Clinical trial NCT03294330
Conditions: Sentinel Lymph Node Melanoma (Skin) Breast Cancer
Sponsor: Milton S. Hershey Medical Center
Start date: 2017-10-11; Completion date: 2021-11-02
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this study is to determine if fluorescence lymphangiography can be used alone to localize sentinel nodes in patients with melanoma or breast cancer. The hypothesis is that sentinel nodes can be identified using only indocyanine green (ICG) and fluorescence lymphangiography, without the need for technetium99 and a gamma probe.

Detailed description:
From the subject's viewpoint, the course of events in this study will be no different than usual care and sentinel node biopsy. Subjects will have a dermal injection of technetium99 (tech99) at the melanoma tumor site prior to surgery (either the day before, or morning of surgery) or a subareolar injection if breast cancer. The surgeon will not look at the lymphoscintigraphy films, and the radiologist should not mark the skin. When the subject is in the operating room and appropriately sedated or anesthetized, tthey will receive a dermal injection of indocyanine green (ICG) 0.3-1.0 ml at the melanoma tumor site or subareola if breast cancer. Incision is made in the axilla or groin, and the SPY machine is positioned over the lymph node basin. Real-time lymphangiography (SPY) is used to identify sentinel nodes. Any fluorescent nodes should be resected and are considered sentinel nodes. The absolute fluorescence will be quantified for each sentinel node. Absolute fluorescence is calculated by the SPY machine.

After the sentinel lymphadenectomy is complete but prior to closing skin, the excised lymph nodes will be examined with the gamma probe (detects tech99 signal) to confirm that they are sentinel nodes. If the node does not have a signal with the gamma probe (but is fluorescent) it is still considered a sentinel node. The lymph node basin will also be examined with the gamma probe, to insure that no sentinel nodes are missed. If a gamma positive sentinel node is identified in the lymph node basin, it should be resected and imaged with SPY. If no sentinel nodes are able to be identified with fluorescent imaging, the gamma probe will be used as per usual practice. The surgeon should spend no more than 30 minutes using SPY to identify sentinel nodes. If after 30 minutes no sentinel node is found, the gamma probe should be used. The data collection form should be completed for each case.

The investigators intend to enroll at least 48 subjects. In order to insure that the data collected accurately represents the effectiveness of the SPY machine, each surgeon will be required to enroll at least 8 subjects into the study. Sentinel node biopsy is a routine surgical procedure, and all involved PIs are experienced in performing sentinel node biopsy. While fluorescence imaging intra-op is novel, the actual procedure itself is no different.

Arms: arm 1: The SPY machine used in conjunction with the IC-green kit will be used exclusively to identify sentinel nodes in patients diagnosed with Melanoma or Breast Cancer who are undergoing sentinel lymph node biopsy.
Interventions: intervention 1: IC-Green KIT
Intervention descriptions: intervention 1: fluorescence lymphangiography with the use of IC-Green

Protocol documents:
Prot_SAP_001.pdf: 
Page 1 of 19 (V.08/27/2018) 
 
 
 
HRP-592 - Protocol for Human Subject  
Research with Use of Test Article(s) 
 
Protocol Title: 
SPY-X: A Study to Assess the Feasibility of Using Real-time Fluorescence Lymphangiography Alone for Sentinel 
Node Localization in Patients with Melanoma or Breast Cancer 
 
Principal Investigator: 
Name: Colette Pameijer  
Department: Surgery 
Telephone: 531-5272 
E-mail Address: cpameijer@pennstatehealth.psu.edu 
 
 
Version Date: 
5.27.2021 
 
 
Clinicaltrials.gov Registration #: 
NCT03294330. 
 
Important Instructions for Using This Protocol Template: 
1. 
Add this completed protocol template to your study in CATS IRB (http://irb.psu.edu) on the “Basic Information” 
page, item 7.  
2. 
This template is provided to help investigators prepare a protocol that includes the necessary information needed 
by the IRB to determine whether a study meets all applicable criteria for approval.  
3. 
Type your protocol responses below the gray instructional boxes of guidance language.  If the section or item is 
not applicable, indicate not applicable. 
4. 
For research being conducted at Penn State Hershey or by Penn State Hershey researchers only, delete the 
instructional boxes from the final version of the protocol prior to upload to CATS IRB (http://irb.psu.edu).  For all 
other research, do not delete the instructional boxes from the final version of the protocol. 
5. 
When making revisions to this protocol as requested by the IRB, please follow the instructions outlined in the Study 
Submission Guide available in the Help Center in CATS IRB (http://irb.psu.edu) for using track changes.  
 
If you need help… 
University Park and other campuses: 
Office for Research Protections Human Research Protection Program 
The 330 Building, Suite 205 
University Park, PA 16802-7014 
Phone: 814-865-1775 
Fax: 814-863-8699 
Email: irb-orp@psu.edu 
College of Medicine and Hershey Medical Center: 
Human Subjects Protection Office 
90 Hope Drive, Mail Code A115, P.O. Box 855 
Hershey, PA 17033 
(Physical Office Location: Academic Support Building Room 1140) 
Phone: 717-531-5687 
Fax number: 717-531-3937 
Email: irb-hspo@psu.edu 
 


