Conditions: Endometrial Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
The goal of this study is to (i) improve detection of sentinel nodes and (ii) reduce additional surgical dissection that is needed in case a sentinel lymph node cannot be detected.

Detailed description:
Primary Objective: To determine the detection rate of bilateral sentinel lymph nodes with the concurrent use of Lymphoseek and Indocyanine Green.

Secondary Objective: (1) To determine the overall detection rate of sentinel lymph nodes with concurrent use of Lymphoseek and Indocyanine Green (2) To determine location and number of Lymphoseek-positive sentinel lymph nodes preoperatively by single-photon emission computed tomography (SPECT/CT imaging) and intraoperatively by a laparoscopic handheld gamma detection device and near- infrared fluorescent imaging (3) To determine the concordance of Lymphoseek-positive sentinel lymph nodes with intraoperatively detected Indocyanine Green-positive sentinel lymph nodes.

Arms:
arm 1: The subject will receive f 0.5 mL each Lymphoseek into the uterine cervix prior to surgery and subsequent SPECT/CT imaging preoperatively. Intraoperatively, following anesthesia induction, Indocyanine Green (0.5 mL) will be injected into the uterine cervix. Using near-infrared imaging, efferent lymphatic vessels and lymph nodes will be visualized and confirmed by detected radioactivity using a laparoscopic gamma counter. The preoperatively obtained SPECT/CT images will help guide the surgery.

Interventions: intervention 1: Lymphoseek intervention 2: Single Photon Emission Computed Tomography (SPECT) intervention 3: Indocyanine Green (ICG) intervention 4: Neoprobe Gamma Detection System NPB11L(Model1102)
Intervention descriptions: intervention 1: Radioactive diagnostic agent intervention 2: Imaging test intervention 3: Cyanine dye used in medical diagnostics manufactured by Akorn Inc. intervention 4: Neoprobe Gamma Detection System NPB11L(Model1102) made by Devicor Medical Products, Inc.

Protocol document:
Prot_SAP_000.pdf: 
Concurrent Use of Lymphoseek and Indocyanine Green for Sentinel Lymph 
Node Detection in Endometrial Cancer - a Prospective Study   
Study Protocol and Statistical Analysis Plan 
NCT04511026 
March 9, 2021 


 
 
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Concurrent use of Lymphoseek and Indocyanine Green for sentinel lymph node detection 
in endometrial cancer – a prospective study 
 
 
 
Coordinating Center 
 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
 
 
 
Protocol Director  
 
Amer Karam, MD 
Gynecologic Oncology Division 
Stanford Cancer Center 
650-724-0456 
650-736-0902 
amkaram@stanford.edu 
 
 
Co-Investigators 
 
Oliver Dorigo, MD, PhD 
Gynecologic Oncology Division 
Stanford Cancer Center 
650-724-0456 
650-736-0902 
odorigo@stanford.edu 
 
Nelson Teng, MD, PhD 
Gynecologic Oncology Division 
Stanford Cancer Center 
650-723-7334 
650-723-7737 
teng@stanford.edu 
 
Elisabeth Diver, MD 
Gynecologic Oncology Division 
Stanford Cancer Center 
650-724-0456 
650-736-0902 
elisabeth.diver@stanford.edu 


 
 
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Babak Litkouhi, MD 
Gynecologic Oncology Division 
Stanford Cancer Center 
650-724-0456 
650-736-0902 
blitkouhi@stanford.edu 
 
Andrei Iagaru, MD 
Nuclear Medicine and Molecular Imaging Division 
Stanford University School of Medicine  
650-725-4711 
650-498-5047 
aiagaru@stanford.edu 
 
Malte Renz, MD, PhD 
Gynecologic Oncology Division 
Stanford University School of Medicine 
650-724-0456 
650-736-0902 
renzmalt@stanford.edu 
 
 
Biostatistician 
Stephanie A.Leonard, PhD 
Maternal and Fetal Medicine Division 
                                               Department of Obstetrics and Gynecology 
Stanford University School of Medicine 
650-721-4329 
stephanie.leonard@stanford.edu 
 
 
Study Coordinator 
 
Neha Aidasani 
Cancer Clinical Trial Office 
Stanford Cancer Center 
650-723-0622 
aidasani@stanford.edu 
 
 
 
 
 
 
 
 
 
             SRC Approval Date:  02/11/2020 


 
 
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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................. 5 
SCHEMA ....................................................................................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 8 
1. OBJECTIVES ........................................................................................................................ 9 
1.1 
PRIMARY OBJECTIVE ......................................................................................................... 9 
1.2 
SECONDARY OBJECTIVES ................................................................................................... 9 
2. BACKGROUND .................................................................................................................... 9 
2.1 STUDY DISEASE .................................................................................................................. 9 
2.1.1     TRACERS FOR SENTINEL LYMPH NODE DETECTION ............................................. 10 
2.2     STUDY AGENT - LYMPHOSEEK ...................................................................................... 11 
2.3 RATIONALE ....................................................................................................................... 11 
2.4 STUDY DESIGN ................................................................................................................. 12 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ....................... 12 
3.1 INCLUSION CRITERIA ........................................................................................................ 12 
3.2 EXCLUSION CRITERIA ....................................................................................................... 12 
3.3 INFORMED CONSENT PROCESS .......................................................................................... 12 
3.4 STUDY TIMELINE .............................................................................................................. 13 
4. TREATMENT PLAN .......................................................................................................... 13 
4.1 CRITERIA FOR REMOVAL FROM STUDY ............................................................................. 14 
4.2 ALTERNATIVES ................................................................................................................. 14 
5. INVESTIGATIONAL AGENT/ PROCEDURE INFORMATION ................................ 15 
5.1 
 LYMPHOSEEK ................................................................................................................ 15 
5.1.1  HANDLING AND DISPENSING OF LYMPHOSEEK ........................................................ 15 
5.1.2  PREPARATION AND ADMINISTRATION OF LYMPHOSEEK ....................................... 15 
5.2 
INDOCYANINE GREEN ................................................................................................... 16 
5.2.1  HANDLING AND DISPENSING OF INDOCYANINE GREEN .......................................... 16 
5.2.2  PREPARATION AND ADMINISTRATION OF INDOCYANINE GREEN ......................... 16 
5.3 
AVAILABILITY ............................................................................................................... 16 
6. DOSE MODIFICATIONS .................................................................................................. 16 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ............................................ 16 
7.1 POTENTIAL ADVERSE EVENTS .......................................................................................... 16 
7.1.1 POTENTIAL ADVERSE EVENTS ASSOCIATED WITH LYMPHOSEEK ............................... 16 
7.1.1.1   POTENTIAL RADIATION RISKS WITH LYMPHOSEEK ............................................... 17 
7.1.2 POTENTIAL ADVERSE EVENTS ASSOCIATED WITH INDOCYANINE GREEN ................. 17 
7.2 ADVERSE EVENT REPORTING............................................................................................ 17 
8. STUDY CALENDAR .......................................................................................................... 18 
9. 
MEASUREMENTS ........................................................................................................... 19 
9.1  
PRIMARY AND SECONDARY OUTCOME MEASURES ......................................................... 19 
9.2  
SECONDARY OUTCOME .................................................................................................. 20 


