Clinical trial NCT02287675
Conditions: Breast Cancer
Keywords: Sentinel Node
Sponsor: Kettering Health Network
Start date: 2015-01-19; Completion date: 2017-08-31
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To compare the kinetics and efficacy of two functionally different diagnostic agents, Lymphoseek (CD206 receptor targeted) and 99mTc-Sulfur Colloid (SC) (Sulfur Colloid non-specific mapping agent) in intraoperative lymphatic mapping (ILM) and Sentinel Lymph Node Biopsy (SLNB).

Detailed description:
Single center, blinded, randomized, parallel-group, comparative study of Lymphoseek and 99mTc-SC in the preoperative and intraoperative detection of lymph nodes in subjects with known breast cancer. All subjects will receive a single dose of 50 μg Lymphoseek radiolabeled with 0.5 millicurie (mCi) Tc 99m or 0.5 mCi of 99mTc-SC. Subjects may also receive up to 1 mL of vital blue dye (VBD) as a companion ILM agent. All radio-labeled agents will be administered in a single intradermal injection.

Arms: arm 1: Lymphoseek (technetium Tc 99m tilmanocept) Injection is indicated for lymphatic mapping with a hand-held gamma counter to assist in the localization of lymph nodes draining a primary tumor site in patients with breast cancer or melanoma and guiding sentinel lymph node biopsy using a hand-held gamma counter in patients with clinically node negative squamous cell carcinoma of the oral cavity. arm 2: Technetium Tc 99m Sulfur Colloid Injection is a radioactive diagnostic agent indicated for use as follows:

In adults, to assist in the:

* localization of lymph nodes draining a primary tumor in patients with
* breast cancer or malignant melanoma when used with a hand-held gamma counter.
* evaluation of peritoneovenous (LeVeen) shunt patency in adults.
Interventions: intervention 1: Lymphoseek intervention 2: Sulfur Colloid
Intervention descriptions: intervention 1: Subjects will receive a single intradermal injection of Lymphoseek followed by SPECT imaging conducted in two phases: initial sequential planar imaging at 30 to 60 second intervals for the first 60 minutes and repeated at 90 minutes and 120 minutes, as indicated, for identification of the SLN followed by SPECT/CT for higher resolution imaging in transaxial, coronal, and sagittal planes. Subjects will then proceed to surgery for lymphatic mapping. Lymphoseek positivity will be based upon radioactivity counts derived from the application of the handheld gamma probe ex vivo. Tumor resection or mastectomy will be performed according to standard procedures. intervention 2: Subjects will receive a single intradermal injection of 99mTc-SC followed by SPECT imaging conducted in two phases: initial sequential planar imaging at 30 to 60 second intervals for the first 60 minutes and repeated at 90 minutes and 120 minutes, as indicated, for identification of the SLN followed by SPECT/CT for higher resolution imaging in transaxial, coronal, and sagittal planes. Subjects will then proceed to surgery for lymphatic mapping. 99mTc-SC positivity will be based upon radioactivity counts derived from the application of the handheld gamma probe ex vivo. Tumor resection or mastectomy will be performed according to standard procedures.

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 33 
 
 
A Prospective, Randomized, Parallel Group, Double-Blinded Clinical Trial 
Comparing Lymphoseek and 99mTc-Sulfur Colloid with Regard to 
Preoperative Imaging and Imaging Drug Kinetics and Intraoperative 
Lymphatic Mapping and Sentinel Lymph Node Biopsy Findings in Subjects 
With Known Breast Cancer 
 
Investigator Initiated Clinical Study Protocol No. KHNIC-P14-001 
 
 
Date of Protocol: 
April 29, 2015 
Principal Investigator: 
Sub-investigators: 
Arash Kardan, MD 
Roxane Weighall, DO   
Carol Sawmiller, MD 
 
 
 
 
Clinical Facility: 
Kettering Medical Center 
3535 Southern Blvd 
Kettering, Ohio 45429 
 
 
 
 
 
Revision History 
Release Date 
 
 
A (Original) 
B (Amendment 1) 
October 20, 2014  
April 29, 2015 
 
 
 
 
 
 
 
-CONFIDENTIAL- 
 
 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 2 of 33 
SYNOPSIS 
Study Title 
A Prospective, Randomized, Parallel Group, Double-Blinded Clinical Trial 
Comparing Lymphoseek and 
99mTc-Sulfur Colloid with Regard to 
Preoperative Imaging and Imaging Drug Kinetics and Intraoperative 
Lymphatic Mapping and Sentinel Lymph Node Biopsy Findings in Subjects 
With Known Breast Cancer 
Clinical Phase 
4 
Name of Radioactive 
Drug Substances 
Lymphoseek® and 99mTc-Sulfur Colloid (99mTc-SC) 
Dose(s) 
An intradermal dose of 0.5 mCi of one of the 99mTc radiopharmaceutical 
agents will be administered to each subject. The total administered volume 
will be 0.5 mL for each radiopharmaceutical. 
Route of 
Administration 
Intradermal injection 
Duration of 
Treatment 
A single injection of one of the 99mTc radiopharmaceutical agents 
Indication 
Lymphoseek (technetium Tc 99m tilmanocept) Injection is indicated for 
lymphatic mapping with a hand-held gamma counter to assist in the 
localization of lymph nodes draining a primary tumor site in patients with 
breast cancer or melanoma and guiding sentinel lymph node biopsy using a 
hand-held gamma counter in patients with clinically node negative squamous 
cell carcinoma of the oral cavity. 
Technetium Tc 99m Sulfur Colloid Injection is a radioactive diagnostic agent 
indicated for use as follows: 
In adults, to assist in the: 
• 
localization of lymph nodes draining a primary tumor in patients with 
• 
breast cancer or malignant melanoma when used with a hand-held 
gamma counter. 
• 
evaluation of peritoneo-venous (LeVeen) shunt patency in adults. 
Study Objectives 
Primary Objective 
• 
To compare the preoperative radiotracer kinetics (rate of injection 
site clearance and rate of sentinel lymph node [SLN] uptake) for 
Lymphoseek and 99mTc-SC. 
Secondary Objectives 
• 
To compare the number and range of intraoperatively detected SLNs 
identified by Lymphoseek and 99mTc-SC on an agent cohort basis 
• 
To compare differences in the ratio of intraoperative counts for 
Lymphoseek vs 99mTc-SC for the hottest harvested axillary SLN 
relative to the primary intradermal injection site.  
• 
To compare subject pain tolerance (i.e., subject’s perceived level of 
discomfort) at the injection site for Lymphoseek vs 99mTc-SC. 
• 
To compare pathologic assessment of the excised lymph node(s) to 
confirm the presence/absence of tumor metastases for Lymphoseek vs 
99mTc-SC. 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 3 of 33 
Inclusion Criteria 
1. The patient must be female and 18 years of age or older. 
2. The patient must be a preoperative clinical Tis, T1, T2, T3, T4, as 
well as clinical N0 and clinical M0 breast cancer 
3. The patient must have a diagnosis of primary breast cancer. 
4. The patient must be a candidate for surgical intervention, either with 
lumpectomy and sentinel lymph node biopsy (SLNB) or with 
mastectomy and SLNB, as the treatment of her breast cancer. 
5. The patient must have an ECOG performance status of Grade 0 – 2 
6. The patient must provide written informed consent with HIPAA 
authorization before participating in the study 
Exclusion Criteria 
1. The patient has clinical or radiological or pathologic evidence of 
metastatic cancer, including any abnormal or enlarged clinical 
palpable lymph nodes or core biopsy/surgical biopsy/fine needle 
aspiration (FNA) evidence of malignant cell within any lymph nodes. 
2. The patient has a known hypersensitivity to vital blue dye (VBD) in a 
case where vital blue dye was planned for use during SLNB. 
3. The patient has a positive pregnancy test or is lactating. 
4. The patient has had prior surgery in the upper, outer quadrant, areola 
or axilla to the indicated breast. 
5. The patient has had pre-surgical neoadjuvant chemotherapy or 
previous breast radiation. 
6. The patient has participated in another investigational drug study 
during the 30 days prior to signing informed consent. 
Concomitant 
Medications 
All medications taken by the subject for seven days prior to surgery will be 
recorded. 
Study Rationale 
To compare the kinetics and efficacy of two functionally different diagnostic 
agents, Lymphoseek (CD206 receptor targeted) and 99mTc-SC (non-specific 
mapping agent) in intraoperative lymphatic mapping (ILM) and SLNB.   
Study Design 
Single center, blinded, randomized, parallel-group, comparative study of 
Lymphoseek and 99mTc-SC in the preoperative and intraoperative detection of 
lymph nodes in subjects with known breast cancer. All subjects will receive a 
single dose of 50 µg Lymphoseek radiolabeled with 0.5 mCi Tc 99m or 0.5 
mCi of 99mTc-SC.  Subjects may also receive up to 1 mL of vital blue dye 
(VBD) as a companion ILM agent. All radio-labeled agents will be 
administered in a single intradermal injection.   
Methodology 
Subjects will participate in 3 study visits (including the Screening Visit 
[Visit 1]) over the course of the study period. Screening will include an 
assessment of eligibility and informed consent, a review of concomitant 
medications, and a random assignment to a treatment group. During Visit 2, 
all subjects will receive either a single intradermal injection of Lymphoseek 
or 99mTc-SC based upon the treatment group assigned at screening, followed 
by SPECT imaging conducted in two phases: initial sequential planar imaging 
at 30 to 60 second intervals for the first 60 minutes and repeated at 90 
minutes and 120 minutes, as indicated,  for identification of the SLN followed 
by SPECT/CT for higher resolution imaging in transaxial, coronal, and 
sagittal planes (see Appendix E). Subjects will then proceed to surgery for 
lymphatic mapping. Lymphoseek and 99mTc-SC positivity will be based upon 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 4 of 33 
radioactivity counts derived from the application of the handheld gamma 
probe ex vivo. Tumor resection or mastectomy will be performed according 
to standard procedures.  Subjects will be contacted by telephone  at day 5 ± 3 
days post-surgery (Visit 3) to assess adverse events.  
Number of Subjects 
The sample size for the study is based on the co-primary endpoints.  In order 
to have an 80% chance of demonstrating that Lymphoseek is superior to 
99mTcSC based on the injection site clearance rate, assuming that the mean 
rate of Lymphoseek is 0.250, the mean rate of 99mTc-SC is 0.05, and the 
common standard deviation is 0.15, at least 10 subjects will need to be 
enrolled in each treatment group.   
In order to have an 80% chance of demonstrating that Lymphoseek is 
superior to 99mTcSC based on the SLN uptake rate, assuming that the mean 
rate of Lymphoseek is 0.1075, the mean rate of 99mTcSC is 0.0875, and the 
common standard deviation is 0.0009, at least 19 subjects will need to be 
enrolled in each treatment group.   
In order to meet the sample size requirements for each endpoint, 
approximately 40 subjects will be enrolled in the study.  These sample size 
calculations were based on a two-sided α=0.05 level of significance for each 
endpoint. 
Approximate 
Duration of Subject 
Participation  
75  days (includes screening period) 
Approximate 
Duration of Study 
14 months 
Plan for Statistical 
Analysis 
The co-primary endpoints of the study are preoperative rate of injection site 
clearance and rate of SLN uptake for Lymphoseek and 99mTc-SC. 
Superiority hypothesis tests comparing the injection site clearance rate and 
SLN uptake rate of Lymphoseek to the injection site clearance rate and SLN 
uptake rate of 99mTc-SC will be conducted at a two-sided α=0.05 (one-sided 
α=0.025) level of significance.    
The secondary efficacy variables are: 
• 
Number of SLNs identified in each subject 
• 
Gamma counts at the primary injection site in the breast and the ex 
vivo gamma counts of the SLNs removed 
• 
Pain scores  
• 
Pathology status of SLNs 
Summary statistics (mean, median, standard deviation, minimum, and 
maximum) will be computed for each of the secondary variables. 
All analyses of kinetics and efficacy will be performed on the ITT population, 
which consists of all enrolled subjects who were randomized, received an 
injection of Lymphoseek or 99mTc-SC, went to surgery, and had at least one 
lymph node removed that was confirmed to be lymph tissue and had a known 
disease status (positive or negative for disease) by histopathology. 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 5 of 33 
TABLE OF CONTENTS 
SYNOPSIS.................................................................................................................................................................... 2 
SIGNATURE PAGE ................................................................................................................................................... 7 
1 
INTRODUCTION .............................................................................................................................................. 8 
1.1 
BACKGROUND .................................................................................................................................................. 8 
1.1.1 
Intraoperative Lymphatic Mapping and Sentinel Lymph Node Biopsy ................................................ 8 
1.1.2 
Lymphoseek ........................................................................................................................................... 9 
1.1.3 
99mTc-Sulfur Colloid (99mTc-SC)............................................................................................................ 9 
1.1.4 
Study Agents and Prior Use ................................................................................................................... 9 
1.2 
RATIONALE .................................................................................................................................................... 10 
1.3 
OBJECTIVES/ENDPOINTS ................................................................................................................................ 10 
2 
STUDY POPULATION................................................................................................................................... 11 
2.1 
ELIGIBILITY ................................................................................................................................................... 11 
2.1.1 
Inclusion Criteria ................................................................................................................................. 11 
2.1.2 
Exclusion Criteria ................................................................................................................................ 11 
2.2 
NUMBER OF SUBJECTS ................................................................................................................................... 12 
2.2.1 
Screen Failures ..................................................................................................................................... 12 
2.2.2 
Withdrawal .......................................................................................................................................... 12 
3 
RESEARCH PLAN .......................................................................................................................................... 13 
3.1 
OVERVIEW ..................................................................................................................................................... 13 
3.2 
VISIT DESCRIPTIONS ...................................................................................................................................... 13 
3.2.1 
Informed Consent Visit (Visit 1) ......................................................................................................... 13 
3.2.2 
Visit 2: Injection and Imaging ............................................................................................................. 14 
3.2.3 
Telephone Follow Up 5 (+3) days post injection (Visit 3) .................................................................. 17 
3.3 
COMPLETION/DISCONTINUATION AND WITHDRAWAL OF SUBJECTS .............................................................. 17 
4 
STUDY DRUGS ............................................................................................................................................... 18 
4.1 
IDENTIFICATION OF LYMPHOSEEK.................................................................................................................. 18 
4.2 
IDENTIFICATION OF 99MTC-SULFUR COLLOID ............................................................................................... 18 
4.3 
IDENTIFICATION OF VITAL BLUE DYE ............................................................................................................ 18 
4.4 
DOSAGE AND ADMINISTRATION ..................................................................................................................... 18 
4.5 
TREATMENT ASSIGNMENT ............................................................................................................................. 18 
4.6 
BLINDING ....................................................................................................................................................... 18 
4.7 
PACKAGING AND LABELING ........................................................................................................................... 19 
4.8 
STORAGE ........................................................................................................................................................ 19 
4.9 
SUPPLY, DISPENSING, AND RETURN ............................................................................................................... 19 
4.10 
DRUG ACCOUNTABILITY ........................................................................................................................... 19 
5 
STATISTICAL AND ANALYTICAL PLANS ............................................................................................. 20 
5.1 
INTRODUCTION .............................................................................................................................................. 20 
5.2 
RANDOMIZATION METHODS .......................................................................................................................... 20 
5.3 
EFFICACY VARIABLES .................................................................................................................................... 20 
5.3.1 
Primary Efficacy Variables .................................................................................................................. 20 
5.3.2 
Secondary Efficacy Variables .............................................................................................................. 20 
5.4 
SAFETY VARIABLES ....................................................................................................................................... 20 
5.5 
SAMPLE SIZE JUSTIFICATION .......................................................................................................................... 21 
5.6 
STATISTICAL ANALYSES ................................................................................................................................ 21 
5.6.1 
Analysis Populations............................................................................................................................ 21 
5.6.2 
Analysis of Baseline and Demographic Characteristics ...................................................................... 21 
5.6.3 
Analysis of Primary Variables ............................................................................................................. 22 
5.6.4 
Analysis of Secondary Variables ......................................................................................................... 22 
5.6.5 
Safety Analyses ................................................................................................................................... 23 
5.7 
HANDLING MISSING VALUES ......................................................................................................................... 23 
5.8 
INTERIM ANALYSES ....................................................................................................................................... 23 
6 
ADVERSE EVENTS ........................................................................................................................................ 24 
6.1 
DEFINITION OF ADVERSE EVENT .................................................................................................................... 24 
7 
REFERENCES ................................................................................................................................................. 26 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 6 of 33 
  LIST OF APPENDICES 
Appendix A Schedule of Events ............................................................................................................... 28  
Appendix B Performance Status Criteria ................................................................................................. 29 
Appendix C Links to Product Labels ....................................................................................................... 30 
Appendix D TNM Staging for Breast Cancer Patients ............................................................................. 31 
Appendix E Imaging Protocol .................................................................................................................. 32 
Appendix F Operating Room and Surgical Procedures Flowchart .......................................................... 33 
 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 7 of 33 
SIGNATURE PAGE 
I have reviewed and approve this protocol.  My signature assures that this study will be conducted 
according to all stipulations of the protocol, including all statements regarding confidentiality.   
 