Page 2 of 19 (V.08/27/2018) 
Table of Contents 
1.0 
Objectives 
2.0 
Background 
3.0 
Inclusion and Exclusion Criteria 
4.0 
Recruitment Methods 
5.0 
Consent Process and Documentation 
6.0 
HIPAA Research Authorization and/or Waiver or Alteration of Authorization 
7.0 
Study Design and Procedures 
8.0 
Subject Numbers and Statistical Plan 
9.0 
Confidentiality, Privacy and Data Management 
10.0 
Data and Safety Monitoring Plan 
11.0 
Risks 
12.0 
Potential Benefits to Subjects and Others 
13.0 
Sharing Results with Subjects 
14.0 
Subject Stipend (Compensation) and/or Travel Reimbursements 
15.0 
Economic Burden to Subjects 
16.0 
Resources Available 
17.0 
Other Approvals 
18.0 
Multi-Site Research 
19.0 
Adverse Event Reporting 
20.0 
Study Monitoring, Auditing and Inspecting 
21.0 
Future Undetermined Research: Data and Specimen Banking 
22.0 
References 
 
 


Page 3 of 19 (V.08/27/2018) 
1.0 
Objectives 
 
1.1 
Study Objectives 
The objective of this study is to determine if fluorescence lymphangiography can be used alone to 
localize sentinel nodes in patients with melanoma or breast cancer. The hypothesis is that sentinel 
nodes can be identified using only indocyanine green (ICG) and fluorescence lymphangiography, without 
the need for technetium99 and a gamma probe. 
 
1.2 
Primary Study Endpoints 
The primary endpoint is the number of sentinel nodes correctly identified with ICG and fluorescence 
imaging alone. 
 
1.3 
Secondary Study Endpoints 
Secondary endpoints include adverse events related to ICG and operative time for sentinel node biopsy. 
 
 
2.0 
Background 
 
1.1 
Scientific Background and Gaps 
 
Sentinel node biopsy is a routine procedure in patients with both melanoma and breast cancer. The 
status of the sentinel node provides prognostic information and guides further treatment options in 
these patients. Sentinel node biopsy (SLN) was first developed using only a blue dye. Technetium99, a 
radioactive protein, was added later and provides the ability to image the patient and identify relevant 
lymph node basins. This feature is particularly important for trunk melanomas that can drain to multiple 
nodal basins. For the last 15 years or so, the standard method of SLN localization includes both tech99 
and blue dye. While the rates of localization overall are excellent, these methods each have drawbacks. 
 
Technetium 99 (tech99) is a radioactive protein that is injected dermally around the melanoma or the 
areola of the breast, usually one day prior to surgery. Lymphoscintigraphy is done 1-2 hours after 
injection and identifies the nodal basin that contains the sentinel node. Tech99 has an excellent track 
record of identifying sentinel nodes, but it does involve an extra trip to the hospital (patients are 
injected the day prior to surgery), the injection is often the most painful part of the entire treatment 
experience, and the signal can be vague and difficult to localize in the operating room. Furthermore, 
there are international concerns about the reliability of the supply of radio-labelled colloid. The reactors 
that currently provide tech99 and other radioactive substances are aging, and shortages of material 
have been threatened in the past. 
 
Blue dye is injected dermally on the day of surgery, after the patient is anesthetized. This is a visual 
adjunct to the radioactive signal from the tech99. These two methods together have a success rate of 
approximately 96% in identifying the sentinel node. Blue dye alone localizes about 50% of sentinel 
nodes, and it can be problematic for the surgeon in that it stains tissues and is toxic to skin grafts.  
 
Infrared lymphangiography using ICG and real time imaging has recently been used as an alternative 
method of sentinel node identification. The PI has recently completed an equivalency trial of tech99, 
Methylene blue (MB) and ICG.  All subjects in this trial received all 3 dyes, and each was used 
simultaneously.  In this study I found that tech99 and ICG are equivalent in their ability to localize 
sentinel nodes. MB was inferior to both, and I rarely use MB in my clinical practice now. With the 
experience and results from the first trial, the next question is whether we can use ICG and fluorescence 
imaging alone, without tech99 and the gamma probe. The SPY Elite and SPY PHI machines are FDA 
approved for perfusion imaging and are the devices used to identify the sentinel lymph nodes after 
injection of ICG.  
 


Page 4 of 19 (V.08/27/2018) 
 
2.1 
Previous Data 
 
Multiple centers have published their experience with fluorescence imaging to identify sentinel nodes, 
in both melanoma and breast cancer.1-4 Ballardini et al5 found that ICG and tech99 are equivalent in 
identifying sentinel nodes in patients with breast cancer, and they suggest that ICG can be used alone. In 
our recently completed SPY trial, 89 subjects were enrolled and received tech99, MB and ICG. The 
tech99 identified a mean of 1.89 sentinel nodes per patient, ICG a mean of 1.87 and MB a mean of 0.71 
sentinel nodes. The ICG was well tolerated, with no adverse effects noted. A drawback to the ICG is that 
the fluorescent signal is visible through the skin only 47% of the time. If the nodal basin is predictable, 
such as for an extremity melanoma or a breast cancer, we can reasonably proceed with dissection in the 
predicted basin. Truncal melanomas however, do not have predictable drainage and therefore the lack 
of visibility is problematic for using ICG alone.  
 
