Evaluation of TraceIT Tissue Marker to Mark the Primary Resection Bed Margins of Oropharyngeal Cancers: a Pilot Study
Phase: NA
Conditions: Oropharyngeal Cancer
Sponsor: Washington University School of Medicine

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Evaluation of TraceIT® Tissue Marker to mark the primary resection bed margins of 
oropharyngeal cancers: a pilot study  
 
Washington University School of Medicine 
Department of Otolaryngology – Head & Neck Surgery 
660 South Euclid Avenue, Campus Box 8115 
St. Louis, MO  63110 
 
Protocol#: 201810117 
  Version Date: 01/02/2019 
 
Principal Investigator:     
Ryan S. Jackson, MD 
Washington University School of Medicine  
E-mail:  jackson.ryan@wustl.edu  
 
 
Sub-Investigators 
 
 
 
Modality 
Wade Thorstad, M.D.  
 
 
Radiation Oncology 
Hiram Gay, M.D. 
 
 
 
Radiation Oncology 
Mackenzie Daly, M.D. 
 
 
Radiation Oncology 
Jason Rich, M.D. 
 
 
 
Otolaryngology 
Sara Kukuljan, R.N.  
 
 
Otolaryngology 
Dorina Kallogjeri, M.D., MPH 
 
Otolaryngology 
 
 
ClinicalTrials.gov #: 
 
NCT03713021 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 
 

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Evaluation of TraceIT® Tissue Marker to mark the primary resection bed margins of 
oropharyngeal cancers: a pilot study 
 
Protocol Revision History 
 
Version Date 
Revision Summary 
08/15/18 
Initial Approval Version 
06/03/19 
Revise inclusion criteria to allow for 
confirmed or highly suspicious 
oropharyngeal cancer; clarify distant 
metastatic disease as exclusionary 
07/02/2019 
Revise the exclusion criteria to remove "5. A 
history of allergic reactions attributed to 
compounds of similar chemical or biologic 
composition to TraceIT or other agents used in 
the study."  According to the package insert 
there is no contraindication for this criteria. 
01/03/2020 
 
 
 
 

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TABLE OF CONTENTS 
 
1.0 
BACKGROUND AND SIGNIFICANCE ........................................................................... 4 
1.1 
Head and Neck Cancer ..................................................................................................... 4 
1.2 
Radiation Therapy and Surgery in the Treatment of Oropharyngeal Cancer .................. 4 
1.3 
Towards Individualized Treatment of Oropharyngeal Cancer ......................................... 5 
1.4 
TraceIt Hydrogel Preclinical Studies ............................................................................... 6 
1.5 
Dose Limits to Head and Neck Subsites .......................................................................... 7 
2.0 
OBJECTIVES ...................................................................................................................... 9 
2.1 
Primary Objective ............................................................................................................ 9 
2.2 
Secondary Objectives ....................................................................................................... 9 
3.0 
ELIGIBILITY CRITERIA................................................................................................... 9 
3.1 
Inclusion Criteria .............................................................................................................. 9 
3.2 
Exclusion Criteria ............................................................................................................. 9 
3.3 
Inclusion of Women and Minorities............................................................................... 10 
4.0 
REGISTRATION PROCEDURES ................................................................................... 10 
4.1 
Confirmation of Patient Eligibility ................................................................................. 10 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 10 
4.3 
Assignment of UPN ....................................................................................................... 10 
5.0 
STUDY DESIGN............................................................................................................... 10 
5.1 
Evaluability .................................................................................................................... 11 
5.2 
Duration of Participation ................................................................................................ 12 
5.3 
Duration of Follow-up .................................................................................................... 12 
6.0 
PHARMACEUTICAL INFORMATION .......................................................................... 12 
6.1 
TraceIT ........................................................................................................................... 12 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 13 
7.1 
Definitions ...................................................................................................................... 14 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
15 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 16 
7.4 
Timeframe for Reporting Required Events .................................................................... 16 
8.0 
STUDY CALENDAR ....................................................................................................... 17 
9.0 
DATA SUBMISSION SCHEDULE ................................................................................. 17 
10.0 DATA AND SAFETY MONITORING ............................................................................ 17 
11.0 STATISTICAL CONSIDERATIONS............................................................................... 18 
12.0 REFERENCES .................................................................................................................. 19 
 
