Clinical trial NCT02910726
Conditions: Pediatric Patients With Solid Tumors
Keywords: indocyanine green fluorescent dye Technetium lymphoscintigraphy sentinel lymph node biopsy 16-1003
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2016-09-13; Completion date: 2022-09-02
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is being done in patients that have tumors to find out how well sentinel lymph nodes (SLNs) can be found with a special dye called indocyanine green (ICG).

Detailed description:

Arms: arm 1: This is a single-center clinical trial to evaluate non-inferiority of ICG-guided SLN biopsy compared with the gold standard TcL-guided SLN biopsy in pediatric patients with solid tumors. Each patient will undergo TcL, consistent with the standard of care, but the surgeon will be blinded to the results preoperatively. Intraoperatively, ICG injection and transdermal lymphography will be used to identify the draining nodal basin and the position of the sentinel nodes. ICG transdermal lymphography will be considered successful if SLNs can be visualized on near-infrared imaging. After the transdermal lymphography results have been recorded, the surgeon will be unblinded to the TcL mapping.
Interventions: intervention 1: Sentinel Lymph Node Biopsy intervention 2: indocyanine green (ICG)
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1003 A(2) 
Approval date: 27-Aug-2019 
 
 
Non-inferiority study of intra-operative indocyanine green fluorescent dye versus 
Technetium lymphoscintigraphy  for sentinel lymph node biopsy in pediatric malignancies 
 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC  PROTOCOL 
 
 
Principal Investigator/Department: 
Todd Heaton, MD 
Surgery/Pediatric Surgical Serv 
Co-Principal 
Investigator(s)/Department: 
Neeta Pandit-Tasker, MD 
Michael LaQuaglia, MD 
Radiology/Nuclear  Med 
Surgery/Pediatric Surgical Serv 
Investigator(s)/Department: 
Emily Zabor 
Epidemiology & Biostatistics 
Consenting  Professional(s)/Department: 
Todd Heaton, MD 
Michael LaQuaglia, MD 
Mariel Marrano, NP 
Charlotte Ariyan, MD 
Edmund Bartlett, MD 
Danielle Bello, MD 
Mary Brady, MD 
Daniel Coit, MD 
Aimee Crago, MD 
Surgery/Pediatric Surgical Serv 
Surgery/Pediatric Surgical Serv 
Pediatrics 
Surgery/Gastric & Mixed Tumor 
Surgery/Gastric & Mixed Tumor 
Surgery/Gastric & Mixed Tumor 
Surgery/Gastric & Mixed Tumor 
Surgery/Gastric & Mixed Tumor 
Surgery/Gastric & Mixed Tumor 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
OneMSK  Sites 
Manhattan 
 
 
Participating Institutions 
Site PI Name 
Site Role 
Texas Children’s Hospital 
Sanjeev Vasudevan, MD 
Data Collection 
St. Jude Children’s Research 
Hospital 
Andrew Davidoff, MD 
Data Collection 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
Page 1 of 21 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1003 A(2) 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 5 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................... 6 
4.1 
Design .................................................................................................................................. 6 
4.2 
Intervention ................................................................................................................................ 7 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 7 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................................ 7 
6.1 
Subject Inclusion Criteria ...................................................................................................... 7 
6.2 
Subject Exclusion Criteria ..................................................................................................... 8 
7.0 
RECRUITMENT PLAN ...................................................................................................................... 8 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 8 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................. 8 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ...................................................... 8 
11.0 
TOXICITIES/SIDE EFFECTS ...................................................................................................... 9 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT .......................... 9 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 9 
14.0 
BIOSTATISTICS ................................................................................................................. 9 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES10 
15.1 Research Participant Registration ......................................................................................... 10 
15.1.1 Registration for Participating Sites…………………………………………………….. 11 
15.2 
Randomization ................................................................................................................... 11 
16.1 
DAT A M ANAGEMENT ISSUES ........................................................................................ 11 
16.1.1 
Data and Source Documentation for Participating Sites…………………………….…..12 
16.1.2 
Data and Source Documentation Submission for Participating Sites …………….….. 12 
16.1  Quality Assurance .............................................................................................................. 13 
16.1.1  Quality Assurance for Participating Sites…………………………………………….  13 
16.2 
Data and Safety Monitoring .................................................................................................... 14 
16.3    Regulatory Documentation………………………………………………………….…………. 14 
16.3.1  Amendments……………………………………………………………………………… 14 
16.3.2 Additional  IRB  Correspondence………………………………………………………… 14 
16.3.3  Document maintenance………………………………………………………………….. 15  
16.4  Noncompliance…………………………………………………………………………………… 16 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1003 A(2) 
Approval date: 27-Aug-2019 
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17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 16 
17.1 
Privacy ............................................................................................................................... 17 
17.2 
Serious Adverse Event (SAE) Reporting ............................................................................... 17 
17.2.1 SAE Reporting for Participating Sites .............................................................................. 18 
17.3   Unanticipated  Problems……………………………………………………………………….. 18 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................. 19 
18.1 Informed Consent Procedures for Participating Sites………………………………………. 19 
19.0 
REFERENCES ...................................................................................................................... 20 
20.0 
APPENDICES ................................................................................................................... 21 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This prospective trial will examine whether indocyanine green (ICG)-guided 
intraoperative transdermal lymphography is non-inferior to pre-operative technetium 
lymphoscintigraphy (TcL) for detecting sentinel lymph nodes (SLN) in pediatric patients with 
solid tumors.  The primary endpoint is the detection rate for TcL-labeled and ICG-labeled 
SLNs.  Secondary outcomes will include safety of ICG, number of positive nodes detected 
with each modality in each patient, and the sensitivity rate with each modality.  The study 
population will include any patient under the age of 30 years who requires a sentinel lymph 
node biopsy for a solid tumor.  Each patient will undergo both TcL prior to SLN biopsy and 
intra-operative ICG transdermal lymphography, thereby simultaneously serving as his/her 
own control.  However, the surgeon will be blinded to the TcL results until after the ICG 
transdermal lymphography results have been recorded, in order to directly evaluate the 
detection rate of the ICG.  Given the estimated sample size of 59 patients and an annual rate 
of  SLN biopsies on patient under 30 years of age of 10 per year at MSK and 17 patients  
from the two collaborating institutions, this study will take approximately 4 years to complete. 
(Schematic provided below) 


