
local radiation therapy in pancreatic cancer confers a further survival advantage to systemic 
chemotherapy.  Objective responses were observed in 2.7% in the gemcitabine alone arm 
(95% CI [0.09%, 14.1%]) and 8.8% in the combined arm (95% CI [1.9%, 23.7%]).  In this 
trial, the dose of gemcitabine was reduced to 600 mg/m2 with radiation and patients required 
a 4-week break prior to resuming full dose gemcitabine.  Grade IV toxicity, principally 
gastrointestinal and hematologic, was more common in the combined group (41.2 vs. 5.7%; 
p<0.0001).  Although there was an improvement in survival, patients who received 
combined chemoradiation had substantially more toxicity when compared to gemcitabine 
alone.  Because of the highly conformal and precise nature of SBRT, we hypothesize that 
this radiotherapy approach will improve local control and decrease radiation-related toxicity 
in patients with locally advanced pancreatic cancer. 
 
Here, we will conduct a multi-institutional randomized trial to compare the effects of 
chemotherapy alone versus chemotherapy and SBRT in patients with locally advanced 
pancreatic cancer.  All patients will receive a modified FOLFIRINOX regimen prior to and 

 
Page 17 of 84 
 
following radiotherapy.  The primary endpoint will be progression-free survival.  
 
 
2.2 
Rationale for SBRT for Pancreatic Cancer  
 
Radiation therapy is a widely accepted treatment for pancreatic cancer. The Gastrointestinal 
Tumor Study Group (GITSG) carried out a series of landmark studies demonstrating the 
effectiveness of radiation therapy as both adjuvant and definitive treatment in pancreatic 
cancer(6, 7).  Modern radiation treatments have increasingly used conformal fields and dose 
escalation to enhance tumor control(8, 9).  Efforts to increase radiation dose to the 
pancreatic tumor without risking normal tissue injury have generally required relatively 
invasive techniques such as interstitial implantation of radioactive metals or intraoperative 
radiotherapy (IORT)(10, 11).   Historically, the local control rates for conventionally 
fractionated radiotherapy have ranged from 25-50%.  Local progression of pancreatic 
cancers can result in considerable morbidity, including gastric outlet obstruction and pain 
(12). 
 
The mortality rate for pancreatic cancer approaches 100%.  Current therapies provide only 
partial palliation of symptoms and slight prolongation of survival.  Better treatment is 
clearly needed. SBRT has the potential of significantly improving local progression free 
survival, which could translate into both more effective palliation and longer patient 
survival.  Koong et al. previously used the CyberknifeTM stereotactic radiosurgery system to 
demonstrate that a single dose of 25 Gy stereotactic body radiotherapy was feasible to 
administer in patients with locally advanced pancreatic cancer(13).  Furthermore, this dose 
of radiation resulted in nearly 100% local progression-free survival and effectively palliated 
symptoms related to the local growth of pancreatic tumors.  Based upon this study, these 
investigators also completed a phase II study assessing the efficacy of combining a standard 
five-week course of chemoradiotherapy followed by a stereotactic radiosurgery boost to the 
primary tumor in patients with locally advanced pancreatic cancer.  In this cohort of 19 
patients, 100% of tumors were without local progression.  However, all patients eventually 
developed metastases with a median time to progression of 5.5 months (Koong et al, 
IJROBP 2005). 
 
Another phase II study treated locally advanced pancreatic cancer patients with gemcitabine 
followed by 25 Gy of SBRT delivered with Cyberknife and maintenance gemcitabine 
chemotherapy.  In this study, the excellent progression free survival was confirmed from 
previous studies (81%).  The median overall survival was 11.4 months, median time to 
progression was 9.7 months and 1 year survival was 50%(14).  There were no significant 
acute GI toxicities however, of the 15 patients alive >6 months after SBRT, 7 (47%) 
experienced Grade 2 or greater GI toxicity, with 2 (13%) of the 15 experiencing Grade 3 or 
greater GI toxicity. 
 
More recently, another phase II study of 25 Gy in a single fraction using a linac-based 
approach (TrilogyTM, Varian Medical Systems, Palo Alto, CA) integrated with gemcitabine 
chemotherapy resulted in a 50% overall survival at 1 year and a 94% freedom from local 
progression at 1 year.  Four patients (15%) developed Grade 2 ulcers and 1 patient (5%) 
developed a duodenal perforation (Schellenberg et al, IJROBP 2011).  
 
Recently, we completed a multi-center phase II trial demonstrating the efficacy of SBRT (33 

 
Page 18 of 84 
 
Gy in 5 fractions) in combination with gemcitabine chemotherapy.  No significant toxicities 
were observed and median overall survival was 18 months.  These data compare favorably 
to other studies reported in the literature.  Based upon these promising data, we hypothesize 
that adding SBRT to a more aggressive systemic chemotherapy (FOLFIRINOX), will result 
in further improvement in OS in patients with locally advanced pancreatic cancer.   
 
The proposed randomized study is a logical extension of the previously reported studies and 
will establish the efficacy of adding SBRT to FOLFIRINOX chemotherapy.  Our prior 
multi-center phase II experience demonstrated the feasibility and efficacy of this approach 
in patients with locally advanced pancreatic cancer.   
 
2.3 
Quality of Life Assessment  
 
The major potential benefit of combining SBRT with chemotherapy for locally advanced 
pancreatic tumors is to improve local control and palliation of symptoms related to local 
progression of these tumors.  In addition, radiosurgical ablation of the primary tumor can 
theoretically prevent distant seeding from the pancreatic tumor itself.  Ultimately, these 
improvements in the treatment of pancreatic cancer may translate into an improved quality 
of life and overall survival.  
 
Quality of life will be assessed using The European Organization for Research and 
Treatment in Cancer quality of life core cancer questionnaire with the pancreatic cancer 
module (EORTC QLQ C-30/ PAN26).  The European Organization for Research and 
Treatment in Cancer Quality of Life Questionnaire (EORTC QOL-C30) is a 
multidimensional, 30-item questionnaire which assesses five functional scales (physical, 
role, cognitive, emotional and social), three symptom scales (fatigue, pain and 
nausea/vomiting), a global health /QOL scale, as well as 6 single items (18).  The EORTC 
QLQ-PAN26 supplements the core questionnaire with 26 items specific for patients with 
pancreatic cancer (19, 20).  These instruments have been validated in patients receiving 
treatment for metastatic and resected pancreatic cancer and are sensitive to identify 
treatment related changes in quality of life.  The quality of life of patients in this study will 
be directly compared between the 2 randomized arms.  These questionnaires were also used 
in our previous phase II multi-institutional study evaluating SBRT and gemcitabine in 
patients with locally advanced pancreatic cancer. 
 
2.4 
Correlative Studies Background  
 
Protein-based biomarkers in blood hold a great promise as diagnostic markers indicative of 
disease states and outcomes in clinical cancer management.  In order to validate large sets of 
candidates markers in bio-banked sample collections, multiplexed and sensitive detection 
technologies with low sample consumption are required.  Such technologies will not only be 
critical for the discovery of biomarker panels potentially leading to increased predictive 
power in diagnostics but may eventually enable early stage disease detection(21-22).  
 
Most conventional immunoassays rely on a solid support for capture of the target protein 
and for the removal of excess secondary reporter antibody by washing.  These sandwich 
assays’ susceptibility to nonspecific binding of the secondary reporter to the surface limit 
their sensitivity. Also, any single non-cognate binding event by a detection antibody will 
give rise to a false positive signal.  This is especially challenging when performing 

 
Page 19 of 84 
 
multiplexed reactions with many detection antibodies thus requiring extensive and careful 
optimization through selection of particular antibody combinations in order to minimize 
non-specific cross reactivity(23-24).  
 
We have developed a method of protein detection (proximity ligation assay) utilizing an 
antibody-based method of detection coupled with a qPCR amplification step (25).  The 
assay consumes 1 μL of sample with low femto-molar sensitivity, five log linear range, and 
can be multi-plexed without cross-reactivity.  The procedure typically relies upon a single 
polyclonal antibody batch for each target protein, simplifying affinity reagent creation for 
novel biomarker candidates.   
 
Based upon our previous studies (26), we will measure plasma levels of the following 
proteins prior to initiating treatment and 3 months following SBRT as outlined in the 
protocol: VEGF, MIF, CTGF, IL-1alpha, IL-7, galectin-1, TNF-alpha, EpCAM, CEA, 
Adam8, CPA1, ErbB2, IGF-2, CA 19-9, SLPI, Ch3L, EGFR, Osteopontin, Mesothelin, CA-
125.  We hypothesize that biomarker profile from this group of proteins will be predictive of 
outcome in this group of pancreatic cancer patients with locally advanced disease. 
 
Collection of specimens as outlined above will not be required from all participating 
institutions.  Additional protein biomarkers may also be assessed. 
 
 
3. 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
 Histologically confirmed adenocarcinoma of the pancreas. 
 
 Determined unresectable by a pancreatic cancer surgeon or a multi-disciplinary or 
gastrointestinal oncology Tumor Board.  
 
 Stable or better disease on re-staging scans following induction mFOLFIRINOX.. 
 
 Typically, pancreatic tumors must be less than 8.0 cm in greatest axial dimension at 
the time of treatment planning but final determination of eligibility will be based 
upon satisfying the radiation normal tissue constraints as specified below in section 
6.1.3 Radiation Treatment Planning. 
 
 No prior systemic therapy EXCEPT patients may be consented and enrolled if they 
have already started mFOLFIRINOX for up to four cycles. 
 
 ECOG 0, 1, or 2 (see Appendix II). 
 
 Patients must have acceptable organ and marrow function as defined below and 
within 30 days of eligibility confirmation:   
 
- 
leukocytes (WBC) 
>3,000/µL 
- 
absolute neutrophil count (ANC) 
>1,500µL 
- 
platelets 
>50,000/µL  

 
Page 20 of 84 
 
- 
total bilirubin  
<1.5 X institutional upper limit of normal 
- 
AST(SGOT) / ALT(SGPT) 
<2.5 X institutional upper limit of normal 
- 
Creatinine not above the upper limit of  normal institutional limits.  
 
 Ability to understand and the willingness to sign an informed consent form. 
 
 Life expectancy > 6 months.  
 
3.2 
Exclusion Criteria 
 
 
 Children/Age<18 (rarely occurs in this age group)
 
 Metastatic disease.  
 
 Prior radiotherapy to the upper abdomen/liver. 
 
 Patients who have received chemotherapy for pancreatic cancer, other than up to 4 
cycles of mFOLFIRINOX as noted above.   
 
 Uncontrolled illness including, but not limited to, ongoing or active infection (or 
infections requiring systemic antibiotic treatment), symptomatic congestive heart 
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
 
 Any concurrent malignancy other than non-melanoma skin cancer, non-invasive 
bladder cancer, or carcinoma in situ of the cervix.  Patients with a previous 
malignancy without evidence of disease for > 5 years will be allowed to enter the 
trial. 
 
 Pregnant and breastfeeding women are excluded; as well as women of child-bearing 
potential who are unwilling or unable to use an acceptable method of birth control 
(hormonal or barrier method of birth control; abstinence) to avoid pregnancy for the 
duration of the study.  Male subjects must also agree to use effective contraception 
for the same period as above.  Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately.  
 
 Women who are not post-menopausal (as defined in Appendix III) and have a 
positive urine or serum pregnancy test or refuse to take a pregnancy test.   
 
 
 
4. STUDY ENROLLMENT  
 
4.1  
General Guidelines 
 
Subjects will be identified per the recommendation of referring surgeons, Combined 
Modality Tumor Board or equivalent combined modality assessment, or through self-
referral and the advice of their attending physician.  No advertisement will be used to recruit 

 
Page 21 of 84 
 
subjects. 
 
See Diagram in Section 16.2 for phases and workflow of study. 
 
4.2  
Registration and Enrollment  
 
Research staff at each participating center will ensure that all requisite procedures and tests 
have been performed and complete an Eligibility Checklist (See Appendix IV) to submit to 
Stanford research staff for review.  Stanford research staff will contact the center regarding 
approval of patient’s study participation, and the patient may then be enrolled and 
registered.   
 
The participating center will register subjects according to their institutional guidelines and 
as per this protocol.   
  
In some patients, an optional additional core biopsy may be obtained for research purposes 
if consent is provided by the patient.  It may be done at the time of fiducial implantation (in 
patients randomized to SBRT) as described in Section 12.1, Laboratory Correlative Studies; 
or as a separate procedure (for patients randomized to mFFX alone).  This option will vary 
by participating institution. 
 
4.3       Informed Consent  
 
Consent will be obtained after a clear and thorough discussion between the patient and the 
principal investigator at each participating center.  Consent may be obtained either prior to 
starting induction chemotherapy or at any point up through the first 4 treatment cycles. Any 
patients deemed by the principal investigator or co-investigators to be mentally or physically 
incapable of consent will not be included in the study.   
 
Patients may be consented by a PI, Co-Investigator, Research Nurse, or Study Coordinator.  
All research staff will have completed institutional trainings related to research, institutional 
regulatory and HIPAA policies, and managing protected health information (PHI). 
 
5. 
INDUCTION CHEMOTHERAPY 
 
5.1  
mFOLFIRINOX 
 
After study enrollment, patients will receive (or continue with) mFOLFIRINOX (omission 
of bolus 5FU) as outlined below, allowing for modifications of dose and schedule as per 
clinical judgment of patient’s treating physician.  For patients who have received 
FOLFIRINOX chemotherapy including a 5FU bolus prior to study entry, once consent is 
signed, the 5FU bolus must be omitted.  Because of its improved safety profile without 
sacrificing efficacy, mFOLFIRINOX is commonly administered in the treatment of 
pancreatic cancer (31). Modified FOLFIRINOX regimen with improved safety and 
maintained efficacy in pancreatic adenocarcinoma. Pancreas 2013 Nov 42(8):1311-5.  
 
mFOLFIRINOX may be administered in a community practice setting as long as the 
treating oncologist assumes responsibility for all reporting and follow-up requirements.  

 
Page 22 of 84 
 
Prophylactic growth factors may be administered at any time before, during, or after 
chemotherapy cycles.  It is recommended that the patient be evaluated at one of the 
participating centers every 3-6 months. As standard practices are changing and Leucovorin 
is not widely used, we will allow the omission of this drug during both induction and 
treatment phases of the study. 
 
 
mFOLFIRINOX to complete a total of 4 cycles, (1 cycle = 14 days) 
 Oxaliplatin 85 mg/m² IV over 2 hours on Day 1, followed by 
 Irinotecan 180 mg/m² IV over 90 minutes on Day 1, followed by 
 Leucovorin* 400 mg/m² IV over 2 hours on Day 1, followed by 
 5FU** 2,400 mg/m² IV over 46 – 48 hours  
*Leucovorin may be administered concurrently with the last 30 minutes of 
oxaliplatin, and the entire 90 minutes of irinotecan. 
  
**5FU is administered via infusion only; there is no bolus injection of 5FU. 
 
 
 
 
 
 
5.2 
Restaging Following mFOLFIRINOX  
 
After induction chemotherapy (up to 4 cycles), patients will have a CT scan for re-staging.  
Re-staging scans should be scheduled within 2 weeks following completion of induction 
mFOLFIRINOX.  To allow for scheduling complications, outside sites may perform the 
simulation (SIM) scan during the final cycle of chemotherapy up to 4 weeks prior to start of 
treatment.  It the subjects are randomized to the SBRT arm and the SIM was more than 4 
weeks prior to treatment start date, a re-SIM will be performed to ensure that the plan is still 
appropriate for tumor treatment.  
 