 
2.2 
Study Rationale 
 
There is a need to develop reliable alternatives to tech99, and there is room to improve the patient 
experience by eliminating unnecessary injections. Prior studies have established that ICG and 
fluorescence imaging can reliably detect sentinel nodes, but these studies have been performed using 
tech99 as well. The goal of this trial is to assess our ability to identify sentinel nodes using only ICG and 
fluorescence imaging. This would be a significant departure from current standard practice, thus we 
have included a safety mechanism in the study, which is that subjects will still receive the tech99 
injection, but the surgeon is blinded to the result. 
 
3.0 
Inclusion and Exclusion Criteria 
 
3.1 
Inclusion Criteria 
 
1. HMC, Vasser Borthers Medical Center, or Emory University School of Medicine patients with 
melanoma or breast cancer with planned standard of care sentinel node biopsy 
For melanoma patients, the melanoma should be located on the upper extremity between and 
including the wrist and shoulder, or the lower extremity between and including the ankle and groin. 
2. Age:  18 years 
3. Sex:  Male or female 
4. Fluent in written and spoken English 
 
3.2 
Exclusion Criteria 
 
1. Melanoma located on the trunk, head or neck 
2. Patient has an allergy to indocyanine green or sodium iodide 
3. Pregnant or nursing women 
4. Patients who have had a prior sentinel node biopsy in the same nodal basin 
5. Prisoner 
6. Cognitive impairment. 
 
3.3 
Early Withdrawal of Subjects 
 
3.3.1 
Criteria for removal from study 
 
Subjects will be removed from the study if they withdraw consent prior to surgery. The study 
itself occurs only in the operating room, with no long term follow-up or involvement of the 
subject. 


Page 5 of 19 (V.08/27/2018) 
 
 
3.3.2 
Follow-up for withdrawn subjects 
 
Subjects will have sentinel node localization as per routine care if they withdraw from the study. 
 
4.0 
Recruitment Methods 
 
4.1 
Identification of subjects 
 
Subjects will be identified by the PI and collaborating surgeons in clinic at HMC, Vasser Brothers Medical 
Center, or Emory University School of Medicine , at the time of their initial consultation. 
 
4.2 
Recruitment process 
 
Subjects will be recruited during their initial consultation or any pre-operative visit. During this visit, 
routine care involves counseling the patient about melanoma or breast cancer and scheduling surgery, 
including the sentinel node biopsy. The surgeon usually doesn’t see the patient again until the day of 
surgery. Subjects will not be recruited on the day of surgery. 
 
4.3 
Recruitment materials 
 
None 
 
4.4 
Eligibility/screening of subjects 
 
NA 
 
5.0 
Consent Process and Documentation 
 
5.1 
Consent Process  
  
5.1.1 
Obtaining Informed Consent 
 
5.1.1.1 
Timing and Location of Consent 
 Consent for the study would be obtained at the end of the clinic visit. 
 
5.1.1.2 
Coercion or Undue Influence during Consent 
Subjects will be counseled that enrollment in the study is completely voluntary, 
and will not change their treatment. They will have a sentinel node biopsy 
whether they participate in the study or not, and the sentinel node is the same 
node whether it is localized with ICG or tech99. Subjects will also be counseled 
that they will still receive the tech99, as a backup plan in case the ICG doesn’t 
work. They can think about the study and consent after the visit, although 
enrollment should occur at least 2 days prior to surgery to allow for notification 
of radiology not to mark the nodal basin. 
 
5.1.2 
Waiver or alteration of the informed consent requirement 
 
A waiver of consent is requested to review medical record information to determine preliminary 
eligibility to participate in the research. 
 
 


Page 6 of 19 (V.08/27/2018) 
 
5.2 
Consent Documentation 
 
5.2.1 
Written Documentation of Consent 
 
The consent process will be documented in writing with the long form of consent documentation: 
• 
The current IRB approved consent form will be obtained. 
• 
We will verify that we are using the most current IRB-approved version of the study specific 
consent form and that the consent form is in language understandable to the 
subject/representative. 
• 
A copy of the consent form will be provided to the subject/representative. Whenever possible the 
consent form will be provided to the subject/representative in advance of the consent discussion. 
• 
If the subject/representative cannot read we will obtain an impartial witness to be present during 
the entire consent discussion to attest that the information in the consent form and any other 
information provided was accurately explained to, and apparently understood by, the 
subject/representative, and that consent was freely given.  
 
 
5.2.2 
Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.) 
 
NA  
 
5.3 
Consent – Other Considerations  
 
5.3.1 
Non-English Speaking Subjects 
Non-English speaking subjects will not be enrolled.  
 
5.3.2 
Cognitively Impaired Adults 
 
5.3.2.1 Capability of Providing Consent 
 
NA 
 
5.3.2.2 
Adults Unable To Consent 
 
Cognitively impaired adults will not be enrolled in the study. 
 
5.3.2.3 Assent of Adults Unable to Consent 
 
NA 
 
5.3.3 
Subjects who are not yet adults (infants, children, teenagers)  
 
5.3.3.1 Parental Permission 
 
 
 
NA. Melanoma is rare in children, and ICG is not approved for pediatric use. 
 
5.3.3.2 Assent of subjects who are not yet adults 
 
NA 
 
 
 
 


Page 7 of 19 (V.08/27/2018) 
6.0 
HIPAA Research Authorization and/or Waiver or Alteration of Authorization 
 
6.1 
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI 
 
Check all that apply: 
  
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable] 
 
 
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable] 
 
 
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3] 
 
 
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3] 
 
 
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3] 
 
6.2 
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI 
 
6.2.1 
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual 
 
6.2.1.1 Plan to protect PHI from improper use or disclosure 
 
Information is included in the Research Data Plan Form. 
 