 
___________________________________ 
 
_______________________________ 
Arash Kardan, MD 
 
 
   
              Date of Signature (DD/MMM/YYYY) 
Nuclear Medicine 
Kettering Medical Center 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 8 of 33 
1 
INTRODUCTION 
1.1 Background  
1.1.1 Intraoperative Lymphatic Mapping and Sentinel Lymph Node Biopsy 
Since its first description for breast cancer by Krag in 1993 [1] and Giuliano in 1994 [2], intraoperative 
lymphatic mapping (ILM) and sentinel lymph node biopsy (SLNB) have become standard-of-care 
technologies widely utilized in the surgical staging and treatment of breast cancer. The utilization of 
ILM/SLNB for breast cancer has resulted in the reduction in the short-term complications and long-term 
morbidities, including lymphedema, that are generally associated with axillary lymph node dissection 
(ALND) [3-6]. Additionally, the utilization of ILM/SLNB has allowed for the avoidance of the need of 
ALND in cases of early-stage breast cancer with limited sentinel lymph node (SLN) involvement in both 
cases of breast conserving surgery [7,8] and mastectomy [8].  
An ideal lymph node mapping agent for ILM/SLNB should exhibit rapid clearance from the injection site, 
rapid uptake and high retention within the first draining lymph node(s), and low uptake by subsequent, 
higher echelon lymph nodes. The ideal lymph node mapping agent should also have biochemical purity, 
molecular size uniformity, and a high level of biologic and radiation safety. Specifically regarding a 
radiopharmaceutical lymph node mapping agent, it should possess characteristics for allowing for 
convenient, rapid, and stable 99mTc labeling.   
For breast cancer, 99mTc-radiotracer agents and blue dye agents, used separately or in combination, have 
been described for use during ILM/SLNB [9]. Likewise, multiple injection routes for ILM/SLNB have 
been described [9]. Definitive evidence for the superiority of the intradermal injection route for the 
administration of a 99mTc-radiotracer agent (i.e., 99mTc-Sulfur Colloid abbreviated here as 99mTc-SC) 
during ILM/SLNB is well established from a prospective, randomized clinical trial comparing the 
intraparenchymal, subareolar, and intradermal injection routes in 400 breast cancer patients [10]. This 
prospective, randomized clinical trial demonstrated that the intradermal radiotracer injection route: (1) 
allowed for the greatest success of identification of an axillary SLN; (2) allowed for minimization of the 
time from injection of radiocolloid to successful identification of an axillary SLN; and (3) resulted in the 
generation of the ‘hottest” axillary SLN and the shortest intraoperative time to harvest. 
Prior to July 2011, 99mTc-SC had been used exclusively off-label for all ILM/SLNB procedures performed 
in the United States over the past 20 years. However, in July 2011, 99mTc-SC eventually received formal 
FDA approval in the United States by Pharmalucence, Inc.  (Billerica, Massachusetts) for ILM during 
SLNB for breast cancer [11,12]. Concurrently, within the past 10 years, a novel, soluble, synthetic (i.e., 
non-biologic), 
receptor-directed 
targeting 
agent, 
99mTc-Tilmanocept 
(Lymphoseek®, 
Navidea 
Biopharmaceuticals, Dublin, Ohio) has been developed for ILM/SLNB [13-16], and has been formally 
evaluated in two multi-institutional, open-label, nonrandomized, “within-patient,” Phase 3 clinical trials 
(NEO3-05: May 2008-June 2009; and NEO3-09: July 2010-April 2011) with 99mTc-Tilmanocept for 
breast cancer patients (Tis-T4/N0/M0) [17]. Resultantly, as of March 2013, Lymphoseek has now 
received formal FDA approval in the United States for ILM during SLNB for breast cancer and for 
melanoma [18] with supplemental approval for guiding sentinel lymph node biopsy for clinically node 
negative squamous cell carcinoma of the oral cavity in June 2014. It has been well documented in three 
prospective (but nonrandomized) clinical trials  of Lymphoseek [17,19, 20] that 99mTc-Tilmanocept, for 
early-stage breast cancer, melanoma, and head and neck squamous cell carcinoma has a high SNL 
localization/detection rate of  > 97% and a low false negative rate of < 5%, demonstrating potentially 
improved performance over that previously reported within the historical literature for 99mTc-SC. Both 
99mTc-SC and Lymphoseek are approved radiopharmaceuticals for use in breast cancer ILM/SLNB.  
However, to date, there is yet to be a prospective, randomized, double-blinded clinical trial that has been 
conducted at any institution in the United States for directly comparing the preoperative radiotracer 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 9 of 33 
kinetics and the intraoperative imaging findings (i.e., ILM and SLNB findings) for Lymphoseek and 
99mTc-SC. 
1.1.2 Lymphoseek 
Lymphoseek is a radiopharmaceutical tracer that accumulates within lymph nodes by specifically 
targeting lymphatic reticuloendothelial cells. Lymphoseek is a soluble macromolecule that has a diameter 
in the 5 to 7 nm range and has a molecular weight of approximately 18 kDa. Lymphoseek consists of 
multiple units of DTPA (diethylene triamine pentaacetic acid) and mannose, each synthetically attached 
to a 10-kDa dextran core. Lymphoseek binds to mannose receptors (i.e., CD206) that reside on the 
surfaces of reticuloendothelial cells  (i.e., macrophages and dendritic cells) that specifically reside within 
lymph nodes. The mannose portion of the macromolecule acts as a ligand binding substrate for the 
mannose receptor (i.e., CD206) to increase uptake and retention specifically within lymph nodes. The 
DTPA portion of the macromolecule serves as a chelating agent for the radiolabeling of the 
macromolecule with 99mTc. The diameter of Lymphoseek is substantially smaller than that of colloid-
based radiolabeled lymph node mapping agents, which generally have a particle diameter size range of 
< 100 to 200 nm when filtered. The small diameter of Lymphoseek permits enhanced diffusion into 
lymph nodes and blood capillaries, resulting in a rapid injection site clearance. Upon entry into the blood, 
Lymphoseek can bind to mannose receptors in the liver, as well as can be filtered and excreted by the 
kidneys and eliminated via the urinary bladder. 
Lymphoseek is a radioactive diagnostic agent indicated for lymphatic mapping with a hand-held gamma 
counter to assist in the localization of lymph nodes draining a primary tumor site in patients with breast 
cancer or melanoma. 
Lymphoseek is an FDA-approved radiopharmaceutical agent. 
1.1.3 
99mTc-Sulfur Colloid (99mTc-SC) 
While Lymphoseek represents a synthetic, receptor-targeted lymph node mapping agent, 99mTc-SC 
represents a non-synthetic/biologic (i.e., containing bovine gelatin),  non-specific (i.e., not receptor-
targeted) lymph node mapping agent that is passively trapped and accumulates within lymph nodes. 
99mTc-SC is an injectable diagnostic radiopharmaceutical agent that is indicated for:  
(1) In adult patients only, to assist in the: (i) localization of lymph nodes draining a primary tumor in 
patients with breast cancer when used with a hand-held gamma counter; and (ii) evaluation of peritoneo-
venous (LeVeen) shunt patency in adults.  
(2) In adults and pediatric patients, for: (i) imaging areas of functioning reticuloendothelial cells in the 
liver, spleen and bone marrow; and (ii) studies of esophageal transit and gastroesophageal reflux, and 
detection of pulmonary aspiration of gastric contents. 
99mTc-SC is an FDA-approved radiopharmaceutical agent. 
1.1.4 Study Agents and Prior Use 
All additional product information related to each radiopharmaceutical study agent is contained within the 
Lymphoseek and 99mTc-SC package inserts, as is shown in Appendix C. 