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Patient Flow Chart 
 
 
 
 
 
 
successful 
unsuccessful 
 
 
 
 
 
 
successful 
 
unsuccessful 
 
 
 
 
 
 
 
 
 
Residual radioactivity 
No residual radioactivity 
 
 
 
Record all ICG and 
TcL measures and 
close incision 
 
• 
<1% of patients will fail to map with both modalities.   In that rare event, the SLN biopsy will be aborted, 
and the patient will count as a failure of TcL and ICG in the primary objective. 
TcL mapping  and 
gamma probe 
evaluation 
Failed ICG mapping, so 
continue with TcL guided 
LN excision 
Excision of all ICG 
positive LNs 
Failure of TcL, 
SLN bx using ICG 
Intra-operative  ICG 
SLN mapping 
TcL of all eligible 
patients 
Excise remaining hot 
nodes, record measures, 
and close incision 


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IRB Number: 16-1003 A(2) 
Approval date: 27-Aug-2019 
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2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
• 
Primary Objective 
o Show that the SLN detection rate using ICG-guided transdermal 
lymphography is not inferior to that of TcL in pediatric solid tumors 
• 
Secondary Objectives 
o Safety of ICG injection 
o Compare the total number of ICG+ and TcL+ SLNs harvested in each patient 
o Compare the percent of patients who have a pathologically positive SLN 
identified with each technique (sensitivity rate) 
 
3.0 
BACKGROUND AND RATIONALE 
 
Pediatric solid tumors vary greatly in their propensity to spread to regional nodes.  After  the 
development of SLN biopsy in melanoma and breast cancer in adults, pediatric surgeons 
adopted the technique and applied it to multiple tumors including melanoma, Spitz nevi, and 
soft tissue sarcomas.  Technetium lymphoscintigraphy is the gold standard for mapping and 
identifying SLNs in pediatric patients with solid tumors. Some surgeons also inject blue dye 
at the site, but its use has decreased because of frequent hypersensitivity reactions (1,2). 
 
The standard procedure for SLN biopsy includes TcL the morning of or day prior to surgery. 
Mapping of the SLN is accomplished with nuclear medicine scans shortly after local Tc 
injection; the scans identify which lymph node basin contains the SLN and how many SLNs 
there are (average 1-2). In the unlikely event (<3%) that mapping fails, the patient is brought 
back 2-3 weeks later for repeat mapping. Once mapping is confirmed, the patient is taken to 
the OR, where a gamma probe is used to identify the hottest point (point with the highest 
gamma count) on the skin overlying the lymph node basin and an incision is made.  The 
gamma probe and blunt dissection are then used to find the hot node and it is then resected. 
Given the lack of specificity and resolution using the gamma probe this can result in 
significant time and dissection. All the hot (gamma probe positive) nodes are removed and 
the procedure is considered complete when the baseline gamma count of the basin is <10% 
of the gamma count of the hottest node. 
 
While technetium mapping is reliable, it has several disadvantages. First, it exposes a child  
to a small amount of radiation. Although the radiation dose is within the range of natural 
background radiation, it adds to the patient’s cumulative radiation exposure. Second, while 
the gamma probes used to identify the SLN intra-operatively are sensitive,  they are not 
specific, have poor resolution, and do not allow for direct visualization during dissection.  The 
inherent error in the probes and the difficulty discerning lymph tissue from the surrounding fat 
can make it difficult to identify small SLNs.  This disadvantage led to the addition of blue dye 
to the SLN procedure, but its use has been limited by the high risk of hypersensitivity to the 
dye. Third, the TcL procedure requires several hours to complete, so most patients spend an 
additional day in the hospital beginning the day prior to the surgery. Last, four injections of 
technetium must be given around the tumor site without sedation, which can be difficult in the 
pediatric population. 