 
 
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10. REGULATORY CONSIDERATIONS ........................................................................... 20 
10.1 INSTITUTIONAL REVIEW OF PROTOCOL ........................................................................... 20 
10.2 DATA AND SAFETY MONITORING PLAN .......................................................................... 20 
10.3 DATA MANAGEMENT PLAN ............................................................................................ 21 
11. STATISTICAL CONSIDERATIONS ............................................................................. 21 
11.1 STATISTICAL DESIGN ...................................................................................................... 21 
11.2 INTERIM ANALYSES ......................................................................................................... 21 
11.3 DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS .................................... 21 
11.4 PRIMARY ANALYSIS ........................................................................................................ 20 
11.4.1 ANALYSIS POPULATION ............................................................................................... 20 
11.4.2 ANALYSIS PLAN ............................................................................................................. 21 
11.5 SECONDARY ANALYSIS ................................................................................................... 22 
11.5.1 ANALYSIS POPULATION ............................................................................................... 21 
11.5.2 ANALYSIS PLAN ............................................................................................................. 21 
11.6  SAMPLE SIZE .................................................................................................................. 22 
11.6 .1 ACCRUAL ESTIMATES ................................................................................................ 22 
11.6 .2 SAMPLE SIZE JUSTIFICATION .................................................................................... 22 
11.6 .3 EFFECT SIZE JUSTIFICATION ...................................................................................... 22 
12. REFERENCES ................................................................................................................... 24 
APPENDICES ............................................................................................................................. 25 
APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST ............................................................. 25 


 
 
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PROTOCOL SYNOPSIS 
 
TITLE 
Concurrent use of Lymphoseek and Indocyanine Green for 
sentinel lymph node detection in endometrial cancer – a 
prospective study 
STUDY PHASE 
Feasibility 
INDICATION 
Sentinel lymph node sampling in clinically uterine confined 
early-stage endometrial cancer 
INVESTIGATIONAL 
PRODUCT OR 
PROCEDURE 
Concurrent use of Lymphoseek and Indocyanine Green in 
minimally invasive surgery 
PRIMARY 
OBJECTIVE(S) 
To determine the detection rate of bilateral sentinel lymph nodes 
with the concurrent use of Lymphoseek and Indocyanine Green 
as compared to each agent alon. 
SECONDARY 
OBJECTIVE(S) 
(1) To determine the overall detection rate of sentinel lymph 
nodes with concurrent use of Lymphoseek and Indocyanine 
Green 
(2) To determine location and number of Lymphoseek-positive 
sentinel lymph nodes preoperatively by single-photon emission 
computed tomography (SPECT/CT imaging) and intraoperatively 
by a laparoscopic handheld gamma detection 
(3) To determine the location and number of Indocyanine Green-
positive sentinel lymph nodes by intraoperative infrared 
fluorescent imaging 
(4) To determine the concordance of Lymphoseek-positive 
sentinel lymph nodes with intraoperatively detected Indocyanine 
Green-positive sentinel lymph nodes, and vice versa, the 
concordance of Indocyanine Green-positive sentinel lymph nodes 
with Lymphoseek-positive sentinel lymph nodes. 
(5) To assess the safety of the concurrent use of Lymphoseek and 
Indocyanine Green 
TREATMENT 
SUMMARY 
Sentinel lymph node assessment 
- 
Preoperatively, within 24 hours prior to surgery, the subject 
will receive in the nuclear medicine suite of Stanford Hospital 
injections of 0.125 mCi or 0.5 mCi  each Lymphoseek into 
the uterine cervix at 3, 6, 9, and 12 o’clock. Immediate and 
delayed static planar images will be obtained with and 
without a transmission source. SPECT-CT of the abdomen 
and pelvis will be obtained for further characterization. 
- 
Subjects will then undergo minimally invasive endometrial 
cancer surgery. The SPECT/ CT images will be available for 
review to the surgeon prior to the start of the surgery.  
- 
In the operating room, following anesthesia induction, the 
uterine cervix will be injected with 0.5 mL each of 
Indocyanine Green at positions of 3, 6, 9, and 12 o’clock. 
- 
The surgery will start with the identification and dissection of 


 
 
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sentinel lymph nodes using near infrared imaging and the 
gamma probe.  
SAMPLE SIZE  
30 patients over 1 year 
STATISTICAL 
CONSIDERATIONS 
The analysis population will include all patients who complete 
the study procedures specified above. We do not expect missing 
data or loss-to-follow up since the outcome is ascertained at the 
time of surgery. Patients who do not adhere to the study treatment 
plan of both injections, SPECT/CT and surgery with sentinel 
lymph node assessment will not be included in the analysis 
population. 
To address our primary objective, we plan to enroll 30 patients 
with concurrent use of lymphoseek and indocyanine green over 1 
year. The primary analysis is the calculation of the bilateral SLN 
detection rate which will be calculated as the number of patients 
with bilateral SLN detection divided by the total number of 
patients.  
With 30 participants and assuming a true bilateral detection rate 
of 80%, the probability of correctly concluding that our approach 
has an acceptable bilateral detection rate (i.e., 24 patients being 
detected with bilateral SLNs) is 61%. The probability of 
incorrectly concluding this (assuming that the true detection rate 
is 69%) is low at 13%. We will deem the approach used in this 
study promising if we observe a bilateral detection rate of at least 
80%. 
 
 


 
 
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SCHEMA 


 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
 
ADL 
Activities of daily living 
AE 
Adverse event 
BSA 
Body surface area 
CBC 
Complete blood count 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CRF 
Case report/Record form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
EMCA 
Endometrial cancer  
FDA 
Food and Drug Administration 
FIGO 
International Federation of Gynecology and 
Obstetrics 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
IC-GREEN 
Indocyanine Green 
IRB 
Institutional Review Board 
IV 
Intravenous 
OP 
Operative 
OR 
Operation room 
PANES 
Preoperative anesthesia 
PD 
Protocol Director 
PLT 
Platelet 
SAE 
Serious adverse event 
SLN 
Sentinel lymph node 
SPECT/CT 
Single-photon emission computed tomography 
SRC 
Scientific Review Committee  
Tc 99m 
Technetium 99m 
WBC 
White blood cell 
WHO 
World Health Organization 
 


 
 
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1. 
OBJECTIVES 
 
1.1 
Primary Objective  
 
To determine the detection rate of bilateral sentinel lymph nodes with the concurrent use of 
Lymphoseek and Indocyanine Green. 
 
