Clinical trial NCT02509585
Conditions: Uterine Cervical Neoplasms
Sponsor: Cardinal Health 414, LLC
Start date: 2016-01-01; Completion date: 2017-07-01
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Prospective, open-label, within-patient, multi-center study of Lymphoseek in the detection of lymph nodes in subjects with known cancer of the cervix. All subjects will receive a single dose of 50 µg Lymphoseek radiolabeled with 2 mCi (74 MBq) Tc 99m.

Detailed description:

Arms: arm 1: 2 mCi (74 MBq), 50 ug of Tc99M tilmanocept single administration
Interventions: intervention 1: Tc99m tilmanocept
Intervention descriptions: intervention 1: A single dose of 2 mCi (74 MBq) and 50 ug of Tc99m tilmanocept administered peritumorally no more than 20 hours before surgery

Protocol documents:
Prot_SAP_000.pdf: 


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SYNOPSIS 
Study title 
A Prospective, Open-Label Trial of Comparing the 
Pathology Status of Lymphoseek®-Identified Sentinel 
Lymph Nodes Relative to the Pathological Pathology Status 
of Nonsentinel Lymph Nodes in Nodal Staging of Subjects 
With Known Cancer of the Cervix Who Are Undergoing 
Lymph Node Dissection 
Study phase 
Phase 2 
Study objective(s) 
Primary 
Estimation of the per subject false negative rate (FNR) 
associated with the pathology status of Lymphoseek-
identified sentinel lymph nodes (SLNs) relative to the 
pathology status of non-SLNs in the pelvic 
lymphadenectomy.  
Secondary 
• Estimation of sensitivity, negative predictive value 
(NPV), and overall accuracy of Lymphoseek-detected 
SLNs relative to the pathology status of non-SLNs.  
• Estimation of detection rate of SLNs by Lymphoseek and 
the rate of tumor detection in non-SLNs. 
• Determination of the proportion of lymph nodes 
identified intraoperatively by a dye (e.g., vital blue dye 
[VBD] or indocyanine green [ICG] )that are also 
identified intraoperatively by Lymphoseek (i.e., 
concordance using the number of lymph nodes stained by 
the dye as the denominator). 
• Determination of reverse concordance comparing dye to 
Lymphoseek (i.e., using the number of lymph nodes  
identified intraoperatively by Lymphoseek as the 
denominator). 
• Comparison of pathologic assessment of the excised 
lymph node(s) to confirm the presence/absence of tumor 
metastases for Lymphoseek and dye on a per-subject 
basis. 
• Comparison of imaging and surgical findings 
 
Safety  
• Evaluation of the incidence of adverse events 
Study drug 
Lymphoseek® 
Dose(s) 
50 µg Lymphoseek radiolabeled with 2.0 mCi (74 MBq) 
99mTc 


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Route of administration 
Intramucosal peritumoral injection in the subepithelial layer 
of the cervix 
Duration of treatment 
Single administration 
Control 
Pathology status of non-SLNs in the pelvic 
lymphadenectomy  
US Indication 
 
Lymphoseek is a radioactive diagnostic agent indicated with 
or without scintigraphic imaging for: 
• Lymphatic mapping using a handheld gamma counter to 
locate lymph nodes draining a primary tumor site in 
patients with solid tumors for which this procedure is a 
component of intraoperative management. 
• Guiding sentinel lymph node biopsy using a handheld 
gamma counter in patients with clinically node negative 
quamous cell carcinoma of the oral cavity, breast cancer, 
or melanoma. 
Main criteria for inclusion 
1. Subject has provided written informed consent with 
HIPAA authorization 
2. Has cervical cancer and is a candidate for surgical 
intervention, with lymph node dissection being a part of 
the surgical plan. 
3. Is at least 18 years of age at the time of consent 
4. Has an ECOG performance status of Grade 0 to 2 
5. Has the following International Federation of 
Gynecology and Obstetrics (FIGO) IA2-IIA1 (≤ 4 cm) 
staging(Appendix 5). Subjects with a single 
enlarged/suspicious node on PET/CT will still be 
considered eligible as consistent with FIGO guidelines.  
6. If of childbearing potential, the subject has a negative 
pregnancy test within 48 hours before administration of 
Lymphoseek, has been surgically sterilized, or has been 
postmenopausal for at least 1 year 
Main criteria for exclusion 
1. The subject has had preoperative chemotherapy, 
immunotherapy, or radiation therapy within the 30 days 
prior to Lymphoseek administration 
2. Has had previous surgery or radiation to node basins that 
would be involved in the ILM procedure 
3. Has a known allergy to dextran 
4. Is breast-feeding or pregnant 
5. Before the administration of Lymphoseek, has received 
any radiopharmaceutical within 7 radioactive half-lives 
of that radiopharmaceutical 
6. Is scheduled for surgery and/or another invasive 
procedure other than the primary surgical intervention 
within the 3 days after Lymphoseek administration 


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7. Has received an investigational product within the 30 
days prior to Lymphoseek administration 
Study design 
Prospective, open-label, within-patient, multi-center study of 
Lymphoseek in the detection of lymph nodes in subjects with 
known cancer of the cervix. All subjects will receive a single 
dose of 50 µg Lymphoseek radiolabeled with 2 mCi (74 
MBq) Tc 99m. 
Methodology 
The proposed study includes: screening, enrollment, pre- and 
post-injection assessments, injection (Lymphoseek and dye), 
imaging and surgery.   
Screening Visit (Day -29 to -1): The screening visit will 
include review of trial eligibility, informed consent, 
collection of medical history, vital signs, physical exams, 
clinical lab results, and review of medications. 
Before Enrollment: Within 48 hours before Lymphoseek 
injection, a urine or serum pregnancy test will be performed 
for subjects of childbearing age.  
Before Lymphoseek Injection:  Vital signs will be 
collected. 
Lymphoseek Injection:  Subjects will receive a single dose 
of 50 µg Lymphoseek radiolabeled with 2 mCi (74 MBq) 
99mTc at least 15 minutes but no more than 15 hours before 
the start of the surgical procedure.  Lymphoseek will be 
administered peritumorally by intramucosal injection.  
Post-injection: Vital signs will be collected. 
Lymphoscintigraphy will be completed prior to surgery and 
no later than 20 hours after Lymphoseek injection. 
Surgery: Dye (e.g., VBD or ICG) may be administered in 
the operating room immediately before surgery.  Fifteen 
minutes to 20 hours after Lymphoseek injection, subjects 
will undergo surgery to remove the primary tumor, and 
lymphatic mapping will be performed.   
36 Hour Post-injection Follow-up:  Vital sign assessment, 
physical examination, and review of adverse events and 
medications will be performed. 


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Planned trial dates 
Start of study  
June 2015 
End of Study 
July 2016 
Planned number of trial 
centers / countries 
Approximately 4 to 6 sites in the United States 
Number of subjects 
Approximately 40 subjects will be enrolled.  This sample 
size was chosen in order to provide exploratory results for 
the primary endpoint of FNR within this subject population.  
This study is not powered with respect to testing any 
statistical hypotheses. 
Primary endpoint 
Per subject FNR 
Secondary endpoints 
• Per-subject  sensitivity, NPV, and accuracy 
• Rate of tumor detection in SLNs and non-SLNs  
• Proportion of lymph nodes identified intraoperatively by 
dye (e.g., VBD or ICG) that are also identified 
intraoperatively by Lymphoseek (i.e., nodal 
concordance) 
• Proportion of lymph nodes identified intraoperatively by 
Lymphoseek that are also identified intraoperatively by 
dye  (i.e., reverse nodal concordance) 
• Number of identified lymph nodes per subject by tracing 
agent (Lymphoseek or dye), per-subject concordance, 
and per-subject reverse concordance 
• Comparison of pathologic assessment of the excised 
lymph node(s) to confirm the presence/absence of tumor 
metastases for Lymphoseek and dye on a per-subject 
basis. 
• Number and anatomical locations of lymph nodes 
identified by preoperative Lymphoscintigraphy  
• Incidence of adverse events 
Plan for statistical analysis 
The following analysis populations will be defined for the 
study: 
• Intent-to-Treat (ITT): enrolled subjects with 
administration of test medicine for whom at least one 
lymph node was removed with histopathology available 
• Per protocol (PP): ITT subjects without major protocol 
violations 
• Safety: enrolled subjects with administration of test 
medicine 
 