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Recently, fluorescent lymphatic mapping with indocyanine green has been shown to be 
equivalent to technetium in cervical, uterine, and breast SLN mapping (3-6).  One of the first 
groups of investigators to exploit these attributes of ICG was Memorial Sloan Kettering’s 
Gynecologic Oncology Service.  Jewell et al. published an analysis of a patient series in 
2014 showing a 95% detection rate for ICG in uterine and cervical cancer SLN biopsy (3).  In 
2015, Imboden et al. published results of their study comparing ICG to blue dye, which 
demonstrated bilateral SLN detection rates of 95.5 and 61%, respectively (4). Xiong et al. 
performed a meta-analysis of ICG SLN data in 2014 and found a pooled detection rate of 
96% (5). ICG also allows for direct transcutaneous visualization and transdermal 
lymphography using near-infrared cameras. Wishart et al. showed a 100% detection rate for 
ICG transdermal lymphography in early breast cancer SLN biopsy (6).  If ICG is shown to be 
non-inferior to TCL for the mapping and identification of SLNs in pediatric solid tumors, then 
the pain, radiation exposure, and time expenditure required for TcL could be eliminated. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a prospective, multi-institutional clinical trial to evaluate non-inferiority of ICG-guided 
SLN biopsy compared with the gold standard TcL-guided SLN biopsy in pediatric patients 
with solid tumors. Each patient will undergo TcL, consistent with the standard of care, but the 
surgeon will be blinded to the results preoperatively.  Intraoperatively,  ICG injection and 
transdermal lymphography will be used to identify the draining nodal basin and the position  
of the sentinel nodes.  ICG transdermal lymphography will be considered successful if SLNs 
can be visualized on near-infrared imaging. After the transdermal lymphography results have 
been recorded, the surgeon will be unblinded to the TcL mapping.  All ICG-positive and TcL- 
positive nodes will be removed and complete excision will be confirmed by intra-operative 
near-infrared imaging and gamma probe evaluation. Thus, in this trial each patient will serve 
as his/her own control. If TcL fails, no repeat TcL will be perfomed, the SLN biopsy will be 
done with ICG alone, and the patient will be recorded as a failure of TcL (i.e. decreasing the 
detection rate for TcL).  If ICG mapping fails, the TcL results will be used to perform SLN 
biopsy and the patient will be considered a failure of ICG (i.e. decreasing the detection rate 
for ICG). In the <1% of patients that fail both TcL and ICG, no SLN biopsy will be performed 
and the patient will be recorded as a failure of both TcL and ICG . These patients will still 
contribute data to the primary endpoint (i.e. decreasing the detection rate for both modalities) 
and safety data, but will not contribute to the other secondary aims. Approximately 59 
patients will be enrolled over a period of approximately 4 years. 
The primary outcome, SLN detection rate, will be compared between ICG-guided 
transdermal lymphography and TcL to determine non-inferiority of ICG in this clinical 
application. Secondary outcomes include the safety of ICG in this clinical scenario, 
comparisons of the total number of excised nodes identified with each detection method in 
each patients, and the sensitivity rate (percent of patients with a pathologically positive SLN) 
for each technique. 


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4.3 
Intervention 
 
On the day of or the day before the scheduled OR procedure, the patient will undergo TcL, 
but the surgeon will be blinded to the results preoperatively.   On the day of surgery, 4 cc of 
1.25 mg/mL ICG will be injected at 4 points directly surrounding the tumor site (1cc per point, 
depth will vary with position of the tumor) after the patient is under anesthesia.  Transdermal 
lymphography and analysis of all possible draining nodal basins will then be performed using 
a near-infrared camera in real time. ICG mapping to the SLN takes approximately 5min.  If  
the SLN cannot be identified 20min after ICG injection, it will be considered a failure of ICG, 
and the TcL results will be used to perform the SLN biopsy. If the ICG does map and a SLN  
is identified, the transdermal lymphography results will be recorded and the surgeon will be 
unblinded to the TCL results. All fluorescent lymph nodes will then be resected using the 
near-infrared camera.  After all ICG-positive nodes have been resected, but before closure, 
gamma probes will be used intraoperatively to ensure all TcL-positive SLNs have been 
removed.  As is standard with TcL SLN biopsy any activity in the nodal bed <10% of the 
“hottest” node removed will be considered background.  This will act as the threshold for all 
TcL positive nodes being removed.  The detection rates for each tracer, ICG and TcL 
positivity for every node removed, and number of ICG and TcL positive nodes per patient will 
be recorded.  If TcL fails, no repeat TcL will be perfomed, the SLN biopsy will be done with 
ICG alone, and the patient will be recorded as a failure of TcL (i.e. decreasing the detection 
rate for TcL). If ICG mapping fails, the TcL results will be used to perform SLN biopsy and  
the patient will be considered a failure of ICG (i.e. decreasing the detection rate for ICG). In 
the <1% of patients that fail both TcL and ICG, no SLN biopsy will be performed and the 
patient will be recorded as a failure of both TcL and ICG with respect to detection rate. These 
patients will still contribute data to the primary endpoint (i.e. decreasing the detection rate for 
both modalities) and safety data, but will not contribute to the other secondary aims. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
ICG is an FDA-approved drug for IV, subcutaneous, and topical use. Safety and  
effectiveness of this agent in pediatric patients have been established (8-10). ICG is currently 
used at MSK for viability and perfusion analysis in colorectal and plastic surgery as well as 
SLN identification in gynecologic cancer. It is supplied in a kit with sterile covers for the near- 
infrared camera and the agent is easily diluted to the goal concentration of 1.25mg/mL prior 
to injection. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Describe the characteristics of the patient/subject population. 
 