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Page 10 of 33 
1.2 Rationale 
The purpose of this study is to compare the efficacy of two functionally different diagnostic lymph node 
mapping radiopharmaceutical agents, Lymphoseek and 99mTc-SC, in a prospective, randomized, double-
blinded fashion for ILM and SLNB in breast cancer patients.   
1.3 Objectives/Endpoints 
Primary Objective 
• 
To compare the preoperative radiotracer kinetics (rate of injection site clearance and rate of SLN 
uptake) for Lymphoseek and 99mTc-SC. 
Secondary Objectives 
• 
To compare the number and range of intraoperatively detected SLNs identified by Lymphoseek 
and 99mTc-SC on an agent cohort basis 
• 
To compare differences in the ratio of intraoperative counts for Lymphoseek vs 99mTc-SC for the 
hottest harvested axillary Sentinal Lymph Node (SLN) relative to the primary intradermal 
injection site.  
• 
To compare subject pain tolerance (i.e., subject’s perceived level of discomfort) at the injection 
site for Lymphoseek vs 99mTc-SC. 
• 
To compare pathologic assessment of the excised lymph node(s) to confirm the presence/absence 
of tumor metastases for Lymphoseek vs 99mTc-SC. 
 
 


Protocol Number/Version: KHNIC-P14-001/B 
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Page 11 of 33 
2 
STUDY POPULATION 
2.1 Eligibility 
Up to 40 evaluable subjects (20 per cohort) will be enrolled in this trial. Evaluable subject is defined as an 
enrolled subject who was randomized, received an injection of Lymphoseek or 99mTc-SC, went to surgery, 
and had at least one lymph node removed.  Determination of study eligibility will be established by the 
investigator on the basis of the inclusion and exclusion criteria. 
The inclusion/exclusion criteria are designed to ensure that study subjects have a diagnosis of primary 
breast cancer and are candidates for surgical intervention as a treatment of breast cancer. 
Subjects who fulfill all respective inclusion and none of the exclusion criteria will be eligible for 
enrollment into the trial. Written, dated informed consent will be obtained from all subjects. 
In the event that a subject has bilateral disease, the subject would not be randomly assigned but instead 
would receive injections of both radiopharmaceuticals, one in each breast.  The subject and surgeon will 
be blinded to which breast is injected with which radiopharmaceutical. 
2.1.1 Inclusion Criteria 
Patients meeting all of the following inclusion criteria by the end of the screening phase should be 
considered for admission to the study: 
1. The patient must be female and 18 years of age or older. 
2. The patient must be a preoperative clinical Tis (see 2.1.4), T1, T2, T3, T4, as well as clinical N0 
and clinical M0 breast cancer (see Appendix D).  
3. The patient must have a diagnosis of primary breast cancer. 
4. The patient must be a candidate for surgical intervention, either with lumpectomy and SLNB or 
with mastectomy and SLNB, as the treatment of their breast cancer.  
5. The patient must have an ECOG performance status of Grade 0 – 2 (see Appendix B). 
6. The patient must provide written informed consent with HIPAA authorization before 
participating in the study. 
2.1.2 Exclusion Criteria 
Patients will not be entered into the study if they meet any of the following exclusion criteria:   
1. The patient has clinical or radiological or pathologic evidence of metastatic cancer, including any 
abnormal or enlarged clinically palpable lymph nodes or core biopsy/surgical biopsy/FNA 
evidence of malignant cell within any lymph nodes. 
2. The patient has a known hypersensitivity to vital blue dye in a case where vital blue dye was 
planned for use during SLNB. 
3. The patient has a positive pregnancy test or is lactating. 
4. The patient has had prior surgery in the upper, outer quadrant, areola, or axilla to the indicated 
breast. 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 12 of 33 
5. The patient has had pre-surgical neoadjuvant radiation or chemotherapy. 
6. The patient has participated in another investigational drug study during the 30 days prior to 
signing informed consent. 
 
2.2 Number of Subjects 
The estimated sample size to determine a difference between the two test agents for the co-primary 
objectives is 19 subjects in each group.  It is anticipated that not less than 20 subjects will be randomized 
and enrolled into each group.  (Power = 0.80; p < 0.05.) 
2.2.1 Screen Failures 
Subjects who sign an informed consent form (ICF) but are ultimately not enrolled in the trial will be 
considered screen failures. Subjects will be assigned a subject identification number at the time the ICF is 
signed. Once all screening study procedures have been completed and eligibility has been confirmed, the 
subject will be eligible for enrollment but the subject will not be considered to be enrolled until the 
morning of drug administration. Demographic data and the reason for the screen failure will be collected 
for all screen failure subjects. 
For subjects who enroll in the trial but withdraw prior to injection of either radiopharmaceutical, 
enrollment will be extended in order to meet sample size requirements. Enrollment will not be extended 
for subjects who withdraw for any reason after receiving an injection of Lymphoseek. 
2.2.2 Withdrawal  
In accordance with the Declaration of Helsinki, each subject is free to withdraw from the trial 
at any time and without providing a reason. 
 
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. 
 
The investigator may withdraw a subject from the trial 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 discretion as long as it is in the best interest of the subject 
• The investigator terminates the study 
• The subject requests to be discontinued from the study 
 
 


Protocol Number/Version: KHNIC-P14-001/B 
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3 
RESEARCH PLAN 
3.1 Overview  
This is a single center, blinded, randomized, parallel-group comparative study of Lymphoseek and 
99mTc-SC colloid  in the preoperative and intraoperative detection of excised lymph nodes in subjects with 
known breast cancer. All subjects will receive a single dose of 50 µg Lymphoseek radiolabeled with 0.5 
mCi Tc 99m or 0.5 mCi of sulfur colloid.  Subjects may also receive up to 1 mL of VBD as a companion 
ILM agent followed by massage of the breast adjacent to the area of injection.  Tc99m-labeled agents will 
be administered in a total volume of 0.5 mL; all radio-labeled agents will be administered in a single 
intradermal injection delivered adjacent to the areola in the upper outer quadrant.  The approximate 
duration of the study is 14 months.  Subject participation in the study will be defined as the time of patient 
screening in the clinic in the preoperative period through completion of their ILM/SLNB procedure and 
Day 5 follow up, which would represent a maximum duration of time of approximately 75 days. 
Recruitment will take place at study investigator’s offices.  The investigator will describe the study to 
potential subjects and answer any questions about the patient’s study eligibility. The surgical plan and 
additional study related procedures will be discussed with the patient.  A study consent form will be 
offered to the subject for them to take home and discuss with family and/or friends. 
3.2 Visit Descriptions 
3.2.1 Informed Consent Visit (Visit 1) 
3.2.1.1 
Informed Consent 
All potential study subjects will be informed of the investigational nature of this research study and will 
be required to read, agree to, and sign a statement of informed consent prior to participation. Consent will 
be obtained using a current IRB/IEC approved informed consent form.   
3.2.1.2 
Screening and Enrollment Activities 
Screening procedures must occur within 45 days prior to Lymphoseek or 99mTc-SC injection.  
Screening procedures include:  
• 
A review of recent medical history obtained when the surgical plan was discussed with the 
patient. 
• 
Demography – Date of birth, gender, and race will be collected. 
• 
Physical examination at the screening visit or in the preceding 45 days with documented findings 
available.  
• 
Collection of  vital signs - heart rate, blood pressure, respiratory rate, and temperature. 
• 
A record  of medications taken seven days prior to the screening visit will be obtained. 
• 
Relevant medical history – Medical history will be obtained on all study patients.  All relevant 
prior medical conditions will be recorded.  Medical conditions will be documented by body 
system, noting the year of onset and if the condition is active.  Additionally, significant illnesses 
experienced within one week prior to screening will be recorded.  Common accepted medical 
terminology should be used. 


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• 
Previously determined pathology findings from breast biopsy 
• 
Eligibility assessment – Conducted by the Investigator and/or his/her designated representative. 
• 
Explanation of the details of the pain assessment rating scale. 
3.2.2 Visit 2: Injection and Imaging 
Randomization assignment (see Section 4.5)  will be determined just prior to the injection visit when the 
order for the test article is placed by the nuclear medicine technician.  Either Lymphoseek or 99mTc-SC 
will be injected at Visit 2.  The respective dosage, administration, and SPECT imaging procedures for 
both agents are described below. 
3.2.2.1 
Pre-Injection 
Prior to receiving the test agent injection, adverse event monitoring will begin. 
Pregnancy testing for women of child bearing potential. A urine or serum pregnancy test will be collected 
before receiving the Lymphoseek or 99mTc-SC injection. If the urine pregnancy test is positive, the subject 
will be withdrawn from the study. 
3.2.2.2 
Injection of Lymphoseek and 99mTc-SC 
The appropriate dose of 99mTc used to label tilmanocept or sulfur colloid should be ordered from the 
Nuclear Medicine Department or radiolabeling facility once the subject has been scheduled for surgery. 
Injection of Lymphoseek or 99mTc-SC will be at study time 0:00.  The only method of injection that will 
be used is a single intradermal administration. 
Intradermal Administration:   The injection dose  of 99mTc radiopharmaceutical agent will be administered 
at a dose of 0.5 mCi and a volume of 0.5 mL, using a tuberculin-type syringe with a 25-gauge or 27-
gauge needle. 99mTc-SC should be filtered with a 0.22 micron filter. The injection will be performed using 
a single, intradermal injection near the areola in the upper, outer quadrant.  This technique will not differ 
based on study group. The subject and physician administering the agent will be blinded to the drug 
administered. No breast massage will be allowed immediately after the intradermal injection of the 
radiopharmaceutical is performed. No local anesthetics agents will allowed to be administered prior to or 
at the time of or in combination with the intradermal injection of the 99mTc radiopharmaceutical agents. 
Immediately after injection, subjects will be asked to rate their level of discomfort using the Wong-Baker 
FACES pain rating scale [21], which ranges from a minimum score of zero (no pain) to a maximum score 
of ten (worst pain possible).  The scale includes a visual analog scale with the following categories, each 
accompanied by a cartoon face indicating the level of pain:  0 No Hurt, 1-2 Hurts Little Bit, 3-4 Hurts 
Little More, 5-6 Hurts Even More, 7-8 Hurts Whole Lot, 9-10 Hurts Worst.  This scale will be shown and 
explained to the subjects at the screening visit, and a copy will be provided for the subject to take home.  
Immediately after injection of Lymphoseek or 99mTc-SC, the subject will be asked to verbally rate the 
level of pain experienced by indicating a number between 0 and 10, based on this scale.   
3.2.2.3 
SPECT Imaging 
The lymphoscintigraphy will be performed in two phases: (1) evaluation of the initial rapid absorption 
and transit phase through lymphatics to the sentinel lymph node(s), (2) additional efforts to facilitate the 
exact location of the SLN for surgical excision. 