Primary endpoint primary analysis: The per subject FNR will 


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be computed using pathologically positive lymph nodes from 
all subjects in the ITT population.  Along with reporting the 
number of false negative subjects and the observed FNR, an 
exact two-sided 95% confidence interval will be computed.  
A sensitivity analysis of the primary endpoint will be 
computed using the PP population. 
All analyses of safety will be conducted on the safety 
population. 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF IN-TEXT TABLES ..................................................................................................11 
LIST OF APPENDICES ..........................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................12 
TRIAL ADMINISTRATIVE STRUCTURE ..........................................................................14 
INSTITUTIONS FOR TRIAL CONDUCT ............................................................................14 
1 
INTRODUCTION ...........................................................................................................15 
1.1 
Background ............................................................................................................15 
1.1.1 
Intraoperative Lymphatic Mapping (ILM) ..................................................15 
1.1.2 
Rationale for Evaluation of SLNB in Cervical Cancer ................................16 
1.2 
Previous Nonclinical Research and Clinical Trial Experience with 
Tilmanocept and Lymphoseek ...............................................................................18 
2 
STUDY OBJECTIVES ....................................................................................................21 
2.1 
Primary Objective ..................................................................................................21 
2.2 
Secondary Objectives.............................................................................................21 
2.3 
Safety Objective .....................................................................................................21 
3 
OVERVIEW OF METHODOLOGY AND DESIGN .....................................................22 
3.1 
Overall Study Design .............................................................................................22 
3.2 
Justification for Study Design and Population.......................................................22 
3.2.1 
Rationale for Subject Selection ....................................................................22 
3.2.2 
Justification for Radiation Exposure With Proposed Lymphoseek 
Radioactive Dose .........................................................................................22 
3.3 
Protocol Adherence ................................................................................................23 
3.4 
Study Duration .......................................................................................................23 
4 
STUDY POPULATION ..................................................................................................24 
4.1 
Eligibility ...............................................................................................................24 
4.1.1 
Inclusion Criteria .........................................................................................24 
4.1.2 
Exclusion Criteria ........................................................................................24 
4.2 
Recruitment ............................................................................................................25 
4.3 
Withdrawal .............................................................................................................25 
4.4 
Replacement ...........................................................................................................25 
4.5 
Subject Identification .............................................................................................25 
5 
INVESTIGATIONAL PRODUCT ..................................................................................27 
5.1 
Identification of Investigational Product ...............................................................27 
5.2 
Investigational Product Dosage and Administration .............................................27 
5.3 
Dye Dosage and Administration ............................................................................27 


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5.4 
Treatment Assignment ...........................................................................................27 
5.5 
Packaging and Labeling .........................................................................................28 
5.6 
Drug Logistics and Accountability ........................................................................28 
6 
THERAPIES OTHER THAN INVESTIGATIONAL PRODUCT .................................29 
6.1 
Prior and Concomitant Therapy .............................................................................29 
6.2 
Post-Study Therapy ................................................................................................29 
7 
SCHEDULE OF EVALUATIONS AND VISIT DESCRIPTION .................................30 
7.1 
Schedule of Evaluations .........................................................................................30 
7.2 
Visit Description ....................................................................................................30 
7.2.1 
Screening Visit (Day -29 to Day 0) .............................................................30 
7.2.2 
Before Enrollment ........................................................................................30 
7.2.3 
Preparation of Lymphoseek .........................................................................31 
7.2.4 
Before Injection ...........................................................................................31 
7.2.5 
Injection of Lymphoseek .............................................................................31 
7.2.6 
Post Injection ...............................................................................................31 
7.2.7 
Day 1: Imaging and Surgery ........................................................................31 
7.2.8 
24 ± 12 hours Postsurgical Safety Follow-up (telephone) ...........................32 
7.2.9 
End of Study ................................................................................................32 
8 
PROCEDURES AND VARIABLES ..............................................................................33 
8.1 
Population Characteristics .....................................................................................33 
8.1.1 
Demographic and Other Baseline Characteristics .......................................33 
8.1.2 
Medical and Surgical History ......................................................................33 
8.1.3 
ECOG Performance Status ..........................................................................33 
8.1.4 
Prior and Concomitant Medication ..............................................................33 
8.2 
Lymphoseek Preparation and Injection .................................................................34 
8.3 
Lymphoscintigraphy (SPECT/SPECT-CT Image Acquisition) ............................34 
8.4 
Surgical Procedures, Lymphatic Mapping, and Lymph Node Biopsy ..................35 
8.4.1 
Timing of Surgical Procedures ....................................................................35 
8.4.2 
Lymphoseek-Designated “Hot” Nodes ........................................................35 
8.4.3 
Surgical Lymph Node Identification ...........................................................36 
8.5 
Histopathology of Lymph Nodes ...........................................................................37 
8.5.1 
Local Lymph Node Evaluation ....................................................................37 
8.6 
Pharmacokinetics ...................................................................................................38 
8.7 
Safety .....................................................................................................................38 
8.7.1 
Adverse Events ............................................................................................38 
8.7.1.1 
Definition of Adverse Event ..............................................................38 
8.7.1.2 
Categories for Adverse Event Assessment ........................................38 
8.7.1.3 
Assessments and Documentation of Adverse Events ........................40 


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8.7.1.4 
Expected Adverse Events ..................................................................40 
8.7.1.5 
Serious Adverse Events .....................................................................41 
8.7.2 
Further Safety Assessments .........................................................................43 
8.7.2.1 
Physical Examination.........................................................................43 
8.7.2.2 
Vital Signs ..........................................................................................43 
8.8 
Other Procedures and Variables.............................................................................44 
8.8.1 
Blood Sampling ...........................................................................................44 
8.8.2 
Laboratory Data for Subject Characterization .............................................44 
9 
STATISTICAL METHODS ............................................................................................45 
9.1 
Introduction ............................................................................................................45 
9.2 
Randomization Methods ........................................................................................45 
9.3 
Pooling of Study Centers .......................................................................................45 
9.4 
Efficacy Variables ..................................................................................................45 
9.4.1 
Primary Efficacy Variables ..........................................................................45 
9.4.2 
Secondary Efficacy Variables ......................................................................45 
9.5 
Pharmacokinetic Variables ....................................................................................46 
9.6 
Safety Variables .....................................................................................................46 
9.6.1 
Primary Safety Variables .............................................................................46 
9.7 
Sample Size Justification .......................................................................................47 
9.8 
Handling of Missing Data ......................................................................................47 
9.9 
Statistical Analysis .................................................................................................47 
9.9.1 
Analysis Populations ....................................................................................47 
9.9.2 
Analysis of Baseline and Demographic Characteristics ..............................47 
9.9.3 
Analysis of Primary Efficacy Variables ......................................................48 
9.9.4 
Analysis of Secondary Efficacy Variables ..................................................48 
9.9.4.1 
Along with reporting the number of SLNs indentified 
intraoperatively by VBD or ICG and the observed nodal 
concordance, an exact two-sided 95% confidence interval will be 
computed. ...........................................................................................49 
9.9.5 
Safety Analyses ............................................................................................50 
9.10 
Interim Analyses ....................................................................................................51 
10 DATA HANDLING AND QUALITY ASSURANCE ...................................................52 
10.1 
Data Recording ......................................................................................................52 
10.1.1 
Electronic CRF design .................................................................................52 
10.2 
Monitoring .............................................................................................................52 
10.3 
Data Processing ......................................................................................................52 
10.4 
Auditing .................................................................................................................53 
10.5 
Archiving ...............................................................................................................53 
10.6 
Premature Termination of the Study ......................................................................53 


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10.6.1 
Study as a Whole .........................................................................................54 
10.6.2 
Study Participant ..........................................................................................54 
11 ETHICAL AND LEGAL ASPECTS...............................................................................55 
11.1 
Ethical and Legal Conduct of the Study ................................................................55 
11.2 
Subject Information and Consent...........................................................................55 
11.3 
Financing/Financial Disclosure .............................................................................56 
11.4 
Publication Policy ..................................................................................................56 
11.5 
Subject Injury .........................................................................................................56 
12 REFERENCE LIST .........................................................................................................57 
 