6.2 
6.1 
Subject Inclusion Criteria 
• Patients <30 years old with an extracoelomic solid tumor, diagnosis confirmed 
at the enrolling institution, requiring SLN biopsy 
• Women of childbearing potential must have a negative pregnancy test (urine 
or blood) pre-operatively as per the standard hospital policy. A woman of 
childbearing potential is defined as one who is biologically capable of 
becoming pregnant. 


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• Patients who are cleared for surgery as noted in Section 8.0 
6.3 
Subject Exclusion Criteria 
 
• History of reaction to ICG, iodides, or technetium radiocolloid 
• Intracoelomic primary tumors or tumors expected to drain to an intracoelomic 
SLN 
• Patients with extensive prior surgery at the primary site or nodal basin 
expected to affect the lymphatic drainage 
• Patients unwilling or unable to sign informed consent 
• Women who are pregnant or breast-feeding. 
 
7.0 
RECRUITMENT PLAN 
 
Any patient meeting the above criteria who is referred to a  surgery clinic at a participating 
institution will be recruited for the study. The consenting professional will be responsible for 
explaining the study to the patient and obtaining written informed consent. The clinical 
research coordinator will be responsible for registering the patient on study. Recruitment of 
59 patients is expected to be completed in approximately 4 years. 
 
8.0 
PRETREATMENT EVALUATION 
 
All standard pre-operative tests including CBC, coagulation studies, electrolytes, and imaging 
(determined by the location and attributes of the tumor) will be obtained within the time limits 
set forth in the participating institution’s pre-operative work-up guidelines.  No additional tests 
will be required prior to our intervention. 
9.0 
TREATMENT/INTERVENTION PLAN 
 
Pre-operative studies as detailed above will be performed in the days leading up to the 
intervention. The injection of ICG at 4 points directly surrounding the tumor site will take  
place at the time of operation after the patient is under anesthesia.  Transdermal 
lymphography and analysis all possible draining nodal basins will then be performed for 
20min using near-infrared cameras in real time in the operating room.  Immediate ICG 
mapping and detection results will be compared with the pre-operatively obtained TcL and 
the standard post-operative pathology results.  Patients will be monitored intra-operatively for 
any adverse reaction to ICG and will be specifically asked about adverse events at the time 
of follow up 1-4 weeks after surgery. 
 
Day w/ respect to operation 
Intervention 
-45 to -1 (Baseline) 
Pre-operative labs and imaging 
-1 to 0 (Visit 1) 
TcL 
0 (Visit 2) 
ICG mapping and SLN biopsy 
7-28 (Visit 3) 
Post-op evaluation and interview for adverse events 
 
 
10.1 EVALUATION DURING TREATMENT/INTERVENTION 


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No additional tests or follow-up over the standard intra-operative and post-operative 
monitoring will be required in this trial. 
The tests included under standard of care are: 
 
• 
CBC 
• 
Coagulation tests 
• 
Pre-operative technetium lymphoscintigraphy (TcL) 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving ICG dye, more than 20 and up to 100 may have: 
• 
Mild burning at the injection site lasting up to a few hours 
• 
Green or yellowish discoloration at the injection site lasting up to several hours 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving ICG dye from 4 to 20 may have: 
• General yellowish skin discoloration lasting up to 24 hours 
• Orange urine discoloration lasting up to 24 hours 
RARE, AND SERIOUS 
In 100 people receiving ICG dye  3 or fewer may have: 
• Allergic reaction – most are mild with pruritus and hives, but some can be serious 
with wheezing/bronchospasm and facial edema 
 
 
 
 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Please refer to sections 4.0 and 9.0 for the overview of the study design, intervention, and 
treatment plan. 
 
 
13.0 
CRITERIAFOR REMOVAL FROM STUDY 
 
• 
Patient refuses to continue with study 
• 
Immediate adverse reaction to ICG injection precluding complete dosing 
 
14.0 
BIOSTATISTICS 
Primary objective 


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Non-inferiority studies concentrate on proving that the tested method is not clinically inferior  
to the standard of care by a particular margin decided upon using prior knowledge of the 
external (to the trial) advantages of the new method.  They are extremely useful in rare 
conditions and when comparing a new test to a standard of care with a very high success 
rate.  Both TcL and ICG have a success rate of 95% and pediatric solid tumors requiring SLN 
biopsy are rare.  In order to perform a standard superiority study comparing ICG to TcL, 
thousands of patients would be necessary, which is not clinically feasible.  As described 
above, from the clinical standpoint, ICG is superior to TcL for patient care because it 
provides much more accurate visualization of SLNs during biopsy, does not expose the 
patient to radiation, does not require painful injections without sedation, and does not require 
additional time commitments from the patient and family.  The non-inferiority margin was, 
therefore, set at 10% using this clinical knowledge. Using an alpha level of 0.05 and a beta 
level of 0.2, and knowing TcL and ICG detect a SLN in 95% of cases, the calculated N per 
group for paired values is 59. Because each patient serves as his/her own control, these 
tests are considered “paired” values.  Adjustment to the non-inferiority study statistics has 
been described by Liu et al (7). Given that each of our patients will be evaluated with both 
TcL and ICG, each case counts towards both groups and our total N = 59. Given the rate of 
15-20 pediatric SLN biopsies per year at our institution, patient accrual should be completed 
within approximately 4 years. 
 