6.2.1.2 Plan to destroy identifiers or a justification for retaining identifiers  
 
Study information will be retained until the sponsor notifies the study team that 
the information can be destroyed and all regulatory and institutional policies are 
met related to data retention. 
 
6.2.2 
Explanation for why the research could not practicably be conducted without access to and 
use of PHI 
 
Information must be obtained from the subject’s electronic medical record during recruitment 
to determine eligibility and, in some cases, to confirm information discussed with the subject in 
regards to their medical history. 
 
6.2.3 
Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization 
 
The waiver is requested only for recruitment to determine subject eligibility to ensure that no 
medical conditions that fall into the exclusion criteria are present and would thus preclude 
enrollment.  This waiver will minimize the enrollment of subjects’ who may ultimately fail to 
meet the study inclusion/exclusion criteria. 
 
 
 


Page 8 of 19 (V.08/27/2018) 
 
 
6.3 
Waiver or alteration of authorization statements of agreement 
 
Protected health information obtained as part of this research will not be reused or disclosed to any 
other person or entity, except as required by law, for authorized oversight of the research study, or for 
other permitted uses and disclosures according to federal regulations.  
 
The research team will collect only information essential to the study and in accord with the ‘Minimum 
Necessary’ standard (information reasonably necessary to accomplish the objectives of the research) 
per federal regulations.  
 
Access to the information will be limited, to the greatest extent possible, within the research team. All 
disclosures or releases of identifiable information granted under this waiver will be accounted for and 
documented. 
 
7.0 
Study Design and Procedures 
 
7.1 
Study Design 
 
Observational pilot study.  
 
From the subject’s viewpoint, the course of events in this study will be no different than usual care and 
sentinel node biopsy. 
 
7.2 
Study Procedures 
 
7.2.1 
Pre-op Procedure 
 
Subjects will have a dermal injection of technetium99 (tech99) at the melanoma tumor site prior 
to surgery (either the day before, or morning of surgery) or a subareolar injection if breast 
cancer. The surgeon will not look at the lymphoscintigraphy films, and the radiologist should not 
mark the skin. 
 
7.2.2 
Operative Procedure 
 
 When the subject is in the operating room and appropriately sedated or anesthetized, he or she 
will receive a dermal injection of indocyanine green (ICG) 0.9 ml at the melanoma tumor site or 
subareola if breast cancer. Incision is made in the axilla or groin, and the SPY machine is 
positioned over the lymph node basin. Real-time lymphangiography (SPY) is used to identify 
sentinel nodes. Any fluorescent nodes should be resected and are considered sentinel nodes. 
The absolute fluorescence will be quantified for each sentinel node. Absolute fluorescence is 
calculated by the SPY machine. 
 
After the sentinel lymphadenectomy is complete but prior to closing skin, the excised lymph 
nodes will be examined with the gamma probe (detects tech99 signal) to confirm that they are 
sentinel nodes. If the node does not have a signal with the gamma probe (but is fluorescent) it is 
still considered a sentinel node. The lymph node basin will also be examined with the gamma 
probe, to insure that no sentinel nodes are missed. If a gamma positive sentinel node is 
identified in the lymph node basin, it should be resected and imaged with SPY. If no sentinel 
nodes are able to be identified with fluorescent imaging, the gamma probe will be used as per 
usual practice. The surgeon should spend no more than 30 minutes using SPY to identify sentinel 


Page 9 of 19 (V.08/27/2018) 
nodes. If after 30 minutes no sentinel node is found, the gamma probe should be used. The data 
collection form (separately uploaded) should be completed for each case. 
 
7.3 
Duration of Participation 
 
Two days (pre-operative and operative procedure visits are associated with the research). 
 
 
7.4 
Test Article(s) (Study Drug(s) and/or Study Device(s)) 
 
7.4.1 Description 
 
The SPY Elite machine is FDA approved for perfusion imaging. The PI has received permission 
from the FDA under IND number 114602 to perform this research study using a dermal injection 
of ICG. The ICG comes as a powder containing 25mg of indocyanine green and sterile water to 
reconstitute the powder for injection. Subjects will receive 2.25 mg of indocyanine green (ICG) 
in a volume of 0.9 mL.  
 
7.4.2 Treatment Regimen 
 
The patient will receive a dermal injection of indocyanine green (ICG) 0.9 mL at the melanoma 
tumor site or subareola if breast cancer while they are in the operating room under general 
anesthesia. This is a one-time injection so no dose adjustments will be made.  
 
7.4.3 Method for Assigning Subject to Treatment Groups 
 
This is an observational study and not a randomized trial.  
 
7.4.4 Subject Compliance Monitoring 
 
All pertinent procedures and data collection will occur in the operating room. Subject 
compliance monitoring is not applicable for this study.   
 
7.4.5 Blinding of the Test Article 
 
There is no blinding involved in this study.  
 
7.4.6 
Receiving, Storage, Dispensing and Return  
 
7.4.6.1 
Receipt of Test Article  
 
ICG will be transported from the Investigational Drug Services (IDS) pharmacy to 
the OR pharmacy the day before surgery or the morning of the surgery 
depending on when the surgery is scheduled at HMC, Vasser Brother’s Medical 
Center, or Emory University School of Medicine. The ICG will come in a 25mg 
vial with 10 mL of Ampule (Solvent). Subjects will receive 2.25 mg of 
indocyanine green (ICG) in a volume of 0.9 mL.  
 