 If there is radiological or clinical evidence of disease progression, patient will not 
continue with the randomized portion of this study, but should be treated according 
to treating physician’s discretion.  (Based upon the study by Conroy et al, the 
progression-free survival at 3 months is estimated to be 75%; therefore the number 
of patients evaluated for the protocol and ultimately enrolled will be adjusted 
accordingly.)  These patients will continue to be followed as part of the study. 
 If a patient has radiologically responding or stable disease, s/he may proceed with 
randomization as described in the following section.  Patients may undergo surgical 
resection at any time if clinically appropriate after surgical evaluation. 
 
 
5.3 
Randomization to +/- SBRT 
 
Participating centers will submit re-staging scan reports (and images as requested) within 5 
business days of the scan’s final report date to Stanford, along with documentation of 
consent.  These should be sent in a secure electronic mail message or fax to the PI (Dr. 
Daniel Chang) and Clinical Research Coordinator Rachel Freiberg with subject line:  
“SECURE:  STUDY PATIENT FOR RANDOMIZATION”.  Stanford research staff will 
randomize the subject by participating site and within the next business day, will send an 
electronic message to the PI and Research Coordinator from the participating center with the 
outcome and instructed treatment plan.  
 

 
Page 23 of 84 
 
Randomization will be done with R software, a randomized block design.  It will be 
performed by a Stanford Statistician or the Stanford study coordinator who will maintain a 
password-protected list and assign patients to the treatment arms as each patient is enrolled 
at each institution. Randomization Arm will be confirmed by two coordinators prior to 
electronic notification and written documentation (Note to File) of the treating physician and 
outside research coordinators. 
 
Subjects randomized to SBRT are allowed up to an 8-week break between induction 
chemotherapy and radiation treatments.  
 
Subjects randomized to mFOLFIRINOX can continue directly with that treatment.  Any 
breaks between mFOLFIRINOX cycles will be determined by the treating Medical 
Oncologist and are permitted for up to 8 weeks.  
 
If a subject exceeds the allowable 8-week break between treatments, s/he may continue 
treatment “off protocol” and as recommended by the treating Medical Oncologist or 
according to local standard of care.  These subjects will be followed for overall survival and 
progression-free survival.  Subsequent data analysis will be performed on an intention-to-
treat basis. 
 
 
 
6. 
RADIATION TREATMENT PLANNING AND SBRT ADMINISTRATION  
 
6.1 
Pre-SBRT Tests, Procedures, and Planning 
 
The following will be completed prior to SBRT:  
 
a) Consultation with medical history and physical examination. 
b)   Pathology with report confirming malignancy. 
c) Labs:  CBC with differential, CMP (Comprehensive Metabolic Panel) and CA199.  
CEA is optional.  Additionally, up to 20ml of additional blood may be drawn for 
research purposes (study bloods may also be collected in follow-up visits).  For 
specific information regarding collection and processing, see Section 12.1 
Laboratory Correlative Studies.   
d) Seed placement:  Gold fiducial seed placement percutaneously, intraoperatively, or 
under endoscopic ultrasound guidance, which may be performed prior to study 
enrollment.  In some patients, an optional additional core biopsy may be obtained for 
research purposes if consent is provided by the patient, and may be done at the time 
of fiducial implantation (See Section 12.1, Laboratory Correlative Studies) or in a 
separate procedure. For patients who are planned to be treated with active breathing 
coordinator (ABC) or 4D kV CBCT IGRT, fiducial seed placement is optional. 
e) Scans:  CT or MR. PET/CT scan is recommended though not required.  
 
f) Signed informed consent. 
g) Negative Pregnancy Test (urine or serum) for females of childbearing potential OR 
menopausal as defined in Appendix III – Definition of Menopausal Status.  
h)  Eligibility confirmation.  
i)  Study registration and randomization. 
j)  Quality of Life Survey:  Baseline collection of EORTC QLQ C-30/ PAN26 QOL. 

 
Page 24 of 84 
 
 
6.1.1 Fiducial Placement  
 
Prior to SBRT, 3 to 5 gold fiducials or ‘seeds’ (99.9% pure, 1-5 mm length, or 
visicoils) will be placed directly into the tumor and/or periphery, and when 
possible in the proximal duodenum directly adjacent to the pancreatic tumor.  
The fiducials will be used as surrogates for targeting the tumor position during 
radiation treatment.  The procedure will be done typically under endoscopic 
ultrasound, or if there is a contraindication to endoscopic placement in 
Interventional Radiology under CT guidance; and is expected to be on an 
outpatient basis.  Fiducials or clips may also be implanted prior to enrollment, as 
when done intraoperatively at the time of attempted surgical resection, which is 
within the standard of care and may occur regardless of patient eligibility. 
 
6.1.2 Radiotherapy Simulation   
 
1) Simulation should be done 5 days or more following placement of fiducials; 
however this may vary per participating institution and is at the discretion of 
each study investigator.   
2) Typically, patients will be positioned supine in an Alpha Cradle or 
equivalent immobilization device will be custom made for each patient.   
3) Standard free-breathing CT and respiratory-correlated 4-D pancreatic 
protocol CT will be obtained on each patient.  The 4D-CT scan will be used 
for characterizing target motion during quiet respiration. For more accurate 
tumor delineation, an arterial phase pancreatic protocol CT may be obtained 
(typically during expiration breath hold, 1.25 mm slices).  The simulation 
scan should include T4/T5 to L5/S1 (upper abdomen).   
4) IV and oral contrast must be used for simulation, unless the patient has an 
allergy that cannot be adequately premedicated.  In these situations, the plan 
should be fused with an IV contrast CT scan or MRI (ideally in a similar 
treatment position).  
5) Motion management can be addressed using respiratory gating or breath-
hold, (Varian, Elekta, Novalis), respiratory tracking (Cyberknife), or 
abdominal compression.  When fiducials are used, fluoroscopy will be used 
to assess motion of implanted gold markers before and after compression.  
The goal is to reduce motion from typically 11-22 mm peak to less than 5 
mm.  If the fiducial motion cannot be decreased to 5 mm or less, then another 
respiratory compensation strategy will be utilized for treatment delivery.  
Prior to simulation, standard guidelines will be followed.  
6) The selection of which radiotherapy treatment machine to use is left to each 
investigator.  As long as the specified dosimetric parameters for SBRT are 
reached, patients may be treated on any IGRT-enabled machine. 
7) All patients must start SBRT within 4 weeks of the simulation scan and 
may have up to an 8 week break between radiation and chemotherapy.  
 
6.1.3 Radiation Treatment Planning 
 
1) When available, an FDG-PET scan is preferred for treatment planning 
purposes and will be acquired on a flat table top whenever possible with the 

 
Page 25 of 84 
 
same immobilization devices used for the treatment planning CT simulation.  
2) An SBRT treatment plan will be developed using EclipseTM, Multi-PlanTM or 
PinnacleTM based on tumor geometry and location at each institution.  
Institutional standards for radiation quality assurance and radiation delivery 
will be utilized.  
3) The final tumor volume (GTV) as identified on the treatment planning CT, 
will be defined by the attending radiation oncologist after reviewing the 
diagnostic CT, respiratory-correlated 4D-CT scan, pancreas protocol CT, and 
the FDG-PET/CT scan. These scans will be used to define the ITV (internal 
target volume).  The final PTV (planning treatment volume) expansion will 
consist of an additional 2-3 mm of margin expansion, except if the margin 
results in expansion into the duodenum or stomach. In these cases, margin 
expansion is allowed to be non-uniform.  The dose will be prescribed to the 
isodose line that completely surrounds the PTV.  It is recommended that 
either 6-12 co-planer fields or 2-4 conformal arcs be used in the radiation 
treatment plan. 
4) When fiducials are used, contours of the fiducials used for target localization 
will be generated on the applicable image sets, to be used for patient setup on 
treatment.   
5) 
Radiation dose to the adjacent normal tissue will be minimized and these 
dose constraints should be met:  
-  Duodenum:  Dmax<40 Gy, V35 < 1cc, V30 < 10cc, V20 < 30cc.  V35,  
V30, and V20 are defined as the volume receiving 35, 30, and 20 Gy, 
respectively. The duodenum (duo@PTV) as defined for these dosing 
parameters includes entire duodenum on the same axial plane as the PTV 
and duodenum 1 cm above and 1 cm below the PTV.  The remainder of 
the normal tissues will be limited as follows:   
-  Liver (excluding tumor):  50% should be limited to <12 Gy 
-  Kidney:  Combined volume for both should have 75% <12 Gy 
-  Stomach:  Dmax<40 Gy, V35 < 1cc, V30 < 10cc, V20 < 30cc. (no more 
than 1 cc of stomach can receive >35 Gy) 
-  Spinal Cord: no more than 1cc can receive >15 Gy 
6)  No more than 1cc of the PTV can receive >130% of the prescription dose. 
7)  Greater than 90% of the PTV should receive 100% of the prescription dose. 
8) If above constraints cannot be met, 100% of the GTV must receive at least 33 
Gy and a request for a minor deviation should be submitted.  If this constraint 
still cannot be met, the patient should be withdrawn from the study and 
treated according to local standard of care.   
 
 
6.2 
SBRT Treatment Delivery 
 
All patients will receive 5 fractions of 8 Gy allowing up to 30% dose heterogeneity, 
delivered over a five-day period (ideally all 5 fractions should be delivered Monday through 
Friday however the 5 fractions may be delivered over 2 weeks as long as the patient receives 
at least 2 fractions per week).  SBRT treatment planning and delivery must be completed at 
a participating site.  The recommended interval between induction chemotherapy followed 
by SBRT and between SBRT followed by chemotherapy is 2-4 weeks.  However, it is 
acceptable to administer SBRT and chemotherapy within 8 weeks of each other. 

 
Page 26 of 84 
 
 
If a patient is unable to adhere to the protocol schedule for SBRT treatment, the patient will 
continue treatment off protocol and as recommended by the treating Medical Oncologist or 
according to local standard of care.  These patients will be followed for overall survival.  
Subsequent data analysis will be performed on an intention-to-treat basis. 
 
All patients must start SBRT within 4 weeks of the simulation scan and may have up to an 
8-week break between radiation and chemotherapy.  
 
For LINAC-based, treatment should entail:  
1)  Initial patient positioning based on either kV or volumetric kV (cone-beam CT) 
imaging with shifts to bony anatomy as appropriate.   
2)  Orthogonal kV/MV or kV/kV projection imaging to verify the location of the 
fiducials prior to delivery of first treatment beam.  A secondary shift based on the 
location of fiducials may be utilized, as indicated by the position of the fiducials.  
For free-breathing treatments, kV fluoroscopic images should be obtained to confirm 
the anticipated position of these fiducials during the entire respiratory cycle. 
3)  Active monitoring of treatment delivery accuracy using kV and/or MV projection 
imaging, either immediately before or during all (or a subset of) treatment fields. 
4)  Patient-specific dosimetric QA performed as per standard practice at each 
participating institution. 
 
For SBRT, treatment should entail: 
1)  Initial orthogonal images obtained to confirm location of fiducial seeds. 
2)  Synchrony respiratory tracking system must be used to correct for respiratory 
associated tumor motion.  This system utilizes a series of optical diodes placed upon 
the patient’s chest wall.  While the orthogonal images are obtained, the computer 
generates a model correlating the position of the chest wall with the position of the 
internal fiducials.  This model is continuously updated during treatment to correct 
for subtle changes in tumor location. 
3)  QA performed as per standard practice at each participating institution. 
 
For LINAC-based, treatment without fiducial markers should entail:  
1) Patient positioning based on either kV fluoroscopy or volumetric kV (cone-beam 
CT), using vertebral body and stent for initial positioning. 
2) 4D CBCT (for quiet free breathing) or active breathing coordinator (ABC) breath 
hold stop and go CBCT to be used for IGRT.  Oral water (with a small volume of 
contrast) may be used to help in visualization of the duodenum.  Any biliary stents 
may also be complimentary in patient positioning. 
3)  QA performed as per standard practice at each participating institution. 
 
 
6.2.1 Use of Radioisotopes / Rad Machines  
 
 
Stereotactic radiotherapy will be performed using TrilogyTM or TrueBeamTM 
(Varian, Palo Alto CA), NovalisTM (BrainLab, Feldkirchen, Germany), or 
SynergyTM (Elekta AB, Stockholm, Sweden), radiation machines that are 
designed to use multiple beams of radiation to concentrate large doses of 
radiation within a tumor.  The Cyberknife (Accuray, Sunnyvale, CA) is another 

 
Page 27 of 84 
 
stereotactic radiotherapy machine that may be used in this study.  Each of these 
machines was specifically designed for image guided radiation therapy (IGRT).  
Because of the innovations in image-guided radiotherapy capabilities associated 
with each of these machines (or future generation machines), it is possible to 
deliver highly accurate, stereotactic radiation treatments.  Uncertainties in tumor 
location are minimized because these machines have on-board, volumetric 
imaging for accuracy in initial patient setup; kV and MV projection imaging 
during treatment is used to monitor delivery accuracy and/or make corrections to 
the patients’ position.   
 
 
The radioactive tracer FDG will be used to perform PET scans, a special imaging 
procedure.  Positron emission tomography (PET) is a type of nuclear medicine 
examination, which is based on the administration of a small amount of a 
radioactive FDG agent.  The tracer (FDG) is a modified form of glucose, a sugar 
normally found in the bloodstream and used by cells in the body for energy.  
FDG is eliminated in the urine.  With special imaging equipment, it is possible to 
detect radiation from the administered radioactive agent and obtain images of the 
body. 
 
 
RISK INFORMATION 
 
 
It is difficult at this time to predict with confidence the percentage rate of 
complications from the proposed SBRT treatment.  However it is reasonable to 
extrapolate from the current experience with radiotherapy in and around the 
pancreas.  Based upon prior phase I and phase II studies, we anticipate that the 
toxicities associated with this treatment will be acceptable. 
 
 
Toxicity commonly associated with radiation includes nausea, vomiting, fatigue, 
anorexia and weight loss.  Severe side effects such as gastrointestinal (GI) 
obstruction, perforation, or hemorrhage are uncommon complications, occurring 
in <5% of patients undergoing standard radiation therapy for pancreatic cancer.  
Although we expect a comparable rate of complications with fractionated 
radiotherapy, it is important to note that vomiting, GI obstruction, GI 
hemorrhage, anorexia and weight loss are also commonly associated with 
pancreatic cancer progression.  Clinical and radiographic assessments will be 
performed in an effort to identify these effects, ascertain their etiology and 
provide the most appropriate palliative measures.  Hepatic and renal toxicity is 
not anticipated given the expectation of limited incidental irradiation of these 
organs.  Complications, if any, will be graded according to the CTCAE, National 
Cancer Institute, version 4.0 or greater.  We will utilize the RTOG scale as 
necessary for grading acute and chronic radiotherapy toxicities. 
 
 
6.2.2 Prophylactic and Supportive Medications for SBRT 
 
 
 
Patients receiving SBRT should be prescribed antiemetics prophylactically and 
for relief of nausea and vomiting symptoms.  We recommend 1 dose of 
ondansetron (Zofran) or prochlorperazine (Compazine) 30-60 minutes prior to 
each SBRT and if needed another dose after 8-12 hours, and as needed twice 

 
Page 28 of 84 
 
daily for 5 days following completion of SBRT.  Additional antiemetic measures 
may be used at the discretion of the treating physician.  Administration of 
Lorazepam is permitted to aid in anxiety and to help with reduction of motion. 
 
