Clinical trial NCT02873598
Conditions: Pancreatic Cancer
Keywords: Induction Chemotherapy Stereotactic Body Radiotherapy (SBRT) Dose Escalation Locally Advanced Pancreatic Cancer (LAPC) Maximum Tolerated Dose (MTD)
Sponsor: University of Colorado, Denver
Start date: 2016-11-17; Completion date: 2022-11-28
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a dose escalation trial to evaluate the safety of stereotactic body radiotherapy (SBRT) delivered in 3 fractions for patients with locally advanced pancreatic cancer (LAPC) who have received induction chemotherapy (FOLFIRINOX or gemcitabine and nab-paclitaxel).

Detailed description:
This is a phase I study, with an expansion cohort, of up to 34 patients to identify the maximum tolerated dose (MTD) of a 3-fraction regimen of stereotactic body radiotherapy (SBRT) for locally-advanced pancreatic cancer patients who have not developed distant progression following induction chemotherapy (FOLFIRINOX or gemcitabine and nab-paclitaxel) as per standard of care. After completion of induction chemotherapy, stereotactic body radiotherapy SBRT will be administered in 3 fractions, every other day, on an outpatient basis. Dose escalation will start with dose level 1 (9 Gy x 3 fractions) and increase by 1 Gy per fraction at each dose level, dose level 2 will be 10 Gy x 3 fractions and dose level 3 will be 11 Gy x 3 fractions.

Arms: arm 1: SBRT will be administered in 3 fractions, every other day, on an outpatient basis, following chemotherapy with either FOLFIRINOX or gemcitabine/abraxane. Dose level 1- 9 Gy x 3 fractions. arm 2: SBRT will be administered in 3 fractions, every other day, on an outpatient basis, following chemotherapy with either FOLFIRINOX or gemcitabine/abraxane. Dose level 2 -10 Gy x 3 fractions arm 3: SBRT will be administered in 3 fractions, every other day, on an outpatient basis, following chemotherapy with either FOLFIRINOX or gemcitabine/abraxane. Dose level 3 - 11 Gy x 3 fractions.
Interventions: intervention 1: FOLFIRINOX or gemcitabine/abraxane intervention 2: SBRT
Intervention descriptions: intervention 1: Patients will have received induction chemotherapy for 3+ months with either FOLFIRINOX or gemcitabine/abraxane with at least stable disease. intervention 2: After completion of induction chemotherapy, stereotactic body radiation therapy (SBRT) will be administered in 3 fractions, every other day, on an outpatient basis. Dose escalation will start with dose level 1 (9 Gy x 3 fractions) and increase by 1 Gy per fraction at each dose level, dose level 2 will be 10 Gy x 3 fractions and dose level 3 will be 11 Gy x 3 fractions.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
A Dose Escalation Trial of SBRT After induction Chemotherapy for Locally Advanced Pancreatic Cancer 
NCT 02873598 
Protocol Version dated April 6, 2020 


Protocol/COMIRB # 16-1139 
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PROTOCOL TITLE: 
A Dose Escalation Trial of Stereotactic Body Radiotherapy (SBRT) 
after Induction Chemotherapy for Locally Advanced Pancreatic 
Cancer  
 
 
PRINCIPAL INVESTIGATOR: 
Sana D. Karam, MD, PhD. 
 
PROTOCOL NUMBER: 
 
16-1139 
 
 
VERSION DATE: 
 
April 6, 2020 
 
 
 
 


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TABLE OF CONTENTS 
 
1.0 
PROTOCOL SUMMARY AND SCHEMA .................................................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ....................................................................................... 5 
3.0 
BACKGROUND AND RATIONALE ............................................................................................. 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 9 
4.1 
Design .............................................................................................................................................. 9 
4.2 
Intervention ...................................................................................................................................... 9 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .................................................................................... 9 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................................ 12 
6.1 
Subject Inclusion Criteria .............................................................................................................. 12 
6.2 
Subject Exclusion Criteria ............................................................................................................. 13 
7.0 
RECRUITMENT PLAN ................................................................................................................. 14 
8.0 
PRETREATMENT EVALUATIONS (PRE-SCREENING) ....................................................... 14 
9.0 
STUDY PROCEDURES - SCREENING ...................................................................................... 15 
10.0 
STUDY PROCEDURES - TREATMENT/INTERVENTION PLAN ........................................ 16 
11.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 19 
12.0 
TOXICITIES/SIDE EFFECTS ...................................................................................................... 20 
13.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................ 21 
14.0 
CRITERIA FOR REMOVAL FROM STUDY ............................................................................ 24 
15.0 
BIOSTATISTICS ............................................................................................................................ 24 
16.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES
 
26 
[Section Intentionally Omitted] .................................................................................................................. 26 
17.0 
DATA MANAGEMENT ................................................................................................................. 26 
17.1 
Data and Safety Monitoring .......................................................................................................... 26 
18.0 
PROTECTION OF HUMAN SUBJECTS .................................................................................... 29 
18.1 
Privacy ........................................................................................................................................... 30 
18.2 
Procedures for Adverse Events – Definitions and Reporting Criteria ........................................... 30 
19.0 
INFORMED CONSENT PROCEDURES .................................................................................... 32 
20.0 
REFERENCES ................................................................................................................................ 32 
21.0 
APPENDICES .................................................................................................................................. 38 


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
AE: adverse event 
CBC: complete blood count 
CBCT: cone beam CT 
COMIRB: Colorado Multiple Institutional 
Review Board 
CRC: clinical research coordinator 
CRDB: clinical research database 
CRF: case report form 
DLT: dose-limiting toxicity 
DSM: data safety monitoring 
DSMC: data safety monitoring committee 
EES: extracellular extravascular space 
EKG: electrocardiogram 
ERCP: endoscopic retrograde 
cholangiopancreatography 
EUS: endoscopic ultrasound 
FNA: fine needle aspiration 
GCP: good clinical practice 
GI: gastrointestinal 
GTV: gross tumor volume 
I: iodine 
IMRT: intensity-modulated radiation therapy 
IRB: institutional review board 
ITV: internal target volume 
KV: kilovoltage 
LAPC: locally advanced pancreatic cancer 
LC: local control 
MTD: maximum tolerated dose 
NTCP: normal tissue complication probability 
OAR: organ at risk 
OS: overall survival 
PC: pancreatic cancer 
PFS: progression free survival 
PO: per os (orally) 
QOL: quality of life 
pCT: perfusion CT 
PI: principal investigator 
PB: privacy board 
PTV: planning treatment volume 
PV: portal vein 
ROI: region of interest 
RT: radiation therapy 
SAE: serious adverse event 
SBRT: stereotactic body radiotherapy 
SIV: site initiation visit 
SMA: superior mesenteric artery 
SMV: superior mesenteric vein 
UAP: unanticipated problem 
VMAT: volumetric modulated arc therapy 
VS: vascular space


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1.0 
PROTOCOL SUMMARY AND SCHEMA 
This is a dose escalation trial to evaluate the safety of stereotactic body radiotherapy 
(SBRT) delivered in 3 fractions for patients with locally advanced pancreatic cancer 
(LAPC) who have received induction chemotherapy (FOLFIRINOX or gemcitabine and 
nab-paclitaxel).  The primary objective is to determine the maximum tolerated dose (MTD) 
of 3-fraction SBRT for patients with LAPC.  We will develop and implement functional 
imaging methods to evaluate post-SBRT effects on normal tissue and tumor cellularity and 
perfusion/permeability that may provide quantitative biomarkers of tumor response as well 
as early indicators of bowel toxicity.   We anticipate (up to) 18 patients to be accrued over 
3 years.   
SCHEMA 
 
 
Locally advanced pancreas 
cancer with no progression 
after 3+ months of standard 
chemotherapy
EUS: fiducials, biopsy
Baseline/Planning  DCE- CT, 
research blood
SBRT- 3 Fractions, research 
blood
DCE- CT within  90 min of 1st fx
DCE- CT at 6 wks, research 
blood


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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
2.1 
Primary objective:   
To identify the maximum tolerated dose (MTD) of stereotactic body radiotherapy (SBRT) 
in locally advanced pancreatic cancer (LAPC) patients who have not developed distant 
progression after following induction chemotherapy (FOLFIRINOX or gemcitabine and 
nab-paclitaxel as per standard of care). 
2.2  
Secondary objectives: 
1) To preliminarily assess the 2 year local control, progression free and overall survival 
rates for LAPC patients after induction chemotherapy and SBRT. Patterns of failure 
will also be investigated. 
2) To identify early changes in the normal small intestine after SBRT for LAPC using 
Perfusion CT derived parameters to document changes in tissue perfusion kinetics and 
heterogeneity that predict for development of gastrointestinal toxicity such as duodenal 
ulcers, strictures, or enteritis. 
3) To investigate vascular and cellular changes resulting from SBRT for LAPC using 
perfusion CT derived parameters that can predict treatment response and to assess any 
correlation between these perfusion CT derived parameters and local control and 
progression-free survival 
4) Evaluate Quality of Life (QOL) in terms of global QOL, physical symptoms, physical 
functioning and emotional well-being after induction chemotherapy and SBRT. Testing 
will be prior to SBRT, 10-12 weeks after SBRT and 6 months after SBRT. 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 
Stereotactic Body Radiotherapy for Locally Advanced Pancreatic Cancer 
Pancreatic cancer (PC) remains a highly lethal cancer with 5-year survival rates of 
approximately 6% [1].  In 2016, an estimated 53,000 new cases of PC will be diagnosed 
with over 41,000 deaths [1].  Surgical resection is the only potentially curative option; 
however, fewer than 20% of patients are eligible. While systemic therapy remains vital, 
local therapy options are also paramount.  In a recent autopsy series, 30% of PC patients 
died with extensive local progression and only minimal systemic disease [2].  Patients with 
unresectable, LAPC are committed to non-curative treatment options using concurrent 
chemotherapy and conventional, fractionated radiation therapy (RT) over 2-6 weeks, 
however, these regimens are associated with significant acute toxicity and minimal impact 
on resectability.  