 

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1.0 
BACKGROUND AND SIGNIFICANCE 
 
1.1 
Head and Neck Cancer 
 
The pattern of spread of head and neck cancer for each anatomical subsite has been 
understood for many decades.  Pioneering surgeons and radiation oncologists treating head 
and neck cancer used this knowledge to design appropriate surgical procedures and 
radiation fields to treat this disease.  However, until the 1960s most patients were treated 
with either surgery or radiation initially, and then the other therapy for an attempt at salvage 
when they recurred.  Resecting all of the potential sites of tumor spread was too morbid, 
and while radiation could reach all potential sites of spread, tumors often failed at the 
central bulky part of the tumor.  Head and neck cancer patients benefited significantly when 
physicians started treating them with surgery followed by radiation therapy as a combined 
treatment.  This sequence of treatment was confirmed in an early landmark RTOG clinical 
trial of preoperative radiation versus postoperative radiation versus radiation therapy alone.  
Postoperative radiation therapy proved to be most successful and has been a standard of 
care for head and neck cancer patients since that time. Unfortunately, the toxicity related 
to surgical therapy for oropharyngeal cancer was significant in that it often required a 
mandibulotomy approach and a mandatory free tissue transfer reconstruction and 
tracheotomy and long-term feeding tube requirements. With the increasing incidence of 
oropharyngeal cancer secondary to Human Papillomavirus (HPV), outcomes have 
significantly improved and have led to investigations aimed at decreasing toxicity while 
maintaining oncologic outcomes.1-3 
 
1.2 
Radiation Therapy and Surgery in the Treatment of Oropharyngeal Cancer 
 
Since the publication of the RTOG trial in 1972, much advancement have been made in 
surgical and radiation therapy technique.4-6  Surgery for oropharyngeal cancer has moved 
from morbid open procedures to transoral endoscopic laser surgery (TLM) and/or transoral 
robotic surgery (TORS).7,8  TLM and TORS can be accomplished entirely transorally 
without the need for morbid approaches such as splitting the lip and mandible.9 Therefore, 
it is rare today to perform reconstruction or tracheotomy in these patients and most patients 
receive oral nutrition immediately after the surgery or within a couple of weeks. In the era 
of HPV related oropharyngeal cancers, de-escalating therapy continues to be investigated. 
Radiation therapy has moved from treating the left and right sides of the head and neck 
with full dose to intensity modulated radiation therapy (IMRT) and proton beam radiation, 
both of which allow for reducing the dose of normal tissue treated.  Reducing dose of 
normal tissue treated has been shown to reduce treatment-related toxicity and improve 
quality of life from both the physician’s, and more importantly, the patient’s perspective.  
At the advent of IMRT, there was concern that tighter radiation fields would spare not only 
normal tissue but also tumor cells and be less effective than 2D technology.  Fortunately, 
patterns of failure data with IMRT have proven that not to be the case as shown in our prior 
publications.10,11   
 
The change from 2D technology to IMRT required radiation oncologists to understand 
head and neck anatomy in 3 dimensions.  To aid radiation oncologists in this transition, 

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several important international standards have been developed to aid in delineation of the 
potential patterns of tumor and lymphatic spread, as well as guidelines for contouring of 
normal tissues in the head and neck.  These guidelines are by necessity population based.  
A member of the radiation oncology community will be assured of reasonable coverage of 
all potential patterns of tumor spread using these guidelines.  It is understood that each 
individual patient’s tumor may extend to only a fraction of the potential pattern of spread 
for a group of patients.  It has not been possible to improve this situation because 
knowledge of individual patient’s microscopic pattern of spread is elusive.  Limiting 
radiation therapy to that required for each patient’s individual tumor would represent a 
significant advance in treatment. 
 