 
 
Patients should also be advised to take a proton pump inhibitor (PPI) from the 
start of SBRT (Day 1) and continuing for 6 months following completion of 
SBRT.  Over-the-counter PPIs are acceptable and an increase in medication dose 
or duration for symptomatic relief is left to the discretion of the treating 
physician. 
 
 
 
For symptoms of diarrhea and/or abdominal cramping, patients can take 
loperamide (Imodium) and/or additional antidiarrheal measures at the discretion 
of the treating physician.  In cases of diarrhea, patients should be instructed to 
increase fluid intake to help maintain fluid and electrolyte balance and should be 
monitored according to the participating center’s guidelines. 
 
Administration of prophylactic growth factors at any time during the study is 
permissible.  This decision will be at the discretion of the PI or patient's treating 
physician. 
 
6.2.3 Other Concomitant Medications 
 
 Medications should be monitored by the treating Medical Oncologist.  Therapies 
considered necessary for the patient's well-being may be given at the discretion 
of the investigator and/or treating physician.  Other concomitant medications 
should be avoided except for analgesics, chronic treatments for concomitant 
medical conditions, or agents required for life-threatening medical problems.  In 
general, medications will be prescribed by the attending medical oncologist. 
 
 
 
Patients’ reports of proton-pump inhibitor (PPI), if applicable, and pain 
medications should be recorded at each visit and entered into REDCap. 
 
 
7. 
Chemotherapy and Follow-up after Randomization 
 
7.1 
Chemotherapy following SBRT 
 
 
For patients randomized to SBRT, mFOLFIRINOX should resume within 8 weeks 
following completion of SBRT.  If this schedule cannot be met, the subject may continue 
treatment “off protocol” and as recommended by the treating Medical Oncologist or 
according to local standard of care.  These patients will be followed for overall survival and 
progression-free survival.  Subsequent data analysis will be performed on an intention-to-
treat basis. 
 
Dosing and modification guidelines for mFOLFIRINOX are provided in Section 9, 
however, chemotherapy schedule modifications and dose reductions are allowed and 
are left to the discretion and clinical judgment of the treating medical oncologist.  A 
total of at least 6 cycles of mFOLFIRINOX is recommended but the total number of cycles 

 
Page 29 of 84 
 
is left to the clinical judgement of the treating oncologist.  As standard practices are 
changing and Leucovorin is not widely used, we will allow the omission of this drug during 
both induction and treatment phases of the study. 
 
Participating centers at all times should follow the Study Calendar (Section 14) and ensure 
that all records and study materials are collected and reported properly. 
 
Since mFOLFIRINOX is an accepted standard of care, chemotherapy may be administered 
in a community setting as long as the treating oncologist assumes responsibility for the 
follow up care and reporting requirements.  It is recommended that the patient be evaluated 
at a participating site every 3-6 months. 
 
 
7.2 
Follow-up  
 
All patients will be monitored with clinic visits, labs, and serial imaging (CT or MR scans 
and PET/CT if possible), and other tests as needed. 
 
 
 
Patients deemed resectable at any time during follow-up may proceed to surgery.  These 
patients will be withdrawn from the protocol and followed for survival. 
 
Patients will have consultations in the first year every three months following study 
treatment as defined in the Study Calendar (Section 14); a follow up at 4-6 weeks is optional 
and may be done to assess subject's resectability, or if clinically indicated by study PIs or 
patient's treating physician.   
 
For years 2 and 3, follow-up is recommended every 6 months, or until death or study 
withdrawal (due to progression, patient withdrawal, or noncompliance as defined in Section 
7.5 Criteria for Removal from Study).  Follow up intervals may be more frequent as 
indicated clinically.  In the event of intolerable toxicity from mFFX, subjects will still be 
followed per protocol although chemotherapy may be altered or discontinued, the decisions 
of which will be left to the treating Medical Oncologist.  Visits should include:  
 
- 
Consultation with physical examination 
 
 
- 
Labs:  CBC, CMP, CA199.  CEA and research bloods are optional. 
- 
Scans:  CT or MR and PET/CT if possible (PET/CT is recommended at 3 month 
follow-up visit but is not required) 
- 
QOL (Quality of Life) Assessment with EORTC QLQ C-30 / PAN26 survey  
- 
Adverse Event (AE) evaluation 
- 
Concomitant Medications:  PPIs and pain medications as applicable 
- 
Other tests as appropriate. 
 
Patients who remain on-study will be followed until death and cause of death should be 
obtained when possible.   
 
7.3 
Duration of Study 
 
It is anticipated that the total duration of the study will last approximately 72 months (60 
months for recruitment and a minimum of 12 months of follow-up per individual).  Patients 

 
Page 30 of 84 
 
may be followed for up to 3 years.   
 
7.4  
Duration of Follow Up 
 
Patients will remain enrolled on this protocol until there is evidence that their disease has 
progressed either locally or distantly; or until study withdrawal for any reason.  These 
patients will be followed for survival.   
 
Progression may be determined by imaging or clinical criteria, i.e., increasing ascites and 
cachexia.  We estimate that most patients will remain a subject in this study for 
approximately one year.  Schedule of follow-up will be as according to the Study Calendar 
in Section 14. 
 
7.5 
Criteria for Removal from Study 
 
Patients will be withdrawn from the study for any of the following reasons:  
  
 disease progression (as defined in Section 15.1.2 Disease Parameters) 
 patient withdrawal 
 pregnancy 
 patient noncompliance, or failure of the patient to follow instructions of the study 
staff 
 protocol director decides that continuing participation could be harmful to the 
patient 
 treatment needed for patient that is not allowed in the study 
 patient is deemed resectable and proceeds to surgery 
 study cancellation 
 other administrative reasons 
 unanticipated circumstances. 
 
Patients will continue mFFX on-study until one of these endpoints; in the event of 
intolerable toxicity from mFFX, subjects will still be followed per protocol although 
chemotherapy may be altered or discontinued, the decisions of which will be left to the 
treating Medical Oncologist.   
 
Patients withdrawn from the study will be followed for overall survival only. 
 
7.6 
Alternatives 
 
Alternative therapies include chemotherapy alone, standard chemotherapy/radiation, or no 
further treatment.  Additionally, patients may choose to receive treatment to improve quality 
of life but which may have no affect on the growth of their cancer.  The risks of 
chemotherapy and standard chemotherapy/radiation include nausea, vomiting, diarrhea, 
fatigue, bone marrow suppression, and sepsis.  The potential benefits of chemotherapy or 
standard chemotherapy/radiation are prolonged survival.  The risk of pursuing no further 
treatment is tumor progression or spread. 
 
 
7.7 
Compensation 

 
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Subjects will not be paid to participate in the study. 
 
 
8. 
PHARMACEUTICAL INFORMATION 
 
8.1 
  
Investigational Agent or Device   
 
 
Not applicable. 
 
8.2 
 
Availability 
 
 
Not applicable. 
 
8.3 
       Agent Ordering 
 
Not applicable. 
 
8.4 
       Agent Accountability 
 
 Not applicable. 
 
 
9. 
TOXICITIES AND mFOLFIRINOX DOSING AND MODIFICATIONS  
 
9.1  
Modified Folfirinox (mFFX) Dosing 
 
Modified Folfirinox dosing is below, however modifications of dose and schedule are 
allowed as per clinical judgment of patient’s treating medical oncologist.  
Recommendations for toxicity management are in Section 9.1.1. 
 
mFOLFIRINOX, 1 cycle = 14 days 
 Oxaliplatin 85 mg/m² IV over 2 hours on Day 1, followed by 
 Irinotecan 180 mg/m² IV over 90 minutes on Day 1, followed by 
 Leucovorin* 400 mg/m² IV over 2 hours on Day 1, followed by 
 5FU** 2,400 mg/m² IV over 46 – 48 hours  
 
*Leucovorin may be administered concurrently with the last 30 minutes of oxaliplatin, 
and the entire 90 minutes of irinotecan 
 
**5FU is administered via infusion only; there is no bolus injection of 5FU 
 
 
 
 
Subjects should be assessed for Adverse Events (AEs) once during each chemotherapy 
cycle, and AEs should be recorded in the AE Tracking Form in Appendix V.  Serious 
Adverse Events (SAEs) should be reported promptly as according to the guidelines in 
this protocol.  (See Section 11 for more information regarding documenting and 
reporting SAEs and AEs.) 
 
Chemotherapy infusion records should be kept in the patient’s study chart, either with 

 
Page 32 of 84 
 
the Medication Administration Record (MAR) or other clinic records which contain:  
Date of infusion, dose completed of each agent, modifications if any and reason for 
modification with supporting source documents as needed.  Laboratory results prior to 
infusion should also be supplied in the patient study chart, as well as the consultation 
note if the patient is seen by the treating physician.    
 
Laboratory results and administration dates and doses of each agent should also be 
entered into REDCap. 
 
 
  9.1.1  Recommended Modifications for Toxicity 
 
Below are recommendations and not requirements; modifications of 
chemotherapy dose and schedule are allowed as per clinical judgment of 
patient’s treating medical oncologist. 
 
 
9.1.1.1 Hematologic Toxicity 
 
NOTE:  mFOLFIRINOX dose modifications for hematologic toxicity are not 
based on CTCAE severity grades. 
 
 For ANC 1,000/mm3–1,200/mm3:  Delay mFOLFIRINOX until ANC > 
1,200/mm3 then resume mFOLFIRINOX at the same dose level. 
 Second or More Occurrence of ANC 1000/mm3-1200/mm3:  Delay 
mFOLFIRINOX until ANC > 1,200/mm3 then resume mFOLFIRNOX 
with one dose level reduction for all subsequent cycles.  NOTE: The dose 
of leucovorin is not reduced. 
 
 For ANC < 1,000/mm3:  Delay mFOLFIRINOX until ANC > 1,200/mm3, 
then resume mFOLFIRINOX with one dose level reduction for all 
subsequent cycles.  NOTE: The dose of leucovorin is not reduced. 
 
 For Febrile Neutropenia (defined as ANC < 1,000/mm3 and temperature ≥ 
100.5°F): Delay mFOLFIRINOX until resolution of fever and ANC > 1,200, 
then resume mFOLFIRINOX with one dose level reduction for all 
subsequent cycles.  NOTE: The dose of leucovorin is not reduced.  
 
 For Platelets 50,000 K/ul – 75,000 K/ul:  Delay mFOLFIRINOX until 
platelets > 75,000 then resume mFOLFIRINOX at the same dose level. 
 Second or More Occurrence of platelets 50,000 K/ul - 75,000 K/ul:  Delay 
mFOLFIRINOX until platelets > 75,000K/ul, then resume 
mFOLFIRINOX with one dose level reduction for all subsequent cycles.  
NOTE: The dose of leucovorin is not reduced.  
 
 For Platelets < 50,000 K/ul:  Delay mFOLFIRINOX until recovery to Plts > 
75,000 K/ul then resume mFOLFIRINOX with one dose level reduction for 
all subsequent cycles.  NOTE: The dose of leucovorin is not reduced. 
 
 
 
9.1.1.2 Non-Hematologic Toxicity 
 

 
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Diarrhea 
 
 For grade 2 Diarrhea (despite optimal medical management: see Section 
9.1.3): 
 First Occurrence:  Delay mFOLFIRINOX until recovery to grade ≤ 1 
or baseline then resume mFOLFIRINOX at the same dose level. 
 Second or More Occurrence:  Delay mFOLFIRINOX until recovery to 
grade ≤ 1 or baseline, then resume mFOLFIRINOX with one dose 
level reduction for all subsequent cycles. NOTE: The dose of 
leucovorin is not reduced. 
 
 For grade 3 Diarrhea (despite optimal medical management: see Section 
9.1.3):  
 First Occurrence:  Delay mFOLFIRINOX until recovery to grade ≤ 1 
or baseline, then resume 5-FU, leucovorin, and oxaliplatin, at the same 
dose level and irinotecan with one dose level reduction for all 
subsequent cycles.  
 Second or More Occurrence:  Delay mFOLFIRINOX until recovery to 
grade ≤ 1 or baseline, then resume mFOLFIRINOX with one dose 
level reduction for all subsequent cycles.  NOTE: The dose of 
leucovorin is not reduced. 
 
 For grade 4 Diarrhea (despite optimal medical management):  Delay 
mFOLFIRINOX until recovery to grade ≤ 1 or baseline then resume 
mFOLFIRINOX with one dose level reduction for all subsequent cycles.  
NOTE: The dose of leucovorin is not reduced. 
 
Nausea/Vomiting 
 
The following dose modifications are based on toxicity experienced during a 
cycle.  
 
 For grade 3 Nausea/Vomiting (despite optimal medical management): 
 First Occurrence:  Delay mFOLFIRINOX until recovery to grade ≤ 1 
or baseline, then resume 5-FU and leucovorin, at the same dose level 
and oxaliplatin and irinotecan with one dose level reduction for all 
subsequent cycles.  
 Second or More Occurrence:  Delay mFOLFIRINOX until recovery to 
grade ≤ 1 or baseline, then resume mFOLFIRINOX with one dose 
level reduction for all subsequent cycles.  NOTE: The dose of 
leucovorin is not reduced. 
 
 For grade 4 Nausea/Vomiting (despite optimal medical management):  
Delay mFOLFIRINOX until recovery to grade ≤ 1 or baseline, then 
resume mFOLFIRINOX with one dose level reduction for all subsequent 
cycles.  NOTE: The dose of leucovorin is not reduced. 
 
Mucositis 
 

 
Page 34 of 84 
 
The following dose modifications are based on toxicity experienced at any 
time during a cycle. 
 
 For grade 3 Mucositis:  
 First Occurrence:  Delay mFOLFIRINOX until recovery to grade ≤ 
1, then resume irinotecan, oxaliplatin, and leucovorin at the same 
dose level and 5-FU with one dose level reduction for all subsequent 
cycles. 
 For Second or More Occurrence:  Delay mFOLFIRINOX until 
recovery to grade ≤ 1, then resume mFOLFIRINOX with one dose 
level reduction in irinotecan and oxaliplatin for all subsequent cycles. 
Dose of 5FU is reduced two dose levels for all subsequent cycles).  
NOTE: The dose of leucovorin is not reduced. 
 
 For grade 4 Mucositis:  
Delay mFOLFIRINOX until recovery to grade ≤ 1, then resume 
mFOLFIRINOX with one dose level reduction for all subsequent cycles.  
NOTE: The dose of leucovorin is not reduced. 
 
Peripheral Sensory Neuropathy 
 
 
NOTE: Dose modifications for sensory neuropathy are not based on CTCAE 
severity grades. 
 
 For paresthesia/dysethesia interfering with function and persisting 
between treatments:  decrease oxaliplatin by one dose level for all 
subsequent cycles.  
 
 For painful paresthesia/dysesthesia or symptoms that interfere with 
function and ADL, but improve (no longer painful or no longer 
interfering with ADL) between treatments:  decrease oxaliplatin by one 
dose level for all subsequent cycles. 
 
 For painful paresthesia/dysesthesia or symptoms that interfere with 
function and ADL that persists between treatments:  Discontinue 
oxaliplatin.  
 
 For persistent disabling or life-threatening paresthesia/dysesthesia:  
Discontinue oxaliplatin.  
 
 For pharyngo-laryngeal dysesthesia: increase the duration of oxaliplatin 
infusion to 6 hours for subsequent cycles.  
 