The primary outcome of this study is the detection rate (% of patients in whom a SLN 
is identified) for ICG and TcL. These percentages will be compared using a non-inferiority 
comparison for matched pair data as described above.  In the unlikely event that SLNs are 
not found with either modality, these patients will still contribute data to the primary endpoint 
(i.e. decreasing the detection rate for both modalities) and safety data, but will not contribute 
to the other secondary aims. 
Secondary objectives 
 
Safety will be analyzed with descriptive statistics of the number and type of adverse 
reactions encountered (per CTCAE guidelines). 
The number of nodes identified by each technique will be compared using a paired Wilcoxon 
signed-rank test. 
 
To evaluate sensitivity, the percent of patients in whom a SLN is found to contain tumor on 
pathology using each technique will be compared with McNemar’s test for matched pair data. 
 
Finally, to determine whether the intensity of each node is associated with pathologic 
positivity, a logistic regression model will be fit with pathologic positivity as the outcome and 
intensity as the predictor, and robust standard errors will account for correlation among 
multiple nodes per patient. This will be done separately for ICG and TcL intensity. 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 


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Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in the section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
The individual signing the Eligibility Checklist is confirming that the participant is eligible to 
enroll in the study. Study staff are responsible for ensuring that all institutional requirements 
necessary to enroll a participant to the study have been completed. See related Clinical 
Research Policy and Procedure #401 (Protocol Participant Registration). 
15.2.1 Registration for Participating Sites: 
 
Central registration for this study will take place through MSK’s Clinical Trials Management 
System (CTMS). 
 
To complete registration and enroll a participant from another institution, the site must first 
contact the MSK study coordinator to notify him/her of the participant registration. 
 
Once the MSK study coordinator is notified, the site will document the participant’s consent 
by associating the participant to the protocol in CTMS. This will generate a study ID number 
that is unique and must be written on all data and correspondence for the participant. 
 
After associating the participant to the protocol, the site will enter the consent status in real- 
time, but no later than 2 business days, from when the informed consent was signed. 
 
The following documents must be saved to CTMS within 2 business days of documenting 
consent status: 
 
• 
The completed or partially completed MSK eligibility checklist 
• 
The signed informed consent and HIPAA Authorization form 
 
 
Supporting source documentation for eligibility questions (e.g. laboratory results, pathology 
report, radiology reports, MD notes, physical exam sheets, medical history, prior treatment 
records, and EKG report) will be sent to the MSK study coordinator within 30 days of consent 
so eligibility can be verified. Once the MSK study coordinator verifies eligibility the site will be 
notified to enter eligibility and on study status in CTMS, which will complete participant 
registration. 
15.3 
Randomization 
 
This study does not involve randomization. 
 
16.1 
DATA MANAGEMENT ISSUES 
 
All experimental data including TcL, ICG mapping and detection, nodal ICG and TcL 
measurements and correlating pathology results will be stored in a REDCap database.Data 
from patients accrued at other institutions will also be submitted to the secure REDCap 


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database.  External institutions will only have access to patient information submitted from 
their respective institution.  The PI and MSK research team will be the only researchers with 
access to other institutions data submissions. 
 
Data will be managed through REDCap (Research Electronic Data Capture), a data 
management software system supported by Clinical Research Administration at MSK. 
Members of the Clinical Research Administration supporting the REDCap software will have 
access to the data for the purpose of ensuring the proper functioning of the database and the 
overall software system. REDCap is a tool for the creation of customized, secure data 
management systems including web-based data entry forms, reporting tools, and a full array 
of security features including user and group based privileges with a full audit trail of data 
manipulation and export procedures. REDCap is maintained on MSK-owned servers that are 
kept in a locked server room with appropriate environmental modifications (e.g., special air 
conditioning), supported by an uninterrupted power supply, and backed up nightly with some 
backup tapes stored off-site. All connections to REDCap utilize encrypted (SSL-based) 
connections. Nationally,  the REDCap software is developed, enhanced, and supported 
through a multi-institutional consortium led by the Vanderbilt University CTSA. REDCap will 
only be used for the housing of survey data. Use of REDCap has been approved by the 
department’s manager of IT Systems and by MSK Information Security. 
 
16.1.1 
Data and Source Documentation for Participating Sites 
 
Data 
The participating site(s) will enter data onto a standardized data collection CRF. Data entry 
guidelines have been generated for this study and blank data collection CRFs will be sent to 
the study staff at each participating site for use. The participating site PI is responsible for 
ensuring these forms are completed accurately, legibly and in a timely manner. 
 
The participating site(s) will enter data remotely into an electronic database using the internet 
based system, REDCap. Data entry guidelines have been generated for this study and site 
staff will receive database training prior to enrolling its first participant. The participating site 
PI is responsible for ensuring these forms are completed accurately and in a timely manner. 
A schedule of required forms is shown in section 16.0.3. 
 