1.3 
Towards Individualized Treatment of Oropharyngeal Cancer 
 
Imaging technology has significantly advanced over the last several decades.  CT, MRI, 
and CT/PET technology has been developed and each successive generation of technology 
results in improved resolution and accuracy of images.  However, no imaging technology 
can define the microscopic extent of malignancy.  PET imaging is complicated in the head 
and neck because the structures of the oropharynx (tonsils, base of tongue, and soft palate) 
all exhibit varying degrees of metabolic activity at baseline.  Differentiating between tumor 
uptake and “normal” uptake is often not possible, especially with regards to the edge of 
even macroscopic disease. 
 
TLM/TORS in conjunction with pathological sampling of resection margins during surgery 
is the only method by which microscopic margins of tumor resection can be defined.  In 
addition, multiple investigations have shown that the distance of the cancer to the surgical 
resection margin is not necessarily a prognostic factor, as long as the surgical margin is 
clear of tumor cells.12,13 This more binary approach to margin analysis implies that 
oropharyngeal cancers treated with transoral surgery are largely limited to the tumor bed 
within the resection margins. If the permanent sections are consistent with the frozen 
section margins, a complete resection of the tumor has been achieved with a 
microscopically clear margin.  Radiation therapy to a small additional margin would be 
expected to eradicate any additional tumor cells that may yet exist with a tumor exhibiting 
perineural invasion, or an infiltrating tumor with separate nests of tumor cells.  A number 
of retrospective studies have shown that with TLM/TORS and postoperative radiation 
using population based standardized radiation fields described above, tumor control is 
achieved in 95-100% of patients.14  Reducing radiation volume to match the needs of an 
individual patient has not yet been possible because it has not been possible to define the 
exact position of negative surgical margins for the radiation oncologist.  Even with detailed 
operative notes combined with pre- and post-operative imaging, the microscopic edge of 
the resected tumor is not clear.   
 
Marking the edges of negative surgical margins during the TLM/TORS oropharyngectomy 
would be of immense benefit. These minimally invasive surgical procedures are an ideal 
setting as the surgical margins are mapped out intraoperatively using frozen section 
pathology and are more easily visible with the aid of operating microscopes and high 
definition 3- dimensional camera systems available. One group has a series of publications 

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describing the use of surgical clips for marking the margins of the oral cavity resection to 
reduce radiation therapy to their reconstruction of the defect.15-18 In the oropharynx, we 
routinely use titanium clips to ligate intermediate to large vessels. Therefore, they would 
not be useful as a fiducial marker for that reason as well as they have a propensity to extrude 
over time. TraceIT Hydrogel is an injectable hydrogel that is visible with CT, CBCT, 
CT/PET, US, and MRI images.  The hydrogel particles are visible through 3 months after 
which they liquefy and are cleared.  TraceIT injection during TLM/TORS may be an ideal 
solution for transmitting the exact location of negative tumor margins to the radiation 
oncologist, allowing a customized treatment volume for each individual head and neck 
cancer patient.   
 
1.4 
TraceIt Hydrogel Preclinical Studies 
 
TraceIT Tissue Marker has 510K clearance (Approval) from the FDA. It was shown that 
TraceIT is substantially equivalent to a product that is already on the market in its intended 
use and principle of operation. Both in vivo and in vitro (bench, cadaver, and animal) testing 
were performed to verify and validate the safety and effectiveness profile of TraceIT. It 
has been approved in both the US and Europe. Investigations using TraceIT have been 
performed to use as a spacer between normal tissue and tissue undergoing radiation in the 
pancreas,19 submandibular gland,20 rectum and bladder,21 and as a fiducial marker for 
gynecologic malignancies.22 No adverse events related to the product in these 
investigations would prohibit its use in the proposed investigation. 
 
