Evaluation of a Novel Absorbable Radiopaque Hydrogel in Patients Undergoing Image-guided Radiotherapy for Pancreatic Adenocarcinoma
Phase: NA
Conditions: Pancreatic Adenocarcinoma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Date: 3/13/18   
Principal Investigator: Amol Narang, M.D. 
Application Number: IRB00151816 
 
 
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NCT03307564    
 
 
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1. 
Abstract 
a. Provide no more than a one page research abstract briefly stating the problem, the 
research hypothesis, and the importance of the research. 
 
Title: Evaluation of a novel absorbable radiopaque hydrogel in patients undergoing image-
guided radiotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma 
 
Pancreatic ductal adenocarcinoma is now the third leading cause of cancer-related death, with a 
devastating 5-year overall survival (OS) rate of nearly 8%, despite having the 12th most 
common incidence of all malignancies in the United States [1]. One-third of patients will 
present with borderline resectable or unresectable, locally advanced pancreatic cancer 
(BR/LAPC) [2-5]. In the cases of LAPC, chemotherapy with or without radiation may be 
recommended to improve the quality of life by relieving symptoms and extending survival [6-
11]. Despite aggressive combined modality therapy, the median survival remains between 9 and 
15 months [12,13]. 
 
Current guidelines for the management of BR/LAPC patients include single- or multi-agent 
chemotherapy or chemoradiation (CRT) in sequence with chemotherapy [14]. Results of studies 
comparing chemotherapy alone to CRT for patients with BR/LAPC are mixed [6,9,12,15].  The 
importance of local control or delaying local progression on improving morbidity and possibly 
mortality in patients with pancreatic cancer is supported by autopsy data demonstrating that 
30% of patients die of locally destructive disease [16]. It follows that in the cases of LAPC, 
advanced radiation therapy techniques using dose-escalation with intensity modulated 
radiotherapy (IMRT) and stereotactic body radiotherapy (SBRT) are potential strategies to 
improve local control.  
 
A consistent challenge to dose-escalation with IMRT or SBRT is the sensitivity of the 
surrounding gastrointestinal organs, particularly the small bowel which is directly adjacent to 
the head of the pancreas (HOP). For BR/LAPC patients treated with CRT, advances in image 
guidance have provided the opportunity to safely deliver higher biologically effective doses of 
radiation therapy using IMRT of >70 Gy (57.25 Gy in 25 fractions, BED 70.36 Gy) compared 

Date: 3/13/18   
Principal Investigator: Amol Narang, M.D. 
Application Number: IRB00151816 
 
 
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to standard fractionation regimens (50.40 Gy in 28 fractions or 50 Gy in 25 fractions, BED 
59.47 Gy and 60 Gy, respectively) [17].  Those patients who underwent dose-escalated CRT 
with BED>70 Gy, did have a superior OS compared to those receiving BED<70 Gy, supporting 
the utility of dose-escalation in improving long-term outcomes. SBRT involves a short course of 
radiation therapy, five fractions or less, and has demonstrated higher rates of local control 
compared to CRT in other disease sites [18]. Early studies evaluating SBRT for pancreatic 
cancer utilized single fractions of 25 Gy, resulting in local control rates of 100% at 1 year but 
unacceptably high rates of gastrointestinal toxicity [19-22]. More recently, hypofractionated 
SBRT (33 Gy total, 6.6 Gy daily fractions) has been evaluated and utilized by our group in an 
effort to reduce the toxicity of therapy, with results demonstrating nearly 80% rate of freedom 
from local progression at one year and an acceptable 11% long-term gastrointestinal toxicity 
[23]. Outcomes with SBRT are thus promising; however, higher local control rates with dose-
escalation may be achievable, but current practice is limited due to risks of toxicity. 
 
The goal of this pilot study is to evaluate the success of an endoscopic ultrasound (EUS) guided 
injection of TraceIT to mark the interface between the pancreas and duodenum in patients with 
a pathologically confirmed diagnosis of BR/LAPC pancreatic adenocarcinoma for whom a 
course of SBRT is indicated. TraceIT is already an FDA approved absorbable tissue marker, 
however, it has not yet been injected into the region between the pancreas and duodenum in 
humans. As this is the first in-human experience to attempt to use the hydrogel tissue marker to 
localize this important boundary, a clinical trial is warranted to investigate the success of this 
procedure.  This study will thus set the stage for a planned future investigation using the 
TraceIT Tissue Marker as an organ spacing material (AGX-17-001-US) by injecting a larger 
volume of the hydrogel to displace the duodenum away from the pancreas to reduce risk of 
duodenum toxicity give the increased distance between the target and the duodenum and with 
the use of imaging localization..  
 