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The mechanism of RT-induced tumor-cell death from fractionated RT is via induction of 
DNA double-strand breaks [3-6]. Fractionation requires daily treatment, leading to daily 
changes in tumor position, necessitating larger fields to ensure tumor coverage.   SBRT 
allows delivery of focal RT with high precision using image guidance at the time of 
treatment to overcome uncertainties related to tumor positioning, thereby minimizing the 
dose to the surrounding normal tissues.  Studies with 15-18 month follow-up have 
demonstrated excellent local control and minimal late toxicity (<5%) using single fraction 
SBRT for bone, nodal, liver, and lung tumors [7-10].  SBRT is particularly appealing for 
LAPC patients, as it may deliver a potentially more effective, focally ablative therapy over 
a short period, versus 5-6 weeks of conventional RT.  This provides significant advantages 
for patients’ quality of life and potential therapeutic benefit.  Phase I and II studies have 
shown local tumor control rates of >90% and even metabolic response by PET/CT after a 
single fraction of 25Gy SBRT [11-14].  Distant metastasis was the most common site of 
failure. However, GI toxicity was significant, with development of Grade 2+ toxicities, 
particularly duodenal strictures and ulcers in approximately 40% of patients.  Thus, a phase 
II, multi-institutional study, aimed at reducing toxicity, used a 5-fraction regimen of SBRT 
with a decreased dose of 6.6 Gy per fraction.  This study has shown a reduced rate of 
Grade 2+ toxicities.  Of 49 patients analyzed to date, 5 (10%) developed grade 2 acute 
toxicities and 1 (2%) an acute grade 4 duodenal ulcer.  Late GI grade ≥3 toxicities occurred 
in 3 patients (6%) [15].   
However, SBRT may be more effective at doses higher than 6.6Gy per fraction.  Studies 
by Kolesnick and Fuks have demonstrated that high dose (>8Gy) per fraction rapidly 
activates the cell membrane enzyme acid sphingomyelinase (ASMase) that hydrolyzes 
sphingomyelin to generate the pro-apoptotic second messenger ceramide, thus initiating 
transmembrane signaling of apoptosis [39]. Endothelial cells are 20-fold enriched in 
secretory ASMase compared with any other cell in the body and are particularly sensitive 
to radiation-induced apoptosis in vitro and in vivo via the ASMase pathway[16]. High-
dose RT appears to induce primarily sublethal lesions in tumor cells that become lethal due 
to apoptotic microvascular dysfunction. The proposed mechanism of tumor cell death 
related to microvascular damage may overcome the apparent radioresistance of pancreatic 
cancer evidenced by the poor local control with conventional RT. 
In this study, we will introduce a 3-fraction regimen starting at 9Gy, a dose that should 
induce microvascular changes.  This innovative therapy has potential to impact the 
majority of pancreatic cancer patients, i.e. who are ineligible for curative resection due to 
involvement of critical blood vessels.  The proposed tumoricidal mechanism of tumor cell 
death related to microvascular damage may overcome the apparent radioresistance of 
pancreatic cancer as evidenced by the poor local control achieved by conventional RT 
techniques. 


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In addition, we will correlate dose to surrounding small bowel with the development of any 
acute or late gastrointestinal toxicity after SBRT.   However, a limiting factor in predicting 
gastrointestinal toxicity is the variability in the accumulated radiation dose to organs at 
risk, in particular, the duodenum. Respiration-induced motion contributes to dose 
variability and requires accurately determining and controlling the motion trajectories of 
tissues during treatment delivery. The recent availability of intra-treatment kilovoltage cine 
radiography makes possible the tracking of implanted fiducial markers. We have 
developed a method of automatically tracking implanted markers in kV images during 
treatment. In a further study, we have developed a means of calculating and correcting for 
respiration-averaged drift in target position.  We will use these capabilities to monitor and 
correct drift in the position of fiducials during respiration gated treatment, thereby 
controlling accumulated dose to the pancreas and to the duodenum, which is fixed to it. 
This innovative therapy has potential to impact the majority of pancreatic cancer patients, 
i.e. those who are unable to undergo a curative resection due to involvement of critical 
blood vessels.  Moreover, SBRT can be easily integrated into a regimen of aggressive 
chemotherapy, preventing unnecessary delays or discontinuation of effective 
chemotherapy regimens during more conventionally fractionated RT.   
3.2 
Functional Imaging 
Conventional anatomical CT is routinely used to evaluate pancreatic neoplasms, however, 
standard bi-dimensional tumor measurements may underestimate response to treatment 
with radiotherapy.  Signal intensity changes may be assessed, but are not reliable for 
demonstrating possible treatment responses.  Apart from radiographic changes in tumor 
size, conventional CT offers no additional method of assessing the viability of the tumor, 
or the response of tumor to therapy.  Furthermore, while tumor shrinkage is useful and is 
the gold standard for response assessment, tumor measurements alone may underestimate 
tumor necrosis and do not consider changes in tumor vascularity.  More recently, 
functional imaging techniques that can assess biological parameters, such as vascularity or 
metabolism, have been explored to better predict tumor response either before or early 
after initiation of therapy. Functional imaging, including perfusion CT (pCT), can help 
assess the biological effects of therapy before changes in tumor size occur. Functional 
imaging can potentially 1) improve pre-treatment prediction of tumor response, 2) predict 
response early after initiating therapy, and 3) monitor tumor biology once size has 
stabilized. 
Clinical CT examinations of the pancreas routinely include the use of iodine (I) based 
contrast agents to assess tumor vascularity and improve tumor conspicuity. Perfusion CT 
can be incorporated into routine CT simulation to quantitatively evaluate the passage and 
distribution of I contrast agents from the circulation to tumors over time. Quantitative 


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perfusion parameters obtained from pCT reflect the rate of exchange of I and include Ktrans 
- a volume transfer constant between blood plasma or vascular space (VS) and 
extracellular extravascular space (EES), kep - the rate constant between EES and VS, BF – 
the rate of transfer of blood from the main vessels to the capillaries, and ve - the fractional 
vascular volume. These parameters can be measured at baseline and compared on follow-
up post treatment scans. This technique was initially applied for evaluation of 
antiangiogenic therapy, but its use has expanded to other cytotoxic agents and may be 
useful to evaluate rapid endothelial damage leading to vascular collapse after SBRT. 
Tumor response to chemotherapy has traditionally been assessed by measurements of 
tumor size. Functional CT imaging can help assess the biological effects of therapy before 
changes in tumor size occur. Functional imaging can potentially 1) improve pre-treatment 
prediction of tumor response, 2) predict response early after initiating therapy, and 3) 
monitor tumor biology once size has stabilized. 
While multiple studies have investigated perfusion imaging in pelvic tumors and breast 
cancers, there are still a limited number of studies exploring the role of perfusion for 
pancreatic cancers [43, 44]. Perfusion has been used to quantify regional 
perfusion/permeability in the normal pancreas or to distinguish pancreatitis and pancreatic 
cancer [44-46]. The use of perfusion to predict treatment response in pancreatic cancer is 
emerging. Changes in perfusion/permeability 3 days after treatment of a pancreatic tumor 
xenograft correlated with tumor volume changes 21 days after treatment with cetuximab 
and irinotecan [23]. Pancreatic tumors with high pre-treatment Ktrans (measure of 
perfusion/permeability) responded better to concurrent chemo/radiotherapy.  In another 
study of 11 pancreatic cancer patients treated with gemcitabine and sorafenib, pre-
treatment Ktrans were higher in 4 patients that showed a response by tumor marker levels 
[43]. While there were no significant changes in tumor size, an overall decrease in Ktrans 
and other perfusion/permeability parameters was observed 4 weeks after treatment.  There 
is also evidence that tumor blood flow can serve a useful predictive/prognostic role.  There 
is evidence that decreased tumor blood flow combined with increased metabolic (i.e. PET) 
activity is associated with more malignant lesions, as well as evidence that tumor blood 
flow correlates with tumor histology. 
Radiation-induced vascular damage can also affect normal organ function [47]. Traditional 
efforts to predict late toxicity have relied on normal tissue complication probability 
(NTCP) models derived from planned radiation dose distributions. Inclusion of clinical and 
imaging factors can improve prediction, thereby implying a range of patient 
radiosensitivities. For example, portal venous perfusion has been found to correlate with 
liver function following radiation therapy, which varied even among patients receiving the 
same dose and dose distributions [48].  Additionally, increased perfusion and permeability 


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can discriminate between actively inflamed and normal small bowel in Crohn’s Disease 
[49]. In acute radiation GI toxicity, increased intestinal permeability and histological injury 
are observed partway into fractionated treatment [50]. Clinical studies [51-53], preclinical 
time-dose fractionation studies [54] and animal studies using modifiers of acute toxicity 
[55] have shown that acute toxicity often contributes to the development of late toxicity. 
The development of perfusion as a biomarker for pancreatic cancer and peripancreatic soft 
tissues following radiotherapy would represent an important clinical advance, in that it 
offers a noninvasive multiparametric approach to assess tumor response and predicting 
potential toxicities, monitor the vascular effects of SBRT and explore, in humans, the 
preclinical model of endothelial dysfunction.  Ultimately, the goal of developing these 
functional imaging-based biomarkers would be to tailor the dose of SBRT for each patient 
based on early assessment of an individual patient’s tumor responsiveness and risk of 
toxicity. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a phase I study of up to 18 patients to identify the maximum tolerated dose (MTD) 
of a 3-fraction regimen of SBRT for locally-advanced pancreatic cancer patients who have 
not developed distant progression following induction chemotherapy (FOLFIRINOX or 
gemcitabine and nab-paclitaxel as per standard of care).  Using pCT to quantify tissue 
perfusion/permeability and associated heterogeneity after SBRT, we will define early 
normal tissue changes associated with GI toxicity requiring early interventions as well as 
tumor changes associated with local control or progression that can dictate further therapy 
choices for patients with LAPC.  
4.2 
Intervention 
After completion of induction chemotherapy, stereotactic body radiotherapy (SBRT) will 
be administered in 3 fractions, every other day, on an outpatient basis. Dose escalation will 
start with dose level 1 (9 Gy x 3 fractions) and increase by 1 Gy per fraction at each dose 
level, dose level 2 will be 10 Gy x 3 fractions and dose level 3 will be 11 Gy x 3 fractions.   
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 
EUS and Fiducial Placement:  
Eligible patients will be enrolled on this protocol and will undergo endoscopic ultrasound 
(EUS)-guided placement of 3-5 fiducial markers for SBRT targeting purposes.  The 
fiducials will be placed directly into or adjacent to the tumor under CT guidance, EUS or 
under direct visualization during laparoscopy.  