Oxaliplatin-induced pharyngolaryngeal dysesthesias 
 
Should a patient develop oxaliplatin-induced pharyngolaryngeal dysesthesia, 
her/his oxygen saturation should be evaluated via a pulse oximeter; if normal, 
an anxiolytic agent may be given and the patient observed in the clinic until 
the episode has resolved. Following resolution of symptoms, patients may 

 
Page 35 of 84 
 
continue/resume oxaliplatin if the reaction is NOT determined to be an 
allergic reaction. 
 
A table comparing pharyngo-laryngodysesthesia to platinum hypersensitivity 
reactions is presented below.  
 
Table 1 - Comparison of the Symptoms and Treatment of 
Pharyngolaryngodysesthesias and Platinum Hypersensitivity Reactions 
Clinical Symptoms 
Pharyngo-Laryngeal 
Dysesthesias 
Platinum 
Hypersensitivity 
Dyspnea 
Present 
Present 
Bronchospasm 
Absent 
Present 
Laryngospasm 
Absent 
Present 
Anxiety 
Present 
Present 
O2 saturation 
Normal 
Decreased 
Difficulty 
swallowing 
Present (loss of 
sensation) 
Absent 
Pruritis 
Absent 
Present 
Urticaria/rash 
Absent 
Present 
Cold-induced 
symptoms 
Yes 
No 
Blood pressure 
Normal or increased 
Normal or decreased 
Treatment 
Anxiolytics, observation 
in a controlled clinical 
setting until symptoms 
abate or at the 
physician’s discretion 
Oxygen, steroids, 
epinephrine, broncho-
dilators; fluids and 
vasopressors, if 
appropriate 
 
Venous Thrombembolic Events 
 
 For grade 2 or 3 venous thromboembolic event:  Continue 
mFOLFIRINOX at the same dose level.  Do not use warfarin for 
therapeutic anticoagulation. 
 
 For grade 4 venous thromboembolic event:  Discontinue 
mFOLFIRINOX. 
 
Liver Function Tests 
 
 For grade 2 Increased Blood Bilirubin:  Skip irinotecan until bilirubin 
improves to ≤ grade 1. 
 For hyperbilirubinemia considered at least possibly related to 
irinotecan, then resume irinotecan with one dose level reduction for 
all subsequent cycles. 
 For hyperbilirubinemia considered unrelated to irinotecan, resume 
irinotecan at the previous dose level. 
 
 For grade 3 or 4 Increased Blood Bilirubin:  Delay mFOLFIRINOX 
until bilirubin improves to ≤ grade 1.  If bilirubin is thought to be due to a 
chemotherapy drug, then resume that drug at the next lower dose level 

 
Page 36 of 84 
 
and the other drugs at the same dose level when total bilirubin improves 
to ≤ grade 1. 
 For hyperbilirubinemia considered at least possibly related to 
treatment (any drug) resume mFOLFIRINOX with one dose level 
reduction in suspect drug(s) for all subsequent cycles. 
 For hyperbilirubinemia considered unrelated to treatment (all drugs), 
resume mFOLFIRINOX at the previous dose levels. 
 
Allergic Reactions 
 
 For grade 2 allergic reactions:  Interrupt infusion(s).  Manage reaction 
according to institutional policy.  Restart the infusion(s) when symptoms 
resolve to ≤ grade 1 and pre-treat before all subsequent doses.  
 
 For grade 3 or Grade 4 allergic reactions:  Discontinue infusion.  
Manage reaction according to institutional policy.  Discontinue 
mFOLFIRINOX. 
 
Irinotecan dosing and UGT1A1*28 allele homozygosity 
 
Caution should be exercised when dosing irinotecan in patients who express 
homozygous for the UGT1A1*28 allele.  The toxicity is dose-dependent.  
The FDA recommends reducing the dose by one dose level for patients 
expressing UGT1A1*28 allele.  For additional information, please refer to 
the package insert. 
 
Other non-hematologic toxicities 
 
 For all other grade 3 non-hematologic toxicities considered at least 
possibly related to mFOLFIRINOX:  Skip the responsible drug(s) until 
toxicity improves to ≤ grade 1, then resume the responsible drug(s) with 
one dose level reduction for all subsequent cycles. 
 
 For grade 4 non-hematologic toxicities considered at least possibly 
related to mFOLFIRINOX:  Discontinue the responsible drug(s). 
 
 
9.1.2 Management of Diarrhea during Systemic Treatment prior to Chemoradiation 
 
 Early Diarrhea (e.g., developing in less than 24 hours after irinotecan 
infusion: 
Lacrimation, rhinorrhea, miosis, diaphoresis, hot flashes, flushing, abdominal 
cramping, diarrhea, or other symptoms of early cholinergic syndrome may 
occur during or shortly after receiving irinotecan.  Atropine, 0.25-1. mg IV or 
SC may be used to treat these symptoms. In patients with troublesome or 
recurrent symptoms, prophylactic administration of atropine shortly before 
irinotecan therapy may be considered.  Additional antidiarrheal measures 
may be used at the discretion of the treating physician.  Combination 
anticholinergic medications containing barbiturates or other agents (e.g., 
Donnatal®) should not be used because these may affect irinotecan 

 
Page 37 of 84 
 
metabolism. Anticholinergics should be used with caution in patients with 
potential contraindications (e.g., obstructive uropathy, glaucoma, 
tachycardia, etc.). 
 
 Late Diarrhea (e.g., developing more than 24 hours after irinotecan 
infusion): 
Manage with loperamide, as per standard of care guidelines and package 
insert for irinotecan. Dose modifications are based on toxicity experienced at 
any time during a cycle.  
 
Patients should be optimally managed with anti-diarrheal medications before 
dose modifications are made. 
 
 
 
 
9.1.3   SBRT Toxicities and Potential Risks  
 
Prior studies investigating 25 Gy given in a single fraction resulted in a 
combined Grade 3 or higher toxicity in 8% of patients.  In our recently 
completed multi-center Phase II study, we did not observe significant toxicities 
related to SBRT with a dose of 33 Gy in 5 fractions. 
 
In another recent study of SBRT for unresectable locally advanced pancreas 
cancer, with a prescription dose of 45Gy (7.5 Gy in 6 fractions), no Grade > 3 
toxicities were reported and FFLP was > 91% at 6 months.(29) 
 
Given these recently reported data of improved FFLP and no increase in toxicity, 
the SBRT prescription dose will be 40 Gy (in 5 fractions of 8 Gy).   
 
Hepatic and renal toxicity is not anticipated given the expectation of limited 
incidental irradiation of these organs and we have not observed any to date in the 
patients treated with SBRT.  Complications, if any, will be graded according to 
CTCAE v4.0 or higher.  
 
10. 
 DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of chemotherapeutic agents in a self-contained, protective environment. Chemotherapy 
treatment is standard-of-care and can be administered at any qualified medical facility.  
Discard unused portions of injectable chemotherapeutic agents that do not contain a 
bacteriostatic agent or are prepared with unpreserved diluents (i.e., Sterile Water for Injection 
USP or 0.9% Sodium Chloride for Injection USP) within eight hours of vial entry to minimize 
the risk of bacterial contamination. 
The total administered dose of chemotherapy may be rounded up or down within a range of 5% 
of the actual calculated dose. 
10.1 
Oxaliplatin  

 
Page 38 of 84 
 
Please refer to the package insert for complete product information. 
Availability 
Oxaliplatin is commercially available a solution in vials containing 50 mg, 100 mg, and 
200mg at a concentration of 5 mg/mL. The vials do not contain any preservative and 
they are intended for single use. 
Storage and Stability 
Intact vials should be stored at room temperature. According to the manufacturer, 
solutions diluted in D5W are stable for 6 hours at room temperature or 24 hours under 
refrigeration. Solutions diluted in D5W to a concentration of 0.7 mg/mL are reported to 
be stable (sterility not tested) for up to 30 days at room temperature or under 
refrigeration.  
Preparation 
The calculated dose of oxaliplatin should be diluted for infusion with 250 mL to 500 mL 
D5W. Oxaliplatin should not be diluted with a chloride-containing solution. Needles, 
syringes, catheters or IV administration sets containing aluminum should not be used 
with oxaliplatin. As with other platinum compounds, contact with aluminum may result 
in a black precipitate.  
Administration 
Oxaliplatin will be administered by intravenous infusion over 2 hours prior to irinotecan, 
and prior to or concurrent with leucovorin. Infusion time may be prolonged (up to 6 
hours) in patients experiencing pharyngolaryngeal dysesthesia. 
Toxicity 
The most commonly observed oxaliplatin toxicities include neurotoxicity, GI toxicity, 
and myelosuppression. Three neurotoxicity syndromes have been seen: acute sensory 
neuropathy develops within hours to 2 days after oxaliplatin administration. Symptoms 
include, paresthesias, dysesthesias, and hypothesia of the hands, feet and perioral region. 
Jaw spasm, abnormal tongue sensation, dysarthria, eye pain and a sensation of chest 
pressure have also been noted. Acute sensory neuropathy symptoms may be exacerbated 
by exposure to cold temperature or cold objects. Symptoms are reversible, usually 
resolving within 14 days and commonly recurring with further dosing. This syndrome 
has been observed in about 56% of patients receiving oxaliplatin with 5-FU and 
leucovorin.  
Acute pharyngolaryngeal dysesthesia is reported to occur in 1-2% of patients. This 
syndrome is characterized by a subjective sensation of difficulty breathing or 
swallowing without laryngospasm or bronchospasm or objective evidence of hypoxia. 
Avoidance of cold drinks, food and air is suggested in order to minimize 
pharyngolaryngeal dysesthesia. Antianxiety agents (e.g., lorazepam) may be used to 
treat pharyngolaryngeal dysesthesias once oxygen saturation has been documented to be 
normal.  
Peripheral neuropathy persisting > 14 days is characterized by paresthesias, 
dysesthesias, and hypothesia. Abnormalities in proprioception may also be seen. 
Symptoms of persistent neuropathy may improve upon discontinuation of oxaliplatin.  
Various agents have been used in an attempt to minimize neurotoxicity of oxaliplatin 
(e.g. carbamazepine, Mg+, Ca++). Calcium and magnesium infusions appear to be 
beneficial in preventing neurotoxicity. Contrary to preliminary findings described in 

 
Page 39 of 84 
 
2007, calcium and magnesium do not appear to interfere with tumor response to 
FOLFOX. Calcium and magnesium infusions are generally given before and after 
oxaliplatin, and should not be prepared in the same infusion solution as FOLFOX or 
FOLFIRINOX components. 
Gastrointestinal toxicities include nausea, vomiting (oxaliplatin is considered to be 
moderately emetogenic) and diarrhea. Grade 3 or 4 neutropenia was reported in 46% of 
patients receiving FOLFIRINOX, and grade 3 or 4 thrombocytopenia was reported in 
9%.  
Allergic reactions, similar to those seen with other platinum compounds, have also been 
observed in patients treated with oxaliplatin. Reactions range from rash to anaphylaxis. 
Rarely, oxaliplatin has been associated with pulmonary fibrosis, which may be fatal. 
Oxaliplatin should be discontinued in the presence of unexplained pulmonary symptoms 
(e.g. nonproductive cough, dysphagia) or pulmonary infiltrates until interstitial lung 
disease or pulmonary fibrosis have been ruled out.  
Recent reports of oxaliplatin extravasation suggest that tissue necrosis may result and 
that oxaliplatin should be considered a vesicant. No standard treatment exists for 
oxaliplatin extravasation although heat and sodium thiosulfate have both been 
suggested. 
Veno-occlusive disease (VOD) of the liver is a rare complication associated with 
oxaliplatin and 5-FU. Clinical manifestations of VOD include hepatomegaly, ascites, 
and jaundice. Histologically, VOD is characterized by diffuse damage in the 
centrilobular zone of the liver. Sequelae of VOD include hepatomegaly, splenomegaly, 
portal hypertension, and esophageal varices. A recent analysis of resected liver 
metastases in 153 patients indicated histological findings consistent with VOD in 6/27 
patients who received 5-FU alone, 4/17 patients who received 5-FU and irinotecan, 
20/27 patients who received 5-FU and oxaliplatin, and 14/16 who received 5-FU, 
oxaliplatin and irinotecan. The remaining 66 patients had not received chemotherapy 
prior to resection. There were no such findings in these patients. 
For more information on toxicities associated with oxaliplatin, please see the package 
insert.  
10.2 
5-Fluorouracil (5-FU)  
Please refer to the package insert for complete product information. 
Availability 
5-FU is commercially available as a 50 mg/mL solution for injection in 10 mL, 20 mL, 
50 mL and 100 mL vials. 
Preparation  
Inspect for precipitate; if found, agitate or gently heat in water bath.  
46-48 hour infusion of 5-FU should be prepared for administration via ambulatory 
infusion pump according to the individual institution’s standards. These solutions may 
be prepared in D5W or 0.9% NaCl. 5-FU should not be mixed in the same solution with 
most parenteral antiemetics.  
Storage and Stability 
Intact vials should be stored at room temperature and protected from light. Slight yellow 
discolor does not usually indicate decomposition. Stability in ambulatory pumps varies 

 
Page 40 of 84 
 
according to the pump, manufacturer of drug, concentration and diluent. Please refer to 
appropriate reference sources for additional information.  
Administration 
In this study, 5-FU is administered as an IV infusion over 46 – 48 hours. There is no 
bolus injection of 5-FU. 
Toxicity 
GI: Nausea, diarrhea, vomiting (mild); stomatitis: 5-8 days after treatment initiation; 
Myelosuppression: neutropenia (9-14 days); thrombocytopenia (7-14 days);  
Dermatologic: Alopecia; nails changes; vein pigmentation; photosensitivity; 
maculopapular rash; palmar–plantar erythrodysethesias, 
CNS effects: cerebral ataxia (rare);  
Cardiotoxicity: MI, angina; asymptomatic S–T changes;  
Ocular effects: excessive lacrimation and less commonly, tear duct stenosis. 
Drug Interactions 
Leucovorin enhances the cytotoxicity of 5-FU by forming a more stable tertiary complex 
with thymidylate synthase. Concommitant adminstration of 5-FU with warfarin has been 
reported to result in increased INR/prolonged prothrombin time. 
10.3 
Leucovorin Calcium (Folinic Acid) (calcium folinate; citrovorum factor; N 5-
formyltetrahydrofolate; 5-formyl-FH4; folinic acid) 
Please refer to the package insert for complete product information. 
Availability 
Leucovorin calcium is commercially available in 50 mg, 100 mg, 200 mg, and 350 mg 
vials for reconstitution, and 50 mL vials of solution at a concentration of 10 mg/mL. 
Storage and Stability 
Intact vials of powder for reconstitution should be stored at room temperature and 
protected from light.  Solutions reconstituted with bacteriostatic water for injection are 
stable for up to 7 days at room temperature.  Solutions reconstituted with sterile water 
for injection should be used immediately. 
Intact vials of solution should be stored under refrigeration and protected from light. 
Solutions further diluted for infusion are stable for 24 hours at room temperature, and 4 
days under refrigeration. 
Preparation 
Leucovorin may be reconstituted with Bacteriostatic Water for Injection or with Sterile 
Water For Injection.  Solutions should be further diluted in D5W, 0.9% NaCl or Ringers 
solution for IV infusion over two hours.  
Administration 
Leucovorin will be administered as a 400 mg/m2 IV infusion over 2 hours after, or 
concurrent with, oxaliplatin and irinotecan. For administration concurrent with 
oxaliplatin (30 minutes) and irinotecan (90 minutes), leucovorin is administered as a 
separate infusion (i.e, not in the same IV solution). 
Toxicity 
The only adverse reactions associated with leucovorin are allergic reactions. These are 