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LIST OF IN-TEXT TABLES 
Table 1.  
Estimated Radiation Absorbed Dose for a 2.0 mCi, 50 µg Dose of 
Lymphoseek in Intradermal Injection of Cancer Patients  (Reference 
Patient is Intradermal Injection of Lymphoseek; Units in mGy) .................20 
Table 2.   
ECOG  Performance Status .........................................................................33 
Table 3.   
Handling of Excised Tissue .........................................................................36 
Table 4. 
Minimum Clinical Laboratory Parameters ..................................................44 
Table 5. 
Approximate Amount of Blood Withdrawn ................................................44 
 
LIST OF APPENDICES 
Appendix 1 Schedule of Events .......................................................................................61 
Appendix 2 Gamma Detector Counts Calculation Sheet ................................................62 
Appendix 3 TNM and FIGO Cancer Staging Definitions ...............................................63 
Appendix 4 Sponsor’s Signatures ....................................................................................64 
Appendix 5 Investigator’s Signature ...............................................................................65 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
# 
number of (also N or n) 
AE 
adverse event 
ALARA 
as low as reasonably achievable 
°C 
degrees Celsius 
cm 
centimeters (10-2 m) 
CRA 
clinical research associate 
CRO 
contract reseach organization 
CRF 
case report form 
DTPA 
diethylenetriaminepentaacetic acid 
EANM 
European Association of Nuclear Medicine 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
°F 
degrees Fahrenheit 
FIGO 
International Federation of Gynecology and Obstetrics 
FNR 
false negative rate 
GCP 
Good Clinical Practices 
H&E 
hematoxylin and eosin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICG 
indocyanine green 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemical 
ILM 
intraoperative lymphatic mapping 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
kDa 
kilodaltons (molecular weight measure; 103 Da) 
lbs 
pounds 
LN 
lymph node 
Lymphoseek 
technetium Tc 99m tilmanocept 
max 
maximum  
MBR 
mannose binding receptor (CD206) 
mCi 
millicurie (10-3 Ci; 3.7x107 Becquerel or Bq) 
MedDRA 
Medical Dictionary for Regulatory Activities 
µg 
micrograms (10-6 g) 
min 
minimum 
mL 
milliliters (10-3 L) 
mm 
millimeters (10-3 m) 
mmHg 
millimeters of mercury 
NCCN 
National Comprehensive Cancer Network 


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nm 
nanometers (10-9 m) 
nmol 
nanomoles (10-9 moles) 
NPV 
negative predictive value 
PLND 
pelvic lymphadenectomy 
PP 
per protocol 
σ 
sigma; standard deviation 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SLN 
sentinel lymph node 
SD 
standard deviation 
SNMMI 
Society of Nuclear Medicine and Molecular Imaging 
Sponsor 
Navidea Biopharmaceuticals 
Tc 99m 
technetium-99m metastable isotope; γ-emitting (t½ = 6.02 h) 
Tilmanocept 
DTPA Mannosyl Dextran (the US Adopted Name for the drug 
substance of Lymphoseek) 
TNM 
tumor, lymph node, metastasis staging 
US 
United States 
USFDA 
US Food and Drug Administration 
UTI 
urinary tract infection 
VBD 
vital blue dye; LymphazurinTM as 1% isosulfan blue for injection; 
USFDA-approved ILM colorimetric agent 
WHO 
World Health Organization 
 
















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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
Estimation of the per subject FNR associated with the pathology status of Lymphoseek-
identified SLNs relative to the pathology status of non-SLNs in the pelvic lymphadenectomy.  
2.2 
Secondary Objectives 
Estimation of sensitivity, negative predictive value, and overall accuracy of Lymphoseek-
detected SLNs relative to the pathology status of non-SLNs.  
Estimation of the detection rate of SLNs by Lymphoseek and the rate of tumor detection in 
non-SLNs. 
Determination of the proportion of lymph nodes identified intraoperatively by a dye (e.g., 
VBD or ICG) that are also identified intraoperatively by Lymphoseek (i.e., concordance 
using the number of lymph nodes stained by the dye as the denominator). 
Determination of reverse concordance comparing dye to Lymphoseek (i.e., using the number 
of lymph nodes  identified intraoperatively by Lymphoseek as the denominator). 
Comparison of pathologic assessment of the excised lymph node(s) to confirm the 
presence/absence of tumor metastases for Lymphoseek and dye on a per-subject basis. 
Comparison of imaging and surgical findings. 
2.3 
Safety Objective  
Evaluation of the incidence of adverse events.  
 




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3.3 
Protocol Adherence 
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
the study conduct; the investigator may not modify or alter the procedures described in this 
protocol. If protocol modifications are necessary, all alterations that are not solely of an 
administrative nature require a formal protocol amendment (see Section 11.1 for the 
involvement of International Ethics Committee(s) IEC(s)/ International Review Board(s) 
IRB(s)). 
If an investigator has deviated from the protocol in order to eliminate an immediate hazard to 
subjects or for other inevitable medical reasons, the investigator shall document all such 
deviations, including the reasons thereof, and submit the document to the sponsor and the 
head of the medical institution as applicable. 
Participating investigators must have 10 cases of intraoperative lymphatic mapping in 
gynecologic cancer patients to participate as a  surgeon for any subjects enrolled in this trial. 
3.4 
Study Duration 
Subjects will be enrolled for approximately 32 days depending on the duration of the 
screening window (up to  30 days). 


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4 
STUDY POPULATION 
4.1 
Eligibility 
Subjects who fulfill all respective inclusion and none of the exclusion criteria will be eligible 
for enrollment into the study.  All inclusion/exclusion criteria must be verified before a 
subject may be considered eligible for injection and imaging (Day 1 procedures).  A subject 
will be considered enrolled in the study on the morning of study day 1 when they arrive at the 
study site.  Written, dated (with time noted) informed consent will be obtained from all 
subjects. A subject who withdraws consent prior to arrival at the study site on day 1 will be 
considered a screen failure. 
4.1.1 
Inclusion Criteria 
1. Subject has provided written informed consent with HIPAA authorization 
2. Has cervical cancer and is a candidate for surgical intervention, with lymph node 
dissection being a part of the surgical plan. 
3. Is at least 18 years of age at the time of consent 
4. Has an ECOG performance status of Grade 0 to 2 
5. Has the following International Federation of Gynecology and Obstetrics (FIGO) 
IA2-IIA1(≤ 4 cm)  staging(Appendix 5) Subjects with a single enlarged/suspicious 
node on PET CT will still be considered eligible as consistent with FIGO guidelines.  
6. If of childbearing potential, the subject has a negative pregnancy test within 48 hours 
before administration of Lymphoseek, has been surgically sterilized, or has been 
postmenopausal for at least 1 year 
4.1.2 
Exclusion Criteria 
1. The subject has had preoperative chemotherapy, immunotherapy, or radiation therapy 
within the 30 days prior to Lymphoseek administration 
2. Has had previous surgery or radiation to node basins that would be involved in the 
ILM procedure 
3. Has a known allergy to dextran 
4. Is breast-feeding or pregnant 
5. Before the administration of Lymphoseek, has received any radiopharmaceutical 
within 7 radioactive half-lives of that radiopharmaceutical  
6. Is scheduled for surgery and/or another invasive procedure other than the primary 
surgical intervention within the 3 days after Lymphoseek administration  
7. Has received an investigational product within the 30 days prior to Lymphoseek 


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administration 
4.2 
Recruitment 
Subjects will be recruited from oncology practices in accordance with the inclusion and 
exclusion criteria listed above. Potentially suitable subjects will be asked by their treating 
physician about their willingness to participate in this study.  
4.3 
Withdrawal 
In accordance with the Declaration of Helsinki, each subject is free to withdraw from the 
study at any time and without providing a reason.   
A subject who withdraws consent prior to arrival at the study site on Day 1 will be 
considered a screen failure. 
Should a subject withdraw after administration of the investigational product all efforts will 
be made to complete and report the observations up to the time of withdrawal as thoroughly 
as possible.  An explanation should be given of why the subject is withdrawing or being 
withdrawn from the study. 
The investigator may withdraw a subject from the study at any time at the discretion of the 
investigator for any of the following reasons:  
• A protocol violation occurs  
• A serious or intolerable AE occurs  
• A clinically significant change in a laboratory parameter occurs  
• At the investigator’s/sponsor’s discretion as long as it is in the best interest of the 
subject  
• The sponsor or investigator terminates the study  
• The subject requests to be discontinued from the study 
 
4.4 
Replacement 
Subjects will be replaced under the following conditions: 
• Subjects who did not receive study medication or did not proceed to surgery or did not 
undergo lymphatic mapping with lymph node biopsy. 
 