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Subjects will be injected with the assigned radiopharmaceutical agent (0.5 mCi) per the randomization 
schema.   
Subjects will undergo standard sequential planar SPECT imaging at 30 to 60 seconds intervals  per the 
procedure detailed in Appendix E.   A SPECT/CT will also be performed for higher resolution imaging in 
transaxial, coronal, and sagittal planes. Vital signs (temperature, respiratory rate, pulse rate, blood 
pressure) will be collected on each subject just prior to injection, and post-injection at 15, 30, 60 and 120 
minutes, respectively,  ± 5 minutes, and recorded on the appropriate study form. Following injection of 
the test article and image acquisition the subject will undergo surgery according to her surgical plan on 
the day of imaging  
3.2.2.4 
Operating Room and Surgery (Overview) 
Operating room and surgical procedures are described in Appendix F. 
The surgeon will be provided with the preoperative imaging results. The surgeon will perform an initial 
external survey of the subject with the hand-held gamma detection probe and gamma detection unit in the 
operating room area and will determine the site(s) of 99mTc radiopharmaceutical agent localization. 
Once the above image review and initial external survey are completed, the subject’s surgical procedure 
will begin. If the planned surgery is lumpectomy the SLN survey and biopsy will occur prior to the 
lumpectomy.  Conversely, per the operating surgeon’s standard approach with mastectomy, SLN survey 
and biopsy will be completed immediately following the mastectomy with a flap of mammory tissue 
remaining attached during the SLN survey and biopsy. All intraoperative data will be recorded on a 
specifically designed SLNB data collection sheet by a designated clinical research coordinator for the 
study. All data from the specifically designed SLNB data collection sheet form will then be transcribed 
into and maintained in a prospective SLNB computerized database by a designated clinical research 
associate for the study.  
All excised lymph nodes will be examined by a pathologist during the surgical case to determine any 
positive findings of malignancy per frozen section.  See Section 3.2.2.4.1 below for details of the specific 
surgical procedures for SLN detection and biopsy and pathology evaluation. 
3.2.2.4.1 Lymphoseek and 99mTc-SC Designated “Hot” Nodes 
Ex Vivo 
Lymphoseek and 99mTc-SC 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 10% or more of the ex vivo count of the hottest node (referred to as the “10% rule”) [22]. Any 
nodal count NOT meeting this threshold criterion will be considered a negative finding (not localized).  
3.2.2.4.2 Surgical Procedures 
After preoperative imaging procedures have been completed, subjects will proceed to surgery for 
lymphatic mapping. Excision of the primary tumor will be performed at the same time and in the same 
setting.  
1. Intraoperatively, subjects will undergo injection of VBD, unless contraindicated, (1% isosulfan 
blue) via the method and injection route of choice of the operating surgeon. Breast massage may 
be performed immediately after VBD injection.  
2. Using the handheld gamma detection system for three 2-second counts or one 10-second count 
obtain and record the reading for the room “background” count.  Then, identify an anatomical 


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region on non-lymphoid tissue, greater than 20 cm from the injection site, and not over the 
abdomen to collect and record a second reading of three 2-second counts or one 10-second count 
to to determine the “normal tissue” count to set the threshold criteria.  Three 2-second counts or 
one 10-second count will be used for all subsequent readings. 
3. Collect and record counts over the injection site, and then conduct an initial transcutaneous 
survey to identify the area of increased radioactivity that is separate from the injection site. The 
survey should  include all of the potential areas, such as the axilla, medial chest, ipsilateral 
supraclavicular area, and ipsilateral neck. 
4. Once an area of increased radioactivity is identified in the axilla, an incision should be placed to 
make as direct an approach as possible to the lymph node.  Subjects will then undergo SLNB 
using a hand-held gamma detection system/probe to detect radiopharmaceutical (“hot”) uptake 
and using visual inspection to detect blue dye (“blue”) uptake.   
5. An in vivo count will be collected prior to excision of each respective lymph node and an ex vivo 
account will be collected immediately following excision of each lymph node.  
a. A sentinel lymph node (SLN) is defined as any lymph node that was either “hot” and 
“blue”, “hot” only, or “blue” only, or a palpable, enlarged, hardened node.  
 
b. A “hot” SLN is defined as the node with the greatest number of counts based on 
radioactivity or counts derived from the application of the handheld gamma detector in 
vivo, or any node that satisfies the 10% rule of 10% or more of the ex vivo count of the 
hottest node. Any nodal count not meeting this 10% rule will be considered a negative 
finding (not localized).  
c. A “blue” SLN is defined as any lymph node that is visibly stained blue, has a visible 
contiguous blue-stained afferent lymphatic, or both. Therefore, a very thorough 
evaluation of the lymphatic basin should be undertaken during the SLNB procedure. This 
should include gamma detection probe survey (for the detection of 
99mTc 
radiopharmaceutical agent localization to lymph nodes), palpation, direct visualization 
(for the detection of vital blue dye localization to lymph nodes). 
d. Digital palpation (for the detection of intraoperatively clinically grossly suspicious (i.e., 
enlarged or hard) lymph nodes) will be conducted as well. It is important to note that one 
or more SLN may be found at the time of SLNB [22]. 
6. All removed lymph nodes must be sent to pathology for further evaluation.  Prior to any 
pathological evaluation, confirmation of ex vivo counts per tissue should be conducted. The 
pathological evaluation of lymph node(s) will include serial sectioning with H&E staining as well 
as IHC stain. 
a. In those cases in which intraoperative frozen section analysis is performed and all SLNs 
are determined to be negative for malignancy on intraoperative frozen section evaluation, 
no further removal of axillary lymph nodes will be undertaken, unless otherwise 
determined necessary at the discretion of the operating surgeon.  
b. In those cases in which intraoperative frozen section analysis is performed and the SLNs 
are determined to be positive for malignancy on intraoperative frozen section evaluation, 
a formal axillary lymph node dissection (levels I and II) may be performed at the 
discretion of the operating surgeon, or may be excluded at the discretion of the operating 


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surgeon if the subject fits the criteria for exclusion of  formal axillary lymph node 
dissection (as based upon the ACOSOG Z0011 criteria).  
c. Any axillary lymph node that is neither “hot” or “blue”, but is determined to be 
intraoperatively clinically grossly suspicious (i.e., enlarged or hard), will also be 
removed. In those cases in which any clinically grossly suspicious lymph nodes removed 
intraoperatively are determined to be positive for malignancy on intraoperative frozen 
section evaluation, a formal axillary lymph node dissection may be performed at the 
discretion of the operating surgeon.  
d. In those cases in which no SLN can be intraoperatively identified at the time of ILM and 
SLNB procedure, a formal axillary lymph node dissection may be performed at the 
discretion of the operating surgeon. 
3.2.2.5 
Post-Operative Procedures 
3.2.2.5.1 Histological Evaluation of Resected Lymph Nodes 
All excised lymph nodes should undergo histopatholgoical evaluation for the presence of tumor according 
to the current institutional standards. Final pathology results need to reflect consistent numbering and 
labeling from intraoperative worksheets to the final report. SLNs need to be individually identified in the 
final pathology report.  
3.2.3 
Telephone Follow Up 5 (+3) days post injection (Visit 3) 
• 
Adverse event assessment 
3.3  Completion/Discontinuation and Withdrawal of Subjects 
A subject will be considered to have completed the study when she completes the follow up assessment 
5 ± 3 days after injection. If a subject is discontinued at any time after enrollment in the study, the 
Investigator will make every effort to complete the follow up/premature discontinuation assessments. 


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4 
STUDY DRUGS 
4.1 Identification of Lymphoseek  
Lymphoseek is a commercially available radiopharmaceutical imaging agent. Information on the product 
and its use are located in the US Structured Product Label (Appendix C). 
4.2 Identification of 99mTc-Sulfur Colloid 
99mTc-Sulfur Colloid is a commercially available radiopharmaceutical imaging agent. Information on the 
product and its use are located in the US Structured Product Label (Appendix C). 
4.3 Identification of Vital Blue Dye 
Subjects shall also undergo injection of VBD (1% isosulfan blue see Appendix C) via the method and 
injection route of choice of the operating surgeon. Isosulfan blue is commercially available for use as part 
of standard of care. The localization of VBD is detected by visual inspection only at the time of the SLNB 
procedure. VBDs flow through the lymphatic channels/vessels, and then passively drain into the lymph 
nodes in a non-targeted fashion, and are recognized by the visual presence of a blue color within the 
lymphatic channels/vessels and  the draining lymph node, making these structures visually discernible 
from surrounding tissues. Allergic reaction to the VBDs are rare, but have been previously reported to 
vary from 0.7% and 2.7% incidences [24]. 
4.4 Dosage and Administration 
Each trial participant will receive either an injection of Lymphoseek (50 µg) or 99mTc-SC with a total 
activity dose amounting to 0.5 mCi. These injections will contain a total volume of 0.5 mL. 
4.5 Treatment Assignment 
In this blinded, randomized, parallel-group study, all subjects will receive an injection of either 
Lymphoseek or 99mTc-SC. A computer-generated list of random numbers will be used for subject 
allocation. Randomization sequence will be created and stratified with a 1:1 allocation using a fixed block 
size of 8.  Randomization envelopes, numbered with sequential subject ID, will be prepared by unblinded 
research office personnel.  Each envelope will contain a card identifying the test article assigned to that 
subject ID.  The  randomization envelopes will be maintained in a secure fashion in the Nuclear Medicine 
department, with access available only to the technician who prepares the test article.  Study personnel 
will inform the nuclear medicine technician when a subject is scheduled for pre-surgical injection and 
provide the subject ID number.  The nuclear medicine technician will select the corresponding envelope 
to the subject ID number and prepare the appropriate test article assigned to that subject ID.  The nuclear 
medicine technician  preparing the test article will initial the card, return the card to the envelope, and 
place the used envelope (containing the initialed randomization card) at the end of the envelope stack 
(used envelopes are to be maintained as a record of test article identification).  On a corresponding hard 
copy log the nuclear medicine technician will record the subject name, ID, and group assignment.    
4.6 Blinding 
Participants, investigators, radiologists, pathologists and staff will be kept blinded to the allocation 
throughout the trial. It is not necessary to un-blind information on any participant during the trial unless a 
drug-related safety signal arises during the study. The nuclear medicine technician preparing the 
radiolabeled product will not be blinded to treatment.  


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4.7 Packaging and Labeling 
The 99mTc radiopharmaceutical agents are prepared in injection form and are identical in appearance and  
are to be dispensed in syringes that are identified with the subject name, ID number, and date (Section 
4.5).  The person conducting the injection is blinded and will, thus, receive only the syringes for injection 
labelled in the manner described above. Only one injection per subject will be performed with the 
exception of subjects who have bilateral breast cancer as addressed in Section 2.1.  
4.8 Storage 
Lymphoseek, Sulfur Colloid, and Isosulfan Blue, will be obtained from commercial sources and should 
be stored according to the package insert instructions. 
4.9 Supply, Dispensing, and Return 
Lymphoseek and 99mTc-SC will be radiolabeled at cGMP qualified facilities. The radiopharmaceutical 
doses can be tracked from their arrival through their disposition. A history of all the exams and doses a 
subject receives in Nuclear Medicine will be maintained by the PI using a system that ensures regulatory 
compliance. 
Lymphoseek and 99mTc-SC will be prepared and injected intradermally according to the instructions and 
indications on the manufacturer US Structured Package Label (See Appendix C). 
No local anesthetic agents (such as procaine, xylocaine, lidocaine, or carbocaine) will be permitted to be 
injected with either radiopharmaceutical, separately, or as a part of the combined solution for injection. 
4.10 Drug Accountability 
The investigator is responsible for accounting for all trial drugs discussed in the previous section. 
 