7.4.6.2 
Storage 
 
The ICG will be stored in the IDS pharmacy at HMC, Vasser Brother’s Medical 
Center, or Emory University School of Medicine until the day before surgery or 
the morning before surgery if it is scheduled for the afternoon. A copy of the 


Page 10 of 19 (V.08/27/2018) 
consent form for each patient will be sent to IDS pharmacy at HMC, Vasser 
Brother’s Medical Center, or Emory University School of Medicine prior to 
surgery. ICG should be stored at room temperature (between 20 – 25 degrees 
Celsius).    
 
 
7.4.6.3 
Preparation and Dispensing 
 
The ICG will be brought from IDS pharmacy at HMC, Vasser Brother’s Medical 
Center, or Emory University School of Medicine to the OR pharmacy the day 
before surgery so it is available for use the next day. If the surgery is scheduled 
for the afternoon then IDS pharmacy may bring the ICG over on the morning of 
surgery, not the day before. The surgeon will prepare the ICG and solvent for 
injection in the operating room prior to the start of the procedure. All aspects of 
the ICG preparation and use will be handled by the surgeon. Once reconstituted 
the ICG can be used for up to six hours, making it possible to use in several 
different cases in one day if the doses are drawn up in a sterile environment at 
the same time. 
 
7.4.6.4 
Return or Destruction of the Test Article 
 
Any remaining ICG will be discarded in the OR at HMC, Vasser Brother’s Medical 
Center, or Emory University School of Medicine.  
 
7.4.6.5 
 Prior and Concomitant Therapy 
 
NA 
 
8.0 
Subject Numbers and Statistical Plan 
 
8.1 
Number of Subjects 
 
A total of 40 subjects will be recruited into this study (we estimate we will enroll 20 subjects from Penn 
State Hershey Medical Center and 20 between Vasser Brother’s Medical Center and Emory University 
School of Medicine.).  
 
The learning curve for sentinel node biopsy is 5 cases. In order to insure that the data collected 
accurately represents the effectiveness of the SPY machine, each surgeon will have the goal of enrolling 
at least 8 subjects into the study. 
 
8.2 
Sample size determination 
 
Sample size of convenience.  This is a feasibility study, and is intended to determine if fluorescence 
lymphangiography can be used alone to localize sentinel nodes in patients with melanoma or breast 
cancer. The sample size of 40 subjects is our estimation of an appropriate number of subjects such that 
we can draw conclusions about this technique for sentinel node biopsy, and allows sufficient numbers 
for multiple surgeons to be involved.  
 
8.3 
Statistical methods 
 
The analysis of these results will be descriptive. We will assess the number of nodes per patient that are 
correctly identified with ICG alone, and the number of patients in whom ICG was successfully used 


Page 11 of 19 (V.08/27/2018) 
alone. Multiple surgeons will be involved, some with more experience than others with this technique. 
We will assess the learning curve by studying the success rate with ICG over time for each surgeon. 
 
9.0 
Confidentiality, Privacy and Data Management  
 
See the attached Research Data Plan form (HRP-598) 
 
10.0 Data and Safety Monitoring Plan 
 
10.1 
Periodic evaluation of data 
 
Collaborating surgeons will be monitored for at least 3 subjects, or until they demonstrate proficiency 
with ICG and the SPY device. Proficiency of each surgeon will be assessed by the PI or a representive 
from Stryker prior to each surgeon enrolling patients. While observing the collaborating surgeons for 
training purposes, the PI or a representative from Stryker will look for competence in and understanding 
of the use of the SPY machine. Each surgeon should demonstrate an understanding of the images that 
they are looking at on the SPY machine during the procedure. After 10 subjects, the PI will review the 
cases to insure that sentinel nodes are being identified for each subject. 
 
 
10.2 
Data that are reviewed 
 
Any adverse events that occur during surgery, whether deemed related to the ICG or not, will be 
reviewed. Adverse events will include reactions to ICG such as hives. Efficacy will be determined by 
success rates of localizing sentinel nodes with ICG alone. 
 
10.3 
Method of collection of safety information 
 
Safety information will be collected from the collaborating surgeons, through case report forms. 
 
10.4 
Frequency of data collection 
 
Safety data collection starts when the patient signs informed consent. Data will be collected on the day 
of surgery, on the standardized data collection form which is separately uploaded. Data should be 
forwarded to the PI within 7 business days of collection. Adverse events should be reported within 7 
business days. 
 
10.5 
Individuals reviewing the data 
 
Data will be reviewed by the PI. Adverse reactions to ICG are extremely rare, and have occurred with 
higher doses of ICG in subjects undergoing retinal angiography. No adverse reactions were seen in the 
prior study with 87 subjects, and none have been reported in the literature concerning sentinel node 
biopsy with ICG. 
 
 
10.6 
Frequency of review of cumulative data 
 
Data will be reviewed monthly. 
 
10.7 
Statistical tests 
 
The number of subjects planned for this study is relatively small, and given the very low complication 
rate seen in the prior study, statistical analysis will not be meaningful. 


Page 12 of 19 (V.08/27/2018) 
 
10.8 
Suspension of research 
 
Any grade 4 or 5 adverse event that occurs in a subject will trigger a suspension of research. 
 