In order to determine the feasibility of injecting TraceIT hydrogel during TORS surgery, 
identifying the marker with CT simulation images, and contouring individual target 
volumes, we performed a study using cadaver heads.  The heads were imaged 
preoperatively and had a TORS procedure during which 0.2 – 0.3 ml TraceIT were injected 
at the superior, inferior, medial, lateral, and deep margins of resection, respectively.  More 
volume than that did not stay in the tissue but began to extrude through the needle insertion 
site. A total of 4 cadaver heads were used; two had base of tongue resections and two had 
tonsil resections.  Postoperative imaging was performed and the CT information was 
transmitted to an Eclipse (Varian Corp) treatment planning workstation.  The markers were 
clearly visible on the CT images.  Standard population-based tumor treatment volume and 
lymphatic treatment volumes were contoured, as well as an individual marker-based tumor 
treatment volume.  Standard and individualized treatment plans were developed.  
Depending on the resection location, DVH curves for the individualized plans were 
significantly improved relative to the standard plans (see table on following page). In 
keeping with the sigmoidal shape of the normal tissue complication probability (NTCP) 
curves, the esophageal and pharyngeal constrictor doses dropped below the range where 
one would expect permanent swallowing problems and/or esophageal strictures in the 
individualized plan relative to the standard plan.  Oral cavity and lip dose were significantly 
improved as well, and one would expect less acute morbidity and less permanent 
xerostomia due to damage to the tiny salivary gland tissue which carpets the oral cavity.  
Parotid and submandibular gland tissue dose was decreased as well, with results differing 
with respect to location of resection.  Depending on the size and extent of tumor, these 
results should be typical for patients with cancer in the oropharynx.  The preliminary 

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preclinical data are compelling and warrant further study in patients with oropharyngeal 
carcinoma. 
 
1.5 
Dose Limits to Head and Neck Subsites 
 
Reduction in radiation dose and volume is important to maintain function of normal 
structures while still adequately treating the oropharyngeal cancer.23,24 The percent 
reduction, though, is only significant if it reduces toxicity to these structures. For instance, 
toxicity rates at a given dose has been well studied and is well documented in the 
Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) guidelines.25 
For example, patients have approximately a 20% risk of symptomatic dysphagia and 
aspiration if the mean dose to the pharyngeal constrictors is 50 Gy. In our pre-clinical 
cadaveric study, the standard treatment plans delivered doses 55 Gy to the ipsilateral and 
contralateral pharyngeal constrictor muscles while the marker-based treatment plan was 
only 42 and 39 Gy, respectively. This reduction would be clinically significant for reducing 
toxicity related to swallowing dysfunction, which is incredibly important in patients 
receiving surgery and radiation for oropharyngeal cancer. In addition, dose and volume 
reduction may have more implications than just limiting toxicity. For example, if 
surrounding tissue has less overall radiation exposure, this could allow future re-irradiation 
of overlapping sites in the instance of treatment failure in patients that currently may not 
tolerate re-irradiation. 
 