1.2 
Secondary Objectives 
 
 
(1) To determine the overall detection rate of sentinel lymph nodes with concurrent use of 
Lymphoseek and Indocyanine Green; 
(2) To determine the location and number of Lymphoseek-positive sentinel lymph nodes 
preoperatively by single-photon emission computed tomography (SPECT/CT imaging) and 
intraoperatively by a laparoscopic handheld gamma detection device and near-infra-red 
fluorescent imaging; 
(3) To determine the concordance of Lymphoseek-positive sentinel lymph nodes detected by 
SPECT/CT and/or gamma probe with intraoperatively detected Indocyanine Green-positive 
sentinel lymph nodes, as well as reverse concordance. 
(4) To assess the safety of the concurrent use of Lymphoseek and Indocyanine Green. 
 
 
 
2. 
BACKGROUND 
 
2.1 
Study Disease 
 
Endometrial cancer accounts for 50% of all gynecological malignancies in the US. The 
majority are diagnosed at an early stage. Although clinically locally confined, endometrial 
cancers may have microscopically spread to lymph nodes; therefore, International Federation of 
Gynecology and Obstetrics (FIGO) revised the endometrial cancer staging in 1988 to make it a 
surgical staging system and included a complete pelvic lymphadenectomy [1]. Despite the 
increased accuracy in staging, complete lymphadenectomy has not been shown in randomized 
trials to increase progression-free or overall survival [2, 3]. Instead, complete lymphadenectomy 
carries the risk of increased morbidity, including lymph edema and nerve damage. To reduce this 
morbidity while maintaining prognostic information, the concept of sentinel lymph node (SLN) 
sampling has been introduced [4, 5].  
Various tracers have been used to identify the first draining lymph node, the sentinel 
lymph node, and assess for tumor involvement. In the thus-far largest multicenter prospective 
trial, detection rates for SLNs in minimally invasive surgery for endometrial cancer using 
Indocyanine Green alone have been reported as only 52% bilaterally and 86% overall [6]. Our 
own institutional data shows detection rates using Indocyanine Green of 69% and 88%, 
bilaterally and overall, respectively [7]. If a sentinel lymph node is detected, surgery is restricted 
to the removal of the SLN and a complete lymphadenectomy is avoided. If no lymph nodes are 
mapped, current guidelines recommend a complete lymphadenectomy on the side where no 
sentinel lymph node was detected. Thus, for 30-50% of patients the morbidity of a complete 
lymphadenectomy cannot be avoided.   


 
 
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2.1.1 Tracers for sentinel lymph node detection 
 
Historically, sentinel lymph node sampling was first described in the late 70’s for penile 
cancer using the injection of radiocolloids [8]. Subsequently, sentinel lymph node sampling has 
become standard of care in cutaneous melanoma and breast cancer [9, 10]. Vulva cancer was the 
first gynecologic malignancy where sentinel lymph node sampling was tested [11, 12]. The role 
of sentinel lymph node mapping in endometrial carcinoma is under evaluation [13].  
In endometrial cancer, as in all other cancer entities, radioactive tracers, or dyes, either 
non-fluorescent or fluorescent, or combinations of radioactive tracers and dyes have been 
employed. The radioactive tracers used are filtered or non-filtered sulfur colloids, most 
commonly radiolabeled with technetium-99m (Tc 99m). The major advantage of radioactive 
tracers is deep tissue penetration and the ability to detect sentinel lymph node locations 
preoperatively. Reported overall detection rates are 92-96% with a bilateral detection rate of 73-
80% [14, 15]. Concerns regarding the use of radioactive colloids are (i) the unspecific and 
passive distribution of the tracer colloids throughout the lymphatic system by lymph flow and/or 
diffusion which diminishes the retention of the tracer in the first draining lymph node and results 
in the leakage of radiotracers to subsequent lymph nodes and thereby the detection of the second 
or third lymph node stations instead of the actual sentinel lymph node; (ii) the need for 
preoperative injection and imaging; and (iii) the handling of radioactivity.  
To simplify the intraoperative detection and avoid the use of laparoscopic gamma 
counters, various dyes have become available, i.e. Isosulfan Blue 1%, Methylene Blue 1%, 
Patent Blue 2.5% sodium. Isosulfan Blue is the only dye that has been FDA-approved for 
sentinel lymph node detection. Overall and bilateral detection rates have been reported at 63-
78% and 40-46%, respectively [16-18]. Disadvantages of Isosulfan Blue are (i) the costs, (ii) a 
significant risk of an anaphylactic reaction (1.1%) and (iii) the comparably poor deep tissue 
penetration, especially of fat tissue. There is evidence from breast cancer on the equivalence of 
Methylene Blue and Isosulfan Blue [19] and reported overall and bilateral detection rate for 
Methylene Blue in robotic-assisted laparoscopic surgery in endometrial cancer are 86% and 52% 
[20]. Methylene Blue is less expensive, and has a lower, but still significant risk of allergic 
reactions. Furthermore, combinations of blue dyes and radioactive tracer colloids have been used 
in endometrial cancer, with reported overall and bilateral detection rates of 90-97% and 65-76%, 
respectively [21-23].  
Recently, Indocyanine Green has emerged as useful imaging dye that requires a near-
infrared camera for localization. One main advantage of a near-infrared fluorescent dye over a 
blue dye is the improved visibility through visceral fat. Overall and bilateral detection rates have 
been reported as 86-96% and 52-88%, respectively [6, 16, 18, 24, 25]. Compared to blue dyes, 
allergic reactions are very rare. Indocyanine Green is now commonly used in many practices 
[13]. However, the thus-far largest prospective multi-center study, the FIRES study, reports an 
overall detection rate of 86% and a 52% bilateral detection rate only. Higher detection rates have 
mainly been reported by single-center studies. Disadvantages of Indocyanine green are (i) the 
required special equipment, i.e. near-infrared camera, and (ii) the problem of leakage which is 
inherent to all unspecific radioactive and colored tracers and thereby the diminished retention in 
the first draining lymph nodes and the possibility of detecting lymph nodes subsequent in the 
lymph node chain.  
 