 
Page 41 of 84 
 
rare. 
10.4 
Irinotecan (CPT-11, CAMPTOSAR®) 
Please refer to the package insert for complete product information. 
Availability 
Irinotecan is commercially available as a 20 mg/mL solution for injection in 2 mL and 5 
mL vials.  
Storage and Stability 
Intact vials should be stored at controlled room temperature 59° to 86° F (15° to 30° C) 
and protected from light. Solutions diluted in D5W are reported to be stable for 24 hours 
at room temperature, or 48 hours under refrigeration and protected from light. 
Preparation 
Irinotecan is diluted in 5% dextrose (D5W) 500 mL to a final concentration of 0.12 – 2.8 
mg/mL. Stability is improved in D5W as compared with NaCl. 
Administration 
In this study irinotecan will be administered as an IV infusion over 90 minutes, 
following oxaliplatin, and prior to, or concurrent with, leucovorin. 
Toxicities 
Neutropenia and/or late diarrhea (diarrhea occurring more than 24 hours after irinotecan 
administration) are frequently dose-limiting. Other commonly observed adverse events 
include nausea and vomiting, anorexia (irinotecan is considered moderately 
emetogenic), abdominal cramping, alopecia, asthenia, lymphocytopenia, and anemia. 
Dehydration has occurred as a consequence of diarrhea, particularly when associated 
with severe vomiting. Patients may experience an acute syndrome of lacrimation, 
diaphoresis, abdominal cramping, and diarrhea (early diarrhea) during or shortly after 
irinotecan administration; this syndrome is thought to be cholinergically mediated and 
may be treated and subsequently prevented with atropine. Elevations of bilirubin and 
alkaline phosphatase have been reported in up to 84% and 13% of patients, respectively. 
Sporadic cases of pulmonary toxicity, manifested as shortness of breath, nonproductive 
cough, and transient infiltrates on chest X-ray have been reported. Infrequent 
occurrences of mucositis or colitis (sometimes with gastrointestinal bleeding) have been 
observed. Irinotecan is metabolized to Sn-38, an active metabolite. SN-38 is conjugated 
by UGT1A1. Homozygosity for the UGT1A1*28 allele increases the risk of severe 
neutropenia with irinotecan, and known homozygotes are not eligible for this trial.  
Further information regarding irinotecan may be obtained from the package insert.  
 
 
11. 
ADVERSE EVENTS, UNANTICIPATED PROBLEMS, AND DEVIATIONS  
 
As Coordinating Center, we will follow guidelines from Stanford’s Research Compliance 
Office and Cancer Clinical Trials Office (CCTO) for defining, identifying, and reporting events 
as defined below.   
 
 
11.1       Serious Adverse Events (SAEs)  

 
Page 42 of 84 
 
 
A Serious Adverse Event (SAE) is defined as: Any adverse event that meets 
any of the following criteria: 
 Fatal (i.e., the adverse event actually causes or leads to death) 
 Life threatening (i.e., the adverse event, in the view of the investigator, 
places the patient at immediate risk of death).  This does not include any 
adverse event that had it occurred in a more severe form or was allowed to 
continue might have caused death 
 Requires or prolongs inpatient hospitalization 
 Results in persistent or significant disability/incapacity (i.e., the adverse 
event results in substantial disruption of the patient’s ability to conduct 
normal life functions) 
 Congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study drug  
•   Significant medical event in the investigator's judgment (e.g., may jeopardize 
the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above).(28) 
 
11.1.1 Reporting SAEs 
 
SAEs should be graded according to the NCI Common Terminology 
Criteria for Adverse Events, Version 4.0, available at 
http://ctep.cancer.gov/reporting/ctc.html. 
 
SAEs Grade 3 and above require prompt reporting – within 24 hours of 
learning of the event.  Reporting should be done by entering the event 
into OnCore (Stanford’s clinical trials management system) and sending 
an email to Stanford Cancer Clinical Trials Office (CCTO) at ccto-
safety@stanford.edu, copying Dr. Daniel Chang and Stanford research 
staff (Research Nurse or Research Coordinators) with subject line:  
“SECURE:  PanCRS STUDY Serious Adverse Event.”  A Case Report 
Form (CRF) describing the event must be supplied and can be sent as an 
attachment to the email.  It could be generated from the OnCore entry (as 
a pdf or report), or using the Case Report Form in Appendix V. 
  
Stanford research staff will notify Stanford IRB via ‘eProtocol’ as per 
regulatory guidelines.  The SAE may also be forwarded to other Stanford 
regulatory boards, e.g., DSMC, as applicable.   
 
Any questions, issues, or need for clarification of the event by Stanford 
IRB will go through Stanford study PIs or Coordinators to the 
participating center research staff.   
 
Participating centers are responsible for reporting the SAE to their IRB 
within their institutional timeframes and guidelines.   
 
Participating sites should also: 
 Place copies of the SAE Report in the patient’s study chart and in the 
regulatory binder (electronic regulatory binder is allowed). 

 
Page 43 of 84 
 
 Follow patient and provide update to Stanford until any of the below:  
o Resolution of event 
o Resolution of event with sequelae 
o Death of patient 
 
11.2      Unanticipated Problems (UPs) 
 
Per Stanford IRB, UPs are events involving risks to participants or others and 
must meet ALL 3 criteria below: 
 
1.  Unexpected: in terms of nature, severity, or frequency, given (a) the research 
procedures described in the protocol-related documents, and (b) the 
characteristics of the subject population being studies; AND 
2.  Related to participation in the research:  or there is a reasonable possibility 
that the incident, experience, or outcome may have been caused by the 
procedures involved in the research; or if a device is involved, probably 
caused by, or associated with the device; AND 
3.  Harmful:  suggests that the research places subjects or others at a greater risk 
of harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized.  
 
UPs generally will warrant consideration of substantive changes in the research 
protocol or informed consent process/document, or other corrective actions, in 
order to protect the safety, welfare, or rights of subjects or others.(27)  Due to 
this, UPs will be reported promptly to Stanford IRB following the below 
guidelines. 
 
A UP may also be an AE or SAE and can be noted as both on CRFs and in 
OnCore.  
 
11.2.1   
Reporting UPs  
 
UPs should be entered into OnCore and reported within 24 hours of 
learning of the event.  Reporting can be done via email to Stanford 
Cancer Clinical Trials Office (CCTO) at ccto-safety@stanford.edu, 
copying Dr. Daniel Chang and Stanford research staff (Research Nurse or 
Research Coordinators), with subject line:  “SECURE:  PanCRS STUDY 
Unanticipated Problem.”  A Case Report Form (CRF) describing the 
event must be supplied and can be sent as an attachment to the email.  It 
could be generated from the OnCore entry (as a pdf or report), or using 
the Case Report Form in Appendix V.  
  
Stanford research staff will notify Stanford IRB via ‘eProtocol’ as per 
regulatory guidelines.  The UP may also be forwarded to other Stanford 
regulatory boards, e.g., DSMC, as applicable.   
 
Any questions, issues, or need for clarification of the UP by Stanford IRB 
will go through Stanford study PIs or Coordinators to the participating 
center research staff.   

 
Page 44 of 84 
 
 
Participating centers are responsible for reporting Unanticipated 
Problems or similar events to their IRB within their institutional 
timeframes and guidelines.   
 
Participating sites should also: 
 Place copies of the UP Report in the patient’s study chart and in the 
regulatory binder (electronic regulatory binder is allowed). 
 Follow patient and provide update to Stanford until any of the below:  
o Resolution of event 
o Resolution of event with sequelae 
o Death of patient 
 
SAE and UP Reporting Requirements 
Hospitalization 
Grade 1 
Grade 2 
Grade 3  
Grade 4/5 
Hospitalization≤  
24 hrs 
UP's within 24 
hours 
UP's within 24 
hours 
Report SAE and UP 
within 24 hours 
Report SAE and UP 
within 24 hours 
Hospitalization≥ 
24 hrs 
UP's within 24 
hours 
UP's within 24 
hours 
Report SAE and UP 
within 24 hours 
Report SAE and UP 
within 24 hours 
SAE Definition: Fatal, life threatening, requires hospitalization or prolongs hospitalization, results in 
persistent  or significant disablility, causes congenital anomaly/birth defect or significant medical 
event.  
Unexpected Problem (UP) Definition: Unexpected in terms of nature, severity, or frequency.   
Related to participation in the research.  And Harmful suggesting that the research places subjects 
or others at a greater risk of harm.  
To report all UP's and SAEs Grade 3 and above: 1)Enter the event into OnCore,  2)send eamil to  
Dr. Daniel Chang and Stanford research staff (Rachel Freiberg) with the subject line: "SECURE:  
PanCRS STUDY Serious Adverse Event" and 3)Include Case Report Form describing the event and 
submit follow up reports for the resolution of the event. For any questions regarding whether an 
event is an SAE or a UP, please email Dr. Chang and Rachel. 
Dr. Albert Koong:  akoong@stanford.edu                           
Rachel Freiberg:     rachelf@stanford.edu 
  
  
 
 
11.3  Adverse Events (AEs) and AE Monitoring 
 
An AE is defined as any untoward medical occurrence in a clinical investigation 
subject, regardless of causal attribution.   

 
Page 45 of 84 
 
 
All AEs should be graded according to the NCI Common Terminology Criteria 
for Adverse Events, Version 4.0, available at 
http://ctep.cancer.gov/reporting/ctc.html.   
 
AEs should be: 
 Assessed at each consultation or follow-up visit, 
 Assessed during each mFFX cycle (prior to infusion is acceptable), and 
 Recorded on the AE Tracking form in Appendix V.   
 
Laboratory tests (CBC with differential and CMP) should also be obtained with 
each mFFX administration, and abnormal values also noted on the AE Tracking 
Form indicating AE Grade if applicable.  
 
AEs should also be:   
- 
Reported to Stanford as per protocol guideline and upon request 
- 
Noted in patient study charts and binder 
- 
Entered into REDCap CRFs 
- 
Reported to the participating center’s IRB as per their institutional 
guidelines.  
 
AEs in REDCap CRF should remain current and may be requested by Stanford 
for study renewals, audits, reports, analyses or other submissions for Stanford 
IRB, SRC, or DSMC.  AEs may also be reviewed by members of the study 
monitoring group in meetings, audits, and/or site visits.   
 
Updates and outcomes of AEs, SAEs, UPs, and deviations may take place during 
teleconferences or more frequently as needed. 
 
11.4      Deviations 
 
A protocol deviation is any unapproved discrepancy from a protocol research 
plan or Good Clinical Practice (GCP) guidelines, except where necessary to 
eliminate an immediate hazard to trial subjects.                                                            
 
11.4.1 Documenting and Reporting Deviations 
 
 
Serious or Major Deviations 
 
Research staff should promptly report serious or major deviations, or 
those that affect participant eligibility, informed consent, or protocol 
endpoints; and/or any deviation that could potentially result in harm to 
participants.  These should be reported within 24 hours of the deviation 
or of learning of the deviation, by entering them into OnCore.  The 
OnCore record should include the following:   
 description of the deviation, 
 corrective action taken, 
 a statement whether the patient was harmed or could have been 
potentially harmed by the deviation, and  

 
Page 46 of 84 
 
 whether the deviation was reported to the participating center’s IRB, 
and/or Stanford IRB. 
 
Stanford research staff should also be immediately notified of the 
deviation, via email to Dr. Daniel Chang, copying the study Research 
Nurse or Research Coordinator with subject line:  “SECURE:  PanCRS 
STUDY Major Deviation.”  A Case Report Form (CRF) describing the 
event is required and could be generated from the OnCore entry (as a pdf 
or report) and attached to the email. 
  
Stanford DSMC reviews deviations in OnCore to ensure completeness of 
the deviation report and ensure the safety of trial participants.  The 
DSMC may request corrective action and/or prompt reporting to Stanford 
IRB.  If reporting to Stanford IRB is required, Stanford’s research staff 
(Study Nurse or Coordinator) will assist with this by entering the 
deviation in ‘eProtocol’.  
 
Any questions, issues, or need for clarification of the event by Stanford 
IRB will go through Stanford study PIs or Coordinators to the 
participating center research staff.   
 
Participating sites should also: 
 Place copies of the Deviation Report or CRF in the patient’s study 
chart and in the regulatory binder (electronic regulatory binder is 
allowed). 
 Follow patient and provide update to Stanford until any of the below:  
o Resolution of event 
o Resolution of event with sequelae 
o Death of patient 
 
Participating centers are responsible for reporting deviations to their IRB 
within their institutional timeframes and guidelines.   
 
 
 
 
Minor Deviations 
 
Deviations not meeting the above criteria for major or ‘serious,’ or that do 
not have a significant effect on the subject’s rights, safety, or welfare, or on 
the integrity of the data -- e.g., conducting a protocol-required visit out of the 
protocol ‘window’ -- should be documented on the Deviation Log in 
Appendix V.     
 
Deviations in OnCore or in Deviation logs should remain current at all time, 
and may be requested by Stanford for study renewals, audits, reports, 
analyses or other submissions for Stanford IRB, SRC, or DSMC.   
 
 
11.5 
Study and Subject Reviews 
 
Teleconferences will be held every other month for purposes of study and subject 
reviews, issues, and updates.  Participating centers will have at least 1 research 

 
Page 47 of 84 
 
team member partake and any pertinent study information will be communicated 
to PIs by the attending research team member(s).  Any issues with patient 
compliance, database entry, toxicities, AEs, UPs, or SAEs, protocol updates or 
reviews, or other items will be discussed in calls.   
 
Also, at times of study renewal and safety or interim analyses, research staff for 
each participating center will compile and submit requested patient data and 
clinical trial efficacy endpoints.  These and other pertinent study data will be 
discussed and reviewed by the monitoring group to confirm whether outcomes 
favor continuation of the study. 
 
Teleconferences will be coordinated by Stanford Research staff and any resultant 
reports will be distributed to participating centers’ PI or assigned research team 
member.  
 
12. 
CORRELATIVE/SPECIAL STUDIES 
 
12.1   Laboratory Correlative Studies  
 
 12.1.1 Analysis of patient plasma for biomarker development  
 
12.1.1.1 Collection of Specimen(s) (optional):  
 
Collaborating centers who partake in this part of the study can have patients elect 
to participate in this portion of the study on the consent form.   
 
Blood Samples 
 
a)  Blood (EDTA preserved) for research purposes may be drawn after re-staging 
scans when patient is enrolled and registered on-study, and then at each follow-
up along with the patient’s clinical labs.  For each collection, up to 20ml (2 large 
lavender tubes at 10ml each) will be drawn.   
 
b)  Immediately after collection, blood will be centrifuged at 3000 RPM for 10 
minutes and plasma collected. The supernatent will be aliquoted for storage at -
80°C into separate tubes.  The pellet will also be stored in a separate tube at -
80°C. 
 
12.1.1.2 Shipping of Specimen(s)  
 
Samples may be shipped to Stanford for analysis.  Samples will be shipped 
overnight by federal express on dry ice and sent in batches.  
 
12.1.1.3 Site(s) Performing Correlative Studies  
 
All biomarker studies will be performed at Stanford by Dr. Daniel Chang or in 
the laboratory of a research collaborator.  
 