 
2. 
Objectives (include all primary and secondary objectives) 
 
Primary Objective:  
To evaluate the success of marking the interface between the pancreas and duodenum with 
TraceIT Tissue Marker via EUS in patients undergoing image-guided radiotherapy for BR/LAPC 
pancreatic adenocarcinoma. 
 
Secondary Objectives:  
 
1) To assess the visibility of TraceIT on daily cone beam CT acquired as standard of care 
for image-guided radiation therapy. 
 
 
2) To examine the hydrogel injection sites for implant location and presence of local 
inflammatory reactions as a result of TraceIT placement in patients who proceed to 
surgical resection.   
 

Date: 3/13/18   
Principal Investigator: Amol Narang, M.D. 
Application Number: IRB00151816 
 
 
3 
 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with 
procedures, drug or device, and any other relevant information to justify the research) 
 
Pre-clinical: Our preclinical study on human cadavers was done in September 2016.  Using three 
human cadaveric specimens, TraceIT Tissue Marker was injected between the HOP and 
duodenum via open laparotomy in one case and endoscopic-ultrasound (EUS) guidance in two 
cases. Cadavers were subsequently imaged using CT and dissected for histologic confirmation of 
hydrogel placement. Compared to pre-injection scans, post-injection axial CT demonstrated 
successful injection of the radiopaque hydrogel as a contrast-enhancing region between the HOP 
and duodenum. After injection, a pancreatic surgeon dissected each cadaveric specimen by 
performing an en-bloc resection of the pancreas and the duodenum, preserving the injection site 
for histologic examination. The tissue was serially sectioned to grossly visualize the injection 
cavity and sections were then formalin-fixed, paraffin embedded (FFPE) and stained with 
hematoxylin and eosin (H&E) for microscopic examination of gel placement. Microscopic 
examination of the FFPE sections following H&E staining revealed a complete separation of the 
full duodenal mucosa from the pancreatic tissue in most regions without injection into the 
muscularis propia (Rao et al., IJROBP, 2017).  
 
We have also conducted two distinct preclinical studies on swine animals. The first study 
assessed for toxicities of direct injection of TraceIT into the pancreas or wall of the duodenum. 
These studies did not reveal any incidence of pancreatitis or evidence of necrosis of the 
duodenum by these injections simulating “worse-case” mis-injections of TraceIT when targeting 
this interface between the HOP and duodenum. In a second porcine study, we were able to 
demonstrate successful placement of TraceIT via EUS in 6 of the 8 swines. Subsequent imaging 
on diagnostic CT and cone beam CT (CBCT) demonstrated adequate visibility of the injected 
TraceIT highlighting the potential utility of TraceIT injection to facilitate visualizing this HOP-
duodenum interface on daily image guidance with CBCT.  
 
Clinical: TraceIT Tissue Marker has several publications for marking purposes demonstrating its 
stability in the esophagus [24], bladder [25], and cervix [26]. Given the unique enzymatic and 
mobile environment in the peripancreatic region, distinct investigation of the injection in the 
pancreas-duodenum space is necessary.  
 
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
This is a prospective, single institution, single arm pilot study to evaluate the feasibility of 
injecting TraceIT Tissue Marker to mark the interface between the pancreas and duodenum. Six 
patients with pathologically confirmed BR/LAPC pancreatic adenocarcinoma for whom a course 
of SBRT is indicated will be enrolled. 
 

Date: 3/13/18   
Principal Investigator: Amol Narang, M.D. 
Application Number: IRB00151816 
 
 
4 
 
Enrolled subjects will be scheduled for TraceIT placement at the time of standard of care fiducial 
placement using an endoscopic transduodenal approach with material delivered using an EUS-
fine needle in accordance with the manufacturer’s instructions. Prophylactic antibiotics will be 
administered prior to fiducial placement in accordance with institutional practices. At the same 
time that the fiducials are being placed, TraceIT will also be placed by loading the hydrogel into 
a syringe and injecting it in the space between the pancreas and the duodenum using a similar 
needle and procedure as is done during the placement of the fiducial. TraceIT injections will be 
limited to 0.3 mL to 1.0 mL of material per injection site. The fiducial placement and antibiotics 
administration are as part of the standard of care. The TraceIT placement is a part of the 
research. There will be no additional radiation exposure to the patient to place TraceIT. 
 