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5.2 
Simulation and baseline pCT:  
The patient will undergo a treatment planning simulation after the re-staging CT scan.  In 
preparation for the planning CT scan, patients will be asked to fast for 2 hours prior to 
simulation and treatment to minimize the volume of stomach contents. A nurse will remind 
patient of these procedures.  In order to visualize the bowel and lymph nodes, the patient 
may also be given bowel and IV contrast prior to the treatment planning CT.  All patients 
will be immobilized in a cradle in order to prevent any inadvertent patient motion.  Patients 
who can tolerate the abdominal compression belt will be fitted with the belt and motion of 
the fiducials with the compression belt inflated will be evaluated by fluoroscopy.  For 
patients who are unable to use the compression belt or there is greater than 5mm of motion 
of the fiducials by fluoroscopy, we will use respiratory gating for motion management.   
With patients in the treatment position, a thin-cut pancreatic protocol CT scan (1 mm cuts) 
is performed with IV contrast for high resolution delineation of the tumor and surrounding 
structures.  For patients who will be treated with respiratory gating, the intravenous 
contrast is administered in a rapid bolus when the patient is being coached to remain in the 
expiratory phase.  For the respiratory gating patients, we will also perform four-
dimensional (4D) CT scans, in which CT data (3 mm cuts) are acquired synchronously 
with a respiratory signal, to evaluate temporal changes of the anatomy as a function of the 
respiratory phase during the imaging, in order to correct for respiratory related liver tumor 
movement.  All patients will have been given an audio coaching CD to review prior to the 
set-up procedure to determine a comfortable breathing rhythm.   
A pre-SBRT pCT image will be performed at the time of simulation in the treatment 
position on the Siemens AS Open CT scanner.  50-100 mL of Iodine contrast will be 
injected at a rate of 3 mL/s followed by a saline flush of 20 mL.  A series of axial images 
with an 8 cm field of view in the superior-inferior direction will be acquired over a period 
of 60-120 s at intervals of 3-5 s. 
5.3  
Target Definition:  
The gross tumor volume (GTV) is delineated on cross-sectional images from the planning 
CT scan.  For patients who will be treated using respiratory gating, the 4DCT scans are 
reconstructed and tumor motion is evaluated on the Eclipse planning station.  The 
respiratory gating interval is selected based on the degree of tumor motion. These scans are 
registered with the IV contrast breath-hold CT scan and the primary tumor is contoured.  If 
there is greater than 5 mm of motion during the expiratory phase/gating window, the GTV 
will be expanded at the extremes of the gating window and an internal target volume (ITV) 
is created.  Any adjacent duodenum, small/large bowel, and stomach will be expanded by 2 
mm to create a planning organ at-risk volume (PRV). A GTV/ITV to PTV margin 
expansion of 5mm will be added and the PRV of the duodenum, small/large bowel or 


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stomach, will be excluded from the PTV using a boolian function.  For compression belt 
patients, a GTV to planning treatment volume (PTV) margin expansion of 5mm will be 
added to account for internal motion.  The same process of excluding the PRVs will be 
performed to minimize PTV overlap with OARs. 
5.4 
Radiation Treatment Planning:   
Intensity-modulated radiation therapy (IMRT) with or without Volumetric Modulated Arc 
Therapy (VMAT) treatment planning will be done to create a multi-field or arc plan or to 
deliver the assigned dose to the target as a single dose. Dose to the adjacent normal tissue 
will be minimized.  Since the small bowel is the most radiosensitive normal structure in 
this region, the dose to it will be limited to no more than 16cm3 can receive >10 Gy, no 
more than 5 cm3 can receive >20 Gy, and the maximum point dose is ≤23 Gy [36]. For 
other abdominal organs at risk (OAR), the institutional normal tissue guidelines for 3-
fraction SBRT treatments will be used.  Dose shall be prescribed to the periphery of the 
PTV and a hot spot of up to 10% of the prescribed dose will be accepted.  In the case 
where normal tissue criteria cannot be met, the dose constraints will take priority over 
tumor coverage.  Dose painting will be allowed to achieve the protocol dose constraints. 
5.5 
Radiation Dose Constraints 
Duodenum 
V15Gy<20cc, V20Gy<10cc  
Other Small Bowel 
V20Gy<5cc  
Spinal cord  
Dmax 21Gy 
Stomach 
V20Gy<5cc 
Liver  
V15Gy<33% 
Large Bowel 
V20Gy<5cc 
Kidney 
V15Gy<33% 
 
5.6 
On Line Image-Guided Localization and Treatment Delivery:  
Image–guided IMRT is the delivery of IMRT with on-line imaging capabilities and 
verification. This is accomplished with standard IMRT treatment planning with position 
verification using 2-dimensional kilovoltage (KV) images to evaluate the position of the 
fiducial markers as well as 3-dimensional cone beam imaging. 3D kilovoltage cone beam 
CT (CBCT) scan is a CT scan taken of the patient and target structure of interest while the 
patient is immobilized on the treatment table. During the treatment, the patient is 
immobilized in a cradle with the compression belt on.  Fluoroscopic images are taken to 
verify that motion of the fiducials or stent is <5mm. For respiratory gated patients, the 
fluoroscopy is not performed.  The patient is then set-up in the treatment position 
according to tattoos, then live images of the patient are obtained with diagnostic x-ray 


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tubes and amorphous silicon detectors. Then the therapists can either initially obtain a KV 
image (gated KV for the respiratory gating patients) to align the fiducial markers or a 
CBCT will be obtained and image registration is performed based on the location of the 
fiducial markers and visible tumor abnormality (if possible) noted in the CT. The patient 
position is then adjusted to move the patient into the exact position corresponding to the 
designed treatment plan. 
Another CBCT scan is then obtained to verify visualization of the fiducial markers, tumor, 
and normal tissues. In the CBCT image, the target structure and surrounding normal tissue 
structures can be visualized. We will upload the target and normal tissue contours on the 
treatment CBCT images. If necessary, adjustments can be made to the patient’s position at 
this time to ensure that the fiducial markers line up with the fiducial markers on the 
planning CT and that the critical normal tissues are not within the high dose region. If the 
patient requires additional repositioning, another set of KV orthogonal images will be 
obtained to confirm tumor localization.  Once the latter is confirmed, the treatment will be 
delivered. Treatment will be delivered with the abdominal compression belt or using 
respiratory gating using the gating interval as determined from the 4DCT obtained at the 
simulation. The patient will be monitored during treatment with intra-fraction imaging 
(IMR) to prevent non-respiratory body motions greater than 3 mm. 
5.7 
Early Post-SBRT CT Imaging:   
To evaluate the effect of the high-dose radiotherapy on the tumor vasculature, patients will 
undergo a pCT within 90 minutes of the first fraction of SBRT. 
5.8 
Follow-up CT Imaging:  
Patients will undergo a follow-up abdominal pCT to evaluate the response to SBRT 6 
weeks (± 1 week) after completion of SBRT.  The patients can resume systemic therapy 
per the discretion of the treating physician after the pCT scan at 6 weeks. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
1. Histologically or cytopathologically confirmed adenocarcinoma of the 
pancreas. 
2. Locally advanced, unresectable pancreatic cancer as confirmed by the 
multidisciplinary input from a hepatobiliary surgeon and as defined on CT as 
having tumor abutment of >180° (> 50%) of the circumference of the superior 
mesenteric artery (SMA) or celiac axis, unreconstructable superior mesenteric 
vein (SMV) or portal vein (PV) involvement. 


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3. No evidence of distant metastasis either prior to or after induction 
chemotherapy. 
4 Completion of at least 3 months, but no more than 12 months of standard 
induction chemotherapy for LAPC, which may include FOLFIRINOX or 
gemcitabine and nab-paclitaxel, preferably within 2-4 weeks but no longer than 
8 weeks. 
5. Pancreatic tumor size ≤ 5 cm.  
6. Age ≥18 years. 
7. ECOG 0-1. 
 
8. Patients must have acceptable organ and marrow function as defined below: 
Leukocytes 
>3,000/µL 
Absolute neutrophil count 
 
>1,500/µL 
Platelets 
>70,000/µL 
Total bilirubin  
Within 2 x upper limit of normal 
AST (SGOT)/ALT (SGPT) 
<2.5 x institutional upper limit of normal 
Creatinine 
 
Within 1.5 x upper limit of normal OR 
Creatinine clearance  
 
>60 mL/min for patients with creatinine 
levels above institutional normal 
 
9. Ability to understand and follow the breathing instructions involved in the 
respiratory gating procedure or to tolerate compression sufficient to reduce 
fiducial motion to <= 5mm. 
10. Ability to understand and the willingness to sign a written informed consent 
document. 
11. Residual or on-going ≥ Grade 3 treatment-related toxicity from previous 
chemotherapy should be resolved. 
6.2 
Subject Exclusion Criteria 
1. Patients who have had prior abdominal radiotherapy. 
2. Patients receiving any investigational agents. 
3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
4.  Contraindication to IV contrast 
5.  Patients in which iodine contrast is contraindicated. 
6. Pregnant and breastfeeding women are excluded.  Women of childbearing 
potential who are unwilling or unable to use an acceptable method of birth 


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control to avoid pregnancy for the entire study period and for up to 4 weeks 
after the study are excluded. This applies to any woman who has experienced 
menarche and who has not undergone successful surgical sterilization or is not 
postmenopausal (defined as amenorrhea for at least 12 consecutive months, or 
women on hormone replacement therapy with serum FSH levels greater than 35 
mIU/mL.  A negative urine or serum pregnancy test must be obtained within 14 
days prior to the start of study therapy in all women of childbearing potential. 
Male subjects must also agree to use effective contraception for the same period 
as above.     
 
7.0 
RECRUITMENT PLAN 
This study will be available to all patients seen at University of Colorado who meet the 
eligibility criteria.  University of Colorado is a referral center for pancreatic cancer and all 
patients considered for this study will be presented at a weekly multidisciplinary 
Pancreatic Multidisciplinary Conference. In addition, the study will be placed on the 
University of Colorado Website to maximize patient recruitment. Patients will be 
identified from surgical, gastroenterology and medical oncology clinics for treatment of 
their disease.  The investigators take due notice of the NIH policy concerning inclusion of 
women and minorities in clinical research populations. 
Patient recruitment will continue for a period of 3 years.  Based on past census values at 
University of Colorado, we expect 10-15 local pancreatic cancer patients will be eligible 
for this study per year.  The target accrual is 18 patients over 3 years. 
 
8.0 
PRETREATMENT EVALUATIONS (PRE-SCREENING) 
To be completed: 
• Histologic or cytologic confirmation of malignancy. 
• Endoscopic retrograde cholangiopancreatography (ERCP) as clinically indicated for 
placement of a biliary stent for obstructive jaundice and/or for brushings/washings to 
confirm malignancy. 
• Endoscopic ultrasonography (EUS) will be performed.  Cytologic confirmation of 
malignancy will be obtained during EUS by core biopsy or Fine Needle Aspiration 
(FNA), if possible. 
• A 12-lead Electrocardiogram (EKG). 
• Within 2-4 weeks of completion of induction chemotherapy (at least 3 months but no 
more than 12 months of standard of care chemotherapy for LAPC, either 
FOLFIRINOX or gemcitabine and nab-paclitaxel), patients will be evaluated with a 
repeat CT of the chest, abdomen and pelvis with a dedicated pancreatic 
protocol/angiogram series.  If there is no evidence of distant disease and the pancreatic 


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tumor is still deemed to be unresectable by a hepatobiliary surgeon, the patient may be 
eligible for the protocol.  If the patient is eligible and enrolled on the study, treatment 
should be initiated within 30 days of the CT scan or it must be repeated. 
• Patients will be seen by a radiation oncologist to discuss the radiotherapy options and if 
the tumor is felt to be amenable to SBRT, the patient can be enrolled on the dose 
escalation protocol. 
 