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Cadaver A 
Markers 
Cadaver A 
Standard 
% 
Difference 
Cadever B 
Markers 
Cadaver B 
Standard 
% 
Difference 
Cadaver C 
Markers 
Cadaver C 
Standard 
% 
Difference 
Cadaver D 
Markers 
Cadaver D 
Standard 
% 
Difference 
cGy 
cGy 
cGy 
cGy 
cGy 
cGy 
cGy 
cGy 
Brain 
372 
438 
-15 
158 
383 
-59 
219 
257 
-15 
1521 
1805 
-16 
Brainstem 
662 
865 
-23 
646 
1682 
-62 
1835 
2038 
-10 
1809 
2072 
-13 
Spinal cord + 5 
2663 
2672 
0 
2642 
2411 
10 
2836 
3051 
-07 
2433 
2755 
-12 
Mandible 
2715 
3413 
-20 
3176 
3469 
-08 
2347 
3080 
-24 
2114 
2819 
-25 
Oral Cavity 
3439 
4458 
-23 
3517 
3949 
-11 
2596 
4013 
-35 
2408 
3712 
-35 
Lips 
1532 
1988 
-23 
1500 
1396 
7 
1237 
1715 
-28 
871 
1199 
-27 
ParynCont R 
3921 
5538 
-29 
5094 
5638 
-10 
3025 
4665 
-35 
3128 
3513 
-11 
PharynContL 
4205 
5499 
-24 
5617 
6002 
-6 
5550 
6032 
-8 
5507 
5959 
-8 
Esophagus 
Upper 
4635 
6077 
-24 
4668 
5961 
-22 
3742 
4439 
-16 
3799 
4060 
-6 
Parotid L 
2628 
2670 
-2 
2834 
3155 
-10 
4319 
4589 
-6 
4689 
5001 
-6 
Parotid R 
1894 
1935 
-2 
4396 
4505 
-2 
656 
807 
-19 
871 
920 
-5 
Submandib L 
5591 
5660 
-1 
5951 
5919 
1 
5154 
5752 
-10 
- 
- 
- 
Submandib R 
3806 
4252 
-10 
4499 
4513 
0 
1301 
1465 
-11 
- 
- 
- 
Supraglottic 
Larynx 
- 
- 
- 
3635 
5380 
-32 
- 
- 
- 
- 
- 
- 
Arytenoid L 
- 
- 
- 
1479 
4001 
-63 
- 
- 
- 
- 
- 
- 
Arytenoid R 
- 
- 
- 
1733 
3122 
-44 
- 
- 
- 
- 
- 
- 
Glottis 
- 
- 
- 
835 
3378 
-75 
- 
- 
- 
- 
- 
- 
Total Sum 
38063 
45465 
-16 
52380 
64864 
-19 
34817 
41903 
-17 
29150 
33815 
-14 
Total Mean 
2927.92 
3497.31 
-16 
3081.18 
3815.53 
-19 
2678.23 
3223.31 
-17 
2650 
3074.09 
-14 
 
 
 
 

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2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To evaluate the reduction in clinical target volumes (CTV) for the primary resection bed 
between the standard of care treatment plan and the treatment plan based on the TraceIT 
hydrogel markers. 
 
2.2 
Secondary Objectives 
 
 
1. To describe the anatomic localization relative to standard treatment fields based on 
anatomy. 
 
 
3.0 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
 
1. Pathologically confirmed (by routine H&E staining) or highly suspicious for  
oropharyngeal squamous cell cancer. 
 
2. Planned treatment includes transoral surgery followed by adjuvant IMRT. 
 
3. At least 18 years of age. 
 
4. Ability to understand and willingness to sign an IRB approved written informed 
consent document. 
 
3.2 
Exclusion Criteria 
 
1. Distant metastatic disease at the time of definitive treatment, and thus study, initiation. 
 
2. History of major head & neck surgery or previous head & neck irradiation. 
 
3. History of or current oral disease that may interfere with interpretation of study 
outcomes. 
 
4. Currently enrolled in another radiation therapy trial that has not completed its primary 
endpoint or that clinically interferes with this study. 
 
 
5. Poor surgical candidate. 
 
7.   Prisoners. 

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3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
STUDY DESIGN  
 
Study participants will be recruited from the head and neck oncology clinic at Washington 
University/Barnes Jewish Hospital. Patients will be offered participation if they are being offered 
a minimally invasive transoral surgery as part of their standard treatment for their head and neck 
malignancy. These are patients that would be recommended transoral surgery despite this 
investigation and this investigation will have no influence on treatment recommendations. 
 

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Consenting and eligible patients will be scheduled for standard of care surgical resection of the 
primary tumor.  Following successful tumor resection, TraceIT Tissue Marker will be applied in 
0.2 to 0.5 mL injections at 5 locations to mark the tumor bed: superiorly, inferiorly, laterally, 
medially, and center of resection.  The marginal injections will be within 3 mm of the resection 
edge and within 5 mm deep.  The center of the resection bed will be injected within 5 mm deep if 
possible (i.e., no critical structure in this region).  Patients will be monitored for adverse events  
following injection of the TraceIT Tissue Marker intraoperativelyby the operating 
surgeon/principle investigator. 
 