Source Documentation 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation should be 
consistent with data recorded on CRFs and entered into the REDCap database. Relevant 
source documentation to be submitted throughout the study includes: 
 
o Diagnosis 
o Patient history/MD notes 
o Operative reports 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1003 A(2) 
Approval date: 27-Aug-2019 
Page 13 of 21 
 
 
 
Source documentation should include a minimum of two identifiers to allow for data 
verification. MSK will maintain the confidentiality of any subject-identifiable information it may 
encounter. 
 
16.1.2 
Data and Source Documentation Submission for Participating Sites 
 
Participating sites should email source documentation to MSK at the contact information 
provided by the MSK study coordinator. Submissions should include a cover page listing all 
documents enclosed per participant. 
 
Participating sites should enter data directly into REDCap and study-specific paper CRFs. 
Source documentation should be sent to MSK at the contact information provided by the 
MSK study coordinator. Submissions should include a cover page listing relevant  records 
enclosed per participant. 
16.1.3 Data and Source Documentation Submission Timelines for Participating Sites 
 
Data and source documentation to support data should be transmitted to MSK according to 
chart 2. 
 
Chart 2: Data and Source Submission Requirements and Timelines 
 
 
Baseline 
Visit 1 
Visit 2 
Visit 3 
SAE 
Off Study 
 Submission Schedule 
Source 
Documentation 
Within 2 days 
(see section 
13.1.1) 
Within 14 days of visit if 
diagnostic or other clinical 
protocol 
Within 3 days of 
event  updates  to 
be submitted as 
available 
Within 14 days of visit if 
diagnostic or other clinical 
protocol 
REDCap  eCRFs 
Within 7 days 
of visit 
 Required Forms 
SAE Form 
X 
 
 
16.2 
Quality Assurance 
 
Completeness of registration data will be monitored by the clinical research coordinator on a 
regular basis. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates, and the extent and accuracy of evaluations and follow-up, will 
be monitored periodically throughout the study. Potential problems will be brought to the 
attention of the study team for discussion and action. Random-sample data quality and 
protocol compliance audits will be conducted by the study team at a minimum of twice per 
year, or more frequently if indicated. 
16.2.1 Quality Assurance for Participating Sites 
 
Each site accruing participants to this protocol will be audited by the staff of the MSK study 
team for protocol and regulatory compliance, data verification and source documentation. 


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IRB Number: 16-1003 A(2) 
Approval date: 27-Aug-2019 
Page 14 of 21 
 
 
 
 
Audits will be conducted annually during the study (or more frequently if indicated) and at the 
end or closeout of the trial. Ideally the first audit will occur shortly after the first patients are 
enrolled. The number of participants audited will be determined by auditor availability and the 
complexity of the protocol. Each audit will be summarized and a final report will be sent to the 
PI at the audited participating site within 30 days of the audit. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001.  The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found 
at:  http://www.cancer.gov/clinicaltrials/conducting/dsm -guidelines /page1.   The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research.  The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at:  
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Monitoring%  
20Plans.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
 
16.4 
Regulatory Documentation 
 
Prior to implementing this protocol at MSK, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSK Institutional Review Board/Privacy Board (IRB/PB). There will be one protocol 
document and each participating site will utilize that document. 
 
The following documents must be provided to MSK before the participating site can be 
initiated and begin enrolling participants: 
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 
• 
Participating Site IRB approved informed consent form 
• 
Participating Site IRB’s Federal Wide Assurance (FWA) number and OHRP Registration 
number 
• 
Curriculum vitae and medical license for each investigator and consenting professional 
• 
Documentation of Human Subject Research and Good Clinical Practice Certification for 
investigators, consenting professionals and key study personnel at the participating site. 


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IRB Number: 16-1003 A(2) 
Approval date: 27-Aug-2019 
Page 15 of 21 
 
 
 
For interventional studies funded by the NIH, GCP training must be renewed every 3 
years. 
 
Upon receipt of the required documents, MSK will formally contact the site and grant 
permission to proceed with enrollment. 
 
16.4.1 Amendments 
Each change to the protocol document must be organized and documented by MSK and 
approved first by the MSK IRB/PB. Protocol amendments that affect MSK only (e.g. change 
in MSK Co-Investigator, MSK translation, etc.) do not require IRB review at the participating 
site(s). All other protocol amendments will be immediately distributed to each participating 
site upon receipt of MSK IRB/PB approval. 
Each participating site must obtain IRB approval for all amendments within 90 calendar days 
of MSK IRB/PB approval. If the amendment is the result of a safety issue or makes eligibility 
criteria more restrictive, participating sites will not be permitted to continuing enrolling new 
participants until site IRB approval of the revised protocol documents is granted and 
submitted to MSK. 
 
Each participating site must provide all site IRB approvals for amendments/modifications and 
the most current approved version of the site informed consent form and HIPAA 
authorization at the time of approval. Documents must be submitted to MSK on a continuing 
basis. 
 
16.4.2 Additional  IRB Correspondence 
 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most current 
approved version of the informed consent form and HIPAA authorization must be submitted 
to MSK within 7 days of expiration. Failure to submit the re-approval in the stated timeline will 
result in suspension of new participant enrollment. 
 