9.0 
STUDY PROCEDURES - SCREENING 
9.1  
To be completed within 30 days prior to SBRT: 
• 
History and physical examination and performance status. 
• 
CT chest, abdomen, pelvis with a dedicated pancreatic protocol. 
• 
Review of CT or MRI scans at Multidisciplinary Conference to determine if 
tumor is locally advanced. 
• 
Documentation of all measurable or non-measurable disease parameters 
including radiographic imaging procedures within four weeks of study entry. 
The definitions of measurable and non-measurable disease will be those 
definitions used in the RECIST criteria as defined by CTEP 
(http://ctep.info.nih.gov/Policies). 
• 
Placement of gold fiducial markers (via EUS or, if not feasible by EUS, by 
direct visualization under laparoscopy). No specific location within the tumor is 
required.  In conjunction with the imaging system, fiducials will serve to 
identify the precise location of the pancreas tumor relative to these markers 
during SBRT and confirm that the tumor does not move significantly with 
respect to the bony skeleton over the course of treatment.  It is expected that 
such fiducial placement will be done on an outpatient basis.  If the patient has a 
plastic stent, this can be exchanged for a metal wall stent. 
• 
Core biopsy or Fine Needle Aspiration (FNA) will be obtained during EUS if 
possible -The sample will be sent for immunomonitoring assays. 
• 
Complete blood count (CBC) with differential and platelet count, serum 
chemistries (Na, Cl, BUN, Creatinine, K, Bicarb, and glucose), LFTs (AST, 
ALT, alkaline phosphatase, total bilirubin), calcium, albumin, total protein, 
LDH, INR and CEA, CA19-9. 
9.2  
To be completed within 14 days prior to SBRT:  
• Serum pregnancy test for all women of childbearing potential. If the test result 
is positive, the patient will not be allowed to participate in this study. 
• Research blood draw for immune monitoring analysis 
• Completion of quality of life (QOL) assessment 


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• Simulation for radiotherapy planning: At least 4 days after the fiducial 
placement, patients will undergo a simulation for RT treatment planning at 
which time the patient is immobilized in a cradle. While immobilized, a thin-
sliced CT with IV and PO contrast is performed.  A 4DCT scan is obtained for 
patients treated with respiratory gating (see section 4.2).  A pCT will also be 
performed in the treatment position.    
 
10.0 STUDY PROCEDURES - TREATMENT/INTERVENTION PLAN 
•  The interval between completion of induction chemotherapy and initiation of SBRT 
should be preferably within 2-4 weeks but no longer than 8 weeks. 
• 
Based on the planning CT scan performed at the simulation, an SBRT treatment plan is 
developed using inverse planning methods.  A dose distribution in which the target 
receives the prescription dose, and the relevant normal tissues are exposed to less than 
the tolerance dose levels is evaluated.  VMAT arc therapy or multi-field IMRT plans 
will be acceptable. 
• 
A total dose of 900cGy will be delivered to the tumor with each fraction for the first 3-
patient cohort. Dose escalation will start with dose level 1 (9 Gy x 3 fractions) and 
increase by 1 Gy per fraction at each dose level, dose level 2 will be 10 Gy x 3 
fractions and dose level 3 will be 11 Gy x 3 fractions.    
• 
Motion management will be achieved by either placement of an abdominal 
compression belt or using respiratory gating per standard of care.   
• 
At the time of treatment, kilo voltage images are taken to evaluate positioning based on 
the fiducial markers. 
• 
Initial shifts are made to bring the patient into the correct position. 
• 
A cone beam CT (CBCT) scan is performed.   
• 
The CBCT scan is registered with the planning CT scan in 3D by aligning the fiducial 
markers from the two scans.  
• 
The position of the fiducial markers or stent on the simulation CT is then compared 
with the position of the fiducial markers or stent seen in the CBCT scan.  Any 
adjustment to the position of the volume to be treated is made by the physician using 
software developed for this purpose. 
• 
If an adjustment is to be made, it is implemented by correcting the position of the 
treatment couch. 
• 
A second CBCT scan is taken to confirm patient is in the correct treatment position. 
Any additional shifts can be made as needed. 
• 
A 2D-KV orthogonal pair is obtained for confirmation of treatment position 
• 
The first fraction of SBRT is then delivered. 


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• 
A pCT is performed within 90 minutes of SBRT.  
• 
2 more fractions of SBRT are delivered. 
• 
A pCT is performed at 6 weeks post SBRT. 
• 
Research blood draw during SBRT and at 6 weeks follow-up. 
 
10.1 Research Samples 
A research biopsy will be performed prior to treatment to analyze tumor and 
stromal expression of biomarkers and correlate these with clinical outcomes.  The 
biopsy will be performed, if possible, at the time of the EUS-guided fiducial 
placement.  The research coordinator will bring the tissue in formalin directly to 
research histology.  Research histology will embed the biopsy to deliver the de-
identified sample to the Human Immune Monitoring Shared Resource for further 
analyses. Peripheral blood will be prior to SBRT treatment, during SBRT 
treatment, and 6 weeks following treatment according to the schedule outlined in 
section 11.  Two 8 ml EDTA blood tubes will be collected at each time point for 
experimental research that will be performed in the University of Colorado Denver 
School of Medicine Human Immune Monitoring Shared Resource.  Blood samples 
will be de-identified prior to transfer to the Human Immune Monitoring Shared 
Resource using study numbers that will be assigned to each blood sample in the 
order they are drawn.  A sample information form will be included with each 
sample describing the de-identified study number, the time the blood was drawn, 
and the time the blood was submitted.  All research samples will be labeled with 
de-identified study numbers.  The PI will maintain a secure record of patient and 
study ID’s.   
10.2 Specimen Analysis 
Peripheral blood mononuclear cells (PBMCs) will be isolated and flow cytometry will be 
used to quantify immune cell phenotypes, to measure tumor-specific T cell responses, and 
to measure cytokines present in plasma.  Biopsy samples from the primary pancreas tumor 
will be obtained by fine needle aspiration and if feasible, core needle biopsy by the 
gastroenterologists at the time of fiducial placement.  Specimen processing will be 
performed by the Tissue Banking Shared Resource and submitted for further analyses as 
described below by the Human Immune Monitoring Shared Resource. 
- 
Baseline and post-treatment immune monitoring. Participants will be asked to provide 
16 mls of blood prior to initiating treatment, during treatment, and after completion of 
treatment to evaluate changes in immune cell frequency and activation status by flow 
cytometry.  Approximately five million PBMCs will be used to determine the frequency of 
tumor-specific T cell responses by stimulating the cells with a mixture of peptides derived 
from known tumor antigens and measuring IFN-gamma production by ELISPOT. 


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Approximately five million PBMCs will be used to analyze the frequency of T cell 
populations and their activation status by flow cytometry.  Any remaining cells will be 
securely stored for up to five years. 
 
- 
Cytokine analysis. Up to 10 ml of plasma will be securely stored for five years following 
study completion for subsequent cytokine analysis.  Multiplex cytokine array will be used 
for subsequent cytokine analysis. Concentration of cytokines related to the function of 
MDSCs (GM-CSF, VEGF, MIP-1 alpha, MIP-1 beta, IL-10, IL-6, and IL-8) and T cells 
(IFN-gamma, TNF-alpha, IL-1-beta, IL-2, IL-4, IL-5, IL-12p70, IL-17) will be analyzed. 
- 
 
- 
Tissue analysis:  Immune cells with also be quantified and characterized in tumor biopsies 
using the Vectra 3 imaging system that enables immunohistochemical analysis of up to six 
immune markers (plus DAPI) in formalin-fixed paraffin-imbedded tissue samples on a 
single slide.  The powerful accompanying inForm software uses trainable algorithm-based 
tools to recognize and segment tissue morphology, phenotype and quantify infiltrating 
immune cells, score positive regions in the tissue, and provide mean fluorescence 
intensities and two-dimensional geometric locations for each cell in the tissue. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
Tests/Procedures 
Before SBRT 
During 
SBRT5 
Follow-up 
Within 
30 days  
Within 14 
days  
SBRT 
 
6 wks 
± 1 
wk  
 
10-12 
wks 
6 
mos±2 
wks 
9 
mos±2 
wks 
12 
mos±2 
wks 
18 and 
24 
months 
± 4 wks 
 
Placement of gold 
fiducial markers 
+ EUS-guided 
FNA or core 
biopsy 
X 
 
 
 
 
 
 
 
 
 
Review at 
Multidisciplilnary 
Conference 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X7 
 
 
 
X 
X 
X 
X 
X 
 
Physical Exam 
and ECOG6 
X 
 
 
 
X 
X 
X 
X 
X 
 
CBC, Metabolic 
panel, LFTs, Ca-
19-9, CEA 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Pregnancy test1 
 
X1 
 
 
 
 
 
 
 
 
Research Blood 
 
X 
X 
X 
 
 
 
 
 
 
CT (chest, abd & 
pelvis) 
X3 
 
 
 
X 
X 
X 
X 
X 
 
Simulation CT, 
4DCT4  
 
X 
 
 
 
 
 
 
 
 
Cone beam scan 
 
 
 
X 
 
 
 
 
 
 
 
Abdominal pCT 
 
X 
X2 
X 
 
 
 
 
 
 
3 fractions of 
SBRT delivered  
 
 
X 
 
 
 
 
 
 
 
Toxicity 
Assessments 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
EORTC QLQ-
C30, EORTC 
QLQ-PAN26 
 
X 
 
 
X 
X 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
1 For women of child bearing potential 
2 To be performed within 30-120 minutes following the first fraction of SBRT 
3 CT scans of the chest/abdomen/pelvis can be done prior to enrollment but must be within 30 days of initiating SBRT. 
4 For respiratory gating patients only 
5Set-up and treatment procedure repeated for each of 3 fractions 
6Physical exam includes HEENT, Pulmonary, Cardiovascular, GI/Abdomen, Extremities, Neurological, Skin and hair 
7 Including smoking history 


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12.0 TOXICITIES/SIDE EFFECTS 
12.1 Preparation for SBRT 
Toxicities may occur from the pancreas core biopsies and placement of the fiducial 
markers.  Potential adverse effects include cholangitis, pancreatitis, bleeding, and 
infection.   
All patients will get standard antibiotic prophylaxis at the time of biopsy. 
12.2 SBRT planning and treatment 
No side effects are expected to result from the CB imaging used for on-line target 
localization.  The additional patient dose from the two cone beam scans is approximately 
10 cGy, which represent less than 1% of the prescription dose.   
Toxicities will be assessed using the NCI Common Terminology Criteria for Adverse 
Events version 4.0 (CTCAE v 4.0).  Possible toxicities may occur from the single fraction 
high dose treatment include: 
12.2.1  Anticipated Toxicities of SBRT 
Likely:  
• stomach pain and intestinal discomfort 
• abdominal bloating and gas 
• nausea 
• diarrhea 
• fatigue 
• tanning 
• skin redness 
• hair loss within the radiation area - which is temporary 
• permanently dry skin in the radiation treatment area 
• loss of appetite and weight loss 
• mild muscle aches in the area treated 
Less Likely:  
• vomiting 
• low blood counts, which could lead to an increased risk of infection 
• weakness and/or bleeding and bruising easily 
Rare, but serious: 
• change in liver or kidney function, which is unlikely to cause symptoms 