Within 6 weeks after surgery, a CT simulation scan will be performed per normal protocol for 
patients receiving surgery followed by adjuvant therapy.  This scan will be used to generate the 
IMRT treatment plan.  Participants will begin IMRT per standard of care following surgery in 
most instances, recognizing that some patients may be delayed due to wound healing, infection, 
etc. These delays will not have impact on this investigation as our end-point is the CT simulation 
scans and treatment planning, not the actual start date of therapy.    
 
Two treatment plans per patient will be performed using the simulation CT scan. One will be the 
standard of care treatment plan and will be the basis of the actual radiation treatment they receive. 
The second treatment plan (research purposes only) will be based on utilizing the TraceIT hydrogel 
markers as a guide for the resection bed. These two treatment plans will then be used to generate 
clinical target volumes and a comparison per patient will be performed between standard target 
volumes and marker-based target volumes. This will be used to generate radiation dose to regions 
of interest for simulation purposes only.  The study does not interfere with the clinical care 
treatment plan. Regions of interest will include the brain, brainstem, oral cavity, lips, pharyngeal 
constrictor muscles, upper esophagus, parotid glands, submandibular glands and laryngeal 
structures.  
 
The treatment planning studies performed in each participant will be performed using an identical 
technique and similar setup, with the test group using the TraceIT hydrogel markers as a guide for 
the resection bed.  Target volume definitions and critical structure contouring will be performed 
using the same methods for treatment planning for any given participant.  The radiotherapy 
prescription will be standardized to the use of image-guided IMRT consisting of the high risk 
planned target volume, and the low risk or elective PTV. The marker-based treatment plans will 
be used as a theoretical treatment to compare to the standard treatment plan. The standard treatment 
plan will be used for the patients actual radiation treatment, thus no deviation from standard of 
care treatment will be prescribed. The international standard plan volumes for tonsil, base of 
tongue, and soft palate will be contoured, as well as by a volume determined from the markers. 
 
5.1 
Evaluability 
 
All patients are evaluable for the primary endpoint (evaluate the volume reduction in 
drawing CTV for the primary resection bed) provided they have had the TraceIT injections 
and undergone the post-op treatment planning study. 
 
Patients who receive the TraceIT injections are evaluable for toxicity related to the tracer 
even if they don’t receive IMRT.  Patients are evaluated during the intraoperative period 

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only for TraceIT-related Adverse Events. 
 
5.2 
Duration of Participation 
 
Participation includes the injection of the TraceIt fiducial marker and the RT simulation 
planning post-surgery. The patient will be withdrawn from the study if: 
 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue participation for any reason will be followed as 
indicated in the study calendar. 
 
5.3 
Duration of Follow-up 
 
Patients will return for standard of care follow-up visits approximately 14 days after 
completion of their surgical procedure and injection of the TraceIT fiducial markers. They 
will then follow up with their radiation oncologist for a treatment planning session for 
which their standard of care treatment plan and their marker-based treatment plans will be 
completed. This will occur approximately 6 weeks after surgery. They will continue to be 
treated and followed as per standard of care, but no further follow-up will be necessary for 
the purposes of this investigation. 
 
 
6.0 
PHARMACEUTICAL INFORMATION 
 
6.1 
TraceIT 
 
6.1.1 TraceIT Description 
 
TraceIT Tissue Marker is a sterile, single use product consisting of a pre-filled glass 
syringe containing the synthetic, radiopaque cross-linked PEG hydrogel with an 
endcap. The pre-filled glass syringe, sterile plastic luer-luer connector, plastic 
receiving syringe, and a 1” needle are packaged inside a poly-Tyvek pouch within 
a larger poly-Tyvek pouch. As some hydrogel/carrier separation can potentially 
occur during storage, two syringes are provided to allow for mixing (by injecting 
back and forth 5 times between the syringes so the material ends up inside the 
plastic receiving syringe) immediately prior to use. TraceIT Tissue Marker is 
provided in a 1mL and 3mL configuration. 
  