Each time Lymphoseek, Sulfur Colloid, and Isosulfan Blueare dispensed to subjects enrolled into this 
study, the following information at a minimum will be recorded on the Drug Accountability Log: the 
patient’s subject number, manufacturer, lot or batch number, radiolabeling facility, radiolabeled date and 
date delivered to Nuclear Medicine. At the completion or termination of the trial, a final drug 
accountability review and reconciliation must be completed, and any discrepancies must be investigated 
and their resolution documented. 


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5 
STATISTICAL AND ANALYTICAL PLANS 
5.1 Introduction 
This is a prospective, double-blind, two-treatment parallel study conducted at a single study center.  Once 
screened, subjects are enrolled in the trial for a period of up to 75 days, which includes a 5 ± 3 day follow 
up period.  The objectives of the statistical analyses are to establish the effectiveness of Lymphoseek 
relative to 99mTc-SC. 
A study center is defined as a treatment administration site of group of treatment administration sites 
under the control and supervision of the same Primary Investigator.  
5.2 Randomization Methods 
Subjects who meet all inclusion and exclusion criteria will be enrolled in the study on Day 0 prior to 
surgery.  Enrolled subjects will be randomized to one of two treatment groups: Lymphoseek or 99mTc 
Sulfur Colloid.  See section 4.5 above for specifics on the randomization procedure. 
5.3 Efficacy Variables 
5.3.1 Primary Efficacy Variables 
The co-primary efficacy endpoints are the injection site clearance rate and the SLN uptake rate for each 
radiopharmaceutical.  Injection clearance rates and SLN uptake rates will be determined by planar SPECT 
imaging and by SPECT/CT. Subjects will undergo standard sequential planar imaging at 30 to 60 seconds 
intervals until the sentinel lymph node is seen.  Once a sentinel node is located, a SPECT/CT will be 
performed for higher resolution imaging in transaxial, coronal, and sagittal planes. 
5.3.2 Secondary Efficacy Variables 
The secondary efficacy variables are: 
• 
Number of SLNs identified in each subject 
• 
Gamma counts at the primary injection site in the breast and the ex vivo gamma counts of 
the SLNs removed 
• 
Pain scores  
• 
Pathology status of SLNs 
For the purposes of the study, an SLN is defined as a lymph node that meets the 10% rule as detailed in 
Section 3.2.2.4.  The number of SLNs will be recorded for each subject, as well as the ex vivo gamma 
counts for each SLN removed.  The gamma counts at the injection site will also be recorded. 
Subjects will report their pain scores once during the injection procedure.  Scores will be reported on a 
scale of zero (no pain) to a maximum score of ten (worst pain possible).   
All SLNs removed will be sent for histological evaluation according to the methods described in Section 
3.2.2.5.1.  Each node will be characterized as positive or negative for disease. 
5.4 Safety Variables 
The safety analysis variables, collected on all subjects at the time points indicated, are as follows: 


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• 
Adverse Events  
• 
Vital Signs (screening, pre injection, and 15, 30, 60, 90, 120 minutes post injection) 
5.5 Sample Size Justification 
The sample size for the study is based on the co-primary endpoints.  In order to have an 80% chance of 
demonstrating that Lymphoseek is superior to 99mTc-SC based on the injection site clearance rate, 
assuming that the mean rate of Lymphoseek is 0.250, the mean rate of 99mTc-SC is 0.05, and the common 
standard deviation is 0.15, at least 10 subjects will need to be enrolled in each treatment group.   
In order to have an 80% chance of demonstrating that Lymphoseek is superior to 99mTc-SC based on the 
SLN uptake rate, assuming that the mean rate of Lymphoseek is 0.1075, the mean rate of 99mTc-SC is 
0.0875, and the common standard deviation is 0.0009, at least 19 subjects will need to be enrolled in each 
treatment group.  These estimates are based on the sample size methods described in Dupont 1998. 
In order to meet the sample size requirements for each endpoint, up to 40 evaluable subjects will be 
enrolled in the study (see 5.7.1 intent-to-treat).  These sample size calculations were based on a two-sided 
α=0.05 level of significance for each endpoint.      
5.6 Statistical Analyses 
The statistical analyses for the efficacy and demographic variables are described below.  Additional 
analyses of the secondary efficacy variables may be described in the Statistical Analysis Plan (SAP) for 
the study.  Unless otherwise stated, all hypothesis tests will be conducted using a two-sided α=0.05 (one-
sided α=0.025) level of significance.  
 
5.6.1 Analysis Populations 
The following analysis populations will be defined. 
 
Intent-to-treat (ITT) Population – The ITT population includes all enrolled subjects who were 
randomized, received an injection of Lymphoseek or 99mTc-SC, went to surgery, and had at least 
one lymph node removed that was confirmed to be lymph tissue and had a known disease status 
(positive or negative for disease) by histopathology. 
 
Safety Population – The safety population includes all enrolled subjects who were randomized 
and received an injection of Lymphoseek or 99mTc-SC.  
 
The analysis of the primary and secondary efficacy variables will be conducted using the ITT population.  
The analysis of all demographic data will be conducted using the safety population.  All subjects will be 
analyzed according to the treatment they received.  
 
5.6.2 Analysis of Baseline and Demographic Characteristics 
Baseline and demographic characteristics of the safety population will be summarized by treatment group 
and overall.  Continuous variables will be summarized via mean, median, standard deviation, minimum, 
maximum, and number of non-missing observations. Categorical variables will be summarized via counts 
and percentages. 
 


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5.6.3 Analysis of Primary Variables 
Injection Site Clearance Rate 
The injection site clearance rate for each ITT subject will be computed using the SPECT/CT imaging 
data.  Gamma counts will be obtained at the injection site by standard sequential planar imaging at 30 to 
60 seconds intervals until the sentinel lymph node is seen.  Once a sentinel node is located, a SPECT/CT 
will be performed for higher resolution imaging in transaxial, coronal, and sagittal planes.The average 
clearance rate for each radiopharmaceutical will be computed and the following test will be conducted 
using a two-sample t-test at a two-sided α=0.05 (one-sided α=0.025) level of significance: 
 H0: µLS ≤ µSC vs.  HA: µLS > µSC, 
 
where µLS is the average injection site clearance rate of Lymphoseek and µSC is the average injection site 
clearance rate of 99mTc-SC.   
SLN Uptake Rate 
The SLN uptake rate for each ITT subject will be computed using the SPECT/CT imaging data.  Gamma 
counts will be obtained at the injection site by standard sequential planar imaging at 30 to 60 seconds 
intervals until the sentinel lymph node is seen.  Once a sentinel node is located, a SPECT/CT will be 
performed for higher resolution imaging in transaxial, coronal, and sagittal planes.  Figures showing the 
percent of peak activity in the node versus time will be constructed for each radiopharmaceutical.  The 
average uptake rate for each radiopharmaceutical will be computed and the following test will be 
conducted using a two-sample t-test at a two-sided α=0.05 (one-sided α=0.025) level of significance: 
 H0: µLS ≤ µSC vs.  HA: µLS > µSC, 
 
where µLS is the average SLN uptake rate of Lymphoseek and µSC is the average SLN uptake rate of 99mTc 
Sulfur Colloid. 
In order for the study to be successful relative to the co-primary endpoints, both of the null hypotheses for 
injection site clearance rate and SLN uptake rate must be rejected in favor of their respective alternatives. 
 
5.6.4 Analysis of Secondary Variables 
Number of SLNs 
The number of SLNs identified for each ITT subject will be recorded, and summary statistics (mean, 
median, standard deviation, minimum, and maximum) on the number of SLNs will be displayed for each 
treatment group.   
Ex Vivo and Injection Site Gamma Counts 
 
The ratio of the ex vivo gamma counts of the hottest SLN removed to the counts at the primary injection 
site in the breast will be computed for all subjects in the ITT population as follows: 
 
R = Ex vivo gamma counts of hottest SLN removed 
  
 
 
         Gamma counts at primary injection site 
 
If three 2-second counts were obtained for either the ex vivo measurements or the injection site 
measurement, then the average of the counts will be used in the ratio calculation.  If one 10-second count 
was obtained, then that single count will be used in the ratio calculation. 


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It is assumed that the ratio data of each treatment group is lognormal, therefore a log transformation (base 
e) of the data will be also performed for each subject as follows: 
 
LnR = loge(R) 
 
Summary statistics of the ratio (R) and the log ratio (LnR) will be displayed for each treatment group and 
will include the mean, median, and standard deviation.  In addition, a 95% confidence interval for the 
mean ratio and the mean log ratio will be computed.   
Pain Scores 
Each subject will rate their level of discomfort using the Wong-Baker FACES pain rating scale 
immediately after injection.  The following summaries will be computed for each treatment group: 
• 
Proportion of subjects with a 0 score (No Hurt) 
• 
Proportion of subjects with a score of 1-2 (Hurts a Little Bit) 
• 
Porportion of subjects with a score of 3-4 (Hurts Little More) 
• 
Porportion of subjects with a score of 5-6 (Hurts Even More) 
• 
Porportion of subjects with a score of 7-8 (Hurts Whole Lot) 
• 
Porportion of subjects with a score of 9-10 (Hurts Worst) 
• 
Mean, median, standard deivation, minimum, and maximum of pain scores 
Pathology Status of SLNs 
The pathology status of SLNs will be assessed on a per subject basis.  The number and percent of subjects 
who have at least one pathology-positive SLN will be calculated for each treatment group.    
5.6.5 Safety Analyses 
Incidence of adverse events as described in section 6 below will be tabulated by treatment group.   
 
5.7 Handling Missing Values 
In the statistical analysis of the efficacy and safety endpoints of the study, all subjects who have missing 
values for a given endpoint will not be used in the respective analysis.     
 
5.8 Interim Analyses 
There are no formal interim analyses planned for this study.  
 


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6 
ADVERSE EVENTS 
The occurrence of any drug-related adverse events is not expected. 
Normal risks of nuclear medicine scans due to the injection of a radiopharmaceuticals include allergic 
reactions, swelling, infections, intravenous injuries, bruising, pain and discomfort. These risks, if 
encountered, would occur as the result of the scheduled clinical lymphoscintigraphy or ILM.  
6.1 Definition of Adverse Event 
The term "adverse event," is synonymous with the term "adverse experience," which is used by the FDA. 
An adverse event is any untoward, undesired, and/or unplanned clinical event in the form of signs, 
symptoms, disease, or laboratory testing, or physiological observations occurring in a human participating 
in a clinical study with a study drug, regardless of causal relationship.  This includes the following: 
• 
Any clinically significant worsening of a preexisting condition. 
• 
Any recurrence of a preexisting condition. 
• 
An AE occurring from overdose of a study drug whether accidental or intentional (i.e., a dose 
higher than that prescribed by a health care professional for clinical reasons). 
• 
An AE occurring from abuse of a study drug (i.e., use for nonclinical reasons) 
• 
An AE that has been associated with the discontinuation of the use of a study drug. 
Note:  A procedure is not an AE, but the reason for a procedure may be an AE. 
Note: Adverse events are determined by the Investigator. If in the Investigator’s opinion/experience an 
event (i.e. nausea in the recovery room) is expected and not uncommon for that surgery, 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. 
A serious adverse event (SAE) is any AE occurring at any dose that results in one or more of the 
following outcomes:  
• 
Death. 
• 
Life-threatening situation (see below). 
• 
Inpatient hospitalization or prolongation of an existing hospitalization (see below). 
• 
Persistent or significant disability or incapacity (see below). 
• 
Congenital anomaly or birth defect. 
Additionally, important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed above.  Examples of such events include: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not require hospitalization; or 
development of drug dependency or drug abuse. 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 25 of 33 
A life-threatening adverse event is any AE that places the subject at immediate risk of death from the 
event as it occurred.  A life-threatening event does not include an event that might have caused death had 
it occurred in a more severe form but that did not create an immediate risk of death as it actually occurred.  
For example, drug-induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life-threatening, even though drug-induced hepatitis of a more severe nature can be fatal. 
Hospitalization is to be considered only as an overnight admission.  Hospitalization or prolongation of a 
hospitalization is a criterion for considering an AE to be serious. In the absence of an AE, the 
participating Investigator should not report hospitalization or prolongation of hospitalization on a form.  
This is the case in the following situations: 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the protocol. Day 
or night survey visits for biopsy or surgery required by the protocol are not considered serious. 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the study 
center (e.g., stent removal after surgery). This should be recorded in the study file. 
Hospitalization for survey visits or annual physicals fall in the same category. 
In addition, a hospitalization planned before the start of the study for a preexisting condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement due to a 
preexisting condition of osteoarthritis of the knee that has not worsened during the study). 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life functions. 
If there is any doubt whether the information constitutes an AE or SAE, the information is treated as an 
AE or SAE. 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 26 of 33 
7 
REFERENCES 
 