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• bowel obstruction, which could result in abdominal pain, nausea and 
vomiting and may require surgery 
• gastric, duodenal or small-bowel ulcer formation that can result in 
abdominal pain, nausea and vomiting, and bleeding, and may require 
surgery 
The risk of significant toxicity would depend on the presence of normal tissue 
structures in close proximity to the target. These normal tissue doses will be 
constrained by the treatment plan to deliver doses no more than those listed in 
section 4.2 (Intervention: Radiation Treatment Planning).  
Patients will be assessed for late toxicities (>3 months post radiation) every 3 
months for the first year.  
13.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME 
ASSESSMENT 
13.1 
Primary objective:    
To identify the maximum tolerated dose (MTD) of stereotactic body radiotherapy (SBRT) 
in locally advanced pancreatic cancer (LAPC) patients who have not developed distant 
progression after induction chemotherapies per standard of care. 
The primary objective is to determine the MTD of SBRT after for patients with LAPC 
(induction FOLFIRINOX and nab-paclitaxel and gemcitabine per standard of care).  This 
will be accomplished by the standard 3+3 dose escalation design.  Dose limiting toxicities 
(DLT) are defined by ≥ Grade 3 treatment-related GI toxicity within 3 months of SBRT. 
These include: (1) Bowel (includes bowel perforation, obstruction, or hemorrhage) and (2) 
Stomach (bleeding ulcer, perforation) as determined by imaging or endoscopic evaluation. 
13.2  Secondary objectives: 
13.2.1  
To preliminarily assess the 2 year local control, progression free and 
overall survival rates for LAPC patients after induction chemotherapy and SBRT. 
Patterns of failure will also be investigated. 
Patients will be followed approximately every 3 months after SBRT. To assess 
recurrence, serum CA19-9 level will be obtained at each visit and CT or MRI imaging 
will be obtained every 3 months (± 2 weeks) until 12 months, and then every 6 months 
(± 4 weeks) for year 2.  
Local control (LC) will be measured from completion of SBRT to the time of 
identification of any local progression by imaging or surgical exploration. Overall 


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survival (OS) will be measured from completion of SBRT until death due to any cause. 
Progression free survival (PFS) will be measured from completion of SBRT to the time 
of tumor progression or death due to any cause. PFS and OS will be estimated using 
the method of Kaplan and Meier. The pattern of patients experiencing local, distant or 
local with distant failure will be estimated using competing risks method. First site of 
failure will be recorded.     
13.2.2.  
To identify early changes in the normal small intestine after SBRT for 
LAPC using pCT derived parameters to document changes in tissue perfusion kinetics 
and heterogeneity that predict for development of gastrointestinal toxicity such as 
duodenal ulcers, strictures, or enteritis. 
We will measure changes in the perfusion/permeability related parameters of 
peripancreatic small intestine before, during and after SBRT for LAPC using pCT and 
correlating these changes with the development of gastrointestinal toxicity such as 
duodenal ulcers, strictures, or enteritis.  Patients will undergo baseline, post-first-
fraction SBRT and post-treatment CT scans on the Siemens AS Open scanner in the 
Department of Radiation Oncology.  Perfusion/permeability parameters reflect the rate 
of exchange of I and include Ktrans (transfer rate of contrast agent between vascular 
space and extravascular and extracellular space (EES), ve and vp (volume fraction of 
EES and vascular space, respectively), F (blood flow at the capillary level), and τ 
(mean transit time across capillary)  [68, 74]. These derived parameters will be 
measured at baseline and re-measured for comparison on post-treatment scans. Patients 
will be followed approximately every 3 months after SBRT. Follow-up evaluations 
will include history and physical with assessment for presence of late toxicity using 
NCI CTCAE v 4.0. 
The region of interest (ROI) will be placed by an experienced radiologist on the entire 
tumor. Tumor margins will be evaluated by reviewing all prior imaging, including CT 
and possible conventional MR sequences (T1 and T2). For pancreas cancer, the actual 
tumor extent is unknown, especially after treatment, so the ROI placement will be 
inherently limited by interobserver variability, which can be studied on its own.  
Data will only be analyzed if seen on functional images. ROI’s will be placed on the 
entire tumor. Tumor heterogeneity will be addressed by measuring standard deviation 
and skewness of the derived metrics. The experienced radiologist will draw the ROI on 
the normal tissue. A physicist and radiologist will review the images being acquired 
together to ensure the same region ROIs are covered in pre and post treatment images. 
The results from the study will provide the minimum size deemed measurable for the 
derived metrics. 


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13.2.3  
To investigate vascular and cellular changes resulting from SBRT for LAPC 
using pCT derived parameters that can predict treatment response and to assess any 
correlation between these pCT derived parameters and local control and progression-
free survival. 
We will measure changes in diffusion and perfusion/permeability related parameters.  
Comparisons will be made between the pre- treatment, post-first-fraction SBRT and 
post-treatment pCT (Ktrans, ve and vp, F, and τ) derived parameters.  The baseline 
measurements as well as intra- and post-treatment changes in these parameters will be 
correlated to disease response of the primary tumor, as defined by RECIST 1.1 i.e. 
complete response (CR), partial response (PR), stable disease (SD) and progressive 
disease (PD). Ktrans is a reproducible biomarkers of response in cancers such as brain, 
prostate and breast tumors and has been comprehensively investigated. We expect 
similar results in this study. However, the other metrics derived from pCTare 
exploratory in nature.  
Progression free survival and local control for LAPC patients treated with 
FOLFIRINOX followed by SBRT will be determined as described in 12.2.1.  The 
clinical outcomes will be compared with finding on pCT.  Each MRI biomarker 
outcome will be studied for potential association with local control and progression-
free survival.  
We will use ROI analysis with mean parameter values to see which measure correlates 
better with disease response. We will analyze heterogeneity using voxel based analysis 
by measuring the standard deviation and skewness. 
13.2.4. 
To evaluate Quality of Life (QOL) in terms of global QOL, physical 
symptoms, physical functioning and emotional well-being after induction 
chemotherapy and SBRT. Testing will be 14 days prior to SBRT, 10-12 weeks after 
SBRT, and 6 months after SBRT. 
The primary objective of the QOL study is to document the patient’s experience of 
treatment for locally advanced pancreatic cancer by examining global QOL, physical 
symptoms, physical functioning and emotional well-being at baseline, during 
treatment, and after treatment. Subjects will be giving 2 questionnaires: (1) EORTC-
PAN26 and (2) EORTC-QLQ-C30. The two questionnaires have a total of 56 
questions, 54 out of which have answers on a scale of 1-4 and 2 questions have 
answers on a scale of 1-7. 
QOL measures including EORTC-QLQ-C30[80] and the Pancreatic Cancer subscale 
(EORTC-PAN26)[81]  will be assessed 14 days prior to SBRT (Time 0), 10-12 weeks 


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after SBRT (Time 1), and 6 months after SBRT (Time 2).  The primary QOL endpoints 
include the EORTC global QOL, physical symptoms, physical functioning and 
emotional well-being. 
14.0 CRITERIA FOR REMOVAL FROM STUDY 
• 
Development of an intercurrent medical condition or need for concomitant treatment 
that precludes further participation in the trial 
• 
Unacceptable toxicity or any adverse event that precludes further participation in the 
trial 
• 
Patient is not treated according to the prescription dose 
• 
The investigator removes the patient from the trial in the best interests of the patient 
• 
Patient death 
• 
Study completion or discontinuation 
• 
Patient withdraws consent to continued participation in the trial or is lost to follow-up 
 
15.0 BIOSTATISTICS 
15.1 
Dose Escalation Study and Clinical Outcomes Analysis 
The primary objective of this trial is to determine the maximum tolerated dose (MTD) of SBRT after 
at least 3 months of induction chemotherapy for patients with LAPC.  Dose limiting toxicities (DLT) 
are defined by ≥ Grade 3 treatment-related GI toxicity within 3 months of SBRT. These include: (1) 
Bowel (includes bowel perforation, obstruction, or hemorrhage) and (2) Stomach (bleeding ulcer, 
perforation).  We will employ a modified 3+3 dose-escalation scheme. 
Dose escalation will be evaluated after 3 evaluable patients who have completed 90 days of follow-
up.  Due to dropout during the 90-day follow-up period, up to 6 patients may be accrued at each 
dose level to yield a cohort of at least 3 evaluable patients. The dose level will be escalated if none 
of the evaluable patients followed for 90 days exhibits any DLT within 90 days of completion of 
SBRT. If a DLT is observed in one patient, an additional cohort of patients will be treated at that 
dose to achieve having at least 6 evaluable patients at that dose level. The dose will be escalated if 
none of the additional patients exhibits any DLT (i.e. at most 1 DLT is observed at that dose level). 
Dose-escalation stops and the previous dose will be considered the MTD if 2 or more patients have 
a DLT. If the previous dose level has been administered to fewer than 6 patients, an additional cohort 
of patients will be enrolled to achieve having at least 6 evaluable patients at that dose level.  If at 
most 1 DLT is observed among all evaluable patients treated at that dose level, that dose level will 
be declared to be the maximum tolerated dose (MTD).  If, however, there are a total of 2 or more 
DLTs, the dose will be de-escalated again.  The MTD will be the greatest dose at which at least 6 
evaluable patients are treated with at most 1 of them experiencing a DLT.   
If 3 patients have completed the 90 day follow-up without a DLT and there have been more patients 
accrued at that dose level, the dose may be escalated based on 0 DLTs among the first 3 evaluable 
patients.  However, if one of the additional patients treated at the lower dose subsequently 
experiences a DLT, the dose escalation will halt.  At that point accrual will continue at the lower 


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dose level to achieve a total of 6 evaluable patients who have completed the 90 day follow up at the 
lower dose; if at most 1 of all patients at that dose level experienced a DLT then dose escalation 
occur and accrual at the higher dose level will resume.  If 2 or more patients have a DLT at that 
level, the previous dose will be considered the MTD (as described above). 
 