 
 
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2.2  
Study agent - Lymphoseek 
 
(99m)Tc-diethylenetriaminepentaacetic acid (DTPA)--mannosyl-dextran (Lymphoseek) 
was first synthesized and described in 2001 by Vera et al. [26]. In contrast to all other dyes and 
tracers used in sentinel lymph node detection, this synthetic radiotracer was specifically designed 
for sentinel lymph node mapping. The molecule has a molecular weight of 35.8 kDa and a 
diameter of 7.1 nm and consists of a dextran backbone and 8 DTPA groups. The DTPA groups 
are used for the chelation of Tc 99m Technetium. 
55 mannose residues are covalently bound to the dextran backbone. These 55 mannose 
residues provide high receptor affinity to the mannose receptor CD 206 which is highly enriched 
on the surface of macrophages and dendritic cells. Lymphoseek has a dissociation constant of 
0.12 nmol/L. This low dissociation constant ensures the effective uptake of the agent by the 
lymph node and improved retention and thus a lower distal lymph node accumulation than seen 
for the nonreceptor-targeted filtered Tc 99m-sulfur colloid [27]. Accordingly, Lymphoseek 
accumulates in fewer lymph nodes with higher specificity [28]. 
Furthermore, the dextran backbone guarantees rapid injection site clearance which entails 
the rapid diffusion from the injection site through lymph and blood vessels. In fact, neutral 
dextrans show an interstitial diffusion coefficient 10-fold greater than for proteins of the same 
hydrodynamic radius, a property which has been attributed to hydrophilicity and flexibility of the 
dextrans and the absence of charge. A radiotracer that clears more rapidly from the injection site, 
even if the tracer delivers equal activity to the sentinel node, will provide higher signal-to-noise 
ratio by reducing the unspecific background and thus better a detection rate than an agent with 
slower clearance [27].  
While Lymphoseek has been FDA-approved in breast cancer, melanoma, and head and 
neck cancer [29], no published studies exist for the use of Lymphoseek in endometrial cancer. 
 
2.3 
Rationale 
 
Lymphoseek is the first FDA-approved receptor-targeted lymphatic mapping agent. 
Lymphoseek is a small synthetic molecule that carries multiple mannose residues and is 
specifically recognized by the mannose receptor which is highly enriched on the cell surface of 
macrophages and dendritic cells. High-affinity receptor binding, guarantees 100% extraction of 
the agent by the lymph node and abrogates tracer leakage and distal lymph node accumulation. 
In addition to its SLN superior accumulation as a consequence of specific lymph node uptake, 
through rapid interstitial passive diffusion and lymph drainage, Lymphoseek clears the injection 
site within 10 minutes and accumulates in sentinel lymph nodes where it remains bound for up to 
30 hours.  
We hypothesize that through these different mechanisms of action, the implementation of 
Lymphoseek into our sentinel lymph node algorithm for endometrial cancer will significantly 
improve bilateral and overall detection rates. The preoperative imaging using SPECT/CT and not 
only planar lymphoscintigraphy will furthermore provide critical preoperative information about 
the location of sentinel lymph nodes, which is especially important in scenarios where the 
sentinel lymph node maps to atypical locations such as the pre-sacral and para-aortic regions 
[30]. The true incidence of these less frequent sentinel lymph node locations is unknown, since 
they cannot be reliably assessed using thus-far available tracers including nonspecific radioactive 


 
 
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tracers, or fluorescent or non-fluorescent dyes. With the a-priori knowledge of the preoperative 
SPECT/CT imaging, the intraoperative use of Indocyanine Green will continue to visually guide 
the surgeon in situ. A laparoscopic gamma counter will help confirm thus identified sentinel 
lymph nodes and the removal in their entirety. We believe that the proposed combined approach 
of Lymphoseek and Indocyanine Green will improve sentinel lymph node detection rates and 
thereby decrease the surgical morbidity associated with a complete lymphadenectomy. 
 
 
2.4 
Study Design 
 
This is an open-label, single-center single-group prospective diagnostic trial.  
 
 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 
 Refer to the Participant Eligibility Checklist in Appendix A.  
 
3.1 
Inclusion Criteria 
 
• The patient has histological diagnosis of cancer of the endometrium of any histology 
or grade. 
• The patient should have received no prior treatment for her endometrial cancer. 
• The patient has clinically uterine confined disease. 
• The patient is a candidate for minimal invasive surgery, with sentinel lymph node 
assessment with IC-GREEN planned as part of standard of care. 
• The patient has an Eastern Cooperative Group (ECOG) performance status of 0-2. 
• If age less than or equal to 55 years, the patient has a negative pregnancy test within 
72 hours before administration of Lymphoseek, has been surgically sterilized, or has 
been postmenopausal for at least 1 year. 
• The patient has provided written informed consent. 
• The patient is at least 18 years of age at the time of consent. 
 
3.2 
Exclusion Criteria 
 
• 
The patient has clinical or radiological evidence of metastatic disease. 
• 
The patient has a known hypersensitivity to Indocyanine Green and/or Lymphoseek. 
• 
The patient has a history of a prior loop electrosurgical excision procedure (LEEP) or 
cone procedure performed on her cervix. 
• 
The patient has participated in another investigational drug study within 30 days of 
scheduled surgery. 
• 
The patient has an iodine allergy. 
• 
The patient is pregnant or lactating. 
 
3.3 
Informed Consent Process 
 
All participants must be provided a consent form describing the study with sufficient 


 
 
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information for participants to make an informed decision regarding their participation.  
Participants must sign the IRB approved informed consent prior to participation in any study 
specific procedure. The participant must receive a copy of the signed and dated consent 
document.  The original signed copy of the consent document must be retained in the medical 
record or research file.  
 
 
3.4 
Study Timeline 
 
Primary Completion: 
 
The study will reach primary completion 12 months from the time the study opens to accrual. 
 
Study Completion: 
 
The study will reach study completion 24 months from the time the study opens to accrual.  
 
 
4. 
TREATMENT PLAN 
 
In this study, the patient will receive cervical injections of Lymphoseek 1 – 24 hours 
prior to surgery and subsequent SPECT/CT imaging preoperatively. Intraoperatively, following 
anesthesia induction, Indocyanine Green will be injected into the uterine cervix. Using near-
infrared imaging, efferent lymphatic vessels and lymph nodes will be visualized and confirmed 
by detected radioactivity using a laparoscopic gamma counter. The preoperatively obtained 
SPECT/CT images will help guide the surgery. The laparoscopic gamma counter will confirm 
that sentinel lymph node tissue was removed by recording gamma counts before and after lymph 
node removal. 
 
Subject participation in this study comprises the following: 
 
• Screening 
 
- 
Screening begins after informed consent is obtained. 
- 
The screening window is Day 1 to Day 42 after signing of informed consent. 
- 
Screening assesses the subject’s eligibility to participate as determined by 
inclusion/ exclusion criteria. 
 
• Sentinel lymph node assessment 
 
- 
Preoperatively, 1 - 24 hrs prior to surgery, the patient will receive in the nuclear 
medicine suite of Stanford Hospital injections of 0.125 mCi or 0.5 mCi  mL each 
Lymphoseek into the uterine cervix at 3, 6, 9, and 12 o’clock. Then, the patient 
will undergo SPECT/ CT imaging. Immediate and delayed static planar images 
will be obtained with and without a transmission source. SPECT-CT of the 
abdomen and pelvis will be obtained for further characterization. The imaging 
process will take approximately 1 hour. 