 
Page 48 of 84 
 
We will utilize proximity ligation assay (PLA) to simultaneously interrogate a 
panel of 60-100 secreted proteins that we have developed for pancreatic cancer 
patients.  PLA is an antibody-based method of detection in which 
complementary single-stranded oligonucleotides are linked to each antibody pair.  
When the 2 antibodies bind in close enough proximity, the local concentration 
increases, allowing for PCR amplification of this signal.  PLA is more sensitive 
than conventional ELISA and can be reliably multi-plexed for the detection of 
multiple protein panels (Fredrikkson et al).  In a pilot study, we have shown that 
when using this method of detection (Chang et al), we can accurately identify 
patients with pancreatic cancer.  In this study, we will expand the number of 
biomarkers and collect plasma at multiple time points during therapy.  The goal 
is to identify a biomarker panel that is predictive of patient outcome and/or 
response to therapy.  We hypothesize that not only is the pattern of secreted 
biomarkers important but the change in these biomarkers may be even more 
critical for prediction of clinical outcomes. 
 
12.1.1.4 Coding of specimens for privacy protection  
 
At the time of enrollment each patient will be given a specific confidential 
identification number (IDN).  Specimens will be stored under the patient’s IDN.  
The information can be shared with other investigators listed on this protocol.  
Study data will be maintained in password protected computer files (protected 
online database through Johns Hopkins). Only research personnel will have 
access to this information. 
 
12.2 
 Collection of Pre- and Post- Treatment Scans, Treatment Planning Scans, and 
Treatment 
              Plans 
 
 
 
12.2.1 Data and Image Collection 
 
 
 
 
 
 
12.2.1.1 All images (CT, PET, or MR) including re-staging scans, treatment 
planning scans and follow-up scans will be transferred electronically to a secured 
database or on password-protected discs or encrypted drives, using an IDN 
assigned at registration for each patient.  Specific parameters will be 
prospectively collected such as treatment volume and dose to adjacent structures. 
 
 
 
 
The JHU database is set up to store ROI geometries and dose distributions along 
with the CT.  This design facilitates the investigation of dosimetric effects on 
tumor response and complication utilizing DVH or other attributes of the 3D 
dose.  For Pinnacle, the data can be directly placed in the JHU database via 
scripts.  For other planning systems, DICOM RT data transfer will be used.   
 
 
13. 
INVESTIGATOR RESOURCES 
 
 
13.1 
Qualifications 
 

 
Page 49 of 84 
 
The study staff will include, but is not limited to, the Principal Investigator, Co-
Investigators, research coordinators, research nurses, and any residents or fellows 
working with the study physicians at each institution.  Also, laboratory personnel in the 
Principal Investigator’s laboratory will be involved in analyzing the plasma and tumor 
specimens collected from patients. 
 
All study staff will have completed the required training specific for their 
responsibilities in this study.  Furthermore, each member of the research team from each 
institution will be given a thorough explanation of the protocol and their responsibilities.  
All research investigators will be required to complete proper training through their 
facility and institutional review boards.  
 
 
13.2 
Use of Cancer Center Facilities  
 
 
Patients will be evaluated and treated in their respective institutions.  All radiotherapy 
for this study will be performed in the department of radiation oncology at the 
participating institution.  Other procedures related to this study (i.e., blood draws, tissue 
biopsy, imaging studies) will be carried out at each institution. 
 
13.3 
Conflict of interest 
 
 
There is no potential conflict of interest among the research personnel involved in this 
study. 
 
 

 
Page 50 of 84 
 
14. 
STUDY CALENDAR 
 
Activity 
Induction Chemotherapy 
 R 
 
A 
 
N 
 
D 
 
O 
 
M 
 
I 
 
Z 
 
E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study 
Treatment 
Follow-up (Time From Completion 
of Study Treatment)j 
Screen-
ing 
Study 
Enroll- 
ment  
Induction 
Chemo / 
mFFXg  
Re- 
stagingc 
SBRTd  mFFX 
2 cyclesf 
4-8 
wksk 
3j 
mos 
6j   
mos 
9j   
mos 
12j  
mos 
Yr 2- 
Q 6j  
mos 
Yr 3-
Q 6j 
mos 
Biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Negative 
Pregnancy testa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Consultation 
X 
X 
Xg 
 
 
 
Xk 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
 
 
 
 
Xk 
X 
X 
X 
X 
X 
X 
Labs: CBCD, 
CMP, CA19-9 
(CEA optional) 
X 
Xb 
Xg 
 
 
Xh  
Xk 
X 
X 
X 
X 
X 
X 
Study/research 
labsi (optional) 
 
Xi 
 
 
 
Xi 
Xk 
X i 
X i 
Xi 
X i 
X i 
X i 
Eligibility  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study 
Registration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
QOL 
 
X 
 
 
 
 
Xk 
X 
X 
X 
X 
X 
X 
Scan: CT or MR 
X 
 
 
Xc 
 
 
Xk 
X 
X 
X 
X 
X 
X 
PET/CTe 
Xe 
 
 
 
 
 
 
Xe 
 
 
 
 
 
AE evaluation 
 
 
 
 
X 
Xh 
Xk 
X 
X 
X 
X 
X 
X 
Seed placement 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Meds: PPI and 
pain medsj 
 
 
 
 
 
Xk 
X 
X 
X 
X 
X 
X 
Sim/setup scans 
 
 
 
 
X 
 
 
 
 
 
 
 
 
SBRT  
 
 
 
 
Xd 
 
 
 
 
 
 
 
 
Maintenance 
mFOLFIRINOX
fh 
 
 
 
 
 
 
X-------Xfh 
 
 
 
 
aPregnancy test by urine or serum, for women who are not post-menopausal as defined in Appendix III.   
b 
Labs should be done within 30 days of eligibility confirmation.  
c
Re-staging scan should be done within 2 weeks following completion of induction mFOLFIRINOX cycles.  
d SBRT should begin within 4 weeks of simulation and 8 weeks of the last chemotherapy; dose is 40 Gy (8Gy in 5 fractions).  
ePET-CTs are recommended but not required; if only 1 follow-up PET-CT is possible, recommendation is at 3 months. 
f mFOLFIRINOX should resume within 8 weeks after study treatment, and any breaks between chemotherapy cycles should 
not exceed 8 weeks.  Patients may continue on maintenance mFFX as tolerated or per clinical judgment of treating 
physician. 
g 
Induction chemo/mFFX prior to enrollment is allowed through the 4th cycle of mFFX.  No more than 4 cycles are 
allowed prior to randomization.  The re-staging scan could be done within 2 weeks of completion of the chemotherapy 
cycle; records from labs and clinic visits are not required; mFFX infusion records should be collected. 
h 
Labs during mFFX cycles are as per institutional standard or treating Medical Oncologist. AEs should be assessed 
with each cycle of mFFX. 
i 
Study labs are optional and for research purposes as explained in Section 12. Correlative/Special Studies; and may 
be drawn if patient agrees to this in the consent form. 

 
Page 51 of 84 
 
j 
Follow-up appointments 1 month before or after will be permitted, e.g. for 6-month follow-up, visit, labs, scan and 
QOL surveys can be done at 5-7 months. 
k 
4-6 week follow-up visit and corresponding activities are optional and may be added if clinically indicated. 
   
15. 
MEASUREMENT OF EFFECT 
 
 
15.1 
Anti-Tumor Effect 
 
Patients will be evaluated for anti-tumor effect by follow-up imaging (CT and PET-CT 
imaging) as outlined above.  Initial follow-up scans post-treatment will be compared to 
the patient’s baseline scan, defined as the scan prior and closest to the date of initiating 
chemotherapy. 
 
15.1.1 Definitions 
 
Patients will be evaluable for toxicity and evaluable for objective response at 
follow-up intervals specified in the Calendar above (Section 14). 
 
 
 
15.1.2 Disease Parameters 
 
Pancreatic tumor response will be based upon standard radiographic criteria for 
the treated lesion and will be prospectively recorded in the combined JHU 
secure database. Radiographic response of the pancreatic tumor by diagnostic 
CT scans will be defined according to RECIST criteria as described below:  
 
 
 
 
CR = complete disappearance of index lesion 
PR = at least 30% decrease in the longest diameter of the index lesion  
PD= more than 20% increase in the longest diameter of the index lesion 
 
SD = does not meet criteria for PR or PD 
 
Pancreatic tumor response will also be assessed by FDG-PET scans (when 
available) according to the following criteria:  
CR = target lesion becomes photopenic or standardized uptake value 
(SUV) ratio of tumor/liver less than or equal to 1 
 
 
PR = decrease in SUV ratio of tumor/liver (at least 30%) 
 
 
PD = increase in SUV ratio of tumor/liver (at least 20%) 
 
 
SD = no significant change in SUV ratio of tumor/liver 
 
Definitions of Progression 
Local tumor progression will be defined as >=20% increased size on follow-
up CT scan as compared to baseline CT (scan prior and closest to the date of 
initiating chemotherapy).   
 
Distant progression will be defined as any tumor found outside of the pancreas 
on CT scan.  Local and/or distant progression by both PET and CT scan will be 
recorded separately.  FDG-PET is not required but highly recommended as a 
complementary method for determining response.  We will also determine PET 
response with the new PERCIST criteria as reported by Wahl et al. (J Nuc Med 
2009; 50:122S-150S). 

 
Page 52 of 84 
 
 
 
15.1.3 Methods for Evaluation of Measurable Disease 
 
 
 
 
Pancreas protocol CT or chest abdomen pelvis CT (biphasic imaging, 1.25 mm 
cuts) will be obtained at follow-up intervals as described in Section 14. Study 
Calendar.  PET-CT scans should be done at baseline (pre-study) and repeated if 
possible at the 3-month follow-up.   
 
 
 
 
Standard radiographic criteria will be utilized for non-target lesions.  Any 
disease outside of the pancreas will be considered metastatic disease.  If 
possible a biopsy 
 
should be obtained to confirm metastasis. 
 
15.1.4 Duration of Response 
 
 
 
The criteria for overall response will be the time from randomization and first 
sign of local progression or development of metastatic disease.  
 
15.1.5 Progression-Free Survival (or other time-to-event parameters) 
 
 
The criteria for time to progression and progression-free survival (PFS) will be 
the time from randomization to documented progression or death.  Individuals 
will be censored at the date of last evaluation for progression if neither event is 
observed.  Overall survival will be defined as time from randomization until 
death from any cause.  Participants will be censored at the date of last contact if 
the date of death is not observed.  Local PFS will be the duration from 
randomization to local progression or death if death occurs before local 
progression.  Metastasis free survival will be the duration from randomization to 
metastasis or death from any cause, if death occurs before metastasis.  
Individuals will be censored at the time of the last evaluation for local or distant 
progression, respectively, if neither progression nor death is observed.    
 
 
 
 
 
15.1.6 Response Review 
 
 
All responses will be reviewed independently by a board certified radiologist at 
the study’s completion.  Each image will be reviewed by the PI from each 
institution periodically and recorded to assess for variability.  Simultaneous 
review of the patient’s chart will also occur at this time. 
 
16. 
MONITORING PLAN AND DATA MANAGEMENT  
 
16.1 
Monitoring Plan  
 
Stanford will serve as the coordinating institution and will conduct study audits to 
review each participating centers’ regulatory binders and patient study charts.  These 

 
Page 53 of 84 
 
audits will ensure guidelines set forth in this protocol are followed for all aspects of the 
study including but not limited to regulatory approvals and renewals; patient eligibility, 
enrollment, treatment, and follow-up; proper documentation and record-keeping; and 
adverse event and deviation reporting.  Audits will be performed yearly by Stanford 
DSMC; more frequent monitoring will occur as needed.  Preliminary reviews may also 
take place by Stanford research staff prior to audits.  
 
Each participating center will create and maintain a paper chart for each subject 
enrolled. Research staff at each center will also enter subject information into REDCap 
as per guidelines set forth in this protocol.  
 
Participating centers will supply radiation treatment plan data upon request by 
uploading scan images and information.  If uploading is not possible, images and 
reports may be supplied electronically or on encrypted and/or password-protected discs 
or drives.  Further data may be requested from each institution for study analyses.   
 
All tools, computers, and systems used for monitoring and analyses will be secure, 
password-protected, and HIPAA compliant.  Shared data will be de-identified and 
unique identifiers will be assigned to ensure patient confidentiality. 
 
See below diagram for phases and workflow of study. 

 
Page 55 of 84 
 
16.3   Trial Monitoring  
 
All outcome data (toxicity and efficacy) will be reviewed yearly by the Principal 
Investigator and key Co-Investigators.  This study will also be monitored by the 
Stanford DSMC as stated above in Section 16.1.  
 
 
Interim reports and/or study renewals will be completed every 10-12 months from study 
open date, which will be defined as date the study is approved by Stanford IRB.  
Additional and/or more frequent reports may be done if determined necessary by the 
study monitoring group (described in Section 11.2.3).  These reports may include 
information about: 
 Patient accrual and follow-up: overall and at each institution 
 The frequency and severity of adverse events due to protocol therapy 
 Compliance rates of treatment delivery with respect to the protocol prescription 
 
Adverse event rates will be compared between treatment groups and with the stopping 
guideline thresholds (Section 17.5.1).  With the exception of a single, planned interim 
efficacy analysis (Section 17.5.2), the interim reports will not contain the results from 
the treatment comparisons with respect the primary outcome (progression free survival) 
or secondary efficacy analyses.  See Section 17.5 Stopping Guidelines for additional 
details. 
 
 
16.4    Data Management  
 
  
Study and subject information will be entered and maintained in REDCap database. 
Research Coordinators at participating institutions will be given access to REDCap and 
enter data directly.  Access will be created once the participating center has obtained all 
regulatory approvals and becomes a participating center in the study.  Once REDCap 
access is established, research staff at each participating center will be provided 
educational materials or training on its use.  
 
  
Participating centers can only view and enter data from their institution; Stanford 
research staff will have access to study and subject data from all participating centers.    
 
Sections or topics required for entry in REDCap include but are not limited to:  
 
Diagnosis and Pathology  
 
Demographics 
 
Consent  
 
Eligibility  
 
On-Study Information 
 
Off-Study Information 
 
Arm Assignment/Randomization 
 
Chemotherapy dates, doses, and modifications as applicable 
 
Deviations 
 
SAEs and AEs 
 
Consultation information 
 
Pertinent medications  
 
Results of scans, laboratory and other tests 

 
Page 56 of 84 
 
 
Quality of Life responses 
 
Other information for entry into REDCap may be requested or added.   
 
Each center must also begin a patient paper study chart to collect and maintain subjects’ 
records and study-related documents.  Patient study charts may be reviewed by Stanford 
research team or Stanford DSMC to ensure data validity, integrity, and safety of subjects 
throughout the trial. 
 
Shared data will be de-identified and unique identifiers will be assigned to ensure patient 
confidentiality. 
 
16.4.1   
Monitoring and Study Data Review  
 
 
 When all participating institutions have successfully received IRB approval and 
started enrolling patients, teleconferences will be held every 2 months between 
research staff from the Coordinating Center and each participating institution.  A 
study monitoring group consisting of PIs and/or Research Coordinators from 
Stanford University, Johns Hopkins, and Memorial Sloan Kettering will discuss 
and monitor study-related events and issues in these calls.  Included in this 
monitoring Group are: 
 Daniel Chang, Stanford 
 Rachel Freiberg, Stanford 
 Albert Koong, and Joe Herman, MD Anderson 
 
Discussions may include enrollment and accrual information; data updates and 
entry issues; adverse events, deviations, or patient-related issues; and other 
study-related matters.  Calls may occur more frequently as needed.  Data review 
and updates will also occur with analysis and completion of Interim Reviews as 
required per protocol. 
 