 
 
 
11.0 Risks 
 
• 
Loss of confidentiality 
• 
Adverse reactions to ICG are extremely rare, and none occurred in the prior trial with 87 subjects.  
• 
Anaphylactic reactions, urticarial reactions and headache have been reported rarely in some patients. 
• 
The risks of sentinel node biopsy are usual care as the subjects will undergo the biopsy regardless of 
their participation in the research.  However, there is the possible risk of longer surgery, with a 
maximum of 30 additional minutes under anesthesia. This added time is of no consequence to the 
patient and carries an unmeasurable risk. Inaccurate identification of the sentinel node may occur 
equally in patients both on and off this study, therefore the risk in this study is no greater than usual 
care. The false negative rate in identifying sentinel nodes is 8%. Tech99 is used as a backup in this study 
in the event that the sentinel node cannot be identified with ICG. 
 
 
12.0 Potential Benefits to Subjects and Others 
 
12.1 
Potential Benefits to Subjects 
There are no direct benefits to the subjects. 
 
12.2 
Potential Benefits to Others 
We may be able to define a group of patients who can have sentinel node localization with ICG and 
fluorescence imaging alone, avoiding the use of tech99. This may reduce costs, and would simplify 
patient care preoperatively. 
 
13.0 Sharing Results with Subjects 
Individual subjects can be told about the success of ICG during their own procedure. General study results will 
not be shared with subjects. 
 
14.0 Subject Stipend (Compensation) and/or Travel Reimbursements 
None  
 
15.0 Economic Burden to Subjects 
 
15.1 
Costs  
 
The sponsor will provide the ICG directly to HMC, Vasser Brother’s Medical Center, and Emory University 
School of Medicine. Each institution will provide the ICG to the study patients. Subjects will be charged 
for Technetium 99. Subjects not enrolled in this study would be charged for blue dye, or for ICG if used 
in non-study patients, thus a charge for dye and injection is a usual part of the procedure. 
 
15.2 
Compensation for research-related injury 
 
It is the policy of the institution to provide neither financial compensation nor free medical treatment 
for research-related injury. In the event of injury resulting from this research, medical treatment is 


Page 13 of 19 (V.08/27/2018) 
available but will be provided at the usual charge. Costs for the treatment of research-related injuries 
will be charged to subjects or their insurance carriers. 
 
16.0 Resources Available 
 
16.1 
Facilities and locations 
 
Surgical procedures will be performed at Penn State Hershey Medical Center, Vasser Brother’s Medical 
Center, or Emory University School of Medicineas per usual care.  
 
16.2 
Feasibility of recruiting the required number of subjects 
 
All physicians involved have an active surgical oncology practice and routinely perform sentinel node 
biopsy. 
 
16.3 
PI Time devoted to conducting the research 
 
The PI has dedicated time to devote to research. Furthermore, a Human Research Technologist has been 
hired to assist in conducting this trial. 
 
16.4 
Availability of medical or psychological resources 
 
All resources and facilities of HMC are available to subjects on study.  In addition to the clinical team, 
this includes resources such as the clinical research coordinator, social workers, representatives from 
the American Cancer Society and various support groups for cancer or specific diseases 
 
16.5 
Process for informing Study Team 
 
The PI or a representative from Stryker will observe three surgeries for each surgical oncologist involved 
in the study to ensure that they are properly trained in the use of the SPY machine. The Human 
Research Technologist will coordinate all communications regarding updates to the protocol.   
 
17.0 Other Approvals 
 
17.1 
Other Approvals from External Entities 
 
Vasser Brother’s Medical Center IRB and Emory University School of Medicine IRB 
 
17.2 
Internal PSU Committee Approvals 
 
Check all that apply: 
  Anatomic Pathology – Hershey only – Research involves the collection of tissues or use of pathologic 
specimens. Upload a copy of HRP-902 - Human Tissue For Research Form on the “Supporting 
Documents” page in CATS IRB. This form is available in the CATS IRB Library. 
 
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals 
 
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA or 
gene therapy).  
 


Page 14 of 19 (V.08/27/2018) 
  Clinical Laboratories – Hershey only – Collection, processing and/or storage of extra tubes of body 
fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids that had 
been collected for clinical purposes, but are no longer needed for clinical use. Upload a copy of HRP-901 
- Human Body Fluids for Research Form on the “Supporting Documents” page in CATS IRB. This form is 
available in the CATS IRB Library. 
 
  Clinical Research Center (CRC) Advisory Committee– All campuses – Research involves the use of 
CRC services in any way.   
 
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest. 
 
  Radiation Safety – Hershey only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload a copy 
of HRP-903 - Radiation Review Form on the “Supporting Documents” page in CATS IRB. This form is 
available in the CATS IRB Library. 
 
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE. 
 