4.5 
Subject Identification 
After the subject provides written informed consent, the site will assign the subject a 7-digit 
subject number. Subject numbers are to be assigned in a sequential manner using the 
following format:  
Digits 1 to 2: Trial number “19”  
Digits 3 to 4: Site number (e.g., “03”)  


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Digits 5 to 7: Sequential subject number (e.g., “001”, “002”, “003”, etc.)  
For example, the first subject consented at Site 03 is subject number “19-03-001”.  
Subjects will maintain the same number given at screening for the entire study.  If a subject is 
a screen failure, the number will not be used for any other subject. 


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5 
INVESTIGATIONAL PRODUCT 
5.1 
Identification of Investigational Product 
Lymphoseek® (also known as technetium Tc 99m tilmanocept) is a radiopharmaceutical that 
accumulates in lymphatic tissue by binding to mannose binding receptors (CD206) that 
reside on the surfaces of dendritic cells and macrophages. 
5.2 
Investigational Product Dosage and Administration 
Subjects will receive 50 µg tilmanocept radiolabeled with 2 mCi (74 MBq) Tc 99m 
administered as four separate injections. The total injection volume for each subject is 0.4 or 
1.0 mL administered across all four  syringes (0.1 or 0.25 mL each).  
The dose will be prepared in 1 mL BD Luer-Lok syringes with a 0.5 inch needle. The needle 
should be replaced at the discretion of the investigator in accordance with site practices. A 
22- to 24-gauge spinal or potocky needle is commonly used. In order to achieve accurate 
delivery of small volumes, final syringe volume adjustments will be made at the pharmacy to 
accommodate volume retained in the syringe hub and needle such that air should not be 
added to the syringe and no syringe flushing should occur. 
Subjects will receive Lymphoseek by injection in a manner consistent with the European 
Association of Nuclear Medicine (EANM) clinical and technical guidelines for 
lymphoscintigraphy and sentinel node localization in gynaecological cancers as adopted by 
the Society of Nuclear Medicine and Molecular Imaging (SNMMI) (Giammarile et al., 
2014). The agents for lymphatic mapping will be administered peritumorally as subepithelial 
(submucosal) instillations into the 4 quadrants of the cervix at the 12, 3, 6, and 9 o’clock 
positions whenever possible. Lymphoseek should not be injected directly into the tumor.  For 
those subjects with little remaining normal cervical tissue, injections should be administered 
in the tissue surrounding the tumor with adjustment of the injection positions as necessary. 
Injection placement in relation to the cervix will be documented in the trial source. Subjects 
will be scheduled for surgery after imaging and no later than 20 hours after Lymphoseek 
injection and imaging. Just before surgical incision, a dye (e.g., VBD or ICG) may be 
injected in close proximity to the tumor.  Preoperative evaluation of the subject will follow 
routine institution practice. 
5.3 
Dye Dosage and Administration 
A dye, such as Lymphazurin (isosulfan blue 1%) or indocyanine green, may be administered 
to subjects as part of their standard of care.  The injection will be performed as deemed 
appropriate by the surgeon and in accordance with the standard of care at the clinical site. 
5.4 
Treatment Assignment 
In this open-label non-randomized study, all subjects will receive the same Lymphoseek 
treatment. 




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6 
THERAPIES OTHER THAN INVESTIGATIONAL PRODUCT 
6.1 
Prior and Concomitant Therapy 
All medications taken 30 days prior to Lymphoseek injection through the 24-hour post-
injection follow-up will be documented. Any subject that has had preoperative 
chemotherapy, immunotherapy, or radiation therapy within the 30 days prior to Lymphoseek 
admnistration will be excluded from the study. 
6.2 
Post-Study Therapy  
There are no post-study therapy restrictions. 


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7 
SCHEDULE OF EVALUATIONS AND VISIT DESCRIPTION 
7.1 
Schedule of Evaluations 
Evaluations will be performed during a period of 2-3 days, in addition to a screening period 
of 30 days maximum.  A schedule of evaluations is provided in the Schedule of Study Events 
(see Appendix 1). 
7.2 
Visit Description 
7.2.1 
Screening Visit (Day -29 to Day 0) 
• Preliminary review of inclusion and exclusion criteria 
• Obtain signed informed consent for study participation 
• Allocation of unique subject number; this number will be used to document the 
subject data in the eCRF and enrollment log 
• Demography – Date of birth, race and ethnicity 
• Medical history – Medical history will be obtained on all study subjects.  All relevant 
prior medical conditions will be recorded in the CRFs. Documented medical 
conditions will also note the month/year of onset and if the condition is active.  
• Cancer staging – Tumor characteristics including FIGO staging information will be 
collected.  
• ECOG performance status will be collected 
• Vital signs – Vital signs will include respiratory rate, pulse rate, and systolic and 
diastolic blood pressures. Prior to obtaining blood pressures and pulse, the subject 
should be in a resting position for at least 1 minute.  Body weight and height without 
shoes will be recorded only at the screening evaluation. 
• Physical exam – Physical examinations will include examination of general 
appearance, skin, eyes, ears, nose, throat, head and neck (including thyroid), lungs, 
heart, abdomen, pelvis, lymph nodes, musculoskeletal, and nervous system.  Physical 
exams that are conducted as standard of care prior to signing informed consent may 
be used if they are performed within 30 days of injection. 
• Clinical laboratory tests - study subjects will have blood obtained for hematology and 
chemistry (See Section 8.8.2).   
• Concomitant medications (within 30 days before injection). 
• Final check of inclusion/exclusion criteria 
 
7.2.2 
Before Enrollment 
Within 48 hours prior to receiving the Lymphoseek injection, a urine or serum pregnancy test 
will be conducted for female subjects of childbearing age.   




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primary tumor will be completed.  Location of both hot and dye-identified nodes will be 
recorded on the sponsor-provided intraoperative worksheets. 
7.2.8 
24 ± 12 hours Postsurgical Safety Follow-up (telephone) 
7.2.9 
Adverse events and medications will be reviewed.End of Study  
The 24 ± 12 hours Postsurgical Safety Follow-up call will serve as the end of study visit.   
FIGO staging will be reassessed post surgery by the PI and included with the final 
disposition.  


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8 
PROCEDURES AND VARIABLES 
8.1 
Population Characteristics 
8.1.1 
Demographic and Other Baseline Characteristics 
Forty female subjects 18 years of age or greater with known cervical cancer will be enrolled. 
Cancer characteristic including tumor size, cancer type and FIGO staging will be collected. 
8.1.2 
Medical and Surgical History 
Medical and surgical history will be obtained on all trial subjects.  All relevant medical 
conditions (current and prior), month/year of onset, and if the condition is currently active 
will be recorded in the CRFs.  Common accepted medical terminology should be used.  
8.1.3 
ECOG Performance Status 
All subjects will be evaluated at screening for Eastern Cooperative Oncology Group (ECOG) 
performance status (Table 2).  The critera below will be used to assign the ECOG grade. 
Table 2.   
ECOG  Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature, 
e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to 
carry out any work activities. Up and about more than 
50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair 
5 
Dead 
 
 
8.1.4 
Prior and Concomitant Medication 
All prior medication(s) used within the last 30 days before injection and concomitant 
medications will be documented. Medications administered for general surgical support and 
anesthesia related to surgery do not need to be captured in the CRFs. 




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 The number and anatomical location of each probable 
lymph node(s) identified preoperatively will be documented and captured in the eCRFs. 
 
8.4 
Surgical Procedures, Lymphatic Mapping, and Lymph Node 
Biopsy 
8.4.1 
Timing of Surgical Procedures 
Between 1 to 20 hours after injection and imaging of Tc 99m Lymphoseek, subjectss will 
proceed to surgery for intraoperative lymphatic mapping. 
 