Standard of care CT planning simulation scans will be performed within 10 days post TraceIT 
hydrogel placement.  These scans will be used to generate the RT treatment plan following Johns 
Hopkins standard of care to deliver up to 33 Gy in 5 fractions using SBRT within 28 days 
following TraceIT placement.  
 
The procedure will be determined successful if injected TraceIT is identified between the region 
of the pancreatic tumor and the duodenum on axial cross-sectional planning CT scan.   
 
Per standard of care, subjects will receive SBRT treatments (up to 33 Gy in 5 fractions) with 
image-guidance using cone beam CT technology for alignment and will be monitored for 
radiation toxicity. There will be no additional radiation exposure to the patient to evaluate 
TraceIT. Following completion of SBRT, patients will proceed with routine standard of care 
follow-up.  
 
If a patient on study undergoes successful surgical resection, the hydrogel injection sites between 
pancreas and duodenum will be examined for implant location and to identify any local 
inflammatory reactions.   
 
b. Study duration and number of study visits required of research participants. 
 
The TraceIT injection will be performed during the endoscopic fiducial placement which is the 
standard of care. Therefore, there will be no additional study visits needed by patients 
participating in this study. 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
There is no blinding on this trial. 
 
d. Justification of why participants will not receive routine care or will have current 
therapy stopped. 
 
Patients will receive the standard of care treatment and will not have routine therapy stopped. 
 
e. Justification for inclusion of a placebo or non-treatment group. 

Date: 3/13/18   
Principal Investigator: Amol Narang, M.D. 
Application Number: IRB00151816 
 
 
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There is no placebo group in this trial. 
 
f. Definition of treatment failure or participant removal criteria. 
 
Patients will not be enrolled if the routine standard-of-care procedure of fiducial placement 
cannot be performed. 
 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
Patients will continue to receive the standard-of-care for their radiation therapy treatment. 
 
 
1. 
Inclusion/Exclusion Criteria 
 
Inclusion criteria: 
Subjects must meet all of the following criteria to be eligible for participation in the study: 
 
1. Age ≥18 years old 
2. BR/LAPC disease as defined by the NCCN guidelines (Figure 1) as follows confirmed 
via CT, EUS or other imaging modality (e.g., PET): 
 
Figure 1: NCCN guidelines version 2.2017 for pancreatic adenocarcinoma  
 
 
 
 
3. SBRT for local therapy of BL/LAPC is indicated and patient has confirmed intent to 
undergo SBRT at Johns Hopkins.  
4. Subjects Screening/Baseline laboratory testing must meet the following laboratory value 
criteria: 
a. White blood cell count: ≥ 3.0 x 109/L 

Date: 3/13/18   
Principal Investigator: Amol Narang, M.D. 
Application Number: IRB00151816 
 
 
6 
 
b. Absolute neutrophil count (ANC): ≥ 1.5 x 109/L  
c. Platelets: ≥ 100 x 109/L 
d. Total bilirubin: ≤ 2.0 times upper limit of normal (ULN) 
e. AST and ALT: ≤ 3.0 times institutional upper normal limit 
f. estimated GFR >50 
g. INR: < 1.5 
Hemoglobin: ≥ 8.0 g/dl 
5. Zubrod Performance Status 0-2 
6. Subject or authorized representative, has been informed of the nature of the study and has 
provided written informed consent, approved by the appropriate Institutional Review 
Board (IRB) of the respective clinical site. 
 
Exclusion criteria: 
Subjects who meet any of the following criteria are not eligible for participation in the study: 
 
1. Previous thoracic radiotherapy 
2. Any GI abnormality that would interfere with the ability to access the injection site 
3. Duodenal invasion detected on endoscopic ultrasound which would exclude candidacy 
for SBRT 
4. Active gastroduodenal ulcer or watery diarrhea 
5. Active bleeding disorder or a clinically significant coagulopathy defined as a PTT>35s or 
INR>1.4 or platelet count less than 100,000 per mm3. 
6. Active inflammatory or infectious process involving the gastrointestinal tract based on 
positive diagnosis or suspected diagnosis in the presence of fever>38°C or 
WBC>12,000/uL. 
7. Compromised immune system: WBC<4000/uL or >12,000/uL. 
8. History of Chronic Renal Failure. 
9. Documented history of uncontrolled diabetes (i.e., symptomatic hyperglycemia that 
cannot be medically managed, fasting blood glucose level above 300 mg/dL, and/or 
frequent swings between hyperglycemia and hypoglycemia) 
10. Currently enrolled in another investigational drug or device trial that clinically interferes 
with this study. 
11. Unable to comply with the study requirements or follow-up schedule. 
12. Any condition or comorbidity that the Investigator believes would interfere with the 
intent of the study or would make participation not in the best interest of the subject. 
13. Women of child bearing potential or sexually active fertile men with partners 
who are women of child bearing potential who are unwilling or unable to use 
an acceptable method to avoid pregnancy for the entire study 
 
2. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
TraceIT Tissue Marker consists of an absorbable polyethylene glycol (PEG) hydrogel 
with covalently bound iodine (~1%). TraceIT Tissue Marker is indicated for use to 
radiographically mark soft tissue during a surgical procedure or for future surgical 

Date: 3/13/18   
Principal Investigator: Amol Narang, M.D. 
Application Number: IRB00151816 
 
 
7 
 
procedures. TraceIT hydrogel is intended to mark tissue for at least 3 months after 
injection. TraceIT Tissue Marker is FDA approved for marking anywhere in the body, 
including the interface between duodenum and pancreas however this has not yet been 
attempted in clinical practice. 
 
b. Justification and safety information if FDA approved drugs will be administered for 
non-FDA approved indications or if doses or routes of administration or participant 
populations are changed. 
 
N/a 
 
c. Justification and safety information if non-FDA approved drugs without an IND will 
be administered.  
 
N/a 
 
3. 
Study Statistics 
a. Primary outcome variable:  
The success of injecting TraceIT using EUS for guidance will be assessed on post-
injection simulation CT scan and determined as successful if TraceIT hydrogel is 
visible between the pancreatic tumor and duodenum on axial CT. 
 
b. Secondary outcome variables: 
1) Visibility of TraceIT on daily cone beam CT acquired as standard of care for 
image-guided radiation therapy, defined as no visibility, poor visibility, or 
acceptable visibility by radiation oncologist. 
2) For patients proceeding to surgical resection, the pathologic specimen will be 
analyzed grossly and on histopathologic specimen sections for TraceIT 
placement location and inflammation surrounding placement site.  
 
c. Statistical plan including sample size justification and interim data analysis. 
 
 
No formal hypothesis or sample size estimation has been established since this is an early 
feasibility study with an intent to collect information concerning the procedural 
characteristics and safety for TraceIT administration within the peri-duodenal space. Six 
(6) subjects should provide sufficient experience to assess the success of the procedure to 
result in injecting of the hydrogel marker in the desired location.  
 
No interim data analysis is planned 
 
d. Early stopping rules. 
 

Date: 3/13/18   
Principal Investigator: Amol Narang, M.D. 
Application Number: IRB00151816 
 
 
8 
 
If TraceIT placement is unsuccessful as defined by the primary variable outcome in all of 
the first 3 patients, then the study will be terminated early as this would be an indication 
that revisions to the procedure would be necessary to facilitate success of the procedure.   
 
4. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected 
frequency. 
b. Steps taken to minimize the risks. 
c. Plan for reporting unanticipated problems or study deviations. 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
e. Financial risks to the participants. 
 
a. Medical risks associated with the study procedures can be divided into those associated with 
the EUS procedure for fiducial/TraceIT hydrogel administration and potential risks 
associated with the hydrogel. 
 
 
Potential Risk Associated with the EUS Procedure and Fiducial Placement 
(STANDARD OF CARE) 
 
 
Likely 
 N/A 
Less Likely 
 Minor bleeding 
 Pain 
 Melena (blood in the stool) 
Unlikely 
 Fever/Infection 
 Major bleeding due to damage to blood vessels 
 Nerve damage 
 Inflammation of the pancreas 
 Temporary issues with breathing or infection to the lung as a 
result of improper swallowing 
 Side-effects or complications related to anesthesia (temporary 
low blood pressure and worsening of pre-existing heart or lung 
problems) 
 Improper placement or migration of the fiducial implant 
 Foreign body reaction to fiducial 
Rare but serious 
 Difficulty breathing or death due to anesthesia 
 Unintentional perforation of organs not intentionally involved 
in the procedure 
 Spread of the cancer to nearby tissues as a result of spillage 
caused by the procedure 
 Infection of the blood or other organs 
 Death 

Date: 3/13/18   
Principal Investigator: Amol Narang, M.D. 
Application Number: IRB00151816 
 
 
9 
 
 
 