 
 
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- 
The patient will undergo minimally invasive endometrial cancer surgery. The 
SPECT/ CT images will be available for review to the surgeon prior to the start of 
the surgery.  
- 
In the operating room, following anesthesia induction, the uterine cervix of the 
patient will be injected with about 2.0 mL total of Indocyanine Green. The 
surgery will start with the identification and dissection of sentinel lymph nodes.  
 
• Follow up (duration of the study) 
- 
The patient will be observed preoperatively after Lymphoseek injection in the 
nuclear medicine suite and postoperatively in the recovery room for possible 
allergic reactions or any other adverse events.  
- 
There will be a routine postoperative visit to be performed that will be conducted 
in person or remotely via telemedicine between 14-28 days after surgery. This 
will be a telemedicine visit where the patient will collect the weight, vitals and the 
physical examination and AE evaluation will be conducted by assistance of the 
physician remotely. There are no risks to participants for missing any follow up 
procedures that can’t be conducted remotely. 
 
4.1 
Criteria for Removal from Study 
 
Subjects MUST discontinue study treatment by cancelling the tilmanocept injection and 
SPECT/CT scan for any of the following reasons: 
 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
• Any clinical AE, laboratory abnormality, or intercurrent illness that, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of 
the subject. 
• Discovery of metastatic disease in the operating room. 
• Pregnancy. 
• Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness. 
 
All subjects who discontinue study treatment should comply with protocol-specified 
follow-up procedures as outlined in Section 7.2. The only exception to this requirement is 
when a subject withdraws consent for all study procedures or loses the ability to consent 
freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric 
or physical illness). If a subject was withdrawn before completing the study, the reason for 
withdrawal must be entered on the appropriate case report form (CRF) page. 
 
4.2 
Alternatives 
 
Injection with Indocyanine Green alone for sentinel lymph node mapping and biopsy in 
clinical uterine confined endometrial cancer is currently considered standard of care.  


 
 
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5. 
INVESTIGATIONAL AGENTS 
 
5.1 
Lymphoseek   
 
 
Kit for the preparation of Lymphoseek contains five Tilmanocept Powder vials, each 
contain 250 mcg of tilmanocept from which 50 mcg is intended for administration to a patient. 
 
5.1.1  Handling and dispensing of Lymphoseek 
 
Lymphoseek must be stored in a secure area according to local regulations.  It must be 
stored in the original packaging at controlled room temperature 20-25° C, excursions permitted to 
15-30° C. Radiolabeled Lymphoseek must be stored in radiation shielding at room temperature 
and used within 6 hours of preparation.  
Waterproof gloves, effective radiation shielding, and appropriate safety measures will be 
used when preparing and handling Lymphoseek. As a radiopharmaceutical Lymphoseek will be 
used under the control of physicians who are qualified by specific training and experience in the 
safe use and handling of radionuclides, and whose experience and training have been approved by 
the appropriate governmental agency authorized to license the use of radionuclides. 
 
5.1.2 Preparation and administration of Lymphoseek 
 
Each patient will receive 4 injections of 0.125 mCi into the cervix at the 12, 3, 6, and 9 
o’clock positions for the same day of surgery (0.125 mCi x 4 or 0.5 mCi +/- 20%) for the same 
day of surgery.  
Each patient will receive 4 injections of 0.5 mCi into the cervix at 12, 3, 6, and 9 o’ clock 
positions for the next day surgery (0.5 mCi x 4 or 2.0 mCi +/- 20%) for the next day of surgery. 
As per manufacturer’s instructions, the reconstitution volume will be 2.5 mL.  
 
 
Radiolabeling 
Technetium Tc 99m pertechnetate, the sodium injection solution from a technetium Tc 
99m generator within 8 hours of its elution will be used. Using a sterile syringe, approximately 
92.5 MBq (2.5 mCi) of Technetium Tc 99m pertechnetate sodium injection solution will be drawn 
in 0.7 mL volume. The syringe will be assayed for technetium Tc 99m activity in a dose 
calibrator. The radioactivity amount, the vial volume, date and time, expiration time and lot 
number will be written on the radioactive product vial label and affixed to the Tilmanocept 
Powder vial. The vial will be placed in a radiation shield, the septum sanitized with an alcohol 
wipe. 
Under aseptic conditions the Technetium Tc 99m pertechnetate sodium injection solution 
will be added to the Tilmanocept Powder vial. Without withdrawing the needle, an equal volume 
of headspace gas will be removed. After removing the needle, the vial will be gently shaken to 
mix contents and then incubated at room temperature for at least 15 minutes. 
  
Reconstitution 


 
 
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Then, the supplied DILUENT for Lymphoseek will be added aseptically to the 
radiolabeled product in the Tilmanocept Powder vial to bring the volume to the reconstituted vial 
volume of 2.5 mL prior to filling the patient dose in syringe(s). To normalize pressure, withdraw 
an equal volume of headspace gas. 
 
For quality control, the reconstituted vial will be assayed for total radioactivity using a 
dose calibrator. The activity of the syringes will be assayed in the dose calibrator before 
application to the patient. 
 
Physical Characteristics 
Technetium Tc 99m decays by isomeric transition with a half-life of approximately 6 
hours. The principal photon that is useful for detection and imaging studies is Gamma-2 with a 
mean energy of 140.5 keV and a mean disintegration of 89.1%. 
 
External Radiation 
The linear mass energy absorption attenuation coefficient for Tc 99m is 18.9 cm-1. The 
first half-value layer is 0.037 cm of lead (Pb). The use of a 0.25 cm thick standard radiation lead 
shield will attenuate the radiation emitted by millicurie amounts of technetium Tc 99m by a factor 
of about 100. The half-life of technetium Tc 99m is approximately six hours.  
 
5.2 
Indocyanine Green 
 
 
Indocyanine Green (IC-GREEN®) is a sterile, lyophilized green powder containing 25 
mg of Indocyanine Green with no more than 5% sodium iodide. Indocyanine Green (IC-
GREEN®) is supplied in a kit containing six 25-mg Indocyanine Green (IC-GREEN®) vials and 
six 10-mL sterile water for injection, USP ampules.  
 
5.2.1  Handling and dispensing of Indocyanine Green 
 
As with all injectable drugs, care should be taken when handling and preparing 
Indocyanine Green. Whenever possible, it should be prepared in a laminar flow hood or safety 
cabinet using standard precautions for the safe handling of injectable agents, applying aseptic 
technique.   
The Indocyanine Green (IC-GREEN®) powder should be dissolved with the sterile water 
for injection, USP provided and the solution should be used within 6 hours after it is prepared. 
The Indocyanine Green (IC-GREEN®) kit will be stored at 20-25°C. 
 
5.2.2 Preparation and administration of Indocyanine Green 
 
 
Cervical injection by the investigator of 0.5 mL each of the 0.5 mg/mL Indocyanine 
Green solution at 12, 3, 6, and 9 o’clock follows anesthesia induction. 
 