8.4.2 
Lymphoseek-Designated “Hot” Nodes 
Room Background Count 
Using the handheld gamma detection system a room background shall be determined by 
recording three 2-second counts or one 10-second count obtained at least 30 cm away from 
the injected subject and any other radiation source.  
Normal Tissue Background Count 
Using the handheld gamma detection system, identify an anatomical region greater than 
30 cm from the Lymphoseek injection site and not over the abdomen. A set of three 2-second 
counts or one 10-second count on non-lymphoid tissue (background counts) are obtained to 
set the threshold criteria. 
In Vivo 
Lymphoseek positivity is based on radioactivity counts derived from the application of the 
handheld gamma probe in vivo, where such counts must satisfy the threshold criterion of 
greater than the quantity of 3 times the square root of the mean normal tissue background 
count (i.e., standard deviation) added to the mean normal tissue background count (referred 
to as the “3σ rule”).  Any nodal count NOT meeting this threshold criterion will be 
considered a negative  finding (not localized). Use Appendix 2 to assist in determining the 3σ 
level from the normal tissue background level. 
Ex Vivo 
Lymphoseek positivity is based on radioactivity counts derived from the application of the 
handheld gamma probe ex vivo (excised from the subject), where such counts must satisfy 
the threshold criterion of greater than the quantity of 3 times the square root of the mean 
normal tissue background count (i.e., standard deviation) added to the mean normal tissue 
background count (referred to as the “3σ rule”).  Any nodal count NOT meeting this 
threshold criterion will be considered a negative finding (not localized).  Use Appendix 2 to 
assist in determining the 3σ level from the normal room background level. 


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8.4.3 
Surgical Lymph Node Identification 
1. If a dye (e.g., VBD or ICG) is to be used, it should be injected according to the 
standard practice of the clinical site. 
2. On entering the subcutaneous tissue, a dye-containing lymphatic vessel or lymph 
node may be seen.  If a dye-containing lymphatic vessel is seen, carefully trace it to 
the proximal LN.  In vivo counts should be recorded and LN  removed. 
OR 
If no dye-containing lymphatic vessel or lymph node is seen, then using a 
combination of visualization and the handheld gamma detector, explore the lymphatic 
basin for the LNs. As dissection proceeds towards the LN, repeated use of the 
handheld gamma detector is helpful in maintaining a line of site to the lymph node. 
The count rate will increase as dissection approaches the Lymphoseek-containing 
lymph node(s).  
3. Once a LN  has been identified, in vivo counts should be taken prior to excision. In 
vivo counts will consist of a set of three 2-second counts or one 10-second count 
(depending on the device) over the lymph node. Determination of a positive finding 
(i.e., localization) is based on the In Vivo definition above.  Any LN count not 
meeting this threshold criterion will be considered a negative (non-localized) finding.   
4. The method used to identify all LN(s) will be recorded (i.e., dyed appearance, 
Lymphoseek positive finding, or both) prior to excision. 
5. To confirm the in vivo procedure, a set of three 2-second counts or one 10-second 
count will be recorded for the excised lymph nodes. The mean count of the ex vivo 
LN will be compared to the mean of normal tissue background counts, and the 
threshold criterion used to determine a positive finding for the in vivo LNs will be 
applied to the ex vivo specimens.  The appearance and time of excision of the lymph 
node will be documented. Determination of a positive finding (i.e., localization) is 
based on the Ex Vivo definition above.  Ex vivo counts must be performed on all 
excised lymph nodes 
Table 3 describes the procedures that should be followed based on the in vivo and ex vivo 
status of the tissue that has been excised. 
Table 3.   
Handling of Excised Tissue  
In Vivo Assessment 
Ex Vivo Assessment 
Procedure 
Radioactive Status 
positive (hot) 
positive (hot) 
Send to pathology for further evaluation. 
positive (hot) 
negative (not hot) or no 
counts obtained 
Incorrect node harvested. Send to pathology for 
further evaluation. Return to resection bed. 
negative or no counts (not 
hot) 
positive (hot) 
Comment on why lymph node was removed. Send 
to pathology for further evaluation. 
Dye Status 
dye-identified node 
N/A 
ANY dye-identified node is sent to pathology for 
further evaluation regardless of radioactive status. 


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6. A thorough evaluation of the remaining lymphatic basin should be undertaken since 
more than one LN may be found. This evaluation should include a combination of 
palpation, visualization, and gamma detector survey for evidence of dye and/or 
increased gamma detector count rates. 
7. Probing of the area will be complete when all selected node counts are negative by 
use of the threshold criterion. The surgeon will continue with visualization and 
palpation according to local practice to ensure that no grossly positive LNs remain at 
the site of resection.  
If a subject has neither a dye-identified node nor any “hot” nodes, continue with 
visualization and palpation according to your medical expertise.  
Pelvic lymphadenectomy will be performed in accordance with institutional standards. 
Additional surgical internvention such as radical hysterectomy should be performed in 
accordance with the subject’s surgical plan and the discretion of the surgeon.  
All removed LNs (SLNs and NSLNs) must be sent to pathology for using the minimum 
requirements of histopathological evaluation outlined in the trial pathology manual.  
For the purposes of analysis, a sentinel lymph node is defined as being hot ex vivo (lymph 
nodes with counts above the 3σ rule threshold). 
8.5 
Histopathology of Lymph Nodes 
8.5.1 
Local Lymph Node Evaluation 
Institutions with SLN ultra staging protocols in place as the standard of care will not be 
required to deviate from their methods when the minimum recommendation of the trial 
pathology manual have been met. Institutions that do not routinely employ ultra staging in 
the assessment of SLNs will be required to assess SLNS in accordance with the trial 
pathology manual as a minimum. The pathological evaluation of SLNs will include at a 
minimum serial sectioning and staining (H&E and if negative IHC additionally). The 
pathological evaluation of NSLNs at a minimum will include bifurcation and staining with 
H&E.  Minimum requirements for fixation, sectioning and staining are outlined in the trial 
pathology manual. 
Final pathology results must reflect consistent numbering and labeling from intraoperative 
worksheets to the final report. SLNs must be individually identified in the final pathology 
report.   
The pathology evaluation of each node shall be reported as follows: 
A - Macrometastases (> 2 mm) 
B - Micrometastases (≤ 2.0 mm and ≥ 0.2 mm) 
C - Isolated tumor cells or < 0.2 mm 


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D - No observable tumor presence 
8.6 
Pharmacokinetics 
No pharmacokinetic investigation will be performed in this study. 
8.7 
Safety 
8.7.1 
Adverse Events 
8.7.1.1 
Definition of Adverse Event 
The definitions below follow International Conference on Harmonization (ICH) – Good 
Clinical Practice (GCP) (see also ICH Guideline for Clinical Safety Data Management:  
Definitions and Standards for Expedited Reporting). 
Adverse Event (AE) 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
By definition for this study, all untoward medical occurrences beginning on the day of 
injection through the 24 hour post injection assessment are to be reported as AEs.  Untoward 
medical events occurring prior to the day of injection will be captured in medical history. 
SAEs will be reported from the time of consent through the end of participation. 
8.7.1.2 
Categories for Adverse Event Assessment 
All AEs will be assessed and documented by the investigator according to the categories 
detailed below. 
Seriousness 
For each AE, the seriousness must be determined according to the criteria given in 
Section 8.7.1.5. 
Severity 
The intensity of an AE is classified according to the following categories, taking into account 
the possible range of the intensity of the event: 
• Mild   
The adverse event is transient and easily tolerated by the subject. 
• Moderate  The adverse event causes the subject discomfort and interrupts the 
subject’s usual activities 


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• Severe  The adverse even causes considerable interference with the subject’s usual 
activities and may be incapacitating or life-threatening. 
 