Potential Risk Associated with the TraceIT Hydrogel Material (RESEARCH) 
There may be side effects and discomforts that are not yet known. 
 
b. Steps taken to minimize the risks: 
 
The risks associated with EUS procedures and fiducial marker/TraceIT administration will be 
minimized via selection of experienced investigators who are skilled in EUS/transduodenal 
fiducial placement procedures.  Additionally, participating gastroenterologist has prior 
experience with placement of the TraceIT hydrogel in human cadavers. Subjects will be selected 
and enrolled using clearly defined inclusion and exclusion criteria to ensure the best possible 
treatment outcome.  Additionally, subjects will receive full and careful follow-up.  
 
The TraceIT hydrogel, is FDA cleared for use as a Tissue Marker and is specifically indicated 
for use to radiographically mark soft tissue during a surgical procedure or for future surgical 
procedures.  The risks associated with the TraceIT hydrogel have been minimized by formulating 
the hydrogel with constituents that have a long history of safe use in implantable medical 
devices.  The study sponsor conducted Biocompatibility testing in compliance with FDA’s Good 
Laboratory Practices regulation and in accordance with ISO 10993 – Biological Evaluation of 
Medical Devices.  Tests were selected and performed according to the type of device, intended 
use, and degree and duration of tissue contact.  The response to TraceIT hydrogel was evaluated 
in healthy tissues including subcutaneous and intramuscular implant locations.  All 
biocompatibility testing results are consistent with a biocompatible material. 
 
Preclinical studies were also done to evaluate the response to TraceIT hydrogel when placed in 
the pancreatic parenchyma and duodenal wall.  No adverse histologic change or safety concerns 
were noted.   
Likely 
 N/A 
Less Likely 
 Minor bleeding 
 Pain 
Unlikely 
 Infection of the blood or other organs Clogging nearby blood 
vessels by the hydrogel material 
 Inflammation of the pancreas or surrounding organs causing 
pain or discomfort 
 Dislodgement of the TraceIT resulting in tracking to another 
site 
 Improper placement of TraceIT into neighboring structures 
(e.g., duodenal wall) 
 Foreign body reaction to TraceIT 
 Delay in starting radiation therapy or surgery 
Rare but serious 
 Potential to worsen local progression of the cancer due to 
undiagnosed/microscopic invasion into the duodenum 

Date: 3/13/18   
Principal Investigator: Amol Narang, M.D. 
Application Number: IRB00151816 
 
 
10 
 
 
Appropriate therapeutic intervention following standard medical practices will be used in the event of 
medical complications.  
 
c. Plan for reporting unanticipated problems or study deviations: 
 
The principal investigator will notify the appropriate regulatory agencies of any serious 
adverse event due to any cause during the course of this investigation. These include the 
Johns Hopkins Cancer Center Data and Safety Monitoring Committee, and the Johns 
Hopkins Medical Institutional Review Board (JHM-IRB) of The Johns Hopkins Medical 
Institutions. The required reporting time period is 3 days for fatal events, and 10 days for all 
other events. 
 
 
d. Legal risks such as the risks that would be associated with breach of confidentiality:  
 
While data will be stored data in securely locked files (computer files will be password 
protected and any paper records will be stored in the research office at Johns Hopkins under 
lock and key) in which only the research team has access, there is always the risk that 
confidentiality will be lost. 
 
e. Financial risks to the participants: None 
 
5. 
Benefits 
a. 
Description of the probable benefits for the participant and for society:  
 
The tissue interface between pancreas and duodenum can be potentially marked using this 
radiopaque hydrogel. There is no benefit to the patient from participation in the study.  Potential 
benefits to society include those to future patients undergoing SBRT treatments, who may 
receive improved treatment as a direct result of the research performed in this study. If this 
procedure is determined to be feasible in this study, future investigations will be planned to use 
the hydrogel to increase the distance between the pancreas and duodenum in the region of the 
pancreatic tumor to serve as a physical spacer so that the duodenum can be displaced away from 
the higher dose region. 
 
6. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, proposed 
bonus, and any proposed reductions or penalties for not completing the protocol:  
 
There will be no compensation for participants. 
 
7. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them: 
Augmenix will provide the device (TraceIT Tissue Marker) and a separate FNA needle 
for injecting TraceIT. 

Date: 3/13/18   
Principal Investigator: Amol Narang, M.D. 
Application Number: IRB00151816 
 
 
11 
 
 
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Application Number: IRB00151816 
 
 
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