  Scientific Review – Hershey only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The scientific 
review requirement may be fulfilled by one of the following: (1) external peer-review process; (2) 
department/institute scientific review committee; or (3) scientific review by the Clinical Research Center 
Advisory committee.  NOTE: Review by the Penn State Hershey Cancer Institute Scientific Review 
Committee is required if the study involves cancer prevention studies or cancer patients, records and/or 
tissues. For more information about this requirement see the IRB website at: 
http://www.pennstatehershey.org/web/irb/home/resources/investigator  
 
18.0 Multi-Site Research 
 
18.1 
Communication Plans 
 
After approval by the IRB at Penn State the protocol will be submitted for IRB approval at Vasser 
Brother’s Medical Center and Emory University School of Medicine. Written confirmation of approval at 
Vasser Brother’s and Emory will be required prior to enrolling subjects at these locations. All updated 
information regarding the protocols will be communicated to all surgical oncologists by the Human 
Research Technologist serving as the research coordinator for this study. Any updates to the consent 
form will result in the HRT sending an updated copy of the form along with a follow up phone call to 
confirm that the newest version of the form will be used with all subsequent patients. New information 
will be communicated via email and receipt will be confirmed by the use of the vote function. All 
pertinent communications will be followed up with a phone call to ensure compliance. 
 
18.2 
Data Submission and Security Plan 
 
A REDCap database will be developed in order to store the collected information. All enrollment, 
consent and data collection forms from Vasser Brother’s and Emory will be scanned and emailed to the 
Human Research Technologist at Penn State Hershey. Files will be sent using the Penn State Hershey 
Secure File Transfer application known as Accellion. This application will allow files to be sent and 
received from Vasser Brother’s and Emory in a secure manner. The hard copy will be kept in a locked file 
in the clinical trials office at Vasser Brother’s and Emory, until the study has closed and the manuscript 
accepted for publication. Files can then be destroyed. Documents should be scanned and emailed as 
soon as they are completed. 


Page 15 of 19 (V.08/27/2018) 
 
18.3 
Subject Enrollment 
 
Subjects will be enrolled during their normally scheduled visit with the surgical oncologist. The study is 
not randomized, and subjects do not need to be coordinated in relation to other subjects. 
 
18.4 
Reporting of Adverse Events and New Information 
 
All adverse events will be reported to the PI within seven days of occurrence. New information will be 
communicated via email and receipt will be confirmed by the use of the vote function. All pertinent 
communications will be followed up with a phone call to ensure compliance.  
 
18.5 
Audit and Monitoring Plans 
 
All surgeons will be monitored by the PI or a representative from Stryker for a minimum of three cases 
with the SPY machine. The data collection form will be approved by all physicians prior to the start of 
the study. After enrolling each patient an analysis of the data forms will be done and the quality of the 
data collection forms will be reviewed. 
 
 
 
 
19.0 Adverse Event Reporting 
 
19.1 
Adverse Event Definitions 
 
Adverse event 
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related 
Adverse reaction 
Any adverse event caused by a drug 
Suspected adverse 
reaction 
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reaction implies a lesser degree 
of certainty about causality than “adverse reaction”. 
• 
Reasonable possibility.  For the purpose of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event. 
Serious adverse 
event or Serious 
suspected adverse 
reaction 
Serious adverse event or Serious suspected adverse reaction: An adverse event 
or suspected adverse reaction that in the view of either the investigator or 
sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
Life-threatening 
adverse event or 
life-threatening 
suspected adverse 
reaction 
An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the Investigator (i.e., the study site 
principal investigator) or Sponsor, its occurrence places the patient or research 
subject at immediate risk of death.  It does not include an adverse event or 
suspected adverse reaction that had it occurred in a more severe form, might 
have caused death. 


Page 16 of 19 (V.08/27/2018) 
Unexpected 
adverse event or 
Unexpected 
suspected adverse 
reaction.   
An adverse event or suspected adverse reaction is considered “unexpected” if 
it is not listed in the investigator brochure, general investigational plan, clinical 
protocol, or elsewhere in the current IND application; or is not listed at the 
specificity or severity that has been previously observed and/or specified. 
 
 
 
For device studies, incorporate the following definitions into the below responses, as written: 
Unanticipated 
adverse device 
effect 
Any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or IDE application (including a supplementary plan 
or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. 
 
19.2 
Recording of Adverse Events 
 
All adverse events (serious or non-serious) and abnormal test findings observed or reported to study team 
believed to be associated with the study drug(s) or device(s) will be followed until the event (or its sequelae) or 
the abnormal test finding resolves or stabilizes at a level acceptable to the investigator. 
 
An abnormal test finding will be classified as an adverse event if one or more of the following criteria are met: 
• 
The test finding is accompanied by clinical symptoms 
• 
The test finding necessitates additional diagnostic evaluation(s) or medical/surgical intervention; including 
significant additional concomitant drug treatment or other therapy 
NOTE: Simply repeating a test finding, in the absence of any of the other listed criteria, does not constitute an 
adverse event. 
• 
The test finding leads to a change in study drug dosing or discontinuation of subject participation in the clinical 
research study 
The test finding is considered an adverse event by the investigator. 
 
19.3 
Causality and Severity Assessments 
 
The investigator will promptly review documented adverse events and abnormal test findings to 
determine 1) if the abnormal test finding should be classified as an adverse event; 2) if there is a 
reasonable possibility that the adverse event was caused by the study drug(s) or device(s); and 3) if the 
adverse event meets the criteria for a serious adverse event. 
 
If the investigator’s final determination of causality is “unknown and of questionable relationship to the 
study drug(s) or device(s)”, the adverse event will be classified as associated with the use of the study 
drug(s) or device(s) for reporting purposes.  If the investigator’s final determination of causality is 
“unknown but not related to the study drug(s) or device(s)”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history. 
 