Specific drug treatment 
Any specific drug treatment will be documented. 
Causal relationships to investigational product and dye 
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of investigational product:  
Definitely related: 
Event can be fully explained by administration of the 
investigational product. 
Probably related: 
Event is most likely to be explained by administration of the 
investigational product rather than the subject’s clinical state or 
other agents/therapies. 
Possibly related: 
Event may be explained by administration of the investigational 
product or by the subject’s clinical state or other agents/therapies. 
Probably not related: 
Event is most likely to be explained by the subject’s clinical state 
or other agents/therapies, rather than the investigational product. 
Definitely not related: 
Event can be fully explained by the subject’s clinical state or other 
agents/therapies. 
For causality assessments, events meeting the categories of definitely, probably, or possibly 
related will be considered to be related to investigational product. 
Causal relationship to study procedure 
The investigator will use the following definitions to assess the relationship of the adverse 
event to the study procedure:  
Definitely related: 
Event can be fully explained by the study procedure. 
Probably related: 
Event is most likely to be explained by the study rather than the 
subject’s clinical state or other agents/therapies. 
Possibly related: 
Event may be explained by the study procedure or by the subject’s 
clinical state or other agents/therapies. 
Probably not related: 
Event is most likely to be explained by the subject’s clinical state 
or other agents/therapies, rather than the study procedure. 


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Definitely not related: 
Event can be fully explained by the subject’s clinical state or other 
agents/therapies. 
For causality assessments, events meeting the categories of definitely, probably, or possibly 
related will be considered to be related to the study procedure. 
8.7.1.3 
Assessments and Documentation of Adverse Events  
Any AE (observed, volunteered, or elicited) should be recorded in detail in the source 
documenation. 
The following information is required: 
• The date and time of onset of any AE 
• The date and time the AE ends 
• The seriousness of the AE will be assessed by the investigator.  If the investigator 
deems that an AE qualifies as an SAE, a special form provided by the sponsor should 
be completed and the event must be immediately reported to the sponsor.  A 
definition of serious adverse events is provided below.   
• The maximum intensity (mild, moderate, or severe) 
• Whether drug treatment was administered for the event 
• The relationship of the AE to the investigational product, dye and to study conduct 
(for definitions, see above) 
• Did the AE cause study discontinuation  
• The outcome of the AE (Resolved, Resolved with sequelae, Ongoing, Unknown, Lost 
to Follow-up, Death) 
 
AEs will be coded according to an internationally recognized dictionary (Medical Dictionary 
for Regulatory Activities or MedDRA). 
8.7.1.4 
Expected Adverse Events 
Expected Conduct-Related AEs 
AEs are determined by the investigator.  If in the investigator’s opinion/experience an event 
is expected and not uncommon for that surgery (i.e., nausea in the recovery room), and it is 
not deemed different in severity from other episodes observed in the same situation, then it is 
up to the investigator’s discretion to determine the event to be adverse. 
An example of an expected conduct-related event is postoperative pain at the site of the 
incision.  






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Sponsor’s notification of the investigators 
The sponsor will inform all investigators about reported relevant events (e.g., SAEs, 
SUSARs) according to all applicable regulations. 
8.7.2 
Further Safety Assessments 
8.7.2.1 
Physical Examination 
Complete physical examinations will be conducted according to the Schedule of Study 
Events (see Appendix 1). 
Physical examination will be performed for the following body systems: 
• General appearance 
• Skin/dermatological 
• Eyes, ears, nose, throat 
• Head and neck (including thyroid) 
• Lungs 
• Heart 
• Abdomen (liver, kidney, spleen, gastrointestinal) 
• Pelvis 
• Lymph nodes 
• Musculoskeletal 
• Nervous system 
 
8.7.2.2 
Vital Signs 
Vital signs comprise the measurement of systolic and diastolic blood pressure, respiration, 
and heart rate.  All vital signs will be measured after the subject has been in a resting position 
for at least 1 minute.  Heart rate should be measured immediately before or immediately after 
blood pressure measurement.   
Vital signs will be measured at screening, baseline (0-10 minutes before investigational 
product injection), 10±3, 30±3, 60±5 minutes post injection, and after scanning. 
Any clinically significant change from baseline that results in a change in subject 
management will be considered an AE. 


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8.8 
Other Procedures and Variables 
8.8.1 
Blood Sampling 
8.8.2 
Laboratory Data for Subject Characterization 
Clinical laboratory tests to be evaluated in this study include hematology (complete blood 
count) and serum chemistry (basic metabolic panel).  Blood samples will be obtained only at 
screening in accordance with the Schedule of Events.  Table 4 shows the minimum 
parameters to be assessed: 
Table 4. 
Minimum Clinical Laboratory Parameters 
Hematology 
hemoglobin (Hb), platelets,  white blood cell (WBC) 
Serum chemistry 
 
creatinine, chloride, potassium, sodium, carbon dioxide 
(CO2)/bicarbonate, blood urea nitrogen (BUN) 
 
All laboratory reports must be promptly reviewed for clinical significance by the 
investigator, and upon review, initialed and dated by the investigator.   
Good clinical practice would suggest that a copy of the safety laboratory results be available 
to the subject and to the subject’s referring physician.     
The expected amount of blood to be withdrawn is shown in Table 5.  
Table 5. 
Approximate Amount of Blood Withdrawn 
 
mLs 
Chemistry 
5 
Hematology 
4 
Total 
9 
 


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9 
STATISTICAL METHODS  
9.1 
Introduction 
This study is a prospective, open-label study conducted at approximately 4 to 6 study centers 
in the US.  The objectives of the statistical analyses are to establish the safety and efficacy of 
Lymphoseek in targeting lymphoid tissue in subjects with cervical cancer who are 
undergoing lymph node mapping. 
A study center is defined as a treatment administration site or group of treatment 
administration sites under the control and supervision the same Primary Investigator. 
9.2 
Randomization Methods 
There is no randomization planned for this study.  All enrolled subjects will receive 
Lymphoseek along with an optional administration of either VBD or ICG. 
9.3 
Pooling of Study Centers 
There will be no selective pooling of study centers.  Subjects from all study centers will be 
pooled for the analysis. 
9.4 
Efficacy Variables 
9.4.1 
Primary Efficacy Variables 
The primary efficacy variable is the per subject false negative rate (FNR), which is the 
number of subjects with pathologically negative Lymphoseek-identified SLN(s) (or no SLNs 
were detected) and at least one pathologically positive non-SLN divided by the number of 
subjects with at least one pathologically positive node (SLN or non-SLN)  
9.4.2 
Secondary Efficacy Variables 
The secondary efficacy variables are the following: 
• Per-subject sensitivity, defined as the number of subjects with at least one 
pathologically positive SLN divided by the number of subjects with at least one 
pathologically positive node (SLN or non-SLN) 
• Per-subject negative predictive value (NPV), defined as the number of subjects with 
no pathogically positive lymph nodes (SLNs or non-SLNs) divided by the number of 
subjects with pathologically negative Lymphoseek-identified SLN(s) (or no SLNs 
were detected) 
• Per-subject accuracy, defined as the proportion of subjects whose lymph nodes were 
either all pathologically negative (i.e, true negative subject) or at least one SLN was 


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pathologically positive (i.e., true positive subject) divided by the number of subjects 
in the analysis population  
• Rate of tumor detection in SLNs, defined as the proportion of subjects with at least 
one pathologically positive SLN divided by the number of subjects in the analysis 
population  
• Rate of tumor detection in non-SLNs, defined as the proportion of subjects with at 
least one pathologically positive non-SLN divided by the number of subjects in the 
analysis population  
• Nodal concordance, defined as the proportion of lymph nodes identified 
intraoperatively by dye (e.g., VBD or ICG) that are also identified intraoperatively by 
Lymphoseek 
• Subject concordance, defined as the number of subjects whose lymph nodes that were 
identified intraoperatively by dye were also all identified intraoperatively by 
Lymphoseek 
• Reverse nodal concordance, defined as the proportion of lymph nodes identified 
intraoperatively by Lymphoseek that are also identified intraoperatively by dye   
 
• Subject reverse concordance, defined as the number of subjects whose lymph nodes 
that were identified intraoperatively by Lymphoseek were also all identified 
intraoperatively by dye 
• Number of SLNs per subject 
• Number of lymph nodes identified intraoperatively by dye   
• Number and anatomical locations of lymph nodes identified by preoperative 
Lymphoscintigraphy  
9.5 
Pharmacokinetic Variables 
Not applicable. 
9.6 
Safety Variables 
9.6.1 
Primary Safety Variables 
The primary safety variables for this study are: 
• Vital signs (screening, at pre- and 10, 30 and 60 minutes  post-injection timepoints)  
• Adverse events 
 