 For this design, the probability of escalation is as follows: 
      True toxicity rate  
5% 
10% 
15% 
20% 
25% 
30% 
40% 
50% 
      Probability of escalation  0.97 
0.91 
0.81 
0.71 
0.60 
0.49 
0.31 
0.17 
Dose escalation will start with dose level 1 (9 Gy x 3 fractions) and increase by 1 Gy per 
fraction at each dose level, dose level 2 will be 10 Gy x 3 fractions and dose level 3 will be 
11 Gy x 3 fractions.  The maximum number of patients needed for this dose escalation 
design is 18.  A patient must be successfully treated according to prescription dose before 
he/she can be evaluated for the safety point, otherwise he/she will be replaced by a new 
patient.  We expect to finish the enrollment (up to 18 patients) within 3 years.  All toxicity 
profiles will be summarized and tabulated by dose level.  
For the first secondary objective, the 2 year local control (LC) rate, progression free-
survival (PFS), overall survival (OS) and patterns of failure for LAPC patients after 
induction chemotherapy and SBRT will be assessed using survival analysis tools such as 
Kaplan-Meier method or cumulative incidence curves if competing risks exist. To provide 
some simple comparison to the historical efficacy rates we will focus on OS due to its 
simplicity. The historical 2-year OS rate is approximately 20% and we expect to improve it 
to 40% by using the proposed treatment modality. Thus we expect that, out of the 22 
patients at MTD level, we shall have at least 8 patients surviving beyond 2 years. Under 
the null hypothesis of 20%, the probability of observing at least 8 patients surviving 
beyond 2 years (i.e., type I error rate) is 5.6%. Due to the small sample size and lack of 
power, we will not use “at least 8 patients (out of 22) surviving beyond 2 years” as a 
formal decision rule for declaring the success of this study. The anticipation of at least 8 
patients (out of 22) surviving beyond 2 years is merely to provide us a preliminary 
estimation of the efficacy signal relative to the historical control in this population. 
For the above efficacy secondary objective, patients at different dose levels will be 
examined separately. 
For the two secondary objectives involving pCT parameters (see Section 12 for details of 
how to obtain these parameters), all relative changes (i.e., percentage of change from the 
baseline, note that there will be two sets of changes, one based on the 90-minute CT and 
the other the 6-week CT) will be computed and correlated with the toxicity and response at 


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6 months post-SBRT by logistic regression. For correlation with OS, LC and PFS, survival 
analysis tools such as Cox model or Fine-Gray competing risks regression model will be 
used. For these two objectives all patients will be combined for statistical analyses. 
For the QOL objective, patients will be assessed at the following time points: within 14 
days prior to SBRT (Time 0); 10 to 12 weeks after SBRT (Time 1), and 6 months after 
SBRT (Time 2). Questionnaires will be administered in the clinic or by e-mail at all 
assessments. The quality of life assessment will include quality of life measures (EORTC 
QLQ-C30 Quality of Life Questionnaire) and the Pancreatic Cancer subscale (EORTC-
PAN26). See Section 12 for more details about the quantification of the answers. The time 
required to complete the assessment is 20 minutes. Analysis of the QOL outcomes will be 
descriptive. Summary statistics will be used to characterize the patient’s experience of 
treatment. Means, standard deviations, medians, and ranges of the QOL endpoints (scales 
and subscales) will be tabulated by dose level and by assessed time.  
For the last secondary objective, we will assess the feasibility of obtaining adequate 
cytology samples for next generation sequencing using sample proportion (the number of 
patients who yielded sufficient material for next generation sequencing at any three time 
points divided by the number of patients who went through the procedure) and its 
confidence intervals. All patients will be combined for this objective. 
16.0 RESEARCH PARTICIPANT REGISTRATION AND 
RANDOMIZATION PROCEDURES 
 
[Section Intentionally Omitted] 
 
17.0 DATA MANAGEMENT 
17.1 
Data and Safety Monitoring 
The sponsor investigator will be responsible for monitoring the trial per the trial 
monitoring plan, in addition to overseeing the safety and efficacy of the trial including any 
specimens collected, executing the data and safety monitoring (DSM) plan, and complying 
with all reporting requirements to local and federal authorities. This oversight will be 
accomplished through additional oversight from the Data and Safety Monitoring 
Committee (DSMC) at the University of Colorado Cancer Center (CU Cancer Center).  
The DSMC is responsible for ensuring data quality and study participant safety for all 
clinical studies at the CU Cancer Center, which is the coordinating institution of this trial.   
A summary of the DSMC’s activities is as follows: 
• Conduct of internal audits 


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• Ongoing review of all serious adverse events (SAEs), unanticipated problems 
(UAPs) and reportable adverse events (AEs) 
• Has the authority to close and/or suspend trials for safety or trial conduct issues 
• May submit recommendations for corrective actions to the CU Cancer Center’s 
Executive Committee 
 
Per the CU Cancer Center Institutional DSM Plan, SAEs, UAPs and reportable AEs are 
reported to the DSMC, IRB and the sponsor investigator per protocol.  All SAEs, UAPs 
and reportable AEs are to be reported to the DSMC within 5 business days of the sponsor 
investigator receiving notification of the occurrence. 
Each subject’s treatment outcomes will be discussed by the site PI and appropriate staff at 
regularly scheduled meetings.  Data regarding number of subjects, significant toxicities, 
dose modifications, and treatment responses will be discussed and documented in the 
meeting’s minutes. 
The sponsor investigator will provide a DSM report to the CU Cancer Center DSMC on a 
six month basis. The DSM report will include a protocol summary; current enrollment 
numbers; summary of toxicity data to include specific SAEs, UAPs and AEs; any dose 
modifications; all protocol deviations; and protocol amendments. The DSM report 
submitted to the DSMC will also include, if applicable, the results of any efficacy data 
analysis conducted.  Results and recommendations from the review of this six month 
report by the DSMC will then be provided to the sponsor investigator in a DSMC review 
letter.  The sponsor investigator is then responsible for ensuring this letter is submitted to 
the site’s IRB of record at the time of IRB continuing review.  The Colorado Multiple 
Institutional Review Board (COMIRB) will be the IRB of record for this study. 
17.2 
Quality Control and Quality Assurance 
Site monitoring visits will be performed by the sponsor investigator’s authorized 
representative on a regular basis, pursuant to the Monitoring Plan. During these visits, 
information recorded on the electronic case report forms (eCRFs) will be verified against 
source documents.  Additional computer programs that identify selected protocol 
deviations, out-of-range data, and other data errors within the electronic data entry may 
also be used to help monitor the study.  As necessary, requests for data clarification or 
correction will be sent to the appropriate site PI. 
Independent auditors from the sponsor investigator’s authorized representative will be 
allowed by the site’s PI to audit.  In addition, audits may be conducted at any time by 
appropriate regulatory authorities and/or the IRB. 
17.3 
Study Monitoring and Frequency of Monitoring Visits 


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The monitoring for this trial will be carried out in full compliance with all Good Clinical 
Practice (GCP) Guidelines, COMIRB policies and regulations and all applicable federal 
regulations.  This study will be monitored for its entire duration until the investigation is 
completed. 
A site initiation visit (SIV) will be conducted for all participating sites prior to enrolling 
any subjects into this trial to document full training of all study personnel who will be 
delegated any specific task on the study.  This visit includes but is not limited to training 
on the IRB approved study protocol, regulatory requirements for study conduct including 
but not limited to GCP guidelines, reporting of adverse events, the review of study 
personnel’s roles and responsibilities, completion of the Delegation of Authority Log and 
Protocol Training, review of the monitoring plan as outlined in the protocol, and to review 
data collection and proper source documentation procedures. 
The monitor will perform both on-site interim monitoring visits and remote monitoring 
off-site for all participating sites in this study.  Data that is collected during the duration of 
this trial will be reviewed by the sponsor to identify data discrepancies, inconsistencies or 
any unclear information both on-site and remotely.  In order to reconcile data 
discrepancies, queries will be sent electronically to the site(s) for data that requires 
clarification.   
This study is considered to be high risk and will need consistent routine monitoring visits.  
An initial monitoring visit will be performed within 2-4 weeks of the first subject being 
enrolled into the trial.  Subsequently, this study will then be monitored every 8-12 weeks 
on-site, with remote monitoring in-between scheduled on-site visits, as necessary based on 
the study needs, at all participating sites. 
The monitor will perform routine on-site monitoring visits that include but are not limited 
to: 
• 
Interface with the Principal Investigator at each visit, if possible, to discuss any 
findings, address concerns, and to update the PI and site staff on current study 
progress. 
• 
Subject source documentation verification   
• 
Verify subject eligibility 
• 
Informed Consent review 
• 
Verify radiation treatment 
• 
Protocol adherence 
• 
Review Case Report Forms and the electronic database 
• 
Regulatory documents review 


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Review and determine if all Adverse Events and Serious Adverse Events have been 
appropriately reported within the specified time periods required by the protocol, GCP, the 
IRB and any other applicable regulatory requirements 
After monitoring visits are completed, the monitor will evaluate and summarize the results 
after each monitoring visit in a written report.  This report will include all pertinent 
findings during the monitoring visit including all identifiable and reportable data and non-
compliant problems ongoing in the study and recommend resolutions for noted 
deficiencies.  Any noted deficiencies that are in need of resolution will need a corrective 
plan of action by the Investigator and/or research staff. 
The Investigator will receive a post interim monitoring visit follow-up letter 7 to 10 
business days following the completion of the monitoring visit, documenting study 
progress and any pertinent findings and outstanding action items that need to be resolved.  
The Investigator will need to sign and date the letter after reviewing, and keep the original 
on site.  The Monitor may review the letter at the next subsequent visit to ensure it has 
been reviewed, signed and dated by the Investigator in a timely manner. 
Upon completion or termination of the study, the sponsor will ensure that each 
participating site undergo a site Close-out Monitoring visit prior to final closure of the 
study.   The Monitor will assure that all necessary site close-out procedures and activities 
have been completed which include but are not limited to query resolution, Case Report 
Form completion, notification to local IRB and regulatory authorities of study closure, 
record retention arrangements finalized, AE and SAE resolution, and all essential 
documents are available and present in the Principal Investigator’s file.  The Monitor will 
complete a final close-out report documenting completion of the Close-out Monitoring 
visit and forward a study Close-out follow up letter to the Investigator(s) at the 
participating site(s) to be reviewed, signed and dated, and file a copy on site for record 
retention. 
18.0 PROTECTION OF HUMAN SUBJECTS 
Participation in this trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to IRB guidelines. 
Inclusion of Women and Minorities: We take due notice of the NIH policy concerning 
inclusion of women and minorities in clinical research populations. Patients of all races, 
both male and female, will be accepted into the protocol. The proposed study population is 
as described in section 7.0 (Recruitment Plan). 


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Exclusion of Children: Children have been excluded from this study. Pancreatic 
adenocarcinoma is an adult cancer.  
Exclusion of Lactating or Pregnant Women: Lactating and pregnant women are also 
excluded because of potential teratogenic effects of radiotherapy that may be harmful to 
the developing fetus or nursing infant. 
Benefits: It is possible that this treatment will result in shrinkage of pancreatic cancer or in 
a stabilization of an otherwise progressing disease. It is not known, of course, whether 
these or any other favorable events will occur. It is not known whether this treatment will 
affect the overall survival of the patients. 
Costs: The patient will be responsible for the costs of standard medical care, including, CT 
scans and SBRT.  Patients will not be responsible for the costs of the pCT following 
SBRT. 
Incentives: No incentives will be offered to patients/subjects for participation in the study. 
Alternatives: For patients with localized pancreatic cancer, alternative treatments may 
include other chemotherapy regimens as well as standard chemoradiation. Patients may be 
eligible for other investigational studies. 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research 
and hospital records are confidential. A limited data set will be shared with Memorial 
Sloan Kettering Cancer Center. A similar was conducted by Dr. Karyn Goodman at 
MSKCC and these data will be combined and analyzed for publication. Patient’s name or 
any other personally identifying information will not be used in reports or publications 
resulting from this study. 
18.1 
Privacy 
University of Colorado’s Institutional Review Board may allow the use and disclosure of 
protected health information pursuant to a completed and signed Informed Consent Form. 
The use and disclosure of protected health information will be limited to the individuals 
described in this form which must be approved by the IRB.  
18.2 
Procedures for Adverse Events – Definitions and Reporting Criteria 
 
18.2.1 Definitions 
 
The definition of “related” being that there is a reasonable possibility that the 
treatment caused the adverse event. 


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An adverse event is UNEXPECTED when the specificity or severity is not 
consistent with the current expectations of treatment complications. 
Adverse Event (AE)  
An AE will be defined as any untoward medical occurrence in a patient or clinical 
trial subject which does not necessarily have a causal relationship with the 
treatment. An AE can, therefore, be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure regardless of whether it 
is considered related to the medical treatment or procedure (attribution of unrelated, 
unlikely, possible, probable, or definite). Abnormal laboratory values or diagnostic 
test results constitute adverse events only if they induce clinical signs or symptoms 
or require treatment or further diagnostic testing. 
Serious Adverse Event (SAE)  
A serious adverse event is any untoward medical occurrence resulting in one or 
more of the following:  
• Results in death  
• Is life-threatening (defined as an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe)  
• Requires inpatient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability/incapacity  
• Is a congenital anomaly or birth defect  
• Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may jeopardize the 
patient or may require intervention (e.g., medical, surgical) to prevent one 
of the other serious outcomes listed in the definition above). Examples of 
such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions not resulting in hospitalization; or the development of drug 
dependency or drug abuse.  
 
18.2.2  Procedures for Recording and Reporting Adverse Events 
As noted above in section 17.1, per the CU Cancer Center Institutional DSM Plan, 
SAEs and AEs are reported to the DSMC, IRB. If the AE or SAE occurs at CU 


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Cancer Center, it will be reported to the PI who will then report it to the DSMC and 
IRB.  All AEs and SAEs are to be reported within 5 business days of receiving 
notification of the occurrence. The PI will also follow their IRB requirements 
regarding AE or SAE reporting. 
Any SAE must be reported to the COMIRB as soon as possible but no later than 5 
calendar days.  
 
19.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent 
form meets the requirements of the Code of Federal Regulations and the Institutional 
Review Board of this Center. The consent form will include the following:  
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions 
and to withdraw from participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific 
information and participants will sign an Informed Consent Form.  
Each participant and consenting professional will sign the consent form. The 
participant must receive a copy of the signed informed consent form. 
 
20.0 
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inhomogeneity. Magn Reson Med, 2006. 55(3): p. 566-74. 
68. 
Mazaheri, Y., et al., Motion correction of multi-b-value diffusion-weighted imaging 
in the liver. Acad Radiol, 2012. 19(12): p. 1573-80. 
69. 
Kristoffersen, A., Statistical assessment of non-Gaussian diffusion models. Magn 
Reson Med, 2011. 66(6): p. 1639-48. 
70. 
Kristoffersen, A., Optimal estimation of the diffusion coefficient from non-averaged 
and averaged noisy magnitude data. J Magn Reson, 2007. 187(2): p. 293-305. 
71. 
Constantinides, C.D., E. Atalar, and E.R. McVeigh, Signal-to-noise measurements 
in magnitude images from NMR phased arrays. Magn Reson Med, 1997. 38(5): p. 
852-7. 
72. 
El Naqa, I., et al., Exploring feature-based approaches in PET images for 
predicting cancer treatment outcomes. Pattern Recognit, 2009. 42(6): p. 1162-
1171. 
73. 
Ganeshan, B., et al., Tumor heteroneity in oesophageal cancer assessed by CT 
texture analysis: Prelimilary evidence of an association with tumor metabolism, 
stage and survival. Clinical Radiology, 2012. 67: p. 157-164. 
74. 
Klein, S., et al., elastix: a toolbox for intensity-based medical image registration. 
IEEE Trans Med Imaging, 2010. 29(1): p. 196-205. 
75. 
Parker, G.J., et al., Experimentally-derived functional form for a population-
averaged high-temporal-resolution arterial input function for dynamic contrast-
enhanced MRI. Magn Reson Med, 2006. 56(5): p. 993-1000. 
76. 
St Lawrence, K.S. and T.Y. Lee, An adiabatic approximation to the tissue 
homogeneity model for water exchange in the brain: I. Theoretical derivation. J 
Cereb Blood Flow Metab, 1998. 18(12): p. 1365-77. 
77. 
Rijpkema, M., et al., Method for quantitative mapping of dynamic MRI contrast 
agent uptake in human tumors. J Magn Reson Imaging, 2001. 14(4): p. 457-63. 
78. 
More JJ and S. DC, Computing a Trust Region Step. Siam J Sci Stat Comp, 1983. 
4(3 ): p. 553-572. 
79. 
Schwarz, G., Estimating the dimensions of a model. The Annals of Statistics, 1978. 
299(20): p. 461. 
80. 
Aaronson, N.K., et al., The European Organization for Research and Treatment of 
Cancer QLQ-C30: a quality-of-life instrument for use in international clinical 
trials in oncology. J Natl Cancer Inst, 1993. 85(5): p. 365-76. 


Protocol/COMIRB # 16-1139 
Version Date – 06 April 2020 
PI - Sana D. Karam, MD, PhD. 
 
Page 38 of 42 
81. 
Fitzsimmons, D., et al., Development of a disease specific quality of life (QoL) 
questionnaire module to supplement the EORTC core cancer QoL questionnaire, 
the QLQ-C30 in patients with pancreatic cancer. EORTC Study Group on Quality 
of Life. Eur J Cancer, 1999. 35(6): p. 939-41. 
 
21.0 APPENDICES 
Appendix 1. ECORTC QLQ-C30 (version 3) 
Appendix 2. EORTC QLQ – PAN26 
 
 


Protocol/COMIRB # 16-1139 
Version Date – 01October.2019 
PI - Sana D. Karam, MD, PhD. 
APPENDIX 1 
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Protocol/COMIRB # 16-1139 
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PI - Sana D. Karam, MD, PhD. 
APPENDIX 1 
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Protocol/COMIRB # 16-1139 
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PI - Sana Karam, MD, PhD. 
 
 
APPENDIX 2 
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Protocol/COMIRB # 16-1139 
Version Date – 01October.2019 
PI - Sana Karam, MD, PhD. 
 
 
APPENDIX 2 
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Consent and Authorization Form
COMIRB#16-1139
PI:  Sana D. Karam MD, PhD.
Version Date: 10.1.19
Page 1 of 11
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
Principal Investigator:
Sana D. Karam, MD, PhD.
COMIRB No:
16-1139
Protocol Version Date:
October 1, 2019
Study Title:
A Dose Escalation Trial of Stereotactic Body Radiotherapy 
(SBRT) after Induction Chemotherapy for Locally 
Advanced Pancreatic Cancer
You are being asked to be in a research study. This form provides you with information 
about the study. A member of the research team will describe this study to you and 
answer all of your questions. Please read the information below and ask questions about 
anything you don’t understand before deciding whether or not to take part.
Why is this study being done?
This study plans to learn more about the safety of stereotactic body radiotherapy (SBRT) 
given in 3 fractions (doses) and how well it works to treat your kind of cancer when used 
after standard chemotherapy.
You are being asked to be in this research study because you have advanced pancreatic 
cancer that has not spread to other areas of your body but cannot be removed with an 
operation.
Other people in this study
Up to 18 people from your area will participate in the study.
What happens if I join this study?
If you join the study, you will be asked to sign this consent form. You will be given a copy 
to keep and the original form will be kept at the clinic. You can withdraw from the study at 
any time and without giving a reason. This will not affect the standard medical care you 
receive. The goal of the study is to see what the highest dose can be for 3-fraction 
SBRT. Subjects with advanced cancers that have already had at least three months of 
standard chemotherapy will be asked to join the study.
Study Procedures
While you are taking part in this study, many of the tests and procedures that will be 
performed are standard of care for your disease. Some “research” procedures are 
performed just for this study and are identified below.
Physical Examination
A physical examination will be completed as part of your standard of care. We will 
also assess if the study drug is affecting your body functions including lungs, heart, 
COMIRB
APPROVED
For Use
20-Oct-2019
04-Sep-2020


Consent and Authorization Form
COMIRB#16-1139
PI:  Sana D. Karam MD, PhD.
Version Date: 10.1.19
Page 2 of 11
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
abdomen, extremities, skin, head (eyes, ears, noses, hair, etc.), and neurologically.

Vital Signs
We will take your blood pressure, heart rate, respiratory rate, body temperature and 
weight.  Height will be measured only during screening.

Concomitant Medications
Your study doctor will let you know which other medications you can and cannot 
take while taking part in this study. From the time you first receive the study drugs 
through 30 days after the last dose, we will record other medications you may be 
taking.

Blood
These tests are sometimes referred to as safety labs so the study doctor can be 
sure it is safe for you to take part in this study and to be given the study drugs. 
Serum pregnancy tests will be performed in women who are able to become 
pregnant. A positive pregnancy test prior to being given the study drugs, will 
exclude you from starting or continuing to take part in the study.

EUS and Fiducial Placement
Endoscopic ultrasound (EUS)-guided placement of 3-5 fiducial markers for SBRT 
targeting purposes. The fiducials will be placed directly into or adjacent to the tumor 
under CT guidance, EUS or under direct visualization during laparoscopy.
Description of Research Procedures

Perfusion CT (pCT) Scan. A computerized tomography scan (CT scan) is a series 
of detailed pictures of areas inside the body taken from different angles. A perfusion 
CT (pCT) will look at the effects on the blood flow to the tumor following the SBRT 
treatment

Questionnaires for quality of life. These questionnaires will ask about you, your 
health, and any symptoms or problems you may be having.

Biopsy
At the time of the EUS and Fiducial Placement Procedure, a fresh biopsy of your 
tumor tissue will be taken and kept for research.

Blood draw
We will be collecting approximately 2 tablespoons of blood for research purposes at 
the time of your normal blood work at 5 time points.