Deviations 
A protocol deviation on this study is defined as any incident involving non-adherence to an 
IRB approved protocol. Deviations typically do not have a significant effect on the rights, 
safety, or welfare of research participants or on the integrity of the resultant data. Deviations 
that represent unanticipated problems involving  risks to participants or others, or serious 
adverse events must be reported according to sections 17.2.1. 
 
Deviations that do not adversely affect the rights and/or welfare of the participant or the 
scientific validity of the study and are related to protocol scheduling changes outside of the 
allowed window due to a holiday (e.g., New Year’s, Thanksgiving, etc.) and/or inclement 
weather or other natural event do not require reporting to the MSK IRB/PB.  However, they 
must be clearly documented in the patient’s medical record. 
 
Prospective Deviations 


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IRB Number: 16-1003 A(2) 
Approval date: 27-Aug-2019 
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Deviations to the research protocol that involve patient eligibility,  an informed consent 
procedure change, and/or treatment/pharmacy alterations that are not allowed by the  
protocol require prospective approval from the MSK IRB/PB prior to the change being carried 
out. Participating sites must contact the MSK PI who will in turn seek approval from the MSK 
IRB/PB. 
 
Retrospective Deviations 
Deviations that include a change or departure from the research protocol without prior 
approval from the MSK IRB/PB are considered retrospective deviations. Retrospective 
deviations must be reported to the MSK PI as soon as possible, who will in turn report the 
deviation to the MSK IRB/PB as per MSK guidelines. 
 
Participating Site IRB Reporting 
 
Participating sites must report all deviations to their institution’s IRB per local guidelines. 
Approvals/acknowledgments from the participating site IRB for protocol deviations must be 
submitted to MSK upon receipt. 
 
Other correspondence 
Participating sites must submit other correspondence to their institution’s IRB according to 
local guidelines, and submit copies of all site IRB correspondence, including approvals and 
acknowledgements, to MSK. 
 
16.4.3 Document maintenance 
The MSK PI and participating site PI will maintain adequate and accurate records to enable 
the implementation of the protocol to be fully documented and the data to be subsequently 
verified. 
 
The participating sites will ensure that all regulatory documents and participating site IRB 
correspondences are maintained in an onsite regulatory binder and are sent to MSK as 
outlined within the protocol. A regulatory binder for each site will also be maintained at MSK; 
this binder may be paper or electronic. 
 
After study closure, the participating sites will maintain all source documents, study related 
documents and CRFs for 3 years. 
 
16.5 
Noncompliance 
If a participating site is found to be noncompliant with the protocol document, accrual 
privileges may be suspended and/or contract payments may be withheld (if applicable), until 
the outstanding issues have been resolved. 
 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Participation in this trial is voluntary. All patients or their legal guardians will be required to 
sign a statement of informed consent, which must conform to MSKCC IRB guidelines. The 
informed consent must contain a full explanation of the possible advantages, benefits, risks, 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1003 A(2) 
Approval date: 27-Aug-2019 
Page 17 of 21 
 
 
 
alternative treatment options, and availability of treatment in the case of injury, in accordance 
with Federal Regulations as detailed in 21CFR50. The investigator is responsible for 
obtaining written informed consent from potential patients or legal guardian before  
performing any trial tests or assessments required by the protocol. A copy of the signed 
document will be given to the patient or legal guardian , and the original will be retained by 
the investigator with his/her copy of the record forms. 
 
Given the nature of these tumors, most patients will be children, adolescents, and young 
adults.  Patients of both sexes and all racial/ethnic backgrounds are eligible for this study. 
Alternative treatments are available and will be discussed with the patient or legal guardian. 
 
Benefits: This study is not expected to help treat the cancer, but it may lead to removal of 
extra lymph nodes for analysis. What we learn from this study may help patients in the future. 
 
Risks: The potential risks of this therapy as described in section 11 of this protocol may 
outweigh the potential benefits in an individual patient. The potential risks are related to the 
adverse effects which could be induced by the ICG dye. 
 
Patients or their legal guardians will be charged for the costs for all routine visits, treatment, 
and non-research testing related to the cancer. Patients will not be charged for the ICG dye, 
the preparation, or for use of the specialized camera used as part of the study. 
 
 
17.2 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). The consent indicates  
that individualized de identified information collected for the purposes of this study may be 
shared with other qualified researchers. Only researchers who have received approval from 
MSK will be allowed to access this information which will not include protected health 
information, such as the participant’s name, except for dates. It is also stated in the Research 
Authorization that their research data may be shared with other qualified researchers. 
 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon 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. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1003 A(2) 
Approval date: 27-Aug-2019 
Page 18 of 21 
 
 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the IRB office per 
IRBSOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event.All other SAEs must be submitted within 30 calendar 
days of the event. 
 
 
The report should contain the following information: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) (drug, device, or intervention) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
 
. 
 