 
16.5 
Confidentiality  
 
Study data will be maintained in password protected databases, computer, and/or 
electronic files.  Only research personnel listed on this protocol will have access to this 
information.  Only the patients unique IDN will be used.  Specimens will be stored 
under the patient’s IDN.  The patient’s name or other public identifiers will not be 
included in any information shared with other investigators.   
 
 
 
17. 
STATISTICAL CONSIDERATIONS  
 
17.1 
Endpoints 
 
 
17.1.1 Primary Endpoints 
   
 To compare the median progression free survival between individuals treated 

 
Page 57 of 84 
 
with mFOLFIRINOX  +/- SBRT. 
 
17.1.2 Secondary Endpoints 
 
 
 
 To compare the one year progression-free survival in pancreatic cancer 
patients following chemotherapy alone or chemotherapy and SBRT. 
 To compare metastasis free survival in pancreatic cancer patients following 
chemotherapy alone or chemotherapy and SBRT. 
 To compare the overall survival in pancreatic cancer patients treated with 
chemotherapy alone or chemotherapy and SBRT. 
 To compare local progression-free survival in pancreatic cancer patients after 
chemotherapy +/- SBRT. 
 To evaluate acute (within 3 months of treatment) grade 2 or greater gastritis, 
fistula, enteritis, or ulcer and any other grade 3-4 gastrointestinal toxicity 
within 3 months of treatment. 
 To identify new biomarkers in pancreatic cancer. 
 To evaluate the quality of life of patients before and after either chemotherapy 
alone or chemotherapy and SBRT. 
 
17.2 
Analysis Populations 
 
Efficacy analysis will be conducted on the intent-to-treat population which includes all 
randomized patients and on the per-protocol population.  The per-protocol population 
will include patients who have completed 6 or more cycles of mFolfirinox treatment +/- 
SBRT. 
 
17.3 
Sample Size  
 
17.3.1 Accrual estimates 
 
The study accrual goal is 172 randomized subjects over 60 months among all 
participating institutions (i.e. 2-3 patients per month).  Due to varying eligible 
patient populations, enrollment may differ at participating centers.   
 
Stanford accrual goal is 6-12 randomized patients annually. 
 
17.3.2 Sample Size Justification 
 
Progression free survival is defined as the time from randomization until 
progression or death.  Individuals who are lost to follow-up prior to death or 
progression will be censored at the date of last progression evaluation.  Based 
upon previous research, the median progression free survival for individuals 
treated with mFolfirinox alone is estimated to be 6 months.  A sample size of 172 
randomized participants (86 per arm) has 91% power to detect an increase to 
10.2 months for individuals treated with mFolfirinox plus SBRT as compared to 
6 months for those receiving mFolfirinox alone assuming that the data follows an 
exponential distribution as well as a 60 months of accrual and a minimum of 12 
months of follow-up after randomization in a 2-sided test with a type 1 error rate 
of 0.05.   

 
Page 58 of 84 
 
 
 
17.3.3 Criteria for Future Studies 
 
We anticipate that fractionated SBRT with IGRT based linac systems will result 
in similar progression free survival at one year (80-90%) to single fraction SBRT 
but with a (20%) decrease in late gastrointestinal toxicity at one year.  The 
current patient population will serve as a comparator for the future trials in terms 
of time to progression and provide additional information with regards to 
radiation treatment planning. 
 
17.4 
Plan of Analysis 
 
 
Demographic and clinical characteristics of patients and the characteristics of treated 
lesions (volume, location, and modality) will be summarized by means, medians, 
standard deviations, ranges and proportions as applicable.  
 
Time to event outcomes (overall survival, metastasis free survival, and progression free 
survival) will be summarized using Kaplan-Meier curves and medians with 95% 
confidence intervals calculated using Greenwood’s formula.  Cox proportional hazards 
models will be used to compare treatment groups and to assess risk factors (e.g. biologic 
markers and PET volume).  The effect of site will be tested in the Cox models; the effect 
of whether or not the patients received Leucovorin will also be tested in the Cox models.  
The level of response (and other categorical outcomes) will be tabulated at each follow-
up interval.  Logistic regression and Cox models will be used to assess the proportion 
with a response category depending upon the level of censoring prior to the annual visit.   
 
The measurements of the volume of the pancreatic tumors based upon CT and PET-CT 
scans will be compared using paired t-tests or Wilcoxon signed-rank tests as appropriate.  
The agreement between pancreatic tumor measurements will be compared among the 
three institutions using correlation coefficients, percentage agreement, and inter-
correlation coefficients.   
 
Quality of life outcomes will be assessed at each time interval and compared using the 
recommended guidelines from the module.  Differences in QOL for the two treatment 
groups will be explored using a repeated measures model in order to account for the 
within-patient correlation.  Special interest will be placed on exploring the aspects of 
QOL which are known to be impacted by SBRT. 
 
 
At this time all research on biomarkers for disease progression is exploratory.  The 
goal is to potentially identify biomarkers that are associated with disease progression.  
Should any biomarkers be identified, their impact on the time to event outcomes will be 
summarized using Kaplan Meier curves and they will be tested using Cox proportional 
hazards models. 
 
Quality of life at each interval will be calculated and compared using the recommended 
guidelines from the module (available by E-mail: c.d.johnson@soton.ac.uk).  Efficacy 
outcomes with repeated measurements over time (e.g. quality of life) will be analyzed 
using a generalized estimating equation (GEE) approach to account for within-patient 

 
Page 59 of 84 
 
correlation. 
 
Adverse events will be tabulated by type and grade at each follow-up.  All adverse 
events will be reported to the Data Safety and Monitoring Board (DSMB), GI Clinical 
Research Groups (CRG) if applicable, and each institution’s IRB, as well as to Stanford 
as the Coordinating Center according to the guidelines set forth in this protocol.  The 
expected toxicity rate is 12% or less and a continuous Bayesian stopping guideline has 
been developed (see section 17.5.1, p 64) representing the 12% toxicity rate. The study 
may be stopped before reaching the accrual goal at the recommendation of any of these 
groups based upon stopping guidelines for toxicity as described below. 
 
17.4.1 Stratification 
 
 
 
We will stratify by ECOG performance status (0 and 1 vs 2). 
 
 
17.5 
Stopping Guidelines 
 
17.5.1 Toxicity Monitoring 
 
Adverse events or toxicities will be monitored throughout the study and follow-
up periods with Grade 4 and higher events reported to Stanford promptly, as 
outlined in Section 11. Toxicities, Adverse Events, and Reporting Requirements.  
Grade 3 and lower adverse events will be recorded on AE logs at each institution 
and reported to Stanford as requested (See Section 11.2.3).  An interim review of 
toxicities between the two arms will be conducted by all co-investigators when 
16 evaluable patients have been enrolled. If there is a >20% increase in G3 or 
higher toxicities in the treatment arm compared with to the control arm, then we 
will revise the protocol as appropriate. 
 
In our recently completed Phase II study using 33Gy in 5 fractions, there were no 
Grade 5 toxicities and the Grade 3-4 toxicity rate attributable to SBRT was 8%.  
For this study, we would expect the observed rate of grade 3 or higher toxicities 
with the first 6 months to be slightly higher due to the toxicity related to 
Folfirinox and to the expansion to additional sites; however, we expect the 
overall rate to be less than 12%.  A toxicity level of 20% would be considered 
the upper boundary. 
 
We have developed a continuous Bayesian stopping guideline with a prior 
distribution of Beta (6, 44), representing a toxicity rate of 15% (just above our 
expected rate).  The guidelines will recommend that the therapy be re-evaluated 
if the posterior probability that the toxicity rate exceeds the 20% boundary is 
greater than 65%.  Once an initial cohort of 10 participants has been enrolled and 
followed for 6 months, toxicity will be monitored continuously.  Table 1 below 
summarizes the stopping guideline boundaries for SBRT related events. 
 
 
 
 
   Table 1 

 
Page 60 of 84 
 
Cohort size 
Observed number of toxicities 
that trigger re-evaluation 
11-14 
5 
15-20 
6 
21-27 
7 
28-33 
8 
34-39 
9 
40-46 
10 
47-52 
11 
53-58 
12 
59-65 
13 
66-71 
14 
72-78 
15 
79-84 
16 
85-86 
17 
 
 
The probability of triggering the stopping guidelines was assessed for a range of 
underlying toxicity rates based upon simulations with 5000 replicates (Table 2).  
In the expected range of toxicity, the probability of stopping to re-evaluate was 
less than 5% if the underlying toxicity was 10%; whereas the probability of 
stopping to re-evaluate for unacceptable levels was 74.2% or higher. 
 
   Table 2 
True underlying  
toxicity rate 
Probability of triggering 
stopping guideline boundaries 
1% 
0% 
5% 
0.1% 
8% 
1.4% 
10% 
4.2% 
12% 
11.3% 
15% 
31.2% 
20% 
74.2% 
25% 
95.7% 
 
 
 
17.5.2 Interim Analysis for Efficacy of Primary Endpoint:  Progression Free 
Survival 
 
A single interim efficacy analysis will be performed at 36 months, the calendar 
mid-point for the trial.  Given the expected median time to progression given in 
Section 17.3.2, we expect to observe the progression endpoint (progression or 
death due to any cause) for 160 participants (83 in the folfirinox alone arm and 
77 in the SBRT + folfirinox arm).  After 36 months, we anticipate observing 71 
progressions, which translates to 44% of the total information.  Monitoring will 
be performed via an O’Brien-Fleming alpha spending function with an interim 
assessment at 44% of information time.  The calculations are made assuming 
two-sided symmetric boundaries with a total of 2 analyses (1 interim and one 
final) and a total alpha 0.05.  The trial will be stopped early for efficacy if the 

 
Page 61 of 84 
 
99.695% confidence interval of the hazard ratio does not contain 1, i.e. a two-
sided alpha spending of 0.00305 on the first interim analysis (0.001525 in each 
direction). 
 
 

 
Page 62 of 84 
 
 
References 
 
1.  
Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43-66. 
2.  
Cameron JL, Riall TS, Coleman J, et al. One thousand consecutive pancreaticoduodenectomies. Ann 
Surg 2006;244:10-5. 
3.  
Burris HA,3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with 
gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 
1997;15:2403-13. 
4.  
Heinemann V, Boeck S, Hinke A, et al. Meta-analysis of randomized trials: Evaluation of benefit from 
gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 2008;8:82. 
5.  
Loehrer PJ, Powell ME, Cardenes HR, et al.  A randomized phase III study of gemcitabine in 
combination with radiation therapy versus gemcitabine alone in patients with localized, unresectable pancreatic 
cancer: E4201. Journal of clinical oncology 2008;26:abst. 4506. 
6.  
Kalser MH, Ellenberg SS. Pancreatic cancer. adjuvant combined radiation and chemotherapy following 
curative resection. Arch Surg 1985;120:899-903. 
7.  
Further evidence of effective adjuvant combined radiation and chemotherapy following curative 
resection of pancreatic cancer. gastrointestinal tumor study group. Cancer 1987;59:2006-10. 
8. 
 McGinn CJ, Zalupski MM. Combined-modality therapy in pancreatic cancer: Current status and future 
directions. Cancer J 2001;7:338-48. 
9.  
Ben-Josef E, Shields AF, Vaishampayan U, et al. Intensity-modulated radiotherapy (IMRT) and 
concurrent capecitabine for pancreatic cancer. Int J Radiat Oncol Biol Phys 2004;59:454-9. 
10.  
Willett CG, Del Castillo CF, Shih HA, et al. Long-term results of intraoperative electron beam 
irradiation (IOERT) for patients with unresectable pancreatic cancer. Ann Surg 2005;241:295-9. 
11.  
Crane CH, Beddar AS, Evans DB. The role of intraoperative radiotherapy in pancreatic cancer. Surg 
Oncol Clin N Am 2003;12:965-77. 
12.  
Willett CG, Czito BG, Bendell JC, et al. Locally advanced pancreatic cancer. J Clin Oncol 
2005;23:4538-44. 
13.  
Koong AC, Le QT, Ho A, et al. Phase I study of stereotactic radiosurgery in patients with locally 
advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2004;58:1017-21. 
14.  
Schellenberg D, Goodman KA, Lee F, et al. Gemcitabine chemotherapy and single-fraction stereotactic 
body radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2008. 
15.  
Chang DT, Schellenberg D, Shen J, et al. Stereotactic radiotherapy for unresectable adenocarcinoma of 
the pancreas. Cancer 2009;115:665-72. 
16.  
Chang BK, Timmerman RD. Stereotactic body radiation therapy: A comprehensive review. Am J Clin 
Oncol 2007;30:637-44. 
17.  
Timmerman R, Bastasch M, Saha D, et al. Optimizing dose and fractionation for stereotactic body 
radiation therapy. normal tissue and tumor control effects with large dose per fraction. Front Radiat Ther Oncol 
2007;40:352-65. 
18.  
Groenvold M, Klee MC, Sprangers MA, et al. Validation of the EORTC QLQ-C30 quality of life 
questionnaire through combined qualitative and quantitative assessment of patient-observer agreement. J Clin 
Epidemiol 1997;50:441-50. 
19.  
Fitzsimmons D, Kahl S, Butturini G, et al. Symptoms and quality of life in chronic pancreatitis assessed 
by structured interview and the EORTC QLQ-C30 and QLQ-PAN26. Am J Gastroenterol 2005;100:918-26. 
20.  
Fitzsimmons D, Johnson CD. Quality of life after treatment of pancreatic cancer. Langenbecks Arch 
Surg 1998;383:145-51. 
21.  
Etzioni R, Urban N, Ramsey S, et al. The case for early detection. Nat Rev Cancer 2003;3:243-52. 
22.  
Aebersold R, Anderson L, Caprioli R, et al. Perspective: A program to improve protein biomarker 
discovery for cancer. J Proteome Res 2005;4:1104-9. 
23.  
de Jager W, Rijkers GT. Solid-phase and bead-based cytokine immunoassay: A comparison. Methods 
2006;38:294-303. 
24.  
Elshal MF, McCoy JP. Multiplex bead array assays: Performance evaluation and comparison of 
sensitivity to ELISA. Methods 2006;38:317-23. 

 
Page 63 of 84 
 
 
25.  
Fredriksson S, Dixon W, Ji H, et al. Multiplexed protein detection by proximity ligation for cancer 
biomarker validation. Nat Methods 2007;4:327-9. 
26.  
Fredriksson S, Horecka J, Brustugun OT, et al. Multiplexed proximity ligation assays to profile putative 
plasma biomarkers relevant to pancreatic and ovarian cancer. Clin Chem 2008;54:582-9. 
27.  
Events and Information that Require Prompt Reporting to the IRB, Stanford University HRPP Policy 
Guidance, Research Compliance Office, GUI-P13, rev 9/2012. 
28.  
Stanford Cancer Institute:  Serious Adverse Event Reporting, Standard Operating Procedure, Version 5, 
May 30, 3012. 
29.  
Tozzi A, Comito T, Alongi F, et al.  SBRT in unresectable advanced pancreatic cancer:  preliminary 
results of a mono-institutional experience. Radiation Oncology 2013;8:148. 
30.   
Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic 
cancer. N England Journal of Medicine 2011; 2:364(19):1817-25. 
31.  
Mahaseth H, Brutcher E, et al. Modified FOLFIRINOX regimen with improved safety and 
maintained efficacy in pancreatic adenocarcinoma.  Pancreas 2013 Nov 42 (8): 1311-5.)  
 