The maximum injection volume of TraceIT hydrogel, for a single location, is 1mL. 
TraceIT hydrogel is visible on ultrasound, computed tomography (CT), and 
Magnetic Resonance Imaging (MRI) for approximately three (3) months and is 
absorbed and cleared from the body within approximately seven (7) months of 
implantation. TraceIT hydrogel implant is MR Safe. The 304-stainless steel 

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applicator needle is MR Unsafe; all other TraceIT Tissue Marker delivery 
components are MR Safe. 
 
TraceIT Tissue Marker is indicated for use to radiographically mark soft tissue 
during a surgical procedure or for future surgical procedures. TraceIT hydrogel is 
intended to mark tissue for at least 3 months after injection.  
 
TraceIT Tissue Marker has been cleared by the FDA for the indication stated above. 
TraceIT Tissue Marker has completed all testing required for an implantable 
medical device.   
 
6.1.2 Supplier 
 
Augmenix (201 Burlington Rd, Bedford, MA 01730 p: 781-902-1624) 
 
6.1.3 Dosage Form and Preparation 
 
It is provided in a 1 mL and 3 mL configuration. 
 
6.1.4 Storage and Stability 
 
TraceIT Tissue Marker should be stored at room temperature, 15° C – 25° C (60° 
F – 77° F). 
 
6.1.5 Administration 
 
See TraceIT Tissue Marker Instructions for Use 
 
6.1.6 Side Effects 
 
Potential side effects from the administration of TraceIT: 
1. 
Injection site pain 
2. 
Vascular occlusion 
3. 
Local inflammatory response 
4. 
Embolic phenomena 
5. 
Bleeding 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below.  Events that are temporally related to the TraceIT injection (beginning at time of 
injection through the intraoperative period) will be evaluated for regulatory reportability as per the 
criteria in this section. 
 

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The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined 
in Section 7.2. 
 
7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for 
all toxicity reporting.  A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health 
and Human Services’ Office for Human Research Protections (OHRP).  A copy of 
this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
 
7.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
7.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 

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not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
7.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) 
the characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
7.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
7.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
7.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 

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• Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
• Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
7.4 
Timeframe for Reporting Required Events  
 
Events that are temporally related to the TraceIT injection (beginning at time of injection 
through the intraoperative period only )  will be monitored. For the purposes of this 
protocol, adverse events related to surgical complications will not be collected and 
documented on CRFs.  
 
 
 

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8.0 
STUDY CALENDAR 
 
 
Screening 
Surgery 
6 wks post-op 
Informed consent 
X 
 
 
H&P 
X 
 
 
Tumor staging 
X 
 
 
Resection 
 
X 
 
TraceIT hydrogel 
placement 
 
X 
 
IMRT treatment 
planning session 
 
 
X 
AE assessment 
 
X 
 
 
 
9.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Surgery Form 
Time of surgery 
Treatment Planning Form 
Time of IMRT treatment planning 
AE Form 
Time of surgery 
 
 
10.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 

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• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date 
• Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have met 
the early stopping rules 
• Summary of toxicities 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
Our pilot data from 4 cadavers show effect sizes ranging from 0.57 and 1.68 for the reduction in 
radiation dose/volume to critical structures. With this, using the lowest effect size of 0.57, a one 
sided alpha error of 0.05 and 80% power, we will need 21 subjects to detect this effect size. 
 
Standard descriptive statistics will be used to describe study population as well as volume and 
planned treatment dosimetry using the standard approach and based on the margins defined by 
fiducial marker. Variables will include patient age and gender, tumor pathologic diagnosis and 
tumor characteristics such as anatomic subsite, stage, and size. Paired samples t-test or its 
nonparametric equivalent Wilcoxon signed rank test will be used to compare the tumor volume 
and planned dose of treatment under each approach. Histograms and Shapiro-Wilks test will be 
used to explore normal distribution of the data. Stratified analysis will be performed to compare 
treatment plans between the 2 approaches for each main cancer site. Secondary endpoints, such as 
adverse events, will be described as frequency and percentage of patients experiencing an adverse 
event.  
 
 

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