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9.7 
Sample Size Justification 
Approximately 40 subjects diagnosed with cervical cancer will be enrolled in the study.  This 
sample size was chosen in order to provide exploratory results for the primary endpoint of 
per subject FNR within this subject population.  This study is not powered with respect to 
testing any statistical hypotheses.   
It is anticipated that approximately 20% of the enrolled subjects will have at least one 
pathologically positive node, resulting in a total of 8 subjects available for the primary 
endpoint analysis.  With an expected FNR of 12.5%, i.e., 1 false negative subject, a sample 
size of 8 subjects will allow for an exact 95% confidence interval half-width of 26% on the 
true subject FNR.  Due to the asymmetric nature of the exact binomial confidence interval, 
the half-width described in this protocol is simply half the entire width of the confidence 
interval and not the distance between the estimate and the confidence limits.     
9.8 
Handling of Missing Data 
There will be no missing value imputation used in this study.  All endpoints will be analyzed 
with subjects who have non-missing data (i.e., a complete case analysis).   
9.9 
Statistical Analysis  
9.9.1 
Analysis Populations 
The following analysis populations will be defined:  
Intent-to-treat (ITT): The ITT population will include all enrolled subjects with 
administration of test medicine for whom at least one lymph node was removed with 
histopathology available. 
Per protocol (PP): The PP population will include all ITT subjects without major protocol 
violations. 
Safety: The safety population will include all enrolled subjects with administration of test 
medicine. 
The analysis of the efficacy endpoints will be conducted on ITT and PP populations.  The 
primary analysis set will be the ITT analysis set.  All safety analyses will be conducted on the 
safety population.   
9.9.2 
Analysis of Baseline and Demographic Characteristics 
Baseline and demographic characteristics will be summarized for all subjects in the safety 
population.  Continuous variables will be displayed via summary statistics (mean, median, 
sample size, standard deviation, minimum, and maximum).  Categorical variables will be 
summarized via counts and percentages. 


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9.9.3 
Analysis of Primary Efficacy Variables 
The per-subject FNR will be computed as follows using all ITT subjects with at least one 
pathologically positive lymph node:  
FNRsubj = 
Subjects with at least one pathologically positive non-SLN and no 
pathologically positive SLNs (i.e., false negative subject) 
Subjects with at least one pathologically positive node (SLN or non-SLN) 
 
Along with reporting the number of false negative subjects and the observed per-subject 
FNR, an exact two-sided 95% confidence interval will be computed. 
The above analyses will be repeated using the PP analysis population.  
 
9.9.4 
Analysis of Secondary Efficacy Variables 
The per-subject sensitivity will be computed as follows using all ITT subjects with at least 
one pathologically positive lymph node:  
SENSsubj = 
Subjects with at least one pathologically positive SLN (i.e., true positive 
subject)  
Subjects with at least one pathologically positive node (SLN or non-SLN) 
 
Along with reporting the number of true positive subjects and the observed per-subject 
sensitivity, an exact two-sided 95% confidence interval will be computed. 
The per-subject NPV will be computed as follows using all ITT subjects with pathologically 
negative Lymphoseek-identified SLN(s) (or no SLNs were detected):  
NPVsubj = 
Subjects with no pathologically positive nodes (SLNs and non-SLNs) (i.e., 
correctly predicted negative subjects)  
Subjects with no pathologically positive SLNs or subjects with no SLNs 
 
Along with reporting the number of correctly predicted negative subjects and the observed 
per-subject NPV, an exact two-sided 95% confidence interval will be computed. 
 
 
The per-subject accuracy will be computed as follows using all ITT subjects:  
 
 
Subjects whose lymph nodes were either all pathologically negative (i.e, true 
negative subjects) or subjects with at least one pathologically positive SLN 


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ACCsubj = 
(i.e., true positive subjects) 
All ITT subjects 
 
Along with reporting the total number of true negative and true positive subjects and the 
observed per-subject accuracy, an exact two-sided 95% confidence interval will be 
computed. 
The rate of tumor detection in SLNs will be computed as follows using all ITT subjects:  
Rate of SLN Tumor Detection = 
Subjects with at least one pathologically positive SLN  
All ITT subjects 
 
Along with reporting the total number of subjects with at least one pathologically positive 
SLN and the observed rate of SLN tumor detection, an exact two-sided 95% confidence 
interval will be computed. 
The rate of tumor detection in non-SLNs will be computed as follows using all ITT subjects:  
 
Rate of SLN Tumor Detection = 
Subjects with at least one pathologically positive  
non-SLN  
All ITT subjects 
 
Along with reporting the total number of subjects with at least one pathologically positive 
non-SLN and the observed rate of non-SLN tumor detection, an exact two-sided 95% 
confidence interval will be computed 
The nodal concordance, P1, will be computed as follows using lymph nodes from all subjects 
in the ITT population: 
P1 = 
Number of SLNs identified intraoperatively by VBD or ICG 
Number of lymph nodes identified intraoperatively by VBD or ICG  
 
9.9.4.1 
Along with reporting the number of SLNs indentified intraoperatively by VBD or 
ICG and the observed nodal concordance, an exact two-sided 95% confidence 
interval will be computed. 
The subject concordance, P2, will be computed as follows using all subjects in the ITT 
population: 
P2 = 
Subjects whose lymph nodes that were intraoperatively identified 
by VBD or ICG were also all identified by Lymphoseek 
Subjects with at least one lymph node intraoperatively identified by VBD or ICG 
 


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Along with reporting the number of subjects in the numerator and the observed subject 
concordance, an exact two-sided 95% confidence interval will be computed.  
The reverse nodal concordance, P3, will be computed as follows using lymph nodes from all 
subjects in the ITT population: 
P3 = 
Number of SLNs identified intraoperatively by VBD or ICG 
Number of SLNs  
 
Along with reporting the number of SLNs indentified intraoperatively by VBD or ICG and 
the observed reverse nodal concordance, an exact two-sided 95% confidence interval will be 
computed. 
The subject reverse concordance, P4, will be computed as follows using all subjects in the 
ITT population: 
P4 = 
Subjects whose SLNs were also all identified by VBD or ICG 
Subjects with at least one SLN 
 
Along with reporting the number of subjects in the numerator and the observed reverse 
subject concordance, an exact two-sided 95% confidence interval will be computed.  
The average number of SLNs per subject will be computed, along with a 95% confidence 
interval. 
The average number of lymph nodes identified intraoperatively by dye per subject will be 
computed, along with a 95% confidence interval. 
The average number of lymph nodes identified by preoperative Lymphoscintigraphy per 
subject will be computed, along with a 95% confidence interval. 
The number and percent of lymph nodes identified by preoperative Lymphoscintigraphy will 
be reported per anatomical location.  
The above analyses of secondary variables will be repeated using the PP analysis population.   
9.9.5 
Safety Analyses 
All AEs will be observed for each subject from injection until termination from the study.  
Additionally, all SAEs will be observed for each subject from time of consent until 
termination from the study. Prior to analysis, all AEs will be coded using MedDRA. Based 
on these coded terms, AEs will be summarized using system organ class and preferred term  
for all subjects in the safety population.  AEs will also be summarized by severity, 
relationship to investigational product, relationship to dye, and relationship to study 
procedure.  All AEs will be listed.      


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Summary statistics (mean, median, sample size, standard deviation, minimum, and 
maximum) will be computed on the raw and change from baseline values for each vital sign 
parameter by timepoint.  The pre-injection timepoint will serve as baseline.  If there are 
multiple vital signs taken at any timepoint, then the latest set of vital signs will be used for 
the analysis.  All vital sign data will be listed. 
Additional analyses of safety variables for this study may be conducted as described in the 
Statistical Analysis Plan document. 
9.10 Interim Analyses 
No formal interim analyses will be conducted during this study.   
 