1. Krag DN, Weaver DL, Alex JC, Fairbank JT. Surgical resection and radiolocalization of the sentinel 
lymph node in breast cancer using a gamma probe. Surg Oncol 1993;2(6):335-339; discussion 340. 
2. Giuliano AE, Kirgan DM, Guenther JM, Morton. Lymphatic mapping and sentinel lymphadenectomy 
for breast cancer. Ann Surg 1994;220(3):391-401. 
3. Petrek JA, Senie RT, Peters M, Rosen PP. Lymphedema in a cohort of breast carcinoma survivors 20 
years after diagnosis. Cancer 2001;92(6):1368-1377. 
4. Lucci A, McCall LM, Beitsch PD, Whitworth PW, Reintgen DS, Blumencranz PW, Leitch AM, Saha 
S, Hunt KK, Giuliano AE; American College of Surgeons Oncology Group. Surgical complications 
associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection 
compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J 
Clin Oncol 2007; 20;25(24):3657-3663. 
5. McLaughlin SA, Wright MJ, Morris KT, Giron GL, Sampson MR, Brockway JP, Hurley KE, Riedel 
ER, Van Zee KJ. Prevalence of lymphedema in women with breast cancer 5 years after sentinel 
lymph node biopsy or axillary dissection: objective measurements. J Clin Oncol 2008;26(32):5213-
5219. 
6. McLaughlin SA, Wright MJ, Morris KT, Sampson MR, Brockway JP, Hurley KE, Riedel ER, Van 
Zee KJ. Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node 
biopsy or axillary dissection: patient perceptions and precautionary behaviors. J Clin Oncol 
2008;26(32):5220-5226. 
7. Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, Leitch AM, 
Saha S, McCall LM, Morrow M.. Axillary dissection vs no axillary dissection in women with 
invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 
2011;305(6):569-575. 
8. Galimberti V, Cole BF, Zurrida S, Viale G, Luini A, Veronesi P, Baratella P, Chifu C, Sargenti M, 
Intra M, Gentilini O, Mastropasqua MG, Mazzarol G, Massarut S, Garbay JR, Zgajnar J, Galatius H, 
Recalcati A, Littlejohn D, Bamert M, Colleoni M, Price KN, Regan MM, Goldhirsch A, Coates AS, 
Gelber RD, Veronesi U; International Breast Cancer Study Group Trial 23-01 investigators. Axillary 
dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-
01): a phase 3 randomised controlled trial. Lancet Oncol 2013;14(4):297-305. 
9. Burak WE Jr, Agnese DM, Povoski SP. Advances in the surgical management of early stage invasive 
breast cancer. Curr Probl Surg 2004;41(11):882-935. 
10. Povoski SP, Olsen JO, Young DC, Clarke J, Burak WE, Walker MJ, Carson WE, Yee LD, Agnese 
DM, Pozderac RV, Hall NC, Farrar WB. Prospective randomized clinical trial comparing intradermal, 
intraparenchymal, and subareolar injection routes for sentinel lymph node mapping and biopsy in 
breast cancer. Ann Surg Oncol 2006;13(11):1412-1421. 
11. Pharmalucence Announces FDA Approval for Use of Sulfur Colloid Injection to Locate Lymph 
Nodes in Breast Cancer Patients. Business Wire (A Berkshire Hathaway Company). Available at: 
http://www.businesswire.com/news/home/20110722005806/en/Pharmalucence-Announces-FDA-
Approval-Sulfur-Colloid-Injection. 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 27 of 33 
12. Technetium Tc 99m sulfur colloid Prescribing Information.  Pharmalucence.  Billerica, MA 01821.  
Available at:  
http://www.pharmalucence.com/images/Sulfur%20Colloid%20Package%20Insert%20August%20201
2.pdf.   
13. Vera DR, Wallace AM, Hoh CK, Mattrey RF. A synthetic macromolecule for sentinel node detection: 
(99m)Tc-DTPA-mannosyl-dextran. J Nucl Med 2001;42(6):951-959. 
14. Wallace AM, Hoh CK, Vera DR, Darrah DD, Schulteis G. Lymphoseek: a molecular 
radiopharmaceutical for sentinel node detection. Ann Surg Oncol 2003;10(5):531-538. 
15. Wallace AM, Hoh CK, Darrah DD, Schulteis G, Vera DR.Sentinel lymph node mapping of breast 
cancer via intradermal administration of Lymphoseek. Nucl Med Biol 2007;34(7):849-853. 
16. Wallace AM, Hoh CK, Limmer KK, Darrah DD, Schulteis G, Vera DR. Sentinel lymph node 
accumulation of Lymphoseek and Tc-99m-sulfur colloid using a "2-day" protocol. Nucl Med Biol 
2009;36(6):687-692. 
17. Wallace AM, Han LK, Povoski SP, Deck K, Schneebaum S, Hall NC, Hoh CK, Limmer KK, 
Krontiras H, Frazier TG, Cox C, Avisar E, Faries M, King DW, Christman L, Vera DR. Comparative 
evaluation of [(99m)Tc] Tilmanocept for sentinel lymph node mapping in breast cancer patients: 
results of two phase 3 trials. Ann Surg Oncol 2013;20(8):2590-2599. 
18. FDA Approves Navidea’s Lymphoseek® (technetium Tc 99m tilmanocept) Injection for Use in 
Lymphatic Mapping. The first receptor-targeted radiopharmaceutical approved for lymphatic 
mapping in breast cancer and melanoma patients.  Navidea Biopharmaceuticals.  Dublin, OH.   
Available at: http://ir.navidea.com/phoenix.zhtml?c=68527&p=irol-newsArticle&id=1795818. 
19. Sondak VK, King DW, Zager JS, Schneebaum S, Kim J, Leong SP, Faries MB, Averbook BJ, 
Martinez SR, Puleo CA, Messina JL, Christman L, Wallace AM. Combined analysis of phase III 
trials evaluating [⁹⁹mTc]tilmanocept and vital blue dye for identification of sentinel lymph nodes in 
clinically node-negative cutaneous melanoma. Ann Surg Oncol 2013;20(2):680-688. 
20. Marcinow AM, Hall N, Byrum E, Teknos TN, Old MO, Agrawal A.  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 Sep;139(9):895-902. 
21. Wong DI, Baker CM. Pain in children: comparison of assessment scales. Pediatr Nurs 1988; 14:9–17. 
22. Povoski SP, Young DC, Walker MJ, Carson WE, Yee LD, Agnese DM, Farrar WB. Re-emphasizing 
the concept of adequacy of intraoperative assessment of the axillary sentinel lymph nodes for 
identifying nodal positivity during breast cancer surgery. World J Surg Oncol 2007;5:18. 
23. Martin RC, Edwards MJ, Wong SL, Tuttle TM, Carlson DJ, Brown M, Noyes D, Glaser RL, 
Vennekotter DJ, Turk PS, Tate PS, Sardi A, Cerrito PB, McMasters KM. Practical guidelines for 
optimal gamma probe detection fo sentinel lymph notes in breast cancer: Results of a multi-
institutional study. Surgery 2000; 128:139-44 
24. Bézu C, Coutant C, Salengro A, Daraï E, Rouzier R, Uzan S. Anaphylactic response to blue dye 
during sentinel lymph node biopsy. Surg Oncol 2011;20(1):e55-59. 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 28 of 33 
Appendix A:  Schedule of Study Events 
 
Assessment 
Screen 
(Day -45 
to 
Day -1) 
 
Pre-
injection 
Day 0 
Post-Injection Lymphoseek/99mTc-SC Day 0 
(hour:minute) 
Surgerya 
5:00-
10:00 
Follow-
up 
(Day) 
5 ± 3) 
 
30 to 60 
minutes 
pre-
injection 
 
0:00 
0:15 
0:30 
1:00 
1:30 
2:00 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Entry criteria 
and 
randomization  
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Physical 
examination 
Xe 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
Xd 
X 
X 
X 
X 
X 
 
 
Urine or serum 
pregnancy test 
 
 
Xc 
 
 
 
 
 
 
 
 
 
Lymphoseek or 
99mTc-SC 
administration 
 
 
X 
 
 
 
 
 
 
 
Pain assessment 
 
 
X 
Xd 
 
 
 
 
 
 
 
Vital blue dye 
administration 
 
 
 
 
 
 
 
 
 
X 
 
Imaging – 
SPECT and 
SPECT/CT 
 
 
 
X 
X 
X 
X 
X 
 
 
Surgery, ILM, 
and harvest 
lymph nodes 
 
 
 
 
 
 
 
 
Xa 
 
Adverse event 
monitoring 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
 
a. 
The interval between administration of 99mTc agent and surgery will vary according to triage and the scheduling of surgery. 
b. 
Adverse event assessments may be collected telephonically. 
c. 
Urine or serum pregnancy test must be completed and determined to be negative preceding administration of Lymphoseek or 99mTc-SC 
in women of childbearing potential. 
d. 
Time point 0:00 is before Lymphoseek or 99mTc-SC injection (a 5 minute pre-injection window is permitted). 
e. 
Physical examinations done within 30 days of injection may be used even if conducted prior to obtaining informed consent if they are 
ordered and conducted at the direction of the Investigator as part of patient standard of care. 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 29 of 33 
Appendix B:  Performance Status Criteria 
 
ECOG Performance Status a 
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 
a 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 
  
 
 
 
 
 
 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 30 of 33 
Appendix C:  Links to Product Labels 
 
Link to 99mTC-Tilmanocept Structured Product Label:  
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=6681aa14-5ae3-4143-9d58-
c2d92a143c03  
Link to 99mTC-Sulfur Colloid Structured Product Label: 
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=eeaf70fd-46bd-4fec-ba9d-2366fdf07888  
Link to Isosulfan Blue Structured Product Label: 
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cbee4532-238b-4f91-86ae-
f8c0c1b6d7da  
    
 
 
 
 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 31 of 33 
Appendix D:  TNM Staging for Breast Cancer Patients 
 
Grade 
Description 
Primary Tumor (T) 
TX 
Primary tumor cannot be evaluated 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ:  Intraductal carcinoma, lobular carcinoma in situ, or Paget's disease 
of the nipple with no tumor 
T1 
Tumor 2 cm or less in greatest dimension 
T2 
Tumor more than 2 cm but not more than 5 cm in greatest dimension 
T3 
Tumor more than 5 cm in greatest dimension 
T4 
Tumor of any size with direct extension to chest wall or skin 
Lymph Node (N) 
NX 
Regional lymph nodes cannot be assessed (e.g., previously removed) 
N0 
No regional lymph node metastasis 
N1 
Metastasis to movable ipsilateral axillary lymph node(s) 
N2 
Metastasis to ipsilateral axillary lymph node(s) fixed to one another or to other 
structures 
N3 
Metastasis to ipsilateral internal mammary lymph node(s) 
Distance Metastasis (M) 
MX 
Presence of distant metastasis cannot be assessed 
M0 
No distant metastasis 
M1 
Distant metastasis (includes metastasis to ipsilateral supraclavicular lymph node(s) 
  Source: American Joint Committee on Cancer, Manual for Staging of Cancer 6th Edition  
 
 
Staging of Cancer 6th Edition , Melanoma 
 
 
 


Protocol Number/Version: KHNIC-P14-001/B 
Date:  April 29, 2015 
Page 32 of 33 
Appendix E:  IMAGING PROTOCOL 
 
 
 
 
 
No 
Injection of Test 
Article 
Sequential, dynamic planar 
imaging at 30-60 second 
intervals for 0-60 minutes 
SLN 
Detected? 
Yes 
No 
SPECT/CT in 
transaxial, 
coronal, and 
sagittal planes 
Yes 
Yes  or  No 
Static  planar 
imaging 
repeated at  
90 minutes 
Static planar  
imaging 
repeated at 120 
minutes 
SLN 
Detected? 
SLN 
Detected? 