 
 
Additional References 
Chang S, Zahn JM, Horecka J, et al. Identification of a biomarker panel using a multiplex proximity ligation 
assay improves accuracy of pancreatic cancer diagnosis. J Translational Med 2009;7:105. 
Herman JM, Chang DT, Goodman KA, Dholakia AS, Raman SP, Hacker-Prietz A, Iacobuzio-Donahue 
CA, Griffith ME, Pawlik TM, Pai JS, O'Reilly E, Fisher GA, Wild AT, Rosati LM, Zheng L, Wolfgang 
CL, Laheru DA, Columbo LA, Sugar EA, Koong AC. Phase 2 Multi-Institutional Trial Evaluating 
Gemcitabine and Stereotactic Body Radiotherapy for Patients with Locally Advanced Unresectable 
Pancreatic Adenocarcinoma. Cancer. 2015 April 1: 121(7):1128-37. 
Huguet F, Andre T, Hammel P, et al. Impact of chemoradiotherapy after disease control with chemotherapy in 
locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol 
2007;25:326-31. 
Krishnan S, Rana V, Janjan NA, et al. Induction chemotherapy selects patients with locally advanced, 
unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy. Cancer 
2007;110:47-55. 
Ko AH, Quivey JM, Venook AP, et al. A Phase II Study of Fixed-Dose Rate Gemcitabine Plus Low-Dose 
Cisplatin Followed by Consolidative Chemoradiation for Locally Advanced Pancreatic Cancer. Int J 
Radiat Oncol Biol Phys 2007;68:809-16. 
Koong A, Christofferson E, Le QT, et al. Phase II Study to Assess the Efficacy of Conventionally Fractionated 
Radiotherapy Followed by a Stereotactic Radiosurgery Boost in Patients with Locally Advanced 
Pancreatic Cancer. Int J Radiation Oncology Biol Phys 2005;63:320-32. 
Simon, R (1989) Optimal two-stage designs for phase II clinical trials.  Controlled Clinical Trials; 10: 1-10. 
Efird, J Blocked Randomization with Randomly Selected Block Sizes. Int J Environ Res Public 
Health2011: 8(1): 15-20. 
 
Block randomization: blockrand package information can be found at  https://CRAN.R-
project.org/package=blockrand 

 
Page 64 of 84 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Page 65 of 84 
 
A P  E N D I C E S  
 

 
Page 66 of 84 
 
 
 
 
 
 
 
 
 
 
 
Appendix I 
 
 
 
 
 
EORTC QLQ-C30 and  
 
EORTC QLQ-PAN26 
 
 
 
 
 
 

 
Page 67 of 84 
 
 

 
Page 68 of 84 
 
 

 
Page 69 of 84 
 
 

 
Page 70 of 84 
 
 

 
Page 71 of 84 
 
Appendix II 
 
 
ECOG Performance Status* 
 
Grade 
Description 
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. 
 

 
Page 72 of 84 
 
 
 
Appendix III 
 
 
Definition of Menopausal Status: 
 
 
Menopausal will be defined according to the following criteria: 
 
Post-menopausal: 
 
•  Woman 60 years of age or older 
•  Woman aged 45-59 years with spontaneous cessation of menses for at least 12 months prior 
to registration 
•  Woman aged 45-59 years with cessation of menses for less than 12 months prior to 
registration AND an FSH level in the postmenopausal range (or >34.4 IU/L if institutional 
range is not available) 
•  Woman aged 45-59 years on hormone replacement therapy who have discontinued hormone 
replacement therapy at diagnosis of breast carcinoma and have an FSH level in the 
postmenopausal range according to institutional/laboratory standards (or 34.4 IU/L if the 
institutional range is not available) 
•  Prior bilateral oophorectomy 
•  Woman younger than 60 years of age who have had a prior hysterectomy (without bilateral 
oophorectomy) AND who have an FSH level in the postmenopausal range (or >34.4 IU/L if 
institutional range is not available) 
Pre- or peri-menopausal:  Not meeting definition for postmenopausal outlined above 
 
 
 
 
 
 
 

 
Page 73 of 84 
 
 
Appendix IV 
 
Eligibility Checklist 
 
Protocol Information 
Title 
Pancreatic Cancer Radiotherapy Study Group (PanCRS) Trial:   A 
Randomized Phase III Study Evaluating Modified FOLFIRINOX 
(mFFX) with or without Stereotactic Body Radiotherapy (SBRT) in 
the Treatment of Locally Advanced Pancreatic Cancer 
Number 
27492 
Principal Investigator 
Daniel Chang 
 
Subject Information 
Subject Name: ______________________________________________ 
Study ID: ____________________________________ 
Gender:    
 Male     
 Female 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria (From IRB approved protocol) 
Yes 
No 
Supporting Documentation* 
1. Histologically confirmed adenocarcinoma of the 
pancreas 
 
 
      
2. 
Induction mFOLFIRINOX up to 4 cycles 
 
 
      
3. 
Stable or better disease on re-staging 
scans 
 
 
      
4. 
Deter
mined unresectable by a pancreatic cancer surgeon or a 
multi-disciplinary or gastrointestinal oncology Tumor 
Board 
 
 
      
5. Typically, pancreatic tumors must be < 8.0 cm in 
greatest axial dimension at time of treatment planning 
but final determination of eligibility will be based upon 
satisfying the radiation normal tissue constraints as 
specified in protocol (Section 6.1.3 - Radiation 
Treatment Planning). 
 
 
      
6. ECOG 0, 1, or 2 
 
 

 
Page 74 of 84 
 
7. 
Acceptable organ and 
marrow function as defined below and within 30 days 
of eligibility confirmation: 
a. Leukocytes 
>3,000/µL 
b. ANC   
>1,500µL 
c. Platelets 
>50,000/µL  
d. Total bilirubin  
<1.5 X institutional  
 
upper limits of normal 
e. AST (SGOT)/ALT (SGPT)  <2.5 X institutional 
                                                  upper limit of normal 
f. Creatinine not above the upper limit of  normal 
institutional limits   
 
 
      
8. Ability to understand and the willingness to sign a 
written informed consent document 
 
 
      
9. Life expectancy >6 months 
 
 
 
 
Exclusion Criteria (From IRB approved protocol) 
Yes 
No 
Supporting Documentation* 
1. Children / Age <18 years 
 
 
      
2. Metastatic disease 
 
 
      
3. Prior radiotherapy to the upper abdomen/liver 
 
 
      
4. Prior chemotherapy for pancreatic cancer, other than up 
to 4 cycles of mFOLFIRINOX 
 
 
      
5. Uncontrolled illness including, but not limited to, 
ongoing or active infection (or infections requiring 
systemic antibiotic treatment), symptomatic congestive 
heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
 
      
6. Any concurrent malignancy other than non-melanoma 
skin cancer, non-invasive bladder cancer, or carcinoma in 
situ of the cervix.  Patients with a previous malignancy 
without evidence of disease for > 5 years will be allowed 
to enter the trial. 
 
 
7. Pregnant and breastfeeding women are excluded, as well 
as women of child-bearing potential who are unwilling or 
unable to use an acceptable method of birth control 
(hormonal or barrier method of birth control; abstinence) 
to avoid pregnancy for the duration of the study.  Male 
subjects must also agree to use effective contraception for 
the same period as above.  
 
 
      
8. Women who are not post-menopausal (as defined in 
Appendix III) and have a positive urine or serum 
pregnancy test or refuse to take a pregnancy test 
 
 
      
*Supporting documentation is required to confirm subject eligibility and can include but is not limited to:  clinic 
notes, laboratory results, pathology results, radiology reports, subject self-report, or MD documentation.   
 
 
 
 
 

 
Page 75 of 84 
 
 
 
 
 
 
 
IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
eligible / 
ineligible] for participation in the 
study. This study is approved by the Stanford Cancer Institute Scientific Review Committee, the Stanford 
IRB, and has finalized financial and contractual agreements as required by Stanford School of Medicine’s 
Research Management Group. 
Study Coordinator Signature: 
Date: 
Printed Name: 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
Treating Physician Signature: 
Date: 
Printed Name: 
 
 
 
 
 
 
 
 
 
 
 
 

 
Page 76 of 84 
 
 
 
Appendix V 
 
Case Report Form and Patient Logs: 
 
 
 
Case Report Form for SAEs, AEs, and UPs 
 
 
Subject Log 
 
 
Protocol Deviation Log 
 
 
AE (Adverse Event) Tracking Form 
 

 
Page 77 of 84 
 
Received On:_____________ 
Date Submitted to CCTO:_____________ 
Date Submitted to SUMC IRB:_____________ 
 
Case Report Form for SAEs, AEs, and UPs 
 
Protocol:  Pancreatic Cancer Radiotherapy Study Group (PanCRS) Trial:   
A Randomized Phase III Study Evaluating Modified FOLFIRINOX (mFFX) with or without  
Stereotactic Body Radiotherapy (SBRT) in the Treatment of Locally Advanced Pancreatic Cancer 
 
Stanford eprotocol #:__27492__ 
 
 
 
 
OnCore #:__PANC0015_ 
Date of Report: __________________ 
Participating Site and 
Location:_____________________________________________________ 
 
Date of Event:________________________ 
Subject’s Initials: _____________________ 
 
 
Subject’s OnCore #:___________________ 
Research Staff Completing Form: 
 
Name: ________________________________________ 
 
 
 
 
Phone: ________________________________________ 
 
Email: ________________________________________ 
Principal Investigator / Treating Physician at study site has reviewed and agrees with 
information in this report: 
Printed Name: _______________________________________ 
 
 
Signature: ___________________________________________ Date: _________________  

 
Page 78 of 84 
 
 
 
 
 
Answer all questions below.  Provide additional pages as needed.   
 
1. Check if event was:   
      
 Serious Adverse Event (SAE)*    
 
 Adverse Event (AE)* 
 
 Unanticipated Problem (UP)# 
 
 
 
*Note Grade: _   (According to CTCAE, V 4 or greater, available at http://ctep.cancer.gov/reporting/ctc.html.) 
 
 
#If also UP, check that it meets criteria for:    Unexpected  
 
 
 
 
Related  
 
 
 
 
Harmful 
 
 
 
2. Check the box of which therapy the event was related or possibly related to:    
 
 mFOLFIRINOX  
 
 SBRT      
 Other, indicate: __________________________  
     
3. Indicate how much treatment the subject received up to the event: 
 
- For mFOLFIRINOX, Cycles_______  and Days or Doses_______ 
 
- For SBRT, fractions______  and cGy_______ 
 
4. Provide a brief description of the event, including: 
 
symptoms reported and when (dates) 
 
results of scans, labs, or other procedures or tests 
 
if hospital ED visit or admission, give dates and length of hospitalization 
 
If Grade 5, indicate date of death, primary cause, if death certificate obtained, and if autopsy 
performed  
 
 
________________________________________________________________________________
__ 
 
________________________________________________________________________________
__ 
 
________________________________________________________________________________
__ 
 
________________________________________________________________________________
__ 
 
________________________________________________________________________________
__ 
 
5. Following the event:   
 
Was therapy discontinued?     
 No   
Yes 
N/A 
 
Was dose modified?   
 
No        
Yes     
N/A 
 
If Yes, note modified dose(s): _____________________________________________________ 

 
Page 79 of 84 
 
 
________________________________________________________________________________
__ 
 
6. Define the action plan and follow-up, including: 
 
Next visit and follow-up schedule if not per protocol 
 
Referrals for tests, procedures, specialty or other clinics 
 
Other pertinent information: 
__________________________________________________________________________________ 
__________________________________________________________________________________ 
__________________________________________________________________________________ 

 
Page 80 of 84 
             Protocol:  Pancreatic Cancer Radiotherapy Study Group (PanCRS) Trial:  A Randomized 
Phase III Study Evaluating Modified FOLFIRINOX (mFFX) with or without Stereotactic Body 
Radiotherapy (SBRT) in the Treatment of Locally Advanced Pancreatic Cancer 
 
 
 
 
 
Stanford eProtocol #:  27492  
 
 
 
OnCore #:  PANC0015  
 
 
 
 
  
Participating Center: ___________________________________________      
 
 
Subject Log 
  # 
Subject Name 
Subject 
Initials 
Subject ID or 
OnCore # 
Date On-Study 
(Date of 
Randomization) 
Treatment 
Arm 
Treatment 
Start Date 
(Day 1) 
Date  
Off-Study 
Reason Off-Study 
1 
 
 
  
 
 mFFX 
 +SBRT 
 
  
  
2 
 
 
 
  
 mFFX 
 +SBRT 
 
  
  
3 
  
 
  
  
 mFFX 
 +SBRT 
 
  
  
4 
  
 
  
  
 mFFX 
 +SBRT 
 
  
  
5 
  
 
  
  
 mFFX 
 +SBRT 
 
  
  
6 
  
 
  
  
 mFFX 
 +SBRT 
 
  
  

 
Page 81 of 84 
 
7 
  
 
  
  
 mFFX 
 +SBRT 
 
  
  
8 
  
 
  
  
 mFFX 
 +SBRT 
 
  
  
9 
  
 
  
  
 mFFX 
 +SBRT 
 
  
  
10 
  
 
  
  
 mFFX 
 +SBRT 
 
  
  
 
 
 
 
 
 
 
Protocol:  Pancreatic Cancer Radiotherapy Study Group (PanCRS) 
Trial:  A Randomized Phase III Study       Evaluating Modified FOLFIRINOX (mFFX) with or without Stereotactic Body 
Radiotherapy (SBRT) in the Treatment of Locally Advanced Pancreatic Cancer 
 
 
 
 
 
Stanford eProtocol #:  27492  
 
 
OnCore #:  PANC0015     
 
 
 
 
 Participating Center: ___________________________________________      
 
Protocol Deviation Log 
# 
Subject 
Initials 
Subject ID or  
OnCore # 
Date of 
Deviation 
Category (see 
next page) 
Code 
(see next 
page) 
Brief Description 
Date IRB 
notified, if 
applicable 
Corrective Action 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 

 
Page 82 of 84 
 
5 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
 
Deviation Categories   
 
A.  Safety  
B.  Informed Consent   
C.  Eligibility 
D.  Protocol Implementation   
E.  Other, specify in log 
 
 
Deviation Codes (associated with Deviation categories) 
 

 
Page 83 of 84 
 
 
Safety (Category A) 
1. Not reporting SAE within 24 hours 
2. Laboratory tests not done 
3. AE/SAE not reported to IRB 
4. Other, specify on log 
 
 
Informed Consent  (Category B) 
5. Failure to obtain informed consent 
6. Consent form used was not current IRB approved 
version 
7. Consent form does not include updates or information 
required by IRB 
8. Consent form missing 
9. Consent form not signed and dated by participant 
10. Consent form does not contain all required signatures 
11. Other, specify in log 
 
 
Eligibility (Category C) 
12. Participant did not meet eligibility criteria 
13. Randomization of an ineligible patient 
14. Participant randomized prior to Baseline Assessment 
15. Randomization or treatment of a patient prior to IRB approval 
of protocol 
16. Other, specify in log 
 
Protocol Implementation (category D) 
17. Failure to keep IRB approval up to date 
18. Participant receives wrong treatment 
19. Participant seen outside of window visit 
20. Use of unallowable concomitant treatments 
21. Prescribed dosing outside of protocol guidelines 
22. Missed Assessment 
23. Missed Visit 
24. Other, specify in log 
 
 

 
Page 84 of 84