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10 DATA HANDLING AND QUALITY ASSURANCE 
10.1 Data Recording 
Data required according to this protocol is captured in the subject’s source documentation 
and are to be entered into the eCRFs (provided by the sponsor) as soon as possible. 
10.1.1 
Electronic CRF design 
Electronic data capture with the sponsor’s eCRF will be used for collecting all data generated 
during the study.  The eCRF application has a built-in plausibility check system, forcing the 
investigators to answer the questions in the appropriate manner, and auto-checks for missing 
data.  The system type and eCRF details will be outlined in a separate document that will be 
provided by the sponsor and maintained in the TMF. 
10.2 Monitoring 
This study will be monitored regularly by a clinical research associate (CRA) from the 
sponsor or a contract research organization (CRO).  Monitoring procedures include one or 
more visits designed to clarify all prerequisites before the study starts.  Interim monitoring 
visits will take place on a regular basis according to a schedule fixed by mutual agreement.  
During these visits, the CRA will check for completion of the entries on the eCRFs, their 
compliance with the protocol and with GCP, and will compare the eCRF entries with the 
source data. 
All data recorded in the eCRF will be captured in the source documentation. 
The CRA will verify the correct use of the investigational product.  The investigational 
product will not be supplied to the investigator site prior to a favorable opinion from the 
IRB/IEC and the regulatory authority and, if appropriate, from the radiation protection 
authorities. 
In addition, the CRA will determine whether all AEs and SAEs have been appropriately 
reported (including adherence to the time periods required for SAEs). 
10.3 Data Processing 
Study data documentation will be maintained specifying all relevant aspects of data 
processing for the study (including data validation, cleaning, correcting, releasing).  This 
documentation will be stored in the TMF. 
For data coding (e.g., AEs, medication, medical/surgical history), internationally recognized 
and accepted dictionaries will be used.  These and the processes used for coding will be 
specified in the data management plan. 


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10.4 Auditing 
A member of the sponsor’s (or a designated CRO) quality assurance unit may arrange to visit 
the investigator in order to audit the performance of the study at the study site and the study 
documents originating there.  The auditor(s) will usually be accompanied by a CRA or the 
study team lead.  The investigator will be informed about the outcome of the audit. 
In addition, inspections by health authority representatives and IEC(s)/IRB(s) are possible at 
any time.  The investigator is to notify the sponsor of any such inspection immediately. 
10.5 Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that 
they are readily available upon authorities’ request. 
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution, or private practice.  Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period. 
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g., relocation or transfer of ownership). 
The investigator site file is not to be destroyed without the sponsor’s approval. 
The investigator’s contract will contain all regulations relevant for the study center. 
10.6 Premature Termination of the Study  
Termination by the Sponsor 
The sponsor may terminate the study at a site any time for any of the following reasons: 
1. Failure to enroll subjects 
2. Protocol violations 
3. Inaccurate or incomplete data 
4. Unsafe or unethical practices 
5. Questionable safety of the investigational product 
6. Suspected lack of efficacy of the investigational product 
7. Administrative decision 
 
 


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Termination by the Investigator 
If the Investigator terminates the study prematurely, the Investigator must do the following: 
• Return all unused investigational products and related study materials to the sponsor. 
• Provide the IRB/IEC and the sponsor with a written statement describing why the study 
was terminated prematurely.  Prompt compliance with this requirement is essential so 
that the sponsor may comply with its regulatory obligations. 
 
10.6.1 
Study as a Whole 
The sponsor retains the right to prematurely terminate the study as a whole at any time.   
At the discretion of the sponsor, the entire study may be canceled for medical reasons (e.g. 
unanticipated adverse events).  In addition, the sponsor retains the right to end the study at 
any time if the study cannot be conducted as specified in the protocol.  
In case of premature termination or suspension of the study, the principal 
investigator/sponsor will promptly inform the investigator/institutions, regulatory authorities, 
and IRB/IEC of the termination or suspension and the reason for that. 
10.6.2 
Study Participant 
Individual subjects may be withdrawn from the study according to the criteria specified in 
Section 4.3. 


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11 ETHICAL AND LEGAL ASPECTS 
11.1 Ethical and Legal Conduct of the Study 
The planning and conduct of this clinical study are subject to national laws. Only when all of 
the requirements of the appropriate regulatory authority have been fulfilled will the study 
begin. The study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki and the ICH-GCP Guidelines of 17 Jan 1997. At the 
discretion of the investigator, the entire study may be canceled for medical reasons. In 
addition, the sponsor retains the right to end the study for medical-scientific or GCP-relevant 
reasons. In case of premature termination the investigators, IRB/IECs and Regulatory 
Authorities will be informed by the Study Manager. As required by local law, current safety-
relevant information will be provided to the IEC / IRB and the regulatory authorities by the 
sponsor. The sponsor will also inform all investigators about relevant safety events according 
to the applicable regulations. 
11.2 Subject Information and Consent 
All relevant information on the study will be summarized in the subject consent form and 
additionally as required by the investigator’s institution in an integrated subject information 
and consent sheet. A sample informed consent form (ICF) is provided as a document separate 
to this protocol. 
Based on this subject ICF, the investigator will explain all relevant aspects of the study to 
each subject, before her entry into the study (i.e., before examinations and procedures 
associated with selection for the study are performed).  
The investigator will also mention that written approval of the IRB/IEC has been obtained.  
Each subject will have ample time and opportunity to ask questions and will be informed 
about the right to withdraw from the study at any time without any disadvantage and without 
having to provide reasons for this decision.  
Following this informative discussion, the subject will be asked if he/she is willing to sign 
and personally date a statement of informed consent. Only if the subject voluntarily agrees to 
sign the ICF and has done so, may he/she enter the study. Additionally, the investigator or 
his/her designee will personally sign and date the form. The subject will receive a duplicate 
of the signed and dated form.  
The investigator will record in the source documentation the consent process including the 
time and date of obtaining informed consent. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject's clinical record must clearly show that informed 
consent was obtained prior to these procedures.  


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The ICF and any other written information provided to subjects will be revised whenever 
important new information becomes available that may be relevant to the subject’s consent, 
or there is an amendment to the protocol which necessitates a change to the content of the 
subject information and/or the written ICF. The investigator will inform the subject of 
changes in a timely manner and will ask the subject to confirm his/her participation in the 
study by signing the revised ICF. Any revised written ICF and written information must 
receive the IRB/IEC's approval/favorable opinion in advance of use. 
11.3 Financing/Financial Disclosure 
Each investigator (including principal and/or any subinvestigators; as well as their spouses 
and dependent children) who is directly involved in the treatment or evaluation of research 
subjects has to provide a financial disclosure according to all applicable legal requirements. 
All relevant documentation will be filed in the sponsor trial master file and the investigator 
site file, as appropriate. 
11.4 Publication Policy 
The sponsor will be responsible for determining when any trial results should be published. 
The sponsor will work jointly with the investigator(s) to publish information in a timely 
manner. The investigator(s) shall not submit any information gleaned under the direct 
support or sponsorship of the sponsor to journals or professional societies without the prior 
written approval of the sponsor.  A "publication" is meant to include any abstract, letter, 
manuscript or public announcement in any form or length that contains information gleaned 
under the direct support or sponsorship of the sponsor. 
11.5 Subject Injury 
In general, if a subject is injured as a direct result of the investigational product but not due to 
medical negligence on the part of the principal investigator or study staff, the sponsor will 
pay for reasonable and necessary medical treatment for the injury, to the extent the expenses 
are not covered by the subject’s medical insurance, a government program, or other 
responsible third party.  If laws or regulations of the locality in which the trial is taking place 
require additional payment of expenses, the sponsor shall comply with such law or 
regulation.  Where applicable, the sponsor has taken specific national insurance. 


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17921035. 
Wallace AM, Hoh CK, Limmer KK, et al.Sentinel lymph node accumulation of Lymphoseek 
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Wallace AM, Han LK, Povoski SP, et al.  Comparative evaluation of [(99m)tc]tilmanocept 
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Appendix 2 
Gamma Detector Counts Calculation Sheet 
  


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Appendix 3 
TNM and FIGO Cancer Staging Definitions 
 




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Appendix 5 
Investigator’s Signature 
Study Title: 
A Prospective, Open-Label Trial of Lymphoseek®-Identified 
Sentinel Lymph Nodes Relative to the Pathological Status of 
Nonsentinel Lymph Nodes in Subjects With Known Cancer of the 
Cervix Who Are Undergoing Lymph Node Dissection 
Study Number: 
NAV3-19 
Original Protocol 
Date: 
27 May 2015 
Amendment 1 
Protocol Date: 
03 November 2015 
I have read the protocol described above. I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol. 
 
 
 
 
Signed: 
 
 
Date:  
 
<enter name and credentials> 
<enter title> 
<enter affiliation> 
<enter address> 
<enter phone number>