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ICF_001.pdf: 
 
 
 
 
Approved:  01May2015 
 
Rev. 01May2015 
Page 1 of 12 
ICF Ver. 2.0 for Protocol # KHNIC-P14-001 (Lymphoseek)  
Kettering Health Network 
Kettering, Ohio 
 
INFORMED CONSENT FORM AND AUTHORIZATION TO USE AND DISCLOSE 
INFORMATION FOR RESEARCH PURPOSES 
 
Name of Research Study: 
A Prospective, Randomized, Parallel Group, Double-
Blinded Clinical Trial Comparing Lymphoseek 
and 99mTc-Sulfur Colloid with Regard to Preoperative 
Imaging and Imaging Drug Kinetics and Intraoperative 
Lymphatic Mapping and Sentinel Lymph Node Biopsy 
Findings in Patients with Known Breast Cancer 
 
Study #:  
KHNIC-P14-001 
 
Sponsor:  
 
Kettering Medical Center 
 
Study Doctor Name:  
 
Arash Kardan, MD 
 
Research Site Addresses:  
 
 
Kettering Medical Center   
Wright State Physicians 
Arash Kardan, MD  
 
Roxane Weighall, DO 
3535 Southern Blvd  
 
2300 Miami Valley Drive, Suite 350,  
Kettering, OH 45429  
 
Centerville, OH 45459 
 
South Dayton Surgeons, Inc. 
3533 Southern Boulevard, Suite 2250 
Kettering, OH 45429 
 
Daytime Telephone Numbers: Dr. Kardan:  937-395-8611 
 
 
 
 
 
Dr. Weighall:  937-424-2469 
 
 
 
 
 
Dr. Sawmiller: 937-534-0330 
 
24-hour Contact Numbers: 
Dr. Kardan:  937-298-4331  
 
(ask operator to page Dr. Kardan) 
 
 
 
 
 
Dr. Weighall:  937-424-2469 
 
 
 
 
 
Dr. Sawmiller: 937-463-1743 (Medical Answering Service) 
 
You should keep a copy of this form. If you have any questions or problems during the 
study, call the phone number(s) above. 


Approved 01May2015 
Rev. 01May2015 
Page 2 of 12 
ICF Ver. 2.0 for Protocol # KHNIC-P14-001 (Lymphoseek)  
PURPOSE OF THIS FORM 
The purpose of this form is to help you decide if you want to be in the research study. It 
is up to you to decide if you want to take part in this study.  You should take part in this 
study only if you want to. 
 
This consent form may contain words that you do not understand.  Please ask the study 
doctor or the study staff to explain any words or information that you do not clearly 
understand.  You may take home an unsigned copy of this consent form to think about 
or discuss with family or friends before making your decision. 
 
Before you decide if you want to take part in this research study, it is important that you 
read the information below.  
 
If you sign this form, it means that you agree to take part in this study.  This form 
describes what the study is about and what will happen.  It also tells you about the risks 
and benefits of the study.   
 
You can change your mind about taking part in this study at any time.  You may leave 
the study at any time, even if you have signed this form.  You do not have to give a 
reason. 
 
After reading this form and talking with the study staff, you should know which parts of 
the study are medical care and which are experimental.  Please ask any questions you 
have. 
 
The sponsor is paying for this research study.  Your study doctor will be paid by the 
sponsor. 
 
When deciding to take part in a research study you should know: 
 
• The main goal of medical care is to help you. 
• The main goal of a research study is to gain information to help patients in the 
future.  
• Parts of this study may involve medical care that is routine for you.  This routine 
care, known as standard care, is the treatment normally given for a certain 
condition or illness. 
• Being in this study does not replace your regular medical care.  
 
SOURCE OF FUNDING FOR THE STUDY 
Funding for this research study will be provided by Navidea Biopharmaceuticals, the 
company that makes Lymphoseek®. 
 
PURPOSE OF THE STUDY: 
You are being asked to be in this study because you are currently undergoing treatment 
for breast cancer. One way to learn more about your cancer is to do a sentinel lymph 
node biopsy (removal).  The primary purpose of this study is to see how well one of two 


Approved 01May2015 
Rev. 01May2015 
Page 3 of 12 
ICF Ver. 2.0 for Protocol # KHNIC-P14-001 (Lymphoseek)  
different approved drugs helps us find the sentinel lymph node, which is the first lymph 
node(s) to which cancer cells are most likely to spread. There can sometimes be more 
than one sentinel node. 
 
DESCRIPTION OF THE STUDY 
This is a research study to compare how well the two study drugs, Lymphoseek® and 
sulfur colloid, find sentinel lymph nodes.  Lymph nodes are small, bean-shaped organs 
located within the body, throughout the lymphatic system (the tissues and organs 
involved in immunity, which aids in the fight against infection and cancer). This is a 
randomized study, meaning you will have a 50/50 chance of receiving either 
Lymphoseek® or sulfur colloid (hereafter referred to as the Study Drug).  Neither you nor 
your study doctor will know which Study Drug you receive. Both of these Study Drugs 
are approved for use in detecting sentinel lymph nodes. If you have cancer in both 
breasts, you will not be randomly assigned but instead will receive injections of both 
Lymphoseek® and sulfur colloid, one in each breast.  You and your study doctor will be 
blinded to which breast is injected with which Study Drug. 
 
In this research, the Study Drug you are randomized to, along with vital blue dye used 
during the surgical procedure, will be used as the tracing agents to find the sentinel 
lymph node(s).    
 
The Study Drug will be injected around the outside edge of the colored area around the 
nipple, which is called the areola.  The injection of the affected breast will occur on the 
day of your surgery. The vital blue dye may also be injected around the outside edge of 
the areola at the time of surgery.  The amount of each injection is very small, about ½ of 
a teaspoon.  The Study Drug, used as a tracing agent, and vital blue dye will travel 
through your lymphatic channels to the nearest lymph node.  The Study Drug will have 
a radioactive substance attached that is called technetium 99m. Since technetium is 
radioactive, it can be detected by a gamma camera (imaging scan) or a hand-held 
probe, similar to a small Geiger counter.  Through this process, the Study Drug will 
travel through the lymph system and attach to cells in the lymph node(s) to help identify 
the nodes that drain from your breast.  The vital blue dye is visible to your study doctor 
only during surgery.  Your study doctor can identify lymph nodes by the blue color.  The 
lymph nodes identified by the Study Drug and/or vital blue dye will be removed by your 
study doctor.  These nodes will be examined by another doctor (pathologist) to see if 
your cancer has spread to them. 
 
During and after surgery, your study doctor will continue to check your safety while 
using the Study Drug and vital blue dye by checking vital signs such as your pulse, 
breathing rate, heart rate, temperature, and blood pressure, along with doing any 
physical examinations needed and assessing any side effects that you report to us. 
 
After your surgery, you will be discharged from the hospital as you would normally 
under your study doctor’s guidance. The study nurse will contact you by phone about a 
week after your surgery to see how you are doing.  Your participation in the study is 
considered completed at that time.  
 


Approved 01May2015 
Rev. 01May2015 
Page 4 of 12 
ICF Ver. 2.0 for Protocol # KHNIC-P14-001 (Lymphoseek)  
About 40 subjects will take part in this study at Kettering Medical Center. 
 
PROCEDURES 
This section will tell what you can expect to happen if you agree to be in the study.  You 
may ask any questions about the study, and then, if you agree to participate, sign this 
consent form.   
 
After you have signed the consent form, the following procedures will be done: 
 
Visit 1:  Informed Consent Visit (Pre-surgery Visit)  
This visit will take place at either your surgeon’s office or the Innovation, Research & 
Grants office at Kettering Medical Center.  
 
• You will provide details about your medical history and answer questions from 
the study doctor.  This information helps the study doctor determine your overall 
health. 
• You will be asked to list the medications you have taken over the last 7 days. 
• Information from a recent physical exam, including measurements of vital signs 
(pulse, breathing rate, temperature, and blood pressure) will be recorded for this 
study. 
• Any new questions you’ve thought of since your doctor first talked to you about 
this study will be answered. 
 
Visit 2:  Administration of the Study Drug (Lymphoseek® or Sulfur Colloid) and Surgery.  
This visit will take place at the hospital beginning in the Nuclear Medicine department 
and then moving to the Surgical Department. 
 
 
Nuclear Medicine Imaging: 
 
• If you are of childbearing potential, you must have a negative urine pregnancy 
test in order to be in the study.  This test will be done before the Study Drug 
injection. 
• You will be asked about any side effects you have had since your screening visit. 
• The Study Drug will be injected by the study doctor on the outside edge of the 
areola of the affected breast. You will be asked to rate your level of discomfort 
just prior to the injection and just after the injection using a visual pain rating 
scale that shows cartoon faces that correlate to a number that goes from 0 for no 
pain to 9-10 worst pain you have experienced. 
• After the injection of the Study Drug, you will have imaging (SPECT/CT) done for 
detecting the movement of the Study Drug through the tissues. The length of 
time for the injection procedure and imaging is approximately 60 minutes but may 
be as long as 150 minutes (2.5 hours). 
• During the injection and imaging process, your vital signs and any side effects 
will be recorded.  


Approved 01May2015 
Rev. 01May2015 
Page 5 of 12 
ICF Ver. 2.0 for Protocol # KHNIC-P14-001 (Lymphoseek)  
Surgery: 
 
• You will be prepared for surgery in the normal manner.   
• After the anesthesiologist puts you to sleep, your surgeon will inject the vital blue 
dye. 
• Your surgeon will use a hand-held radiation-detecting probe similar to a Geiger 
counter to measure the Study Drug in the lymph node(s). 
• As part of the surgical procedure, your surgeon will remove one or more lymph 
nodes for evaluation by the pathologist.   
• Your surgeon will complete your surgery and you will be followed in the usual 
manner as instructed by your surgeon. 
 
Visit 3: Follow-up (After Surgery, by Telephone) 
 
• About a week after your surgery, the study nurse will call you and ask about any 
side effects you have had since your surgery. 
 
Ask us if you have any questions about the tests and procedures for the study. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
WHAT WILL I BE ASKED TO DO IN THIS STUDY?  
Before you decide whether to be in this study, you should think about how the tests and 
study visits will affect your time away from work and your schedule.   
 
To be in this study, you must agree to: 
 
• Follow directions from the study staff. 
• Make and keep study appointments. 
• Give urine samples as requested. 
• Tell the study staff about all of the medicines you have taken for 7 days before 
beginning the study. 
• Tell the study staff about any changes to your health during the study. 
• Not be part of any other research study while participating in this study. 
 