Consent and Authorization Form
COMIRB#16-1139
PI:  Sana D. Karam MD, PhD.
Version Date: 10.1.19
Page 3 of 11
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
Screening Study Procedures
Within 30 days prior to SBRT:

Placement of gold seed into the tumor to help guide the 
delivery of radiation therapy

Medical history

Physical exam and performance test

Blood tests

CT scan (chest, abdomen and pelvis)

Tumor biopsy – research procedure
Within 14 days prior to SBRT:

Pregnancy test for women of child-bearing potential

Simulation CT scan

Toxicity (side effects) assessment

Abdominal perfusion CT (pCT) scan – research procedure

Quality of Life Questionnaires – research procedure

Blood tests for Immune monitoring analysis – research 
procedure
During Treatment Procedures

Cone beam CT scan prior to each treatment with SBRT

SBRT – 3 treatments

Toxicity (side effects) assessment

Abdominal perfusion CT (pCT) scan – research procedure

Blood tests for Immune monitoring analysis - research 
procedure
Follow-up Procedures (after SBRT):
Week 6 (plus or minus 1 week):

Toxicity (side effects) assessment

Abdominal perfusion CT (pCT) scan – research procedure

Blood tests for Immune monitoring analysis – research 
procedure
Week 10-12:

Medical History

Physical exam and Performance Test

Blood tests


Consent and Authorization Form
COMIRB#16-1139
PI:  Sana D. Karam MD, PhD.
Version Date: 10.1.19
Page 4 of 11
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)

CT scan (chest, abdomen and pelvis)

Toxicity (side effects) assessment

Quality of Life Questionnaires – research procedure
6 Months (plus or minus 2 weeks):

Medical History

Physical exam and Performance Test

Blood tests

CT scan (chest, abdomen and pelvis)

Toxicity (side effects) assessment

Quality of Life Questionnaires – research procedure
9 Months and 12 Months (plus or minus 2 weeks):

Medical History

Physical exam and Performance Test

Blood tests

CT scan (chest, abdomen and pelvis)

Toxicity (side effects) assessment
Every 6 Months during Years 2-5 (plus or minus 4 weeks):

Medical History

Physical exam and Performance Test

Blood tests

CT scan (chest, abdomen and pelvis)

Toxicity (side effects) assessment
Annually (Year 5+)

In person or by phone call health check. We may also use 
publically available sources to obtain this information if we are 
unable to reach you.
How long will I be in this study?
We think that your active participation in the study will last about 5 years. After 5 years, 
we will continue to collect information on your health status.
What are the possible discomforts or risks?
Discomforts you may experience while in this study include:


Consent and Authorization Form
COMIRB#16-1139
PI:  Sana D. Karam MD, PhD.
Version Date: 10.1.19
Page 5 of 11
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
Anticipated Toxicities of SBRT
Likely:

stomach pain and intestinal discomfort

abdominal bloating and gas

nausea

diarrhea

fatigue

tanning

skin redness

hair loss within the radiation area - which is temporary

permanently dry skin in the radiation treatment area

loss of appetite and weight loss

mild muscle aches in the area treated
Less Likely:

vomiting

low blood counts, which could lead to an increased risk of infection

weakness and/or bleeding and bruising easily
Rare, but serious:

change in liver or kidney function, which is unlikely to cause symptoms

bowel obstruction, which could result in abdominal pain, nausea and 
vomiting and may require surgery

gastric, duodenal or small-bowel ulcer formation that can result in 
abdominal pain, nausea and vomiting, and bleeding, and may require 
surgery
The risk of significant toxicity would depend on the presence of normal tissue structures 
in close proximity to the cancer that will be treated.
Risks of Having Blood Taken:
In this study, depending on study visit, we will need to get about 8-26 tablespoons (4-13 
tubes) of blood from you over the course of the study. We will get blood by putting a 
needle into one of your veins and letting the blood flow into a vacuum tube. You may 
feel some pain when the needle goes into your vein. A day or two later, you may have a 
small bruise where the needle went under the skin.
Risk of CT Scan:
Other possible risks include as part of this study we will perform a CT scan of your 
chest. CT is a way of taking detailed pictures inside your body by using X-rays. X-rays 
are a type of radiation.


Consent and Authorization Form
COMIRB#16-1139
PI:  Sana D. Karam MD, PhD.
Version Date: 10.1.19
Page 6 of 11
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
You get some radiation from your environment.  You get radiation from bricks and 
concrete, from some foods, and from radon gas, which is an invisible gas that seeps out 
of the ground.  The amount of radiation that this CT scan will deliver to your body (give 
you) is about the same as you would get from living in your environment for 1 year.
Risks of EUS and Fiducial Placement:
In this study, you will be asked to provide one biopsy for research, which will happen at 
the same time as the EUS and Fiducial Placement. There is a small chance that you 
could get an infection where the needle goes in. You may also experience pain, 
redness, swelling, minor bleeding or bruising at the site where the cut was made or the 
needle inserted. You may experience mild to moderate pain at the site of the needle 
puncture. There is also a small chance that you could have an allergic reaction to the 
numbing medicine. After your skin heals up, you may have a small scar where we take 
the samples.
Risk of Biopsy:
There are some risks to having a biopsy at the time of your fiducial placement into the 
pancreas. There is a small chance that you could get an infection where the needle goes 
in. You may also experience pain, swelling, or minor bleeding at the site where the 
needle inserted. You may experience mild to moderate abdominal pain after the 
procedure
Risks of loss of confidentiality:
There is a risk that people outside of the research team will see your research 
information. We will do all that we can to protect your information, but it cannot be 
guaranteed.
Other possible risks include:
While you take part in this study, you will have tests and procedures that are standard of 
care for your disease. These include CT scans, MRIs, endoscopic ultrasound (EUS), 
and stereotactic body radiation therapy (SBRT). There are risks associated with these 
procedures. You should talk to your study doctor about any questions you may have 
about these risks.
The study may include risks that are unknown at this time.
What are the possible benefits of the study?
This study is designed for the researcher to learn more about the shrinkage of 
pancreatic tumors and the potential of stabilizing the progression the cancer.  However, 
there is no guarantee that your health will improve if you join this study. Also, there could 
be risks to being in this study. If there are risks, these are described in the section 
describing the discomforts or risks.


Consent and Authorization Form
COMIRB#16-1139
PI:  Sana D. Karam MD, PhD.
Version Date: 10.1.19
Page 7 of 11
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
Are there alternative treatments?
There may be other ways of treating your cancer. You have the following choices 
available to you:

Getting treatment or care for your cancer without being in a study

Taking part in another study

Get treatment only for your pain and symptoms, but no treatment for the cancer 
itself

Get no treatment at all
You should talk to your doctor about your choices. Make sure you understand all of your 
choices before you decide to take part in this study. You may leave this study and still 
have these other choices available to you.
Who is paying for this study?
This research is being sponsored by The University of Colorado Cancer Center.
Will I be paid for being in the study?
You will not be paid to be in the study.
Will I have to pay for anything?
It will not cost you anything to be in the study for research treatments. All standard of 
care costs will be billed to you or your insurance. Check with your insurance company 
for their coverage of participation in studies.
Is my participation voluntary?
Taking part in this study is voluntary. You have the right to choose not to take part in this 
study. If you choose to take part, you have the right to stop at any time. If you refuse or 
decide to withdraw later, you will not lose any benefits or rights to which you are entitled.
Can I be removed from this study?
The study doctor may decide to stop your participation without your permission if the 
study doctor thinks that being in the study may cause you harm, or for any other reason.
What happens if I am injured or hurt during the study?
If you have an injury while you are in this study, you should call Dr. Karam immediately. 
Her phone number is 720-848-0141.
We will arrange to get you medical care if you have an injury that is caused by this 
research.  However, you or your insurance company will have to pay for that care


Consent and Authorization Form
COMIRB#16-1139
PI:  Sana D. Karam MD, PhD.
Version Date: 10.1.19
Page 8 of 11
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
Who do I call if I have questions?
The researcher carrying out this study is Sana D. Karam, MD, PhD. You may ask any 
questions you have now. If you have questions, concerns, or complaints later, you may 
call Dr. Karam at 720-848-0141. You will be given a copy of this form to keep.
You may have questions about your rights as someone in this study. You can call Dr. 
Karam with questions. You can also call the responsible Institutional Review Board 
(COMIRB).  You can call them at 303-724-1055.
A description of this clinical trial will be available on http://www.Clinical Trials.gov. This 
Web site will not include information that can identify you. You can search this Web site at 
any time.
Who will see my research information?
The University of Colorado Denver (UCD) and its affiliated hospital(s) have rules to 
protect information about you. Federal and state laws including the Health Insurance 
Portability and Accountability Act (HIPAA) also protect your privacy. This part of the 
consent form tells you what information about you may be collected in this study and who 
might see or use it.
The institutions involved in this study include:

University of Colorado Denver

University of Colorado Hospital
We cannot do this study without your permission to see, use and give out your 
information. You do not have to give us this permission.  If you do not, then you may not 
join this study.
We will see, use and disclose your information only as described in this form and in our 
Notice of Privacy Practices; however, people outside the UCD and its affiliate hospitals 
may not be covered by this obligation.
We will do everything we can to maintain the confidentiality of your personal information 
but confidentiality cannot be guaranteed.
The use and disclosure of your information has no time limit. You can cancel your 
permission to use and disclose your information at any time by writing to the study’s 
Principal Investigator (PI), at the name and address listed below. If you do cancel your 
permission to use and disclose your information, your part in this study will end and no 
further information about you will be collected. Your cancellation would not affect 
information already collected in this study.


Consent and Authorization Form
COMIRB#16-1139
PI:  Sana D. Karam MD, PhD.
Version Date: 10.1.19
Page 9 of 11
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
Sana D. Karam, MD, PhD. 
University of Colorado Denver
Department of Radiation Oncology 
Anschutz Cancer Pavilion Campus 
Mail-Stop: F-706
1665 Aurora Court
Aurora, CO 80045
Both the research records that identify you and the consent form signed by you may be 
looked at by others who have a legal right to see that information, such as:

Federal offices such as the Food and Drug Administration (FDA) and the Office 
of Human Research Protections (OHRP) that protect research subjects like you.

People at the Colorado Multiple Institutional Review Board (COMIRB)

The study doctor and the rest of the study team.

The University of Colorado Cancer Center, who is the institution paying for this 
research study.

Officials at the institution where the research is conducted and officials at other 
institutions involved in this study who are in charge of making sure that we follow 
all of the rules for research
We might talk about this research study at meetings. We might also print the results of 
this research study in relevant journals. But we will always keep the names of the 
research subjects, like you, private.
You have the right to request access to your personal health information from the 
Investigator.
The investigator (or staff acting on behalf of the investigator) will use your 
information for the research outlined in this consent form. They will also make all or 
some of the following health information about you collected in this study available 
to: Memorial Sloan Kettering Cancer Center, which we are sharing a limited data set.
Information about you that will be seen collected, used and disclosed in this study:

Name and Demographic Information (age, sex, ethnicity, address, phone 
number, etc.

Your social security number

Portions of your previous and current Medical Records that are relevant to this 
study, including but not limited to Diagnosis(es), History and Physical, laboratory 
or tissue studies, radiology studies, procedure results


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