5.3 
Availability 
 
Lymphoseek will be provided already reconstituted and radiolabeled by outside pharmacy. 
Indocyanine Green (IC-GREEN ®) will be provided by the Pharmacy of Stanford Hospital and 


 
 
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prepared in the operating room by the registered nurse in the usual fashion. 
 
 
6. 
DOSE MODIFICATIONS 
 
There will not be any dose modifications for either Lymphoseek or Indocyanine Green. If 
anaphylactic or urticarial reactions occur, the patient will be treated with the appropriate agents, 
e.g. epinephrine, antihistamines, and corticosteroids. 
 
 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
 
7.1 
Potential Adverse Events  
 
7.1.1 Potential Adverse Events associated with Lymphoseek 
 
The most common adverse reactions (incidence <1%) are injection site irritation and/or 
pain. In open label, single-arm clinical trials, 553 patients with either breast cancer, melanoma, 
or squamous cell carcinoma of the oral cavity, skin, lip received Lymphoseek. No patient 
experienced serious adverse reaction. Injection site irritation (0.7%) and pain (0.2%) were 
reported [29]. 
Lymphoseek may pose a risk of hypersensitivity reactions due to its chemical similarity 
to dextran. No hypersensitivity reactions have been reported in the literature.  
 
7.1.1.1  
Radiation Risks with Lymphoseek 
 
Any radiation-emitting product may increase the risk for cancer. Adherence to dose 
recommendations and safe handling will minimize the risk of excessive radiation exposure to 
either patients or health care workers which includes the radiation exposure in the operating 
room (OR). No additional protection for the OR staff is required.  
 
7.1.2 Potential Adverse Events associated with Indocyanine Green 
 
Most common adverse reactions are anaphylactic or urticarial reactions. They have been 
reported in patients with and without history of allergy to iodine. If such reactions occur, the 
patient will be treated with the appropriate agents, e.g. epinephrine, antihistamines, and 
corticosteroids. In breast cancer and melanoma, extensive information on Lymphoseek’s safety 
exist but we will continue to monitor and report its safety in this population. Monitoring for 
adverse events to Lymphoseek will start after its injection into the uterine cervix. 
 
7.2 
Adverse Event Reporting 
 
Adverse events will be graded according to CTCAE v4.03.  Both Serious and Non-
Serious Adverse Events will be clearly noted in source documentation and listed on study 
specific Case Report Forms (CRFs).  The Protocol Director (PD) or designee will assess each 
Adverse Event (AE) to determine whether it is unexpected according to the Informed Consent, 


 
 
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Protocol Document, or Investigator’s Brochure, and related to the investigation. All Serious 
Adverse Events (SAEs) will be tracked until resolution, or until 30 after the last dose of the study 
treatment. 
SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported 
to the Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study 
specific CRF regardless of the event’s relatedness to the investigation. Following review by the 
DSMC, events meeting the IRB definition of ‘Unanticipated Problem’ will be reported to the 
IRB using eProtocol within 10 working days of DSMC review, or within 5 working days for 
deaths or life-threatening experiences.  


 
 
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8. 
STUDY CALENDAR 
   
Pre-Study 
0 – 42 days before 
surgery 
 
Pre-OP 
1 – 24 hours 
before surgery 
 
 
Intra- OP 
Post-OP/ Off 
Studyd 
14 – 28 days after 
surgery 
 
Lymphoseek injection 
 
 
 
Xa 
 
 
 
 
IC-GREEN injection 
 
 
 
Xb 
 
 
Informed consent 
 
X 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
Physical exam 
 
X 
 
 
 
X 
 
Vital signs 
 
X 
 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
Weight 
 
X 
 
 
 
X 
 
Performance status 
 
X 
 
 
 
 
 
Adverse event 
evaluation 
 
 
 
X 
 
X 
 
X 
 
SPECT/CT imaging 
 
 
 
X 
 
 
 
 
Laparoscopic gamma 
detection 
 
 
 
X 
 
 
Laparoscopic near-
infrared fluorescence 
detection 
 
 
   
X 
 
 
B-HCG 
 
 
Xc 
 
 
 
 
a: Lymphoseek: 0.125 mCi x 4 each at 3, 6, 9, 12 o’clock (or 0.5 mCi +/- 20%) in the uterine cervix 
for same day surgery;  
0.5 mCi x 4 each at 3, 6, 9, 12 o’clock (or 2.0 mCi +/- 20% ) in the uterine cervix for next day surgery 
b:   IC-GREEN: injection of 0.5 mL each at 3, 6, 9, 12 o’clock in the uterine cervix after induction of 
anesthesia. 
c: Serum or urine pregnancy test (women of childbearing potential). 
d: Off-study evaluation at postop visit, i.e., 14 – 28 days after surgery, in person or remote telemedicine 
visit.   


 
 
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9. 
MEASUREMENTS 
 
9.1 
Primary Outcome 
 
Bilateral SLN Detection (yes/no): For each subject, an assessment will be made of whether there 
was bilateral sentinel lymph node detection. A sentinel lymph node will be defined as being 
detected if it is detected on the pre-operative SPECT/CT imaging scan or intraoperatively using 
near-infrared imaging or the handheld gamma detection device. If at least one SLN is detected on 
each side, then this outcome will be considered a ‘Yes’. 
 
9.2  
Secondary Outcome 
(1) Overall detection (yes/no): For each subject, an assessment will be made of whether there 
was overall sentinel node detection. A sentinel lymph node will be defined as being detected if it 
is detected on the pre-operative SPECT/CT imaging scan or intraoperatively using near-infrared 
imaging or the handheld gamma detection device. If at least one SLN is detected (on any side), 
then this outcome will be considered a ‘Yes’. 
 
(2) Location and number of SLNs detected by Lymphoseek: The location and number of sentinel 
lymph nodes detected by Lymphoseek will be assessed. A sentinel lymph node will be defined as 
being detected by Lymphoseek if it is detected using the pre-operative SPECT/CT imaging scan 
and/or intraoperatively using the gamma detection device.  
 
(3) Location and number of SLNs detected by Indocyanine Green: The location and number of 
sentinel lymph nodes detected by Indocyanine Green will be assessed. A sentinel lymph node 
will be defined as being detected by Indocyanine Green if it is detected intraoperatively using 
near-infrared imaging only and not by the gamma detection device. 
 
(4) Adverse events and severe adverse events will be monitored and reported.  
 
10. 
REGULATORY CONSIDERATIONS 
 
10.1 
Institutional Review of Protocol 
 
The protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the Stanford IRB and Stanford Cancer Institute Scientific Review Committee 
(SRC).  Any changes made to the protocol will be submitted as a modification and will be 
approved by the IRB prior to implementation.  The Protocol Director will disseminate the 
protocol amendment information to all participating investigators. 
 