RISKS AND DISCOMFORTS 
It is possible the drug you are given could cause adverse (bad) reactions or discomfort. 
You should talk to your study doctor about any side effects that you have while taking 
part in the study. 
 
You may have a local injection site reaction from the Study Drug including swelling, 
redness, burning, or itching. These reactions are generally mild and do not require 
treatment. 


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In clinical trials of Lymphoseek®, no patients experienced serious adverse reactions and 
the most common adverse reactions were injection site irritation and/or pain (less than 
1%).  You should tell your study doctor if you have had any prior bad reactions the drug 
dextran, as this may make you more likely to have a bad reaction to Lymphoseek®. 
 
Adverse reactions from sulfur colloid that have been reported are rash, allergic reaction, 
urticaria (hives), severe whole body allergic reaction, and low blood pressure. 
 
Less frequently reported adverse reactions are fatal cardiopulmonary arrest, seizures, 
dyspnea, bronchospasm, abdominal pain, flushing, nausea, vomiting, itching, fever, 
chills, perspiration, numbness, and dizziness. 
 
Vital blue dye has been shown to produce an allergic reaction in a small number of 
people.  These reactions may include itching, swelling and in rare instances, shock.   
 
Serious allergic reactions may be life-threatening.  You will be monitored to see if you 
develop this type of reaction.  If you do, you will receive prompt treatment. 
 
If the Study Drug along with the vital blue dye does not work, and no sentinel lymph 
node is identified, all of the lymph nodes in the area may be removed by your study 
doctor. 
 
The effects of the Study Drug on sperm or egg development or on a developing child 
are not known.  Females wanting to be in this study must not be pregnant or nursing.  If 
you become pregnant while taking part in this study, notify the study doctor at once. 
 
Vital blue dye has also caused a change in color around the injection site that can be 
seen for up to 48 hours after injection. 
 
The Study Drug uses radiation. Radiation occurs naturally in the environment and is 
used in treating and examining subjects for medical reasons. Radiation exposure is 
cumulative (adds up over time). Radiation exposure increases other health risks 
including cancer. The amount of radiation received from the Study Drug is only slightly 
more than you would receive from a chest x-ray or about the amount of radiation you 
are exposed to naturally from the environment over a period of a few months. 
 
In addition to the risks or discomforts listed here, there may be other risks that are 
currently not known.   Also, the risks or discomforts described may occur more often or 
be more severe than has been seen before.   
 
You should get medical help and contact the study doctor or staff if you have any of 
these or any other side effects during the study. 
 
 


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OTHER RISKS 
When taking any new drug, you should be careful until you know how it affects you 
before you: 
 
• Drive,  
• Operate machinery, or  
• Need to be alert.  
 
NEW FINDINGS 
You will be told about any new information that might change your decision to be in this 
study.  You may be asked to sign a revised consent form if this occurs. 
 
BENEFITS 
You may or may not receive a medical benefit from being in the study, depending upon 
the whether the Study Drug helps guide your surgeon in identifying a sentinel node(s).  
The information learned from this study may also benefit patients in the future.  
 
COSTS 
The Study Drug will be provided to you at no charge.  The sentinel node biopsy 
procedure is considered standard or routine medical practice and it will be charged to 
you, your insurance company, or third-party provider.  Any procedures or tests 
performed for the study outside of routine medical care for your condition will not be 
charged to you, your insurance company, or third-party payer.  You, your insurance 
company, or other third-party payers will be billed for all other medicines and/or medical 
procedures used during the study to treat other medical conditions. 
 
Participating in this research may lead to additional costs to you.  In some cases, it is 
possible that your insurance company will not pay for these costs because you are 
taking part in a research study. 
 
Ask your study doctor to discuss the costs that will or will not be covered.  This 
discussion should include the costs of treating possible side effects.  Otherwise, you 
might have unexpected expenses from being in this study. 
 
PAYMENT FOR PARTICIPATION 
You will be paid $75.00 for completion of each study visit/encounter (Visits 1, 2 and 3), 
for a total of $225.00 for your participation in this study. 
 
ALTERNATIVE TREATMENT 
You do not need to be in this study to receive Lymphoseek® or sulfur colloid to identify 
sentinel lymph nodes. You can receive the same treatment without being in this study.  
 
HOW WILL MY INFORMATION BE PROTECTED? 
All information that you give will be kept strictly confidential.  The information collected 
about you usually will not directly identify you (for example, by name, address, or social 
security number).  Instead, your initials and a code number will be used for your 
information.   
 


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Your records may be reviewed by: 
 
• The study sponsor. 
• People who work with the sponsor on the study. 
• Government agencies, such as the FDA.  
• Copernicus Group Independent Review Board (IRB).  The IRB is a group of 
scientists and non-scientists who review the ethics of research. The goal of the 
IRB is to protect the rights and welfare of study subjects.  
 
These people may look at your records to make sure the study has been done the right 
way.  They also want to make sure that your health information has been collected the 
right way, or for other reasons that are allowed under the law. 
 
If information about this study is published, you will not be identified. 
 
There is a risk of loss of confidentiality in research studies. Every effort will be made to 
protect you and your health information to the extent possible.  
 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR RESEARCH 
PURPOSES 
Federal regulations give you certain rights related to your health information.  These 
include the right to know who will receive the information and how it will be used.  The 
study doctor must obtain your authorization (permission) to use or release any health 
information that might identify you. 
 
What information may be used and given to others? 
The study doctor will get your personal and medical information. 
 
For example: 
 
• Past and present medical records. 
• Research records. 
• Records about phone calls made as part of this research. 
• Records about your study visits. 
• Information that includes personal identifiers, such as your name, or a number 
associated with you as an individual. 
• Information gathered for this research about: 
 
o Physical exams. 
o Laboratory, x-ray, and other test results. 
 
• Records about any study drug you received. 
 
Who may use and give out information about you?  
The study doctor and the study staff. 
 


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Who might get this information? 
The sponsor of this research – Kettering Medical Center.  “Sponsor” means any 
persons or companies that are: 
 
• working for or with the sponsor, or 
• associated with the sponsor to conduct this research study, such as Navidea 
Biopharmaceutical, the company funding this research. 
 
Your information may be given to: 
• The U.S. Food and Drug Administration (FDA), 
• Department of Health and Human Services (DHHS) agencies, 
• Governmental agencies in other countries, and 
• Copernicus Group Independent Review Board. 
 
Why will this information be used and/or given to others?  
• to do the research, 
• to study the results, and 
• to make sure that the research was done right. 
 
If the results of this study are made public, information that identifies you will not be 
used. 
 
What if I decide not to give permission to use and give out my health 
information?  
Then you will not be able to be in this research study. 
 
May I review or copy my information?  
Yes, but only after the research is over. 
 
When will my permission end? 
There is no date at which your permission ends.  Your information will be used 
indefinitely.  This is because the information used and created during the study may be 
analyzed for many years, and it is not possible to know when this will be complete. 
 
May I withdraw or revoke (cancel) my permission? 
Yes.  Your authorization will not expire unless you change your mind and revoke it in 
writing.  You may withdraw or take away your permission to use and disclose your 
health information at any time.  You do this by sending written notice to the study 
doctor.  If you withdraw your permission, you will not be able to stay in this study.  When 
you withdraw your permission, no new health information identifying you will be 
gathered after that date unless you have a side effect related to the study.  Information 
that has already been gathered may still be used and given to others. 
 
If you withdraw from the study but do not withdraw your Authorization, new health 
information may be collected until this study ends.   
 


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Is my health information protected after it has been given to others? 
There is a risk that your information will be given to others without your permission.  Any 
information that is shared may no longer be protected by federal privacy rules. 
 
COMPENSATION FOR INJURY 
 
INSTITUTION LIABILITY: 
If you experience an illness or injury as a direct result of participating in this study, you 
may obtain immediate care at Kettering Medical Center. Kettering Medical Center will 
cover the reasonable and necessary medical expenses to treat such injury or illness. 
The Study Doctor will determine if the injury or illness was a result of your participation 
in the study.  Kettering Medical Center will pay for your treatment only if the need for 
treatment was caused by the study procedures.  It is important for you to follow the 
directions of the Study Doctor, your surgeon and the study staff, as well as the 
information provided in the informed consent. Kettering Medical Center will not pay for 
injuries due to your personal conduct outside of the study, for lost wages, discomfort, or 
costs due to the worsening of any underlying condition. It is up to you or your insurance 
company to pay the costs to treat any medical condition not caused by this study. 
 
You do not give up any legal rights by signing this consent form. 
 
VOLUNTARY PARTICIPATION AND WITHDRAWAL 
Your participation in this study is voluntary.  You may decide not to participate in this 
study.  If you do participate, you may freely withdraw from the study at any time.  Your 
decision will not result in any penalty or loss of benefits to which you are entitled.  Your 
decision will not change your future medical care. 
 
Your participation in this study may be stopped at any time by the study doctor without 
your consent because: 
 
• the study doctor or your surgeon thinks it necessary for your health or safety;  
• you have not followed study instructions; 
• Kettering Medical Center has stopped the study;  
• administrative reasons require your withdrawal; 
• or for any other reason. 
 
QUESTIONS 
If you have any questions about this research study, you may call the study site.  If you 
think you have an injury or illness from the study drug, contact the study doctor or study 
surgeon.  
 
Study Doctor Name:  
 
Arash Kardan, MD 
 
Study Surgeons:  
Roxane Weighall, DO 
 
Carol Sawmiller, MD 
 


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Daytime Telephone Numbers: Dr. Kardan:  937-395-8611 
 
 
 
 
 
Dr. Weighall: 937-424-2469 
Dr. Sawmiller: 937-534-0330 
 
24-hour Contact Numbers: 
Dr. Kardan:  937-298-4331  
 
(ask operator to page Dr. Kardan) 
 
 
 
 
 
Dr. Weighall: 937-424-2469 
 
 
 
 
 
Dr. Sawmiller: 937-463-1743 (Medical Answering Service) 
 
You should contact the study doctor first if you have questions, complaints, or concerns 
about the study. 
 
Please call Copernicus Group IRB at 1-888-303-2224 if: 
 
• You want to talk to someone other than the study doctor or study staff. 
• You have a hard time reaching the study doctor or study staff. 
• You have questions about your rights as a research subject. 
 
Please visit the Copernicus Group IRB website www.cgirb.com for more information 
about research studies and the role of a research subject. 


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SUBJECT’S STATEMENT OF CONSENT AND AUTHORIZATION 
 
A Prospective, Randomized, Parallel Group, Double-Blinded Clinical Trial Comparing 
Lymphoseek and 99mTc-Sulfur Colloid with Regard to Preoperative Imaging and Imaging 
Drug Kinetics and Intraoperative Lymphatic Mapping and Sentinel Lymph Node Biopsy 
Findings in Patients with Known Breast Cancer 
 
I have read the document (or it has been read to me).  I am aware that I am being 
asked to participate in a research study.  I have had the opportunity to ask questions 
and have had them answered to my satisfaction. 
 
I voluntarily agree to participate in this study. 
 
I authorize the use and disclosure of my health information to the parties listed in the 
authorization section of this consent for the purposes described above. 
 
By signing this consent form I have not given up any of my legal rights. 
 
CONSENT SIGNATURE: 
 
 
____________________________________________ 
_____________________ 
Signature of Subject 
 
 
Date 
 
 
____________________________________________ 
_____________________ 
First and Last Name of Subject (Print) 
 
 
 
Time of Consent Signature  
 
Study Personnel Statement 
The information about the study was described to the subject in language he/she 
understood. 
 
 
____________________________________________ 
_____________________ 
Signature of Person Obtaining Consent 
 
 
Date 
 
 
____________________________________________ 
_____________________  
First and Last Name of Person Obtaining Consent (Print) 
Time