19.4 
Reporting of Adverse Reactions and Unanticipated Problems to the FDA   
 
19.4.1 Written IND/IDE Safety Reports 
The Sponsor-Investigator will submit a written IND Safety Report (i.e., completed FDA Form 
3500A) to the responsible new drug review division of the FDA for any observed or volunteered 
adverse event that is determined to be a serious and unexpected, suspected adverse reaction.  
Each IND Safety Report will be prominently labeled, “IND Safety Report”, and a copy will be 
provided to all participating investigators (if applicable) and sub-investigators. 
 


Page 17 of 19 (V.08/27/2018) 
Written IND Safety Reports will be submitted to the FDA as soon as possible and, in no event, 
later than 15 calendar days following the Sponsor-Investigator’s receipt of the respective 
adverse event information and determination that it meets the respective criteria for reporting. 
 
For each written IND Safety Report, the Sponsor-Investigator will identify all previously 
submitted IND Safety Reports that addressed a similar suspected adverse reaction experience 
and will provide an analysis of the significance of newly reported, suspected adverse reaction in 
light of the previous, similar report(s) or any other relevant information. 
 
Relevant follow-up information to an IND Safety Report will be submitted to the applicable 
review division of the FDA as soon as the information is available and will be identified as such 
(i.e., “Follow-up IND Safety Report”). 
 
If the results of the Sponsor-Investigator’s follow-up investigation show that an adverse event 
that was initially determined to not require a written IND Safety Report does, in fact, meet the 
requirements for reporting; the Sponsor-Investigator will submit a written IND Safety Report as 
soon as possible, but in no event later than 15 calendar days, after the determination was made. 
 
 
19.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions 
 
In addition to the subsequent submission of a written IND Safety Report (i.e., completed FDA 
Form 3500A), the Sponsor-Investigator will notify the responsible review division of the FDA by 
telephone or facsimile transmission of any unexpected, fatal or life-threatening suspected 
adverse reaction.  
 
The telephone or facsimile transmission of applicable IND Safety Reports will be made as soon 
as possible but in no event later than 7 calendar days after the Sponsor-Investigator’s receipt of 
the respective adverse event information and determination that it meets the respective criteria 
for reporting. 
 
 
19.5 
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB 
 
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures. 
 
19.6 
Unblinding Procedures 
NA 
 
19.7 
Stopping Rules 
 
NA 
 


Page 18 of 19 (V.08/27/2018) 
20.0 Study Monitoring, Auditing and Inspecting 
 
20.1 
Study Monitoring Plan  
 
 
20.1.1 Quality Assurance and Quality Control 
The study will be monitored by the Clinical Trial Monitoring Team from the Department of 
Public Health Sciences at Penn State Hershey College of Medicine. The monitors will provide an 
independent review of the regulatory and subject records and the data collected to assure 
compliance with the protocol, GCP, and applicable federal regulations. The monitoring will occur 
at regular intervals after the enrollment of the first subject and the times will be predetermined 
by the monitoring plan developed by the Clinical Trial Monitoring Team.  
 
 
20.1.2 Safety Monitoring 
 
The Principal Investigator will confirm that all adverse events (AE) are correctly entered into the 
AE case report forms by the coordinator; be available to answer any questions that the 
coordinators may have concerning AEs; and will notify the IRB, FDA, sponsor and/or DSMB of all 
applicable AEs as appropriate. All assessments of AEs will be made by a licensed medical 
professional who is an investigator on the research. 
 
 
21.0 Future Undetermined Research: Data and Specimen Banking 
 
21.1 
Data and/or specimens being stored 
NA 
 
21.2 
Location of storage 
NA 
 
21.3 
Duration of storage 
NA 
 
21.4 
Access to data and/or specimens 
NA 
 
21.5 
Procedures to release data or specimens 
NA 
 
21.6 
Process for returning results 
NA 
 
22.0 References 
1. 
Cloyd JM, Wapnir IL, Read BM, Swetter S, Greco RS. Indocyanine green and fluorescence 
lymphangiography for sentinel lymph node identification in cutaneous melanoma. Journal of surgical 
oncology. Dec 2014;110(7):888-892. 
2. 
Fujisawa Y, Nakamura Y, Kawachi Y, Otsuka F. Indocyanine green fluorescence-navigated sentinel 
node biopsy showed higher sensitivity than the radioisotope or blue dye method, which may help to 
reduce false-negative cases in skin cancer. Journal of surgical oncology. Jul 1 2012;106(1):41-45. 
3. 
Hirche C, Murawa D, Mohr Z, Kneif S, Hunerbein M. ICG fluorescence-guided sentinel node biopsy for 
axillary nodal staging in breast cancer. Breast cancer research and treatment. Jun 2010;121(2):373-378. 


Page 19 of 19 (V.08/27/2018) 
4. 
Stoffels I, Dissemond J, Poppel T, Schadendorf D, Klode J. Intraoperative Fluorescence Imaging for 
Sentinel Lymph Node Detection: Prospective Clinical Trial to Compare the Usefulness of Indocyanine 
Green vs Technetium Tc 99m for Identification of Sentinel Lymph Nodes. JAMA surgery. Jul 
2015;150(7):617-623. 
5. 
Ballardini B, Santoro L, Sangalli C, et al. The indocyanine green method is equivalent to the (9)(9)mTc-
labeled radiotracer method for identifying the sentinel node in breast cancer: a concordance and 
validation study. European journal of surgical oncology : the journal of the European Society of 
Surgical Oncology and the British Association of Surgical Oncology. Dec 2013;39(12):1332-1336.