10.2 
Data and Safety Monitoring Plan 
 
The investigators will review AEs and SAEs in real time and report these events 
according to the Stanford Cancer Center Cancer Clinical Trials Office Standard Operating 
procedures.  
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 


 
 
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monitoring entity for this study. The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  This may include review of the 
following types of documents participating in the study: regulatory binders, case report forms, 
eligibility checklists, and source documents.  In addition, the DSMC will regularly review 
serious adverse events and protocol deviations associated with the research to ensure the 
protection of human subjects.  Results of the DSMC audit will be communicated to the IRB and 
the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
 
10.3 
Data Management Plan 
 
The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study. Study specific Case 
Report Forms (CRFs) will document outcomes for data analysis. Case report forms will be 
developed and maintained both on paper and electronically using the REDCap database system 
by the clinical research team. CRFs will be kept in a locked office, only accessible to the 
research team. 
 
 
11. 
STATISTICAL CONSIDERATIONS 
 
11.1 
Statistical Design 
 
This is an open-label, single cohort, feasibility study to assess the detection rate of 
bilateral sentinel lymph nodes with concordant use of Lymphoseek and Indocyanine Green in 
patients with endometrial cancer. 
 
11.2 
Interim analyses 
 
No interim analysis will be conducted. 
 
11.3 
Descriptive Statistics and Exploratory Data Analysis 
 
We will provide descriptive statistics for the study population. The primary and 
secondary outcomes will be summarized using frequencies and percentages. 
 
11.4 
Primary Analysis 
 
11.4.1. Analysis Population 
 
The analysis population will include all patients who complete the study procedures 
specified above. We do not expect missing data or loss-to-follow up since the outcome is 
ascertained at the time of surgery. Patients who do not adhere to the study treatment plan of both 
injections, SPECT/CT and surgery will not be included in the analysis. 
 


 
 
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11.4.2. Analysis Plan 
 
The analysis for this study is primarily descriptive as the primary objective is to 
determine the detection rate of bilateral SLNs. The bilateral SLN detection rate will be calculated 
as the number of patients with bilateral SLN detection divided by the total number of patients. If 
the bilateral detection rate is at least 80%, we will deem this approach promising in detecting 
bilateral SLNs.  
 
11.5. Secondary Analysis 
 
11.5.1  
Analysis Population 
 
The population for secondary analysis will include all patients in the safety population, 
i.e. the analysis population plus those women who underwent lymphoseek injection but were 
removed from the study for any reason.  
 
11.5.2   
Analysis Plan 
 
Descriptive statistics will be used to analyze the secondary outcomes. The overall 
detection rate of sentinel lymph nodes will be calculated as the number of patients with overall 
SLN detection divided by the total number of patients. To assess the safety of the concurrent use 
Lymphoseek and Indocyanine Green, we will calculate the number and rate of adverse events. 
We will describe the location and number of Lymphoseek-positive SLNs by method of detection 
(pre-operative or intraoperative). We will calculate the number of patients with SLNs found by 
Lymphoseek and by Indocyanine Green and conduct a McNemar’s test (or mid-p McNemar’s 
test) to determine the concordance of Lymphoseek-positive and Indocyanine Green-positive 
sentinel lymph nodes. 
 
11.6 Sample Size 
 
11.6.1  
Accrual estimates 
 
 
 
100 patients are seen annually at our gynecologic oncology clinics and would be considered 
eligible to participate in this study.  We expect 33% to be willing to participate in the study. We 
anticipate accruing 30 patients over one year/s.   
 
 
11.6.2 
 Sample size justification 
 
To address our primary objective, we plan to enroll 30 patients who have concurrent use of 
lymphoseek and indocyanine green. The sample size is based on a convenience sample from 
patients routinely followed in the Stanford gynecologic oncology clinic. With 30 participants and 
assuming a true bilateral detection rate of 80%, the probability of correctly concluding that our 
approach has an acceptable bilateral detection rate (i.e. 24 patients being detected with bilateral 
SLNs) is 61%. The probability of incorrectly concluding this (assuming that the true detection 
rate is 69% - the rate observed with current practice at Stanford) is low at 13%. We will deem the 


 
 
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approach used in this study promising if we observe a bilateral detection rate of at least 80%. The 
exact 95% confidence interval for the assumed bilateral detection rate of 80% is 61% to 92%. 
 
11.6.3 Effect size justification 
 
The bilateral detection rate using current techniques at Stanford is approximately 69%. Based 
on this, we would consider a bilateral detection rate of 80% to be promising. 
 


 
 
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12. REFERENCES 
 
1. 
Mikuta, J.J., International Federation of Gynecology and Obstetrics staging of 
endometrial cancer 1988. Cancer, 1993. 71(4 Suppl): p. 1460-3. 
2. 
Benedetti Panici, P., et al., Systematic pelvic lymphadenectomy vs. no lymphadenectomy 
in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst, 
2008. 100(23): p. 1707-16. 
3. 
group, A.s., et al., Efficacy of systematic pelvic lymphadenectomy in endometrial cancer 
(MRC ASTEC trial): a randomised study. Lancet, 2009. 373(9658): p. 125-36. 
4. 
Abu-Rustum, N.R., et al., Sentinel lymph node mapping for grade 1 endometrial cancer: 
is it the answer to the surgical staging dilemma? Gynecol Oncol, 2009. 113(2): p. 163-9. 
5. 
Holloway, R.W., et al., Sentinel lymph node mapping and staging in endometrial cancer: 
A Society of Gynecologic Oncology literature review with consensus recommendations. 
Gynecol Oncol, 2017. 146(2): p. 405-415. 
6. 
Rossi, E.C., et al., A comparison of sentinel lymph node biopsy to lymphadenectomy for 
endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. 
Lancet Oncol, 2017. 18(3): p. 384-392. 
7. 
Renz, M., et al., Immediate intraoperative sentinel lymph node analysis by frozen section 
is predictive of lymph node metastasis in endometrial cancer. J Robot Surg, 2019. 
8. 
Cabanas, R.M., An approach for the treatment of penile carcinoma. Cancer, 1977. 39(2): 
p. 456-66. 
9. 
Krag, D.N., et al., Sentinel-lymph-node resection compared with conventional axillary-
lymph-node dissection in clinically node-negative patients with breast cancer: overall 
survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol, 2010. 
11(10): p. 927-33. 
10. 
Giuliano, A.E., et al., Axillary dissection vs no axillary dissection in women with invasive 
breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA, 2011. 
305(6): p. 569-75. 
11. 
Levenback, C.F., et al., Lymphatic mapping and sentinel lymph node biopsy in women 
with squamous cell carcinoma of the vulva: a gynecologic oncology group study. J Clin 
Oncol, 2012. 30(31): p. 3786-91. 
12. 
Oonk, M.H., et al., Size of sentinel-node metastasis and chances of non-sentinel-node 
involvement and survival in early stage vulvar cancer: results from GROINSS-V, a 
multicentre observational study. Lancet Oncol, 2010. 11(7): p. 646-52. 
13. 
Network, N.C.C., NCCN clinical practice guidelines in oncology (NCCN Guidelines) 
Uterine Neoplasms. NCCN.org, 2017. version 1.2017. 
14. 
Niikura, H., et al., Tracer injection sites and combinations for sentinel lymph node 
detection in patients with endometrial cancer. Gynecol Oncol, 2013. 131(2): p. 299-303. 
15. 
Sawicki, S., P. Lass, and D. Wydra, Sentinel Lymph Node Biopsy in Endometrial Cancer-
-Comparison of 2 Detection Methods. Int J Gynecol Cancer, 2015. 25(6): p. 1044-50. 
16. 
Tanner, E.J., et al., Factors associated with successful bilateral sentinel lymph node 
mapping in endometrial cancer. Gynecol Oncol, 2015. 138(3): p. 542-7. 
17. 
Holloway, R.W., et al., A Prospective Cohort Study Comparing Colorimetric and 
Fluorescent Imaging for Sentinel Lymph Node Mapping in Endometrial Cancer. Ann 
Surg Oncol, 2017. 24(7): p. 1972-1979. 
18. 
Sinno, A.K., et al., A comparison of colorimetric versus fluorometric sentinel lymph node 