17.2.1 SAE Reporting for Participating Sites 
 
Responsibilities of Participating Sites 
 
• 
Participating sites are responsible for reporting all SAEs to their local IRB per local 
guidelines. Local IRB SAE approvals/acknowledgments must be sent to MSK upon receipt. 
• 
Participating sites are responsible for submitting the SAE Report form found in Appendix A to 
MSK within 3 calendar days of learning of the event. 
• 
When a life-threatening event or death is unforeseen and indicates participants or others are 
at increased risk of harm, participating sites should notify the MSK PI as soon as possible but 
within 24 hours of the time the site becomes aware of the event. 
 
 
SAE contact information: 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1003 A(2) 
Approval date: 27-Aug-2019 
Page 19 of 21 
 
 
 
Email: cavallim@mskcc.org to the attention of 16-1003 Research Staff 
AND 
Email: heatont@mskcc.org 
 
 
Responsibilities of MSK 
 
• 
MSK Research Staff are responsible for submitting all SAEs to the MSK IRB/PB as specified 
in 17.2. 
• 
The MSK PI is responsible for informing all participating sites about all unexpected SAEs that 
are either possibly, probably or definitely related to the study intervention within 30 days of 
receiving the stamped SAE from the MSK IRB/PB. 
• 
The MSK PI is responsible for informing all participating sites within 24 hours or on the next 
business day about a life-threatening event or death that is unforeseen and indicates 
participants or others are at increased risk of harm. 
 
17.4 
Unanticipated Problems 
 
Unanticipated problems involving risks to participants or others (UPs) are defined as any 
incident, experience or outcome that meets all of the following criteria: 
• 
Unanticipated (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; and 
• 
Related or possibly related to participating in the research (possibly related means there 
is a reasonable probability that the incident, experience or outcome may have been 
caused by procedures involved in the research); and 
• 
Suggests that the research place participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
 
Participating sites are responsible for reporting all UPs to MSK as soon as possible but within 
3 calendar days of learning of the event. UPs that are SAEs must be reported to MSK via 
SAE Report form as per section 14.3. All other UPs must be reported to MSK in a memo 
signed by the site PI. 
 
MSK is responsible for submitting UPs to the MSK IRB/PB according to institutional 
guidelines. In addition, MSK is responsible for notifying participating sites of all non-SAE UPs 
that may affect the sites. 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain to 
participants the full details of the protocol and study procedures, as well as the risks involved, 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 


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IRB Number: 16-1003 A(2) 
Approval date: 27-Aug-2019 
Page 20 of 21 
 
 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
18.1 
Informed Consent Procedures for Participating Sites 
 
The investigators listed on the Consenting Professionals Lists and/or Delegation of Authority 
Log at each participating site may obtain informed consent and care for the participants 
according to good clinical practice and protocol guidelines. 
 
A note will be placed in the medical record documenting that informed consent was obtained 
for this study, and that the participant acknowledges the risk of participation. 
19.1 
REFERENCES 
 
1. Howman-Giles R, Shaw H, Scolyer R, et al. Sentinel lymph node biopsy in pediatric 
and adolescent cutaneous melanoma patients. Ann SurgOncol. 2010;17:138–143. 
2. Alcorn KM, Deans KJ, Congeni A, et al. Sentinel lymph node biopsy in pediatric soft 
tissue sarcoma patients: utility and concordance with imaging. J Pediatr Surg. 2013; 
48: 1903-6. 
3. Jewell EL, Huang JJ, et al. Detection of sentinel lymph nodes in minimally invasive 
surgery using indocyanine green and near-infrared fluorescence imaging for uterine 
and cervical malignancies. Gynecol Oncol. 2014 May;133(2):274-7. 
4. Imboden S, Papadia A, et al. A comparison of radiocolloid and ICG fluorescent 
imaging, sentinel lymph node mapping in patients with cervical cancer undergoing 
laparoscopic surgery. Ann Surg Oncol. 2015 Dec; 13(6):574-80. 
5. Xiong L, Gazyakan E, et al. Indocyanine green fluorescence-guided sentinel node 
biopsy: a meta-analysis on detection rate and diagnostic performance. Eur J Surg 
Oncol. 2014 Jul;40(7):843-9. 
6. Wishart GC, Loh SW, Jones L, Benson JR. A feasibility study (ICG-10) of indocyanine 
green (ICG) fluorescence mapping for sentinel lymph node detection in early breast 
cancer. Eur J Surg Oncol. 2012 Aug;38(8):651-6. 


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IRB Number: 16-1003 A(2) 
Approval date: 27-Aug-2019 
Page 21 of 21 
 
 
 
7. Liu J, Hsueh H, et al. Tests for equivalence or non-inferiority for paired binary data. 
Statistics in Medicine 2002; 21:231-45. 
8. Patel J, Marks K, et al. Measurement of cerebral blood flow in newborn infants using 
near infrared spectroscopy with indocyanine green. Pediatr Res. 1998 Jan;43(1):34-9 
9. Kusaka T, Isobe K, et al. Estimation of regional cerebral blood flow distribution in 
infants by near-infrared topography using indocyanine green. Neuroimage. 2001 
May;13(5):944-52. 
10. Nagano K, Kusaka T, et al.Estimation of circulating blood volume in infants using the 
pulse dye densitometry method. Paediatr Anaesth. 2005 Feb;15(2):125-30. 
 
 
20.0 
APPENDICES 
 
Appendix A: SAE Report Form