 
 
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mapping during robotic surgery for endometrial cancer. Gynecol Oncol, 2014. 134(2): p. 
281-6. 
19. 
Blessing, W.D., et al., A comparison of methylene blue and lymphazurin in breast cancer 
sentinel node mapping. Am J Surg, 2002. 184(4): p. 341-5. 
20. 
Desai, P.H., et al., Accuracy of robotic sentinel lymph node detection (RSLND) for 
patients with endometrial cancer (EC). Gynecol Oncol, 2014. 135(2): p. 196-200. 
21. 
Ballester, M., et al., Detection rate and diagnostic accuracy of sentinel-node biopsy in 
early stage endometrial cancer: a prospective multicentre study (SENTI-ENDO). Lancet 
Oncol, 2011. 12(5): p. 469-76. 
22. 
Bats, A.S., et al., The sentinel node technique detects unexpected drainage pathways and 
allows nodal ultrastaging in early cervical cancer: insights from the multicenter 
prospective SENTICOL study. Ann Surg Oncol, 2013. 20(2): p. 413-22. 
23. 
Touhami, O., et al., Predictors of non-sentinel lymph node (non-SLN) metastasis in 
patients with sentinel lymph node (SLN) metastasis in endometrial cancer. Gynecol 
Oncol, 2015. 138(1): p. 41-5. 
24. 
Jewell, E.L., 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. 133(2): p. 274-7. 
25. 
Plante, M., et al., Sentinel node mapping with indocyanine green and endoscopic near-
infrared fluorescence imaging in endometrial cancer. A pilot study and review of the 
literature. Gynecol Oncol, 2015. 137(3): p. 443-7. 
26. 
Vera, D.R., et al., A synthetic macromolecule for sentinel node detection: (99m)Tc-
DTPA-mannosyl-dextran. J Nucl Med, 2001. 42(6): p. 951-9. 
27. 
Baker, J.L., et al., Comparison of [(99m)Tc]tilmanocept and filtered [(99m)Tc]sulfur 
colloid for identification of SLNs in breast cancer patients. Ann Surg Oncol, 2015. 22(1): 
p. 40-5. 
28. 
Wallace, A.M., et al., Lymphoseek: a molecular radiopharmaceutical for sentinel node 
detection. Ann Surg Oncol, 2003. 10(5): p. 531-8. 
29. 
FDA, Prescribing information on Lymphoseek. 2016. 
30. 
Marcinow, A.M., et al., Use of a novel receptor-targeted (CD206) radiotracer, 99mTc-
tilmanocept, and SPECT/CT for sentinel lymph node detection in oral cavity squamous 
cell carcinoma: initial institutional report in an ongoing phase 3 study. JAMA 
Otolaryngol Head Neck Surg, 2013. 139(9): p. 895-902. 
 


 
 
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APPENDICES 
APPENDIX A: Participant Eligibility Checklist  
A Participant Eligibility Checklist must be completed in its entirety for each subject prior to 
registration. The completed, signed, and dated checklist must be retained in the patient’s study 
file and the study’s Regulatory Binder.  
 
The study coordinator, treating physician and an independent reviewer must verify that the 
participant’s eligibility is accurate, complete, and legible in source records. A description of the 
eligibility verification process should be included in the EPIC or other Electronic Medical 
Record progress note.  
 
 
Protocol Title: 
Concurrent use of Lymphoseek and Indocyanine Green 
for sentinel lymph node detection in endometrial cancer – 
a prospective trial    
Protocol Number: 
 
Principal Investigator: 
Amer Karam, MD 
 
II. Subject Information: 
 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III. Study Information: 
SRC Approved 
 IRB Approved 
 Contract signed 
 
IV. Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Age 18 or older 
 
 
 
2. Patient has histological diagnosis of 
cancer of the endometrium. 
 
 
 
3. Patient should have received no 
prior treatment. 
 
 
 
4. Patient has a clinical negative node 
status at study entry. 
 
 
 
5. Patient is a candidate for minimal 
invasive surgery with lymph node 
assessment. 
 
 
 
6. Eastern Cooperative Group (ECOG) 
 
 
 


 
 
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performance status of 0-2 
7. If age less than or equal to 55 years, 
the patient has a negative pregnancy 
test within 72 hours before 
administration of Lymphoseek, has 
been surgically sterilized, or has 
been postmenopausal for at least 1 
year. 
 
 
 
8. Willing and able to provide a written 
informed consent document for the 
trial. 
 
 
 
Exclusion Criteria 
(From IRB approved protocol) 
 
1. Patient has participated in another 
investigational drug study within 30 
days of scheduled surgery. 
 
 
 
2. Patient has clinical or radiological 
evidence of metastatic disease. 
 
 
 
3. Patient has a history of a prior loop 
electrosurgical excision procedure 
(LEEP) or cone procedure 
performed on her cervix. 
 
 
 
4. Patient has a history of previous 
abdominal retroperitoneal surgery or 
abdominal/pelvic lymphadenectomy. 
 
 
 
5. Patient has a known hypersensitivity 
to Indocyanine Green and/or 
Lymphoseek. 
 
 
 
 
6. The patient has an iodine allergy 
 
 
 
7. The patient is pregnant or lactating. 
 
 
 
*All subject files must include supporting documentation to confirm subject eligibility.  
The method of confirmation can include, but is not limited to, laboratory test results, 
radiology test results, subject self-report, and medical record review.   
 
IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
 


 
 
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Treating Physician Signature: 
Date: 
Printed Name: 
 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
 
Study Coordinator Signature: 
Date: 
Printed Name: