A Phase II Study Evaluating Panitumumab-IRDye800 vs. Sentinel Node Biopsy and (Selective) Neck Dissection for Metastatic Lymph Node Identification in Patients With Head and Neck Cancer
Phase: PHASE2
Conditions: Head and Neck Squamous Cell Carcinoma, Squamous Cell Carcinoma of the Head and Neck (SCCHN), Head and Neck Cancer
Sponsor: Eben Rosenthal

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A Phase 2 Study Evaluating Panitumumab-IRDye800 vs 
Sentinel Node Biopsy and (Selective) Neck Dissection for 
Metastatic Lymph Node Identification in Patients with Head 
and Neck Cancer 
 
Study Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
 
Protocol Director 
Fred Baik, MD 
Assistant Prof of Otolaryngology – Head & Neck 
Surgery 
Department of Otolaryngology 
Division of Head and Neck Surgery 
 
 
 
Co-Investigator 
Eben Rosenthal, MD 
 
 
 
 
 
  
Co-Investigator 
Vasu Divi, MD 
Assistant Prof of Otolaryngology – Head & Neck 
Surgery 
Department of Otolaryngology 
Division of Head and Neck Surgery 
 
 
 
Co-Investigator 
Andrei Iagaru, MD 
Associate Prof of Radiology, Dept of Radiology 
Division of Nuclear Medicine 
Stanford University Medical Center 
 
 
 
  

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Co-Investigator 
A  Dimitrios Colevas, MD 
Stanford Cancer Institute 
  
 
 
 
Co-Investigator 
Floyd Christopher Holsinger, MD 
Prof of Otolaryngology – Head and Neck Surgery 
Department of Otolaryngology 
 
Stanford University Medical Center, 
 
 
   
Co-Investigator 
Edward J Damrose, MD, FACS 
Prof of Otolaryngology – Head and Neck Surgery 
Department of Otolaryngology 
 
Stanford University Medical Center, 
 
  
 
 
Co-Investigator 
Karuna Dewan, MD 
Assistant Professor 
OHNS/Laryngology Division 
Stanford University Medical Center;  
  
  
 
 
Co-Investigator 
Michael Jay Kaplan, MD 
Prof of Otolaryngology – Head and Neck Surgery 
Department of Otolaryngology 
 
Stanford University Medical Center, 
 
 
 
Co-Investigator 
Harlan Pinto, MD 
Associate Professor 
 
Stanford Cancer Center 
Stanford University Medical Center;  
  
 
 
 
Biostatistician 
Vandana Sundaram, MPH 
Sr. Biostatistician, Quantitative Sciences Unit (QSU) 
Department of Medicine (Biomedical Informatics) 
Stanford University 
 
 
Postdoctoral Researcher 
Nynke S van den Berg, PhD 
Department of Otolaryngology 
Center for Clinical Sciences Research 
Stanford University 
 
 
Study Coordinator 
Grace Yi 
Cancer Clinical Trials Office 
Stanford University Medical Center 
 
 
 
 
Study Coordinator 
Roan Courtney Raymundo 
Cancer Clinical Trials Office 
Stanford University Medical Center 
 
 
 
 
 
IRB number:  IRB-43013 
OnCore:  
ENT0065  
IND number: 
 

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Document History 
Version Date 
Notes 
29 September 2017 
Version submitted to IRB 
26 October 2017 
SRC Pre-Review Comments 
30 November 2017 
SRC Comments + Adding Device Appendix 
3 October 2018 
 Clarification of cohort structure and recruitment based on NCCN guidelines 
version January 2018 for use of Sentinel Node Biopsy (SNB) in head and neck 
cancer. (Cohort 1 – T1-2 and N0, Cohort 2 – any T and N+) 
 Clarification that panitumumab-IRDye800 infusion will be 1 to 5 days before 
surgery, not 2 to 5 days before surgery 
 Clarification of the rationale for use of panitumumab-IRDye800  
 Addition of additional description/clarification of SNB and neck dissection 
procedure for cohort 1 and 2 respectively. 
 AEs will be graded according to CTCAE v5.0, not 4.03 
 Clarification of additional PKs to be collected on days 1-3 post-operation per 
availability up to once per day on days 1, 2, and 3 post-operation. 
 Removed Nicholas Oberhelman as study coordinator 
 Updated fluorescence imaging device (Appendix B) list to reflect incorporation 
of upgraded devices: 
o Spy-Phi for intraoperative in vivo and ex vivo imaging 
o FIGS for intraoperative in vivo and ex vivo imaging 
o (Stand-alone) da Vinci Firefly for intraoperative ex vivo imaging and 
laboratory imaging   
o VEVO LAZR-X for intraoperative in vivo and ex vivo imaging and 
laboratory imaging 
o Removal of SPY/LUNA imaging devices  
26 September 2019 
 Change of Principal Investigator / Protocol Director from Eben Rosenthal t
Fred Baik.  Dr Rosenthal is now listed as co-investigator.  
 Personnel update:  Included Roan Raymundo and Grace Yi as study coordinators
Other personnel changes are only made in eProtocol.  
 Protocol modifications: 
- 
Removal of “Received an investigational drug within 30 days prior to first 
dose of panitumumab-IRDye800” as an exclusion criteria (Section 3.2 and 
Appendix A). 
- 
Addition of photoacoustic imaging as correlative study (as discussed in 
IRB-35064). 
- 
Update Appendix B to reflect the most recent fluorescence imaging devices 
(also updated in eProtocol). 
- 
Administrative changes.  

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15 November 2019 
 Administrative changes 
- 
Changed Dr. Eben Rosenthal (now co-I) to Dr. Fred Baik in Appendix A: 
Participant Eligibility Checklist 
- 
Changed “Sponsor-Investigator” to “Sponsor” in Section 7 and Section 11.1 
 
9 December 2019 
 Removed Stefania Chirita as CRC, addition of Roan Raymundo as CRC 
1 February 2021 
 
Based on published Panitumumab-IRDye800 QTc interval safety data, Day  
0 and Day 15 ECGs have been removed 
 
Clarified expected Adverse Event collection window to only designated  
study dates 
 
Adverse Event and Serious Adverse Event reporting clarification 
 
Day 1 to 3 Post-operative (optional visit) has been removed from  
Study Calendar 

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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................. 7 
STUDY SCHEME ......................................................................................................................... 9 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 10 
1. 
OBJECTIVES ...................................................................................................................... 11 
1.1. 
PRIMARY OBJECTIVE ................................................................................................... 11 
1.2. 
SECONDARY OBJECTIVE .............................................................................................. 11 
2. 
BACKGROUND .................................................................................................................. 11 
2.1 
STUDY DISEASE ............................................................................................................ 11 
2.2 
STUDY AGENTS ............................................................................................................. 15 
2.3 
RATIONALE ................................................................................................................... 15 
2.4 
STUDY DESIGN .............................................................................................................. 16 
2.4.1.  Number of subjects ................................................................................................................................................. 16 
2.4.2.  Dosing ........................................................................................................................................................................... 16 
2.4.3.  Workflow of the Clinical Trial ........................................................................................................................... 18 
2.4.3.1.  Panitumumab-IRDye800 Infusion ............................................................................................................... 18 
2.4.3.2.  Preoperative Sentinel Node Mapping ........................................................................................................ 18 
2.4.3.3.  Intraoperative Imaging Protocol ................................................................................................................. 19 
2.4.3.5.  Pathological Correlates .................................................................................................................................... 21 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ....................... 22 
3.1 
INCLUSION CRITERIA ................................................................................................... 22 
3.2 
EXCLUSION CRITERIA .................................................................................................. 22 
3.3 
INFORMED CONSENT PROCESS .................................................................................... 23 
3.4 
ENROLLMENT PROCESS ............................................................................................... 23 
3.5 
STUDY TIMELINE .......................................................................................................... 23 
4. 
TREATMENT PLAN ......................................................................................................... 23 
4.1 
TREATMENT SCHEDULE ............................................................................................... 23 
4.2 
ADMINISTRATION OF PANITUMUMAB-IRDYE800 ....................................................... 23 
4.3  
ADMINISTRATION OF LYMPHOSEEK (99MTC-TILMANOCEPT) ..................................... 24 
4.4 
DEFINITION OF DOSE-LIMITING TOXICITY (DLT) ..................................................... 26 
4.5 
SURGICAL IMAGING ..................................................................................................... 26 
4.6 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ........ 26 
4.7 
CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 27 
4.8 
ALTERNATIVES AND RISK PROTECTION / MITIGATION .............................................. 27 
5. 
INVESTIGATIONAL AGENT INFORMATION ........................................................... 27 
5.1 
DESCRIPTION OF STUDY DRUG .................................................................................... 27 
5.1.1.  
Panitumumab-IRDye800 ............................................................................................................................ 27 
5.1.2.  
Lymphoseek ....................................................................................................................................................... 30 
5.2 
EXPECTED TOXICITIES................................................................................................. 32 
5.2.1 
Panitumumab – panitumumab-IRDye800 ............................................................................................... 32 
5.2.2 
Lymphoseek (99mTc-Tilmanocept) ................................................................................................................ 34 
5.3 
AVAILABILITY .............................................................................................................. 34 

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5.4 
AGENT ORDERING ........................................................................................................ 34 
5.5 
AGENT ACCOUNTABILITY ............................................................................................ 35 
6. 
DOSE MODIFICATIONS.................................................................................................. 35 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES ........................................... 35 
7.1 
ADVERSE EVENT (AE) ................................................................................................. 35 
7.2 
SERIOUS ADVERSE EVENT ........................................................................................... 35 
7.3 
ASSESSMENT OF CAUSALITY ........................................................................................ 36 
7.4 
SEVERITY OF ADVERSE EVENTS .................................................................................. 36 
7.5 
SAFETY MONITORING AND REPORTING ...................................................................... 36 
7.5.1.  Monitoring and Recording of Adverse Events ............................................................................................ 36 
7.5.2. 
Reporting Adverse Events and Serious Adverse Events ...................................................................... 37 
8. 
CORRELATIVE/SPECIAL STUDIES ............................................................................. 38 
9. 
STUDY CALENDAR .......................................................................................................... 39 
9.1  
STUDY PROCEDURES TABLE ........................................................................................ 39 
9.2  
STUDY PROCEDURES .................................................................................................... 40 
9.3  
DESCRIPTION OF EVALUATIONS / PROCEDURES ......................................................... 43 
10.1  
PRIMARY OUTCOME MEASURE ................................................................................... 43 
10.2  
SECONDARY OUTCOME MEASURE .............................................................................. 43 
11. REGULATORY CONSIDERATIONS ............................................................................. 43 
11.1 
INSTITUTIONAL REVIEW OF PROTOCOL ..................................................................... 43 
11.2 
DATA AND SAFETY MONITORING PLAN ...................................................................... 44 
11.3 
DATA MANAGEMENT PLAN.......................................................................................... 44 
12. STATISTICAL CONSIDERATIONS ............................................................................... 44 
12.1 
STATISTICAL DESIGN ................................................................................................... 44 
12.1.1.  Primary Objective and Endpoint ................................................................................................................... 44 
12.1.2.  Secondary Objective and Endpoint ............................................................................................................... 45 
12.1.3.  Sample Size Justification and Power Considerations ........................................................................... 45 
13. REFERENCES .................................................................................................................... 45 
APPENDIX A:  PARTICIPANT ELIGIBILITY CHECKLIST............................................ 51 
APPENDIX B – IMAGING DEVICES APPENDIX ............................................................... 54 

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PROTOCOL SYNOPSIS 
 
TITLE 
A Phase 2 Study Evaluating Panitumumab-IRDye800 vs Sentinel 
Node Biopsy and (Selective) Neck Dissection for Metastatic Lymph 
Node Identification in Patients with Head and Neck Cancer 
STUDY PHASE 
Phase 2 
INDICATION 
Clinically-suspected or biopsy-proven diagnosis of head and neck 
squamous cell carcinoma (HHSCC).  Subjects diagnosed at any T stage 
who are scheduled to undergo surgical resection with a neck dissection 
or sentinel node biopsy (SNB) as part of standard of care are eligible.  
INVESTIGATIONAL 
PRODUCT  
A panitumumab-IRDye800 dose of 50 mg, will be systemically infused 
1 to 5 days before surgery.  Panitumumab-IRDye800 has been 
manufactured under current good manufacturing practice (cGMP) by 
LICOR Biosciences Inc.  Eben Rosenthal (co-PI) currently holds the 
IND (119474). 
On the day before surgery 2 mCi Lymphoseek (99mTc-tilmanocept) will 
be administered locally around the primary tumor for sentinel node 
mapping.  Lymphoseek is obtained in unit doses from Cardinal Health.   
TREATMENT 
SCHEDULE  
A panitumumab-IRDye800 dose of 50 mg, will be systemically infused 
1 to 5 days before surgery.  On the day before surgery, to subjects 
undergoing sentinel node biopsy, the standard dose of ~2 mCi 
Lymphoseek will be administered locally around the primary tumor 
after which lymphoscintigraphy and SPECT/CT imaging will be 
performed per standard of care to determine the number and location of 
foci of radiopharmaceutical uptake indicating sentinel nodes.  
On the day of surgery, intraoperative fluorescence imaging will be 
performed using an intraoperative optical imaging device (a list of 
devices is provided in Appendix B).  Per standard of care, for the 
subjects undergoing sentinel node biopsy, a gamma probe will be used 
to search for radioactive lymph nodes as well.  Ex vivo fluorescence 
imaging and gamma counting of the excised specimens will be 
performed prior to and after pathological assessment.  At all steps, 
equipment will be used that does not violate or destroy the pathological 
tissues. 
PRIMARY 
OBJECTIVE(S) 
The primary objective of the study is to determine if near-infrared 
fluorescence 
imaging 
of 
panitumumab-IRDye800 
can 
identify 
metastatic disease in regional neck lymph nodes of subjects with head 
and neck squamous cell carcinoma (HNSCC). 
SECONDARY 
OBJECTIVE(S) 
Determine if panitumumab-IRDye800 can identify sentinel nodes with 
the same accuracy as Lymphoseek.  

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SAMPLE 
SIZE 
AND 
STUDY DURATION 
It is anticipated that 20 subjects will be enrolled into the study.  Each 
subject will be followed for 30 days following the last dose of study 
medication. 
 
Based 
on 
the 
enrollment 
rate 
from 
the 
panitumumb-IRDye800 trial in HNSCC, it is anticipated that the study 
will require 2 years to be completed.  
STATISTICAL 
CONSIDERATIONS 
To answer the primary objective we will calculate the sensitivity and 
specificity of the intraoperative findings on whether the lymph node is 
fluorescent 
(ie, presence 
of 
panitumumab-IRDye800) 
to 
the 
histopathological (gold standard) status of the lymph nodes.  
Analysis for the secondary objective:  We will determine if 
panitumumab-IRDye800 can identify sentinel nodes with the same 
accuracy as Lymphoseek. Similar to the primary analysis, we will 
calculate the specificity and sensitivity of Lymphoseek for metastatic 
lymph node identification, using histology as the gold standard, and 
compare these to the fluorescence imaging-based results.  Since false 
negatives are of particular concern, we will calculate the diagnostic odds 
ratio to better understand the odds of obtaining a false negative using 
panitumumab-IRDye800 relative to the odds of obtaining a false 
negative using Lymphoseek-based sentinel node biopsy. 

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STUDY SCHEME 
Figure 1.  Schematic overview of the clinical trial in which we will directly compare panitumumab-IRDye800 to the reference 
standards sentinel node biopsy and neck dissection. Key steps of the clinical study are mentioned.  
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
99mTc 
Technetium-99m 
AE 
Adverse Event 
BID 
Twice Daily 
BSA 
Body Surface Area 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CMAX 
Maximum Concentration of Drug 
CNS 
Central Nervous System 
CRF 
Case Report/Record Form 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-Limiting Toxicity 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
The Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
eLND 
Extensive Lymph Node Dissection  
FDA 
Food and Drug Administration 
GMP 
Good Manufacturing Practice 
Hgb 
Hemoglobin 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
HTN 
Hypertension 
ICG 
Indocyanine green 
ILD 
Interstitial Lung Disease 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
LLN 
Lower Limit of Normal  
LN 
Lymph Node 
MTD 
Maximum Tolerated Dose 
NIR 
Near-Infrared 
NHS 
N-hydroxysuccinimide 
PAI 
Photoacoustic imaging 
PLT 
Platelet 
ROI 
Region of Interest 
SAE 
Serious Adverse Event 
SN 
Sentinel Node 
SNB 
Sentinel Node Biopsy  
SNR 
Signal to Noise Ratio 
SPECT 
Single Photon Emission Computed Tomography 
TBR 
Tumor to Background Ratio 
ULN 
Upper Limit of Normal 
UNK 
Unknown 
WBC 
White Blood Cell 
WHO 
World Health Organization 

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1. 
OBJECTIVES 
1.1. 
Primary Objective 
The primary objective of the study is to determine if near-infrared fluorescence imaging of 
panitumumab-IRDye800 can identify metastatic disease in regional neck lymph nodes of 
subjects with head and neck squamous cell carcinoma (HNSCC). 
1.2. 
Secondary Objective  
Determine if panitumumab-IRDye800 can identify sentinel nodes with the same accuracy as 
Lymphoseek.  
2. 
BACKGROUND 
2.1 
Study Disease 
Squamous cell carcinoma of the head and neck affects more than 61,760 people in the United 
States annually, with a 5-year survival rate being <60% (1,2).  The presence of lymph node 
(LN) metastasis is considered the most important negative prognostic factor for survival in 
patients with primary HNSCC (3,4).  Despite advanced anatomic and metabolic imaging 
techniques, occult LN (micro-) metastasis remain in the clinically and radiographically negative 
neck (cN0).  In fact, 10 to 30% of cN0 patients present with occult LN metastasis (4).  Even 
more so, treatment of the neck is often indicated when the risk of LN metastasis exceeds 
15 to 20% (5,6).  To address this surgically, the current NCCN guidelines recommend either 
elective regional neck node dissection or sentinel node (SN) biopsy (SNB) (7).  
Elective lymph node dissection causes significant morbidity:  The gold standard for detection 
of regional metastatic disease in HNSCC traditionally has been a (elective) neck dissection.  
However, shoulder dysfunction and pain due to accessory nerve (cranial nerve XI) injury are 
common after neck dissection (8–11).  Moreover, 60 to 80% of subjects undergoing a neck 
dissection with sectioning of the nerve have pain, limited abduction of the shoulder, and 
anatomic deformities such as scapular flaring, droop, and protraction (12).  To reduce morbidity, 
there has been a gradual migration away from extensive dissection to more limited dissection 
offered by SNB where only the primary tumor draining LN(s) are removed for detailed 
histologic examination (13–18).  SNB has already replaced regional lymphadenectomy in 
melanoma and breast surgery to avoid the associated deficits associated with this more 
aggressive approach, and is now also advocated for HNSCC (7).  
Sentinel node biopsy:  SNB is performed as a surgical staging method to detect occult nodal 
disease in those tumor types with a high metastatic rate and where LN disease predicts outcome 
and informs adjuvant treatment decisions.  Assuming the orderly spread of tumor cells through 
the lymphatic system (19), excision and evaluation of the primary tumor-draining LNs only 
(so-called SN(s) will allow accurate determination of the tumor status of the regional LNs in the 
neck.  SNB thus allows the selection of node-positive subjects that will benefit from additional 
surgical or adjuvant therapy, while sparing node-negative patients an unnecessary neck 
dissection. 
Typically, to identify the SN(s) preoperatively, a local injection of a non-tumor specific 
radiotracer is given around the primary tumor followed by lymphoscintigraphy to visualize 

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drainage of the radiotracer through the lymphatic system to the SN(s) (20–22).  The addition of 
single photon emission computed tomography combined with computed tomography 
(SPECT/CT) was shown to allow for localization of the SN within its anatomical context, 
providing the surgeon with a 3D map to plan the surgical procedure (22).  During the surgical 
procedure, these SN(s) can then be identified and excised using a gamma ray detection probe that 
localizes the radioactive signal in the nodes (20,23).  More recently, mobile gamma cameras 
were introduced to provide the surgeon with additional (visual) feedback with regard to having 
localized and removed the radioactive LNs (24). 
Meta-analysis of SNB in breast cancer, head and neck cancer, and melanoma have validated the 
accuracy of SNB in predicting occult LN metastasis (13,17,25,26).  More recently, for HNSCC, 
the validity of the approach was also shown.  In a large multicenter study including 227 SNB 
procedures from 6 centers, Alkureishi et al., showed that the procedure was successful in 93% 
subjects whereby in 34% (42 subjects) of cases HNSCC subjects were upstaged whereby in 10 
subjects only micro-metastasis were present (27).  Where the centers participating in the 
Alkureishi et al., paper used colloid-based SN tracers, more recently a mannose-receptor 
targeting tracer for SNB was introduced, Lymphoseek (28–34).  In head and neck cancer, using 
Lymphoseek an even higher sensitivity was reported:  in 98% of subjects (81/83) at least one SN 
could be found with false-negative rate of 2.6% (ie, tumor-positive LN was not detected by 
Lymphoseek) and a negative predictive value of 98% (28). 
Sentinel node biopsy vs elective regional node dissection:  Besides decreased morbidity, SNB 
offers other advantages over a neck dissection:  i) Identification of aberrant draining patterns and 
“skip metastasis” (35–37);  and ii) Improved (micro-) metastasis identification at 
(histo-)pathology; fewer SNs are harvested which are more meticulously evaluated by the 
pathologist, resulting in improved diagnostic accuracy (38,39).  However, challenges remain:  
i) Local tracer injection is complicated in areas deep in the oral cavity;  ii) Near-injection site SN 
identification can be challenging due to overshadowing of signal at the primary tumor signal 
(40,36,22);  iii) Often multiple SNs are identified during surgery (22) increasing the risk of 
complications (41) (eg, nerve damage, lymphedema, scar tissue formation);  iv) neck dissection 
after a positive SNB is complicated due to the presence of scar tissue;  and v) A false-negative 
SNB occurs in 3 to 10% of subjects (ie, the SN is tumor-negative, but at follow-up metastasis in 
remaining regional LNs are found (42–45).  Moreover, although LN mapping is superior to 
radiographic and clinical exam, it is still limited by the need for direct injection of the dye or 
radiolabeled compound.  Upstaging with LN assessment can thus only be assessed in tumor 
types that are accessible for local injection.  This is significant because it influences standard 
of care (LN surgery or complete lymphadenectomy) in these subject populations only.  
Identification of regional disease will inform prognostic information and/or determine the need 
and extent of adjuvant therapies for additional tumor types.  Most importantly, however, the 
tracers used for SNB are not tumor-specific and thus SNB, similar to neck dissection, does not 
allow for intraoperative tumor-positive LN identification (21,46,47).  In fact, for both SNB and 
neck dissection (histo-)pathological evaluation is required to determine the presence of 
(micro-) metastasis and thus a method to intraoperatively identify metastatic LNs is 
lacking.  Thus, HNSCC subjects would benefit from an alternative technique that, allows 
for intraoperative lymph node staging. 

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Fluorescent, tumor-targeted antibodies for intraoperative cancer detection:  Clinical data 
has provided evidence that novel tumor-targeted antibodies can improve detection, and survival 
in a variety of cancer types (48).  By fluorescently labelling these antibodies (eg, using the 
near-infrared fluorescent dye IRdye800) it was shown that the sensitivity and specificity of 
(microscopic) tumor detection in the operative setting could be significantly improved (49–52).  
Improved visualization can thus significantly improve surgical techniques and outcome.   
The epidermal growth factor receptor (EGFR) is found overexpressed in 80 to 90% of subjects 
with HNSCC (53).  Our group has shown that EGFR-based optical imaging can detect 
subclinical disease (non-palpable tumor) within the resection bed approximately 72 hours after 
systemic administration of a fluorescently labeled anti-EGFR antibody (54–56).  The potential of 
optical imaging to guide surgical resection by capitalizing on the overexpression of EGFR has 
also been supported by the findings of other groups in a variety of solid tumors (57–59).  
Moreover we’ve shown the feasibility of real-time fluorescence imaging-based identification of 
HNSCC using the anti-EGFR antibody cetuximab-IRdye800 (49,60,61).  In our phase 1 study, in 
all subjects, tumor tissue could be clearly discriminated from normal tissue, and a high 
fluorescence intensity strongly correlated with the presence of tumor (36,41).  Moreover, we 
showed that with another anti-EGFR antibody, cetuximab-IRdye800 we could identify 
metastatic LNs with a high 97.2% sensitivity;  92.7% specificity;  99.7% negative and 
50.7% positive predictive value (62).  More recently we switched to panitumumab-IRDye800 – 
our phase 1 study (IRB-35064) evaluating the safety and dosing of panitumumab-IRDye800 in 
HNSCC is reaching completion.  Preliminary results of this phase 1 study are in line with our 
previous clinical studies using cetuximab-IRdye800 and suggests that we will be able to 
We propose to evaluate the fluorescently-labelled anti-EGFR antibody, 
panitumumab-IRdye800, for its ability to intraoperatively identify sentinel and LN 
(micro-)metastasis. We propose to directly compare fluorescence imaging of 
panitumumab-IRDye800 imaging findings to that of SNB and neck dissection whereby we 
will use (histo-)pathology as gold standard for determining the true tumor-positive LNs.  
Potential benefits of panitumumab-IRdye800 for metastatic LN identification over SNB:  
1) Panitumumab-IRDye800 is a tumor-targeted tracer that can allow intraoperative identification 
of metastatic lymph nodes (for the other techniques pathology is required to confirm).  
2) Panitumumab-IRDye800 is systemically injected, and thus can allow metastatic LN 
identification also at sites that are not-accessible for a SN tracer (ie, tumor in the 
hypopharynx).  
3) Panitumumab-IRDye800 provides a tumor-specific approach whereas the SN tracer is not 
tumor-specific.  
4) Panitumumab-IRDye800 can be injected several days before the operation and thus scheduling 
logistics would be improved (SN tracer is preferable injected the day of surgery) 
5) If successful with the optical dye, similar studies could be conducted with a radiolabeled dye.  

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2.2 
Study Agents 
The investigational agent for this study, panitumumab-IRDye800, is unapproved by FDA, and an 
Investigational New Drug application (IND) is required for this study.  [Note:  the antibody 
moiety of the investigational agent is approved by FDA as Vectibix (panitumumab)].  
Lymphoseek is an FDA-approved agent for oral cavity SNB.  
This protocol will be added to existing IND-119474 (IND Holder:  Eben Rosenthal, MD). 
2.3 
Rationale 
Overall impact of the proposed study on surgical oncology:  Introduction of this technology 
to the operating room in the manner we propose would represent a paradigm shift in oncologic 
surgery as there are currently no techniques available that allow intraoperative detection of 
metastatic LNs.  The use of optical imaging would be a significant improvement in real-time 
identification of cancer in LNs.  
Our study would demonstrate important proof-of-principle and translate concepts that molecular 
biologists have used for more than a decade to identify and label cancer in real-time.  At the 
same time it will allow us to evaluate the value the panitumumab-IRDye800 approach can have 
when compared to the current standards.  
Not only can this have strong impact on subjects with HNSCC, the development of a cancer 
specific contrast agent of this type can also be applied to other solid tumors that express EGFR 
for which LN status of prognostic value.  Furthermore, if the principle of targeted optical 
imaging is validated using EGFR, other therapeutic antibodies could be assessed for imaging 
potential.  Successful completion of this study will thus have a lasting impact on the field of 
surgical oncology. 
Our proposed study offers the potential to improve current standard of care in the 
following ways: 
1. Despite the variety of techniques available for metastatic LN detection, consensus is 
lacking (46,68)   
2. Currently 
no 
intraoperative 
technique 
is 
available 
to 
directly 
identify 
tumor-positive LNs:  Panitumumab-IRDye800 has already shown to allow for real-time 
fluorescence imaging of the primary tumor (IRB-35064).  
3. Real-time feedback:  Presence of regional disease can be assessed intraoperatively.  
4. Minimally-invasive approach:  Presence of regional disease can be assessed 
intraoperatively, leading to fewer healthy LNs removed. 
5. Use in other cancer types:   
- 
EGFR is highly-expressed in multiple cancer types, allowing application to other 
tumor types beyond HNSCC.  
- 
Our proposed technique can even be extended to tumors that are not accessible for 
superficial injections for SNB but for which LN status plays an important role, 
eg, colorectal cancer.   

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6. High feasibility:  We have previously conducted dose-escalation phase 1 clinical trials 
using cetuximab-IRDye800 and panitumumab-IRDye800 in HNSCC ((69) and (65,68), 
respectivley).  
2.4 
Study Design 
- 
The primary purpose for the protocol is Image Guidance.  The primary objective of the 
study is to determine if near-infrared fluorescence imaging of panitumumab-IRDye800 
can identify metastatic disease in regional neck LNs of subjects with HNSCC. 
- 
There are 2 cohorts. 
- 
The study is open-label.  No masking is used.  
- 
The study is non-randomized.  
- 
The primary outcome is number and location of LNs that are near-infrared 
fluorescent and that contain tumor as defined by (histo-)pathology.  
The study is an open-label study to determine if near-infrared fluorescence imaging of 
panitumumab-IRDye800 can identify metastatic disease in regional neck LNs of subjects with 
HNSCC.  Panitumumab-IRDye800-based findings will be compared to LN biopsy and neck 
dissection.  A schematic overview of the clinical trial is given in Figure 1.  
2.4.1.  Number of subjects 
A total of 20 subjects will be enrolled in our exploratory study.  
Rationale for including cN0 and cN+ subjects:  Based on NCCN guidelines, version 1 2018, 
SNB is justified in subjects with a T1 or T2 stage primary tumor and a cN0 neck that are at 
(high) risk for having LN metastasis.  The strength of SNB lies in the identification of “skip 
lesions” (ie, metastatic spread to a LN outside the expected drainage area) and aberrant drainage 
patterns (ie, drainage to LNs that are outside the expected drainage template) (12-14).  Including 
cN0 subjects will thus provide us with the unique opportunity to directly compare the 
performance of panitumumab-IRdye800 for metastatic LN identification to that of Lymphoseek 
and thus validate our approach against the reference standard.  
Panitumumab-IRDye800 will be evaluated in subjects with any T stage and a cN+ neck to study 
how well panitumumab-IRDye800 can detect metastatic lesions in the LN(s).  
2.4.2.  Dosing  
Subjects will be infused with 50 mg panitumumab-IRDye800 and 2 mCi Lymphoseek.  
Panitumumab-IRDye800 will be systemically infused 1 to 5 days prior to surgery, whereas 
2 mCi Lymphoseek will be administered locally on the day before surgery (Table 1).  

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Table 1:  Cohort structure 
Cohort 
Preoperative 
nodal 
stage 
Number of 
subjects 
Dose 
panitumumab-IRDye800 
Dose 
Lymphoseek 
1 
T1 or T2 stage and 
node negative (ie, cN0) 
10 
50 mg 
2 mCi 
2 
Any T stage and node 
positive (ie, cN+) 
10 
50 mg 
none 
2.4.2.1.  Rationale for panitumumab-IRDye800 dosing 
The dose we use in the current study is derived from the optimal dose as determined in Stanford 
IRB 
protocol 
IRB-35064 
whereby 
we 
evaluated 
the 
safety 
and 
dosing 
of 
panitumumab-IRDye800 in HNSCC.  In this study, we also investigated the necessity of an 
unlabeled-panitumumab loading dose.  We found no significant differences in fluorescence 
intensities around the primary tumor site and similar TBRs when no loading dose was 
administered.  Moreover, the 50 mg dose was found safe (no Grade 2 or greater toxicity 
reported) and easy to administer (unpublished data; see safety reports IRB-35064).  
2.4.2.2.  Safety Monitoring 
Following our current IRB-35064, during and after the panitumumab-IRDye800 infusion, 
subjects will be monitored for allergic reactions.  Safety measurements will be taken, including, 
as hemodynamic monitoring, ECGs, blood tests, and physical examination - see Section 9 for a 
specific list of measurements taken at the different timepoints (ie, screening, day of surgery). 
If three or more participants of the study experience dose limiting toxicity (DLT), then the study 
will be stopped and the data reviewed.  Dose-limiting toxicity (DLT) will be defined as any 
Grade 2 or greater toxicity that is considered possible, probably or definitely related to the study 
drug and considered clinically significant by the investigator, and occurs within 15 days of 
receiving treatment, which represents more than 4 half-lives of the drug.  Restarting the study 
will require reassessment after discussion and approval by the Data Safety Monitoring 
Committee.  Because panitumumab is an approved agent with a known DLT rate of 1%, we 
expect this study to further confirm the safety of conjugated panitumumab-IRDye800 at lower 
doses than the dose used in a therapeutic setting.  
The known rate of severe infusion reactions of panitumumab is 1% (package insert, June 2017); 
therefore, we expect a DLT rate of approximately 1% or higher with panitumumab-IRDye800.  
Assuming the true DLT rate is as high as 5% and a significance level of 0.05, the probability of 
stopping early (three or more DLT in the first 12 subjects) is 0.002. 
For Lymphoseek, no infusion reactions have been reported (see package insert) (28–30,32–34).  
The most common adverse reactions (incidence < 1%) are injection site irritation and pain (see 
Section 5.2.2.).  Therefore, there is no implementation of additional safety measures warranted 
for this study.   
2.4.2.3.  Pharmacokinetic intervals   
Clearance of panitumumab occurs through the binding in the liver and through the 
reticuloendothelial system as occurs with endogenous immunoglobulin.  Because the 

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pharmacokinetics of single dose panitumumab are well known and the pharmacokinetics of 
panitumumab and panitumumab-IRDye800 are nearly the same in non-human primate studies 
(see toxicology section), only limited pharmacokinetics will be performed.  Blood levels of 
panitumumab-IRDye800 and free IRDye800 will be monitored on Day 0 before infusion and 
approximately 1hour after end of infusion), on Day 1 as available, on the day of surgery 
(Day 1 to 5 post-infusion), Day 1 to 3 post-surgery as available, Day of discharge, and Day 30 
post-infusion of the study drug.  
2.4.3.  Workflow of the Clinical Trial  
Below we provide a concise summary of the clinical trial workflow with regard to the different 
steps that are taken upon receiving of written informed consent from the study subject.  
2.4.3.1.  Panitumumab-IRDye800 Infusion  
Subjects will be infused with 50 mg panitumumab-IRDye800 1 to 5 days prior to surgery.  
Further details on the infusion can be found in Section 4.1 and 4.2.  
2.4.3.2.  Preoperative Sentinel Node Mapping 
Currently, SNB of squamous cell carcinoma of the head and neck is not performed at Stanford.  
It is however in the NCCN guidelines (7) where it is advocated as an alternative to neck 
dissection for loco-regional staging of the neck in subjects with either T1 or T2 stage and N0 
status.  For the subject work-up we will follow literature references on Lymphoseek in HNSCC 
(28), and the standard operating protocol the Division of Nuclear Medicine has in place for SNB 
of melanoma using Lymphoseek.  
Current Procedural Terminology (CPT) codes are available for injection of the 
radiopharmaceutical Lymphoseek and (sentinel) lymph node mapping (38792 and 78195, 
respectively) in oral cavity cancer (ICD-10 codes C01-C06.9).  The costs of the SNB procedure 
will therefore be billed to the subject’s medical insurance. 
Lymphoseek will be locally administrated the day before surgery.  Peritumorally, 4 x 0.1 mL of 
Lymphoseek will be administrated.  A total dose of maximally 2 mCi will be administered (28).  
Further details on Lymphoseek administration and radiation exposure are described in 4.1 and 
4.3, respectively. 
Preoperative SN mapping in subjects with HNSCC will be performed according to the protocol 
the Division of Nuclear Medicine has for Lymphoseek-based SN mapping in melanoma.  
Dynamic images will be acquired in anterior projection over the head and neck starting 
immediately after the injections have been completed.  Lymphoscintigraphic imaging is 
performed at a 1 minute/frame for 30 minutes using a 128x128 matrix, followed by static spot 
views with/without a transmission source.  Single photon emission computed tomography 
combined with computed tomography (SPECT/CT) imaging of the head and neck will follow the 
planar dynamic imaging.  Acquisition parameters for a multi-detector system are 3-degree 
angular sampling, 128 x 128 matrix, 360-degree rotation and 20-30 sec per stop.  
Following completion of image acquisition the Nuclear Medicine physician will review the 
images to determine the direction of the lymphatic flow and the potential accumulation in a 
sentinel LN.  Using SPECT/CT images, he/she will determine the number and location of the 
SNs.  

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Rationale for SPECT/CT imaging:  The value of SPECT/CT lies in the anatomical localization 
of the spot views seen on the dynamic planar images.  Moreover, SPECT/CT may help to 
localize foci of abnormal Lymphoseek accumulation more accurately than planar imaging or 
SPECT alone.  
Radiation risks associated with SPECT/CT imaging:  It has been recommended that when 
SPECT/CT imaging is performed for anatomical correlation with the functional study, a 
low-dose CT scan is recommended.  The radiation dose from low-dose CT scans will be 
approximately 0.6 mSv (70).  This value is up to 80-85% lower than the radiation dose received 
when performing a diagnostic CT.  As reported by Montes, et al, the main radiation risk for these 
low doses, in which stochastic effects predominate, is an increased probability of cancer 
induction – ranging 0.003 to 0.010% (71).  
2.4.3.3.  Intraoperative Imaging Protocol  
On the day of surgery, 1 to 5 days post-infusion of panitumumab-IRDye800, intraoperative 
fluorescence imaging and gamma tracing will be performed.  
Optical imaging devices to be used:  Imaging with the optical imaging devices will be 
performed intraoperatively in situ and on the back table (see Appendix B for a list of the imaging 
devices).  Additional ex vivo devices will also be used to image the specimens on the back table 
(see Appendix B for a list of the imaging devices). 
All in vivo devices are FDA approved for measuring intraoperative blood flow after indocyanine 
green (ICG) injection.  Because IRDye800 and ICG have overlapping excitation and emission 
spectra, each device can also be used for imaging subclinical disease based on our preclinical 
studies in head and neck cancer (see Appendix B for a list of the imaging devices). 
Sentinel node biopsy (stage T1/2, cN0)  
Step 1) In situ gamma tracing and fluorescence imaging of the sentinel nodes:  
1. Prior to opening the skin, the surgeon will screen the neck for the presence of radioactive 
node(s) (ie, SNs) by sweeping the gamma probe over the intact neck.  If any radioactive 
nodes are detected, the location of detected radioactive nodes will be marked on the skin 
using indelible ink and a still image of the marked will be collected for documentation.  
2. After opening the skin, a photo of the neck will be taken for documentation.  Hereafter the 
surgeon will perform fluorescence imaging of the neck to evaluate if there are any 
fluorescent nodes visible.  Fluorescent nodes will be marked on the photo of the neck.  Video 
and still images of the fluorescence imaging procedure will be collected. 
3. Hereafter, as per standard of care, the surgeon will perform SNB using the gamma probe.  
For this, the surgeon will evaluate the neck with the gamma probe for the presence of 
radioactive nodes.  Upon localizing of radioactive nodes, the count rate of the node will be 
determined.  Then, just prior to the resection of the radioactive node, in situ fluorescence 
imaging will be performed to evaluate the fluorescence-based visibility of the node.  For each 
radioactive node, the respective in situ location will be documented (level Ia, Ib, IIa, IIb, III, 
IV or V) as well as the radioactive status (count rate) and fluorescence status (yes/no).  
Hereafter the node will be harvested by the surgeon.  This process will be repeated until no 
radioactive nodes are detected anymore in situ.  

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Step 2) Wound bed imaging:  
As per standard of care SNB, upon completion of SNB, the neck will be screened once more 
with the gamma probe as such to determine the presence of  any remaining radioactivity 
(ie, a radioactive signal detected > 10% of the background that correlates with any substrate 
(node).  Areas in the wound bed determined radioactive-positive will be surgically re-evaluated, 
and, upon checking the fluorescence-status, removed, if deemed necessary by the surgeon.  If 
any nodes are found, gamma tracing will be performed to determine the radioactive status.  
Step 3) Pathological imaging:  
The fluorescence and/or radioactive status of all excised nodes will be confirmed ex vivo on the 
back table using both a closed-field imaging device and an open-field device as well as the 
gamma probe, respectively.  Hereafter all excised nodal specimens will be sent for 
(histo-)pathology.  After the tissue has been processed and evaluated by the pathologist, imaging 
findings will be compared to gold-standard histological-assessment performed by the pathologist 
(including a hematoxylin and eosin (H&E) staining) to determine the correlation between 
fluorescence, radioactivity and the presence/absence of tumor tissue in the LN(s).  Also findings 
will be compared to preoperative lymphoscintigraphy and SPECT/CT imaging (ie, correlation 
between preoperative imaging findings and intraoperative imaging findings).  
Neck dissection only (T1-4, cN+)  
After the neck has been opened by the surgeon, it will be inspected by the surgeon for the 
presence of suspicious nodes.  Real-time fluorescence imaging of the LNs in the neck will then 
be performed at 4 time points:  
Step 1) In situ imaging:  After having opened the skin and exposure of the neck LNs, in situ 
fluorescence imaging will be performed to evaluate the fluorescence-based visibility of the LNs.  
For each fluorescent LN, the respective location will be documented (level Ia, Ib, IIa, IIb, III, IV 
or V) after which it will be harvested by the surgeon.  This process will be repeated until no 
fluorescent LNs are seen in situ.  Hereafter, the standard of care completion neck dissection will 
be performed.  
Step 2) Ex vivo imaging:  The neck dissection specimen will be evaluated for the presence of 
fluorescent LNs using both a closed-field imaging device and an open-field device.  All 
additional fluorescent LNs will be identified, documented and collected separately;  
we acknowledge that the penetration depth of the fluorescence signal is limited and therefore 
deeper located LNs might not be detectable in situ (under step 1), but after having taken out the 
specimen and having “flipped” the specimen this might be possible.  
Step 3) Wound bed imaging:  This will be conducted for any remaining fluorescence (ie, any 
remaining fluorescent LNs).  Areas in the wound bed determined fluorescence-positive will be 
surgically re-evaluated, and, if deemed necessary by the surgeon, removed.  
Step 4) Pathological imaging:  All excised nodal specimens will be imaged once more in the 
closed-field device to confirm that all fluorescent LNs have been removed from the neck 
dissection specimen.  If not, the number and location of remainder fluorescent LNs will be 
documented after which they will be harvested; we will use the image taken under step 2 for 
reference as such to make sure that we did not create any confounding factor due to tissue 

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preparation to harvest nodes at step 2.  Hereafter all excised nodal specimens will be sent for 
(histo-)pathology.  After the tissue has been processed and evaluated by the pathologist, 
fluorescence imaging-based findings will be compared to gold-standard histological-assessment 
performed by the pathologist (including a hematoxylin and eosin (H&E) staining) to determine 
the correlation between fluorescence and the presence/absence of tumor tissue in the LN(s). 
2.4.3.4.  Laboratory Imaging Protocol  
Once the LNs have been removed from the subject and sent for pathology review, additional 
imaging will be performed with non-significant risk devices (Pearl and Odyssey imaging systems 
– LICOR Biosciences, Lincoln, NE) of pathological specimen(s) using non-invasive imaging 
modalities that do not expose the subject to radiation or other interventions, or alter the standard 
pathological processing of the tissues (see Appendix B for a list of the imaging devices).  Normal 
waste tissues will also be imaged.  The research imaging modalities will not be used in the 
patient-care setting.  Imaging will be done in collaboration with the Department of Pathology to 
ensure preservation of tumor-related information.  Data from the research use of the device will 
not be used for diagnosis or other medical decision-making.   
2.4.3.5.  Pathological Correlates 
Tissue specimens will be collected by pathology after which they will be formalin-fixed and 
paraffin-embedded according to standard procedures.  
Specifically, for the LN specimens we will investigate the following:  
To 
determine 
biological 
characteristics 
associated 
with 
fluorescence 
intensity 
measurements, formalin-fixed paraffin-embedded blocks from the collected specimens will be 
obtained from pathology after routine analysis and imaged on the Pearl and Odyssey as 
previously described in preclinical models (72,73).  This will allow high-resolution evaluation of 
the location of the fluorescence signal in the tissue.  Subsequently 5 micron sections will be cut 
for histological analysis of:  1) Size of the epithelial tumor compartment in percent of total;  
2) Tumor characteristics (ie, size, proliferation);  and 3) EGFR.  Methods have been previously 
described by us using in vivo models (74–78).  
We will then determine if these characteristics are associated with fluorescence (yes/no) from the 
Pearl and Odyssey imaging systems.  We will use the two-sided Fisher’s exact test to determine 
the level of association between tumor characteristics (ie, size, proliferation) and EGFR status 
and fluorescence (yes/no).  Likewise, we will test the association between the size of the 
epithelial tumor compartment and fluorescence (yes/no) with the two-sided Wilcoxon rank sum 
test.  
To determine where panitumumab-IRDye800 localizes in the fluorescent LNs, 5 micron 
sections will be cut and undergo immunohistochemistry for localization of various immune cells, 
including B and T-cells, macrophages and dendritic cells.  Immunohistochemistry findings will 
then be correlated with fluorescence intensities measured on the Pearl and Odyssey imaging 
systems.  We expect that panitumumab-IRDye800 both specifically and non-specifically occurs 
in the LNs.  Specific uptake in the LNs will occur if metastasis are present in the nodes.  
Non-specific uptake of panitumumab-IRDye800 in the LNs can occur by a mechanism similar to 
the principle of SNs mapping, ie, due to accumulation of tracer at the injection site, overflow 
from the tumor to the LNs will occur where this tracer will get trapped in immune cells (79).  

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The two-sided Fisher’s exact test will be used to determine the level of association between each 
of these characteristics and panitumumab-IRDye800 fluorescence (yes/no). 
2.4.3.6.  Statistical Analysis  
The statistical analysis, including sample size justification and power considerations are given in 
Section 12.  
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 
Inclusion Criteria 
a. Biopsy confirmed diagnosis of squamous cell carcinoma of the head and neck 
b. Subjects with recurrent disease or a new primary will be allowed 
c. Planned standard of care surgery with curative intent for squamous cell carcinoma  
d. * SNB only cohort:  Subjects diagnosed with a T1-T2 stage tumor, any subsite within 
the head and neck that is amenable to local sentinel node tracer injection and are 
scheduled to undergo surgical resection of the tumor, including a sentinel node biopsy  
e. * Neck dissection only cohort:  Subjects diagnosed with any T stage, any subsite within 
the head and neck that are scheduled to undergo surgical resection, including a (modified) 
neck dissection 
f. Age ≥ 19 years 
g. Karnofsky performance status of at least 70% or ECOG/Zubrod level 1 
h. Have acceptable hematologic status, coagulation status, kidney function, and liver 
function including the following clinical results: 
i. 
Hemoglobin ≥ 9 gm/dL 
ii. 
White blood cell count > 3000/mm3  
iii. 
Platelet count ≥ 100,000/mm3  
iv. 
Serum creatinine ≤ 1.5 times upper reference range 
*Only one criterion to be checked for each participant – either “d” or “e”. 
3.2 
Exclusion Criteria 
a. -Myocardial infarction (MI);  cerebrovascular accident (CVA);  uncontrolled congestive 
heart failure (CHF);  significant liver disease;  or unstable angina within 6 months prior 
to enrollment 
b. History of infusion reactions to monoclonal antibody therapies 
c. Pregnant or breastfeeding 
d. Magnesium or potassium lower than the normal institutional values 
e. Subjects receiving Class IA (quinidine, procainamide) or Class III (dofetilide, 
amiodarone, sotalol) antiarrhythmic agents 
f. Subjects with a history or evidence of interstitial pneumonitis or pulmonary fibrosis 

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g. Hypersensitivity to dextran and/or modified form thereof 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants must 
sign the IRB-approved informed consent prior to participation in any study specific procedure.  
The participant must receive a copy of the signed and dated consent document.  The original 
signed copy of the consent document must be retained in the medical record or research file.  
3.4 
Enrollment Process 
After signing an informed consent, subjects will be assigned a unique subject identification 
number based on the OnCore number and sequential numeric code (ie, SLN0028-001, -002, etc).  
The subject identification number will be used on all subject specific Case Report Forms (CRFs) 
and serious adverse event (SAE) forms.  Participant information should be entered into OnCore 
within 5 business days. 
3.5 
Study Timeline 
Primary Completion: 
The study will reach primary completion 18 months from the time the study opens to accrual; we 
anticipate enrolling 1 to 2 subjects per month from the start of the study.  
Study Completion: 
The study will reach study completion 24 months from the time the study opens to accrual.  
The anticipated study start date:  December 2018 – January 2019 
The anticipated study completion date:  December 2020 
4. 
TREATMENT PLAN 
4.1 
Treatment Schedule 
Subjects will receive intravenous panitumumab-IRDye800 (50 mg) 1 to 5 days prior to surgery.  
Then on the day before surgery, subjects in Cohort 1 will receive a local injection with 2 mCi 
Lymphoseek followed by lymphoscintigraphy and SPECT/CT imaging to determine the number 
and location of LNs.  In the operation theatre, using a combination of fluorescence imaging and 
radio-tracing, the LNs of the neck will be evaluated and scored (Section 2.4, Figure 1).  
4.2 
Administration of panitumumab-IRDye800  
Administration of panitumumab-IRDye800 will be performed consistent with institutional policy 
for administration of panitumumab.  The solution will be diluted to a total volume of 100mL 
using 
0.9% 
sodium 
chloride 
injection, 
USP. 
 
Dosage 
level 
will 
be 
50 mg 
panitumumab-IRDye800 (< 1/12 of a therapeutic dose of panitumumab).  Administration of 
panitumumab-IRDye800 will occur by IV over 15 (± 5) minutes.  Subjects will be observed for 
30 (± 10) minutes after administration.  Additional treatment for infusion reactions and 
electrolyte imbalances may be given following institutional policy. 
Premedication will be delivered prior to the infusion for each subject at the discretion of the 
treating physician according to routine institutional protocols for delivery of panitumumab.  

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Treatment will be given in an infusion facility that routinely administers experimental 
chemotherapeutic infusions and is equipped with emergency equipment and medication along 
with medical personnel in the event that the subject experiences a severe reaction.  
The infusion(s) will be stopped if deemed necessary with the onset of any significant signs of 
reaction.  Steroids and other supportive medications may be administered and infusion resumed 
at the discretion of the treating physician.  If a subject experiences a serious reaction that 
prevents completing the study infusion(s), the subject will be observed; but will not complete 
their study infusion(s).  Any subject who does not receive the full panitumumab-IRDye800 dose 
will be considered withdrawn from the study and not count towards cohort accrual. 
With a single dose at the levels proposed the half-life is expected to be approximately 2.3 days or 
less.  Clearance of panitumumab occurs through the binding in the liver and through the 
reticuloendothelial system as occurs with endogenous immunoglobulin. 
4.3  
Administration of Lymphoseek (99mTc-Tilmanocept)  
Lymphoseek is supplied as a unit dose from Cardinal Health.  
The radiopharmaceutical Lymphoseek will be administered locally at the Division of Nuclear 
Medicine.  A total of 4 peri-tumoral injections of 0.1 mL of Lymphoseek will be given with a 
total dose of 2 mCi Lymphoseek injected.  Per physicians discretion, local anesthesia may be 
used (ie, viscous lidocaine, lidocaine spray).  
Radiation risk Lymphoseek:  Exposure to radiation causes both direct DNA damage 
(single-strand or double-strand DNA breaks) via ionization (energy is transferred to electrons 
and the atom loses an electron becoming ionized) and indirect damage via the formation of free 
radicals.  Adhere to As Low as Reasonably Achievable (ALARA) principles (dose 
recommendations) and ensure safe handling (time, distance, and shielding) to minimize the risk 
for excessive radiation exposure to either patients or health care workers. 
Technetium-99m decays by isomeric transition with a physical half-life of approximately 6 
hours.  The estimated local radiation dose varies greatly on the time to surgery and the 
adminstered dose as well as the injected location (27).  The recommended dose of Lymphoseek 
is 0.5 mCi (18.5 MBq) as a radioactivity dose and 50 mcg as a mass dose for a 1-day protocol 
(i.e., surgery is performed within 15 hours) and 2 mCi (74 MBq) for a 2-day protocol (i.e., 
surgery is performed the day after injection of Lymphoseek).  
No specific adsorbed radiation dose for Lymphoseek has been reported in patients with oral 
cavity carcinoma, however, for breast cancer and melanoma adsorbed radiation doses are 
reported in the package insert of Lymphoseek when a dose of 0.5 mCi is injected (Table 2).  The 
effective dose equivalent for males and females are 0.20 and 0.25 mSv in melanoma and 
0.30 and 0.33 mSv in breast cancer, respectively.  These doses are in line with previous SNB 
reports from amongst others Memorial Sloan Kettering Cancer Center (80).  As for the absorbed 
radiation dose for the surgical staff in the operation room, this is < 0.0001 mSv per operation 
with a maximum dose of < 0.0002 mSv to the surgeon (27) – these doses are further minimized 
when the surgery is performed > 24 hours after radiotracer administration.  Monitoring of the 
operation room personnel and additional shielding is therefore not required.   

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For a 2 mCi administrated Lymphoseek dose, using Table 2 as reference, we estimated the 
effective dose equivalent for males and females being 0.810 and 1.05 mSv in melanoma and 1.18 
and 1.32 mSv in breast cancer, respectively.  Extrapolating this to our HNSCC subjects, the 
total amount of radiation from one SNB procedure using Lymphoseek will then range 
1.41 to 1.78 mSv in males and 1.65 to 1.97 mSv in females – this includes a 0.6 mSv dose 
that the subject will receive when the low-dose CT is acquired.  This is approximately 4% 
of the total radiation a person will receive in one year from the environment.  
Table 2:  Estimated absorbed radiation dose from 0.5 mCi Lymphoseek in  
subjects with breast cancer and melanoma 
 

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4.4 
Definition of Dose-Limiting Toxicity (DLT)  
AEs will be graded according to the CTCAE v5.0 (http://evs.nci.nih.gov/ftp1/CTAE/about.html). 
Dose-limiting toxicity (DLT) will be defined as any Grade 2 or greater toxicity that is ALL of 
the following: 
 
Determined by the investigator to be possible, probably or definitely-related to 
panitumumab-IRDye800 or Lymphoseek 
 
Considered by the Investigator to be clinically significant for subjects who received 
panitumumab-IRDye800 or Lymphoseek.  For this study, clinically significant is defined 
based on NCI definition – a result that is large enough to affect a subject’s disease state in a 
manner that is noticeable to the subject and/or caregiver or requires intervention 
 
Occurred within 15 days of receiving treatment with panitumumab-IRDye800 or 
Lymphoseek 
The Stanford Data Safety Monitoring Committee (DSMC) will be notified of all DLTs.  The 
DSMC will evaluate safety data from all subjects through Day of discharge.  If 3 or more 
subjects experience a DLT, then study enrollment will be halted pending DSMC review. 
4.5 
Surgical Imaging  
Lymphadenectomy specimen assessment.  Please see Section 2.4 for more detail.  The neck 
will be imaged using near-infrared fluorescence and white light optical imaging systems and 
gamma tracing will be performed (Cohort 1 only).  Imaging and tracing will be performed prior 
to lymphadenectomy, and after lymphadenectomy.  Subsequently, the lymphadenectomy 
specimens will be imaged on a ‘back table’ prior to sending the specimens to pathology.  The 
number and location of the fluorescent, and/or radioactive LNs will be documented.  
The imaging information obtained will not be used for diagnosis or any other medical 
decision-making.  Added surgical time for these images is expected to be minimal since these the 
images can be recorded for later review as still and video images.  Once the specimens have been 
delivered to pathology, additional imaging will be performed as described above in Section 2.4. 
4.6 
General Concomitant Medication and Supportive Care Guidelines 
Other than chemotherapy (including any EGFR targeting agent), subjects may continue any 
medication they are receiving at study entry for underlying medical conditions.  All medications 
taken at time of study entry will be recorded.  Any changes in concomitant medication, including 
additions, discontinuations, and dose changes, occurring during the study will be recorded. 
Medications administered from the day of admission for standard of care surgery until the day of 
discharge will not be collected, unless given for a reportable adverse event or reportable serious 
adverse event (See AE section for AE definition). 
Premedication and supportive care for infusion reactions and/or electrolyte imbalances may be 
administered per institutional policies at the discretion of the treating physician. 

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4.7 
Criteria for Removal from Study 
Treatment will be stopped and subjects will be removed from study due to unacceptable AEs, or 
withdrawal of consent.  Any subject who does not receive the panitumumab-IRDye800 will be 
considered withdrawn from the study and will not count towards enrollment goals. 
Subjects will be considered off study once they have completed the 30-day safety observation 
period. 
4.8 
Alternatives and Risk Protection / Mitigation  
Alternatives 
 This study is in the setting of tumor and LN node excision of suspected squamous cell 
carcinoma, and the experimental component is infusion of panitumumab-IRDye800, and 
Lymphoseek with planar and SPECT/CT imaging, which may help the surgeon visualize 
LN status and location.  Additionally, using a handheld gamma counter post-injection 
may also help the surgeons to locate nodes with Lymphoseek uptake.  Both approaches 
have been shown to decrease overall time in surgery.  The surgery itself is considered 
regular medical care.  Therefore, the alternative to participating in this study is to have 
the surgery without panitumumab-IRDye800 and/or Lymphoseek administration.  
Procedures to protect against and minimize potential risks:  
 This study is designed enroll appropriate subject populations (see Section 3.1 
Inclusion Criteria, and Section 3.2 Exclusion Criteria).  
 Subjects will be monitored regularly for AEs by the investigators and the study team after 
investigational panitumumab-IRDye800 and surgery, through 30 days (± 7 days) 
post-panitumumab-IRDye800 infusion. 
 Subjects will be given a 24-hour emergency number in case problems arise between 
clinic visits. 
 Subject records will be kept in a secure location at Stanford University Medical Center 
accessible only to authorized personnel. 
5. 
INVESTIGATIONAL AGENT INFORMATION 
5.1 
Description of Study Drug   
5.1.1.  Panitumumab-IRDye800 
Unlabeled Panitumumab 
Panitumumab (PLS-125147, Vectibix) is a fully-humanized IgG2 monoclonal antibody that 
is FDA-approved therapeutic antibody targeting the epidermal growth factor 
receptor (EGFR) and is indicated as a single agent for the treatment of metastatic colorectal 
carcinoma with disease progression.  It is also approved in Canada and the European Union.    
FDA Summary Basis of Approval excerpts are provided and summarized below.  Panitumumab 
was evaluated for pharmacologic activity in preclinical rodent studies and for toxicity and 
pharmacokinetics in nude mice and cynomolgus monkeys.  Tissue binding studies demonstrated 
that it bound with moderate to strong intensity to surface expressed EGFR in samples of both 

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human and cynomolgus monkey skin, tonsil, breast, and prostate, and in the genitourinary tract 
epithelium of monkeys.  
In preclinical xenografts rodent studies, it was found that combination therapy with 
Panitumumab and chemotherapy or other anti-tumor treatments resulted in additive benefit.  
Pharmacokinetic profiles of Panitumumab in cynomolgus monkeys following systemic 
administration of single doses of 7.5, 15, 30, or 60 mg/kg showed linear, dose-related increases 
in Cmax and dose-related decreases in clearance with a concomitant increase in the half-life.  
Steady state of the drug could be achieved following repetitive dosing approximately 5 to 6 
doses of panitumumab.  The half-life of panitumumab after single administration depends on the 
dose.  It is known that when panitumumab is administered to humans as a single dose between 
0.5 mg/kg and 1.5 mg/kg the half-life is 0.8 days; at 2.0 mg/kg the half-life is 2.3 days; and at 
6.0 mg/kg the half-life 7.3 days (FDA Drug Approval Package, Clinical Pharmacology 
Biopharmaceutics Review, application 125147).  
Panitumumab’s therapeutic activity occurs by binding to the tumor cell expressed EGFR which 
1) competitively inhibits the binding of its normal ligands including epidermal growth factor and 
transforming growth factor-alpha, which are implicated in tumor growth, and 2) stimulates 
receptor internalization, leading to a reduction of EGFR signaling.  Over-expression of EGFR is 
also detected in many cancer types including pancreatic, head and neck, lung, colon and brain.  
Toxicity profiles associated with administration of panitumumab are known.  Severe 
dermatologic and gastrointestinal toxicities were noted after repeated dosing in cynomolgus 
monkeys who received weekly treatment at therapeutic dosing:  7.5; 15; 30;  or 60 mg/kg 
panitumumab for 4;  13  or 26 weeks.  These doses correspond to approximately 1.25 to 10-fold 
greater than the therapeutic human dose of 6 mg/kg.  The dermatologic toxicities associated with 
Panitumumab treatment were observed both in humans and preclinical toxicology studies 
(cynomolgus monkeys) following repeat administration and were not associated with single-dose 
administration.  In clinical trials the dermatologic toxicities were generally Grade 2 in severity, 
with approximately 12% of subjects (95/789) reporting Grade 3 or higher skin changes.  The 
package insert for panitumumab describes other toxicities associated with repeat administration 
including:  electrolyte disturbances (hypomagnesemia and hypocalcemia), pulmonary fibrosis 
and ocular toxicities.  Non-dose related toxicities include infusion reaction of approximately 4% 
(package insert).  During clinical trials, no subjects had life-threatening or fatal infusion reaction 
to Panitumumab with severe events occurring in 1 % (NCI CTC grade 3 to 4).  Most of the 
potential infusion reactions were mild in intensity and did not require treatment or interruption of 
panitumumab dosing.  For additional toxicity information please see the package insert. 
IRDye800CW 
IRDye800CW N-hydroxysuccinimide (NHS) ester infrared dye (LiCor, Lincoln, NE) has a 
molecular weight of 1166 Da and is supplied as a lyophilized powder.  It can be dissolved in 
water or DMSO at concentrations up to 20 mg/mL.  The dye in Phosphate Buffered Saline (PBS) 
has an absorbance maximum of 773 nm and an emission maximum of 792 nm.  IRDye800CW is 
a near infrared fluorescent imaging dye that can be easily bound to proteins through the NHS 
Ester group (Figure 3) and has emission and absorption wavelengths as described in Figure 4.  
Much of the information around IRDye800 remains proprietary, however, LiCor has filed a 

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master drug file with FDA (MF 25167) and produces the dye under cGMP conditions with 
appropriate documentation.  
IRDye800CW has not been formally tested in humans and is not FDA-approved.  
IRDye800CW has been assessed in rodents at 20 mg/kg without noticeable toxicity (81).  This 
dose is several hundred times the proposed dose in the current trial.  Although there are currently 
no publications available to demonstrate use of bioconjugated IRDye800, bevacizumab (Avastin) 
conjugated 
to 
IRDye800 
is 
currently 
under 
investigation 
in 
Europe 
(http://clinicaltrials.gov/ct2/show/NCT01508572), but has not been tested in the US in any form 
that we are aware of, and is not approved for any indication.  There have been no AEs associated 
with the administration of the bevacizumab-IDye800 (personal communication with 
Principal Investigator Dr van Dam).  
 
Figure 3.  IRDye800CW NHS-ester.  Molecular formula and molecular characteristics 

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Figure 4.  Absorption and emission spectra of IRDye800.  Peak absorbance occurs at 773 nm and the 
peak emission is detected at 792 nm. 
Panitumumab-IRDye800 
Panitumumab-IRDye800 is produced by mixing panitumumab and IRDye800 in PBS at pH 8.5 
and allowing the reaction to proceed at 20 to 25ºC.  The conjugation reaction is followed by a 
buffer exchange into pH 7.4 PBS.  The desired stoichiometry for the product is approximately 
1.5 dye molecules per antibody molecule.  
Panitumumab-IRDye800 was manufactured from commercially-sourced panitumumab and 
cGMP IRDye® 800CW N-hydroxysuccinimide (NHS) ester infrared dye (LI-COR Biosciences) 
at the GMP biologics facility at LI-COR Biosciences Inc.  Formal testing of 
panitumumab-IRDye800 for stability, sterility and antigen specificity is contained within the 
IND 119474 CMC section according to an FDA approved process.  The manufacturing and 
quality processes are documented elsewhere. 
5.1.2.  Lymphoseek 
Lymphoseek is an FDA approved agent for lymphatic mapping and guiding SNB 
procedures.  The details we’ve listed below are copied from the package insert of Lymphoseek.  
The active ingredient in Lymphoseek, a radiodiagnostic agent, is 99mTc-tilmanocept (Figure 5).  

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Chemically, 
99mTc-tilmanocept 
consists 
of 
Technetium-99m, 
dextran 
3-[(2-aminoethyl)thio]propyl 17-carboxy-10,13,16- tris(carboxymethyl)-8-oxo-4-thia-7,10,13,16 
tetraazaheptadec-1-yl 3-[[2-[[1-imino-2-(D mannopyranosylthio)ethyl]amino]ethyl]thio]propyl 
ether complexes.  
The 
molecular 
formula 
of 
99mTc-tilmanocept 
is 
[C6H10O5]n.(C19H28N4O9S99mTc)b.(C13H24N2O5S2)c.(C5H11NS)a.  It contains 3-8 conjugated 
DTPA (diethylenetriaminepentaacetic acid) molecules (b); 12-20 conjugated mannose molecules 
(c) with 0-17 amine side chains (a) remaining free.  
The calculated average molecular weight of tilmanocept ranges from 15,281 to 23,454 g/mol.  
Mechanism of action:  Lymphoseek is a macromolecule consisting of multiple units of DTPA 
and mannose, each covalently attached to a 10kDa dextran backbone.  The mannose acts as a 
ligand for the mannose binding receptor (CD206), DTPA serves as the chelating agent for 
labeling with Technetium-99m.  
Lymphoseek accumulates in lymphatic tissue and selectively binds to the mannose binding 
receptor located on the surface of macrophages and dendritic cells residing in the lymphatic 
tissue. 
Pharmacodynamics:  In in vitro studies, 99mTc-tilmanocept exhibited binding to human 
mannose binding receptors with a primary binding site affinity of Kd = 2.76 x 10-11 M. 
In clinical studies, 99mTc-tilmanocept has been detectable in LNs within 10 minutes and up to 30 
hours after injection. 
Pharmacokinetics:  In dose-ranging clinical studies, injection site clearance rates were similar 
across all Lymphoseek doses (4 to 200 mcg) with a mean elimination rate constant in the range 
of 0.222 to 0.396/hr, resulting in a drug half-life at the injection site of 1.8 to 3.1 hours. 
The amount of the accumulated radioactive dose in the liver, kidney, and bladder reached a 
maximum 1 hour post administration of Lymphoseek and was approximately 1% to 2% of the 
injected dose in each tissue.  

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Figure 
5: 
 
Chemical 
structure 
of 
Lymphoseek 
before 
(upper 
panel) 
and  
after (lower panel) labeling with Technetium-99m. 
5.2 
Expected Toxicities 
5.2.1 
Panitumumab – panitumumab-IRDye800 
With the exception of infusion reactions and allergic responses, the toxicities associated with 
panitumumab-based therapy are usually dose dependent and associated with prolonged therapy.  
Because panitumumab will be delivered at sub-therapeutic doses and will only be administered 
once, we anticipate the primary adverse events will be related to dose independent reactions 
including infusion reaction or allergic response.  
In our current head and neck study using panitumumab-IRDye800, among the 55 subjects we 
have treated, we have only observed one possibly related grade 1 adverse event (elevated QTc) 
and no infusion reactions or DLTs. 
5.2.1.1 Dermatologic and Soft Tissue Toxicity (Black Box Warning) 
In one study, dermatologic toxicities occurred in 90% of subjects and were severe (NCI CTC 
Grade 3 and higher) in 16% of subjects (package insert).  The clinical manifestations included, 

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but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, 
paronychia, dry skin, and skin fissures.  Subjects who develop dermatologic or soft tissue 
toxicities should be monitored for the development of inflammatory or infectious sequelae.  Life 
threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and 
sepsis have been observed in subjects treated with panitumumab.  Panitumumab should be 
withheld or discontinued for toxicities associated with severe or life-threatening inflammatory or 
infectious complications. 
5.2.1.2 Infusion reaction 
Because the study proposes to administer a single sub-therapeutic dose, the most likely adverse 
event we anticipate is an infusion reaction.  Minor (Grade 1) infusion reactions from 
panitumumab occur at a frequency of approximately 4%, with severe reactions (anaphylaxis) 
reported in 1% of subjects (package insert).  Serious infusion reactions—requiring medical 
intervention and immediate, permanent discontinuation of panitumumab—include rapid onset of 
airway obstruction (bronchospasm, stridor, and hoarseness), hypotension, shock, loss of 
consciousness, myocardial infarction, and/or cardiac arrest.  
5.2.1.3 Cardiac Toxicity 
Preclinical studies performed at UAB (2013) identified a small, but statistically significant 
increase in QT-intervals using cetuximab.  These studies in non-human primates after 
administration of cetuximab-IRDye800 identified an increase in the QTc interval for cetuximab 
alone compared to cetuximab-IRDye800.  There was also a statistically significant difference 
between the QTc interval between the cetuximab and cetuximab-IRDye800 that will require 
assessment of interval ECG and exclusion criteria of subjects at risk for arrhythmias, see 
exclusion criteria.  Screening ECG will be obtained as part of the study.  We reference the full 
toxicology report for cetuximab-IRDye800 (IND 115706) recently submitted to the FDA. 
5.2.1.4 Pulmonary Fibrosis/Interstitial Lung Disease (ILD) 
Pulmonary fibrosis occurred in less than 1% of subjects in clinical studies using panitumumab.  
Subjects with a history or evidence of interstitial pneumonitis, pulmonary fibrosis, were excluded 
from most clinical trials (package insert).  The estimated risk in a general population is therefore 
unknown.  Cases of ILD, including fatalities, have been reported in subjects treated with 
Panitumumab.  Interrupt therapy for the acute onset or worsening of pulmonary symptoms. 
5.2.1.5 Hypomagnesemia and Electrolyte Abnormalities 
In one study, hypomagnesemia (NCI-CTC Grade 3 or 4) requiring oral or intravenous electrolyte 
repletion occurred in 2% of subjects.  Hypomagnesemia occurred 6 weeks or longer after the 
initiation of panitumumab (package insert).  Both hypomagnesemia and hypocalcemia occurred 
in some subjects.  Electrolytes should be monitored periodically during treatment and for 
8 weeks after the completion of therapy when used as anti-cancer treatment.  For this study, 
electrolytes will be monitored for 30 days after administration of panitumumab-IRDye800.  
Replete electrolytes as necessary using standard infusion guidelines. 
5.2.1.6 Photosensitivity  
Exposure to sunlight can exacerbate dermatologic toxicity (package insert).  Advise subjects to 
wear sunscreen and hats and limit sun exposure while receiving panitumumab. 

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5.2.1.7 Ocular Toxicities 
Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported 
with the use of panitumumab (package insert).  Monitor for evidence of keratitis or ulcerative 
keratitis.  Interrupt or discontinue therapy for acute or worsening keratitis.  
5.2.1.8 Other Toxicities 
It is also possible that other panitumumab related toxicities will appear (fatigue or diarrhea), but 
because the proposed dose is a fraction of the therapeutic dose and is administered only once, 
these are likely not to be the dose limiting toxicities in this clinical trial.  We do not expect 
significant toxicities from IRDye800 because rodent toxicology studies have not demonstrated 
toxicity (81), and it has similar chemical structure as indocyanine green (which has been 
delivered to humans in gram quantities for decades without significant toxicity).  
5.2.2 
Lymphoseek (99mTc-Tilmanocept) 
Below we provide a summary of the toxicity results that are mentioned in the Lymphoseek 
package insert.  There are no contra-indications for Lymphoseek.  In clinical trials and 
subsequent to FDA approval in March 2013, there have been no reported hypersensitivity 
reactions or serious adverse events. 
5.2.2.1.  Adverse Reactions 
None of the 553 subjects studied with either breast cancer, melanoma or SCC of the oral cavity, 
lip or skin that received Lymphoseek experienced serious adverse reactions.  Injection site 
irritations [0.7% (4 subjects)] and pain [0.2% (1 subject)] were reported (28–30,32–34).  
5.2.2.2.  Precautions 
Hypersensitivity reactions:  Lymphoseek might pose a risk of hypersensitivity reactions due to 
its chemical similarity to dextran.  Serious hypersensitivity reactions have been associated with 
dextran and modified forms of dextran (such as iron dextran drugs). 
Prior to administration of Lymphoseek, subjects should be asked about previous hypersensitivity 
reactions to drugs, in particular dextran and modified forms thereof.  Resuscitation equipment 
and trained personnel should be available at the time of Lymphoseek administration, and subjects 
observed for signs or symptoms of hypersensitivity following injection.  
5.3 
Availability 
Panitumumab-IRDye800 is being manufactured at the GMP biologics facility at the 
Frederick National Laboratory by the NCI NExT Program using cGMP IRDye800CW and 
commercially-available panitumumab.  Formal testing of the panitumumab-IRDye800 for 
stability, sterility and antigen specificity is contained within the IND CMC section according to a 
FDA-approved process.  The manufacturing and quality processes are documented elsewhere. 
Lymphoseek kits are commercially available through Navidea Biopharmaceutical, Inc.  
5.4 
Agent Ordering 
Frederick National Laboratory by the NCI NExT Program will ship panitumumab-IRDye800 as 
an investigational agent, to be stored at the investigational pharmacy under a material transfer 
agreement.  The investigational pharmacy will be responsible for storage and dispensing of the 

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drug following a standard institutional process after the subject is screened and enrolled in the 
study.  
Lymphoseek is supplied as a unit dose from Cardinal Health.  
5.5 
Agent Accountability 
The Protocol Director (PD) will be responsible for the accounting of panitumumab-IRDye800.  
The documentation of lot numbers, dose and administration records and storage of drug will be 
the responsibility of the PD as well, and are described in detail in the CMC documentation.  The 
PD will be responsible for ensuring study drug is correctly labeled and the appropriate dose 
provided per the protocol.  
6. 
DOSE MODIFICATIONS 
There are no dose modifications allowed in this study. 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Adverse Event (AE) 
An adverse event (AE) is any event that is presents during the trial that was not observed at 
baseline or has worsened from baseline. 
7.2 
Serious Adverse Event 
A SAE is defined (21CFR312.32) as any adverse experience that suggests a significant hazard, 
contraindication, side effect, or untoward medical occurrence that: 
 Results in death, 
 Is life-threatening (Note:  the term “life-threatening” refers to an event in which the 
subject was at risk of death at the time of the event rather than to an event which 
hypothetically might have caused death if it were more severe), 
 Requires (or prolongs) hospitalization, 
 Causes persistent or significant disability/incapacity, 
 Results in congenital anomalies or birth defects, or 
 Other conditions which in the judgment of the Investigator represent significant hazards 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject, or may 
require intervention to prevent one of the other outcomes listed in the above definition.  These 
should be considered serious. 
Any pregnancy which occurs during this clinical trial must be reported to the PD up to 30 days 
after the study infusion and treated as a SAE with regard to the reporting time frame to Sponsor.  
Any pregnancy must be followed until conclusion of the pregnancy (delivery or termination).  
Administration of study drug will be discontinued in a subject who becomes pregnant.  If a male 
subject reports a pregnancy of his spouse or significant other, data regarding the outcome of this 
pregnancy will be collected after obtaining informed consent of the pregnant individual. 

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7.3 
Assessment of Causality 
For any AE that occurs during this study, it will be the responsibility of the Investigator to assess 
the relationship of the event to study treatment.  
For this clinical trial, the following criteria will be used: 
 Unrelated:  There is no temporal relationship between the event and the administration 
of the study drug, and/or the event is clearly due to the subject’s medical condition, other 
therapies, or accident. 
 Possibly Related:  There is some temporal relationship between the event and the 
administration of the study drug and the event is unlikely to be explained by the 
participant’s medical condition or other therapies. 
 Probably Related:  The temporal relationship between the event and the administration 
of the study drug is compelling, and the participant’s medical condition or other therapies 
cannot explain the event. 
 Definitely Related:  The temporal relationship between the event and the administration 
of the study drug is compelling, the participant’s medical condition or other therapies 
cannot explain the event and the event follows a known or suspected response pattern to 
the medication. 
7.4 
Severity of Adverse Events 
AEs will be graded per NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0) 
(http://evs.nci.nih.gov/ftp1/CTCAE/about.html). 
 Mild (Grade 1) 
 Moderate (Grade 2) 
 Severe (Grade 3) 
 Immediately life-threatening/Fatal (Grade 4 and 5) 
7.5 
Safety Monitoring and Reporting 
7.5.1.  Monitoring and Recording of Adverse Events 
Both serious and non-serious AEs will be clearly noted in source documentation and listed on 
study-specific Case Report Forms (CRFs).  The PD or designee will assess each AE to determine 
whether it is unexpected according to the Informed Consent, Protocol Document, or 
Investigator’s Brochure, and related to the investigation.  
All adverse events (AEs), regardless of seriousness or relationship to study drug, are to be 
collected only on designated study dates from signing of informed consent through 30 days after 
administration of study drug, and recorded in the study-specific worksheets, with the following 
exceptions: 
 AEs that are solely laboratory values; are not related to the study drug; AND are 
clinically non-significant may not be collected.  

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 Non-serious AEs that occur within 30 (+/-7) days after surgical resection of the tumor; 
are not related to the study drug; are not clinically significant; AND are expected in the 
post-surgery clinical setting may not be collected. 
 SAEs that occur from signing of informed consent to prior to Day 1 may not be collected 
unless assessed as possibly, probably or definitely related to a study procedure. 
All patients enrolled in this study receive surgical intervention in the course of their standard of 
care.  As a consequence of this surgery, patients may experience certain expected and normal 
adverse events.  The following post-operative adverse events will be captured only in the 
patient’s Electronic Health Record (EHR) source documentation and not in the adverse event 
log.  If the adverse event exceeds the grading listed below or occurs outside the post-operative 
time window, the adverse event will be recorded in the Adverse Event Logs. 
 Surgical wound site and associated, expected secondary signs and symptoms, 
including: 
o CTCAE v5.0 Grade 1 erythema, edema, and pruritis. 
o CTCAE v5.0 Grade 1 pain associated with surgical wound, including 
headaches – mild pain, little to no limit on adult daily life. 
o CTCAE v5.0 Grade 1 nausea, vomiting, and dysphagia. 
o CTCAE v5.0 Grade 1 weight loss, anemia, and electrolyte abnormalities. 
o CTCAE v.5.0 Grade 2 trismus. 
 
Whenever possible, symptoms should be grouped as single syndrome or diagnosis.  The 
Investigator should specify the date of onset, maximal intensity, corrective therapy given, 
outcome, and his/her assessment of causality. 
Any AE that is not resolved by the end of the study and considered to be potentially related to 
study drug, or was the cause for the subject’s withdrawal will be followed as clinically indicated 
until its resolution, or if non-resolving, until considered stable.  All SAEs will be tracked until 
resolution, or until 30 days after the last dose of the study treatment. 
7.5.2. 
 Reporting Adverse Events and Serious Adverse Events 
Non-serious adverse events will be reported annually to FDA via an Annual Report 
(IND 119474) and to IRB via Continuing Review. 
The PD (aka Principle Investigator) must immediately report within 24 hours of knowledge of 
event to the Sponsor (ie, IND Holder, Eben Rosenthal, MD), any serious adverse event, whether 
or not considered related to study drug.  SAEs of all grades will be reported to the Sponsor using 
the Stanford Cancer Institute SAE CRF.  The investigator must provide a detailed description of 
the event, the treatment regimen, relevant laboratory and evaluations and assessment of the 
relationship of the AE to the study drug.  All relevant information should be reported as it 
becomes available. 
SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the 
Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study 
specific CRF regardless of the event’s relatedness to the investigation.  Following review by the 
DSMC, events meeting the IRB definition of an “Unanticipated Problem” (UP) will be reported 

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to the IRB using eProtocol within 10 working days of DSMC review, or within 5 working days 
for deaths or life-threatening experiences. 
Adverse events deemed serious, unexpected (ie, not described in the protocol, Investigator’s 
Brochure or informed consent documents) and related to study drug must be reported to Sponsor  
using the FDA MedWatch form 3500a within 24 hours of knowledge of event.  The Sponsor is 
responsible for deciding whether the event meets IND Safety Reporting criteria. 
Events will be submitted to Sponsor Dr. Eben Rosenthal, at: 
Eben 
Rosenthal, 
M.D 
Professor 
of 
Otolaryngology-Head 
and 
Neck 
Surgery 
& 
Radiology 
875 
Campus 
Dr  
Room: 
 
CC-2213, 
M/C 
5739 
Stanford, 
CA 
94305 
650-723-2967 
It will be the responsibility of the Sponsor to provide to the FDA all information concerning 
significant hazards, contraindications, side effects or precautions felt significant to the safety of 
the drug being studied.  The PD is responsible for accurate and timely communication to the 
Sponsor of any events reportable to FDA.  Subjects will be instructed prior to participation on 
the importance of reporting any symptoms (new or worsening), and/or any physical changes 
throughout their participation in the study.  These events will be recorded accordingly in the 
CRF.  Abnormal laboratory and/or clinical assessments will also be captured in the appropriate 
CRF. 
8. 
CORRELATIVE/SPECIAL STUDIES  
Confirm our phase 1 study in HNSCC (IRB-35064), we will continue collecting 
pharmacokinetics data, hence the blood draws.  We will also continue collecting imaging data on 
the primary tumor.  This data will be used for:  1) drug delivery studies to gain better insight in 
the panitumumab-IRdye800 distribution in the tumor (including, but not limited to, 
photoacoustic imaging);  and 2) to further study if the drug can be used to define (intraoperative) 
margins.  Furthermore preoperative standard of care imaging obtained during routine evaluation 
will be used to correlate with pathological findings.  

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9. 
STUDY CALENDAR 
9.1  
Study Procedures Table 
Enrolled subjects will follow schedule of evaluations provided below: 
 
Screening/ 
Pre-treatment 
(≤ 30 days before 
treatment) 
Day 0 
Day 
0 to 4 
Day 
of 
Surgery 
(Day 1 to 5) 
Day of 
discharge12 
Day 15 
(±4 days12) 
Day 30 
(±4 days) 
Informed Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Examination 1 
X 
X 
 
 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
 
Height and weight 
X 
X 
 
 
 
 
 
Performance Status 1 
X 
 
 
 
X 
X 
 
ECG 
X 2 
 
 
 
 
 
 
Chemistries 3 
X 
X 
 
X 
 
X 
 
Hematology 4 
X 
 
 
 
 
X 
 
Serum pregnancy 11 
X 
X 11 
 
 
 
 
 
PK - fluorescent-labeled 
antibody 5 
 
X 
X 5 
X 
X 
X 
 
PK – Immunogenicity 6 
 
X 
 
 
 
X 
 
IV infusion of 
Panitumumab-IRdye800 7  
X 
 
 
 
 
 
 
Local administration of 
Lymphoseek 13 
 
 
X 
 
 
 
 
Sentinel node mapping 
(lymphoscintigraphy + 
SPECT/CT imaging) 13 
 
 
X 
 
 
 
 
Surgical Resection 
 
 
 
X 8 
 
 
 
Tumor imaging 
 
 
 
X 9 
 
 
 
Pathological evaluations 10 
 
 
 
X 
 
 
 
Adverse events 15 
 
X 
X 
X 
 
X 
X 
Concurrent medications 14 
X 
X 
X 
X 
 
X 
X 
1. 
A physical examination and performance status assessment will be done at screening; Day 0; Day of discharge; and Day 15.  
Examinations collected for surgical procedure are acceptable for screening purposes.  Examinations do not have to be repeated on 
Day 0 if completed within 21 days of infusion. 
2. 
ECG will be obtained at screening to evaluate baseline.  A previous ECG that was obtained as part of standard of care may be used 
as the screening ECG as long as it was obtained within 21 days of infusion. 
3. 
Chemistries to include a standard basic metabolic profile with magnesium and phosphorus.  Chemistries and other blood work 
collected for surgical procedure are acceptable for screening purposes.  Chemistries do not have to be repeated on Day 0 if 
completed within 21 days of infusion.  On Day of Surgery and Day 15 only magnesium and phosphorus are collected. 
4. 
Hematology (ie, CBC W/O DIFF) values include WBC; RBC; Hgb; hematocrit and platelet counts.  Blood work collected for 
surgical procedure are acceptable for screening purposes.  

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5. 
Serum level of panitumumab-IRDye800 will be drawn on Day 0 prior to dose and 30 (± 10) minutes after the end of infusion, on 
Day 1 if applicable, day of surgery, up to once a day on Days 1, 2, and 3 post-operative as available, Day of discharge, and Day 15 
to assess circulating fluorescent-labeled antibody and unconjugated dye.  
6. 
Blood will be obtained pre-infusion and 15 days after infusion and banked for future immunogenicity testing.  Immunogenicity 
testing time points will not vary with dose.  
7. 
Infusion of study drug to be given over 15 (± 5) minutes followed by a 30 (± 10) minute observation period. 
8. 
Surgical excision occurs 1 to 5 days after the panitumumab-IRDye800 infusion based on subject availability/scheduling.  
9. 
Tumors will be imaged intraoperatively using the devices listed in Appendix B to determine threshold of detection. 
10. All resected tissues will be evaluated for near-infrared fluorescence (NIR) fluorescence prior to and after pathological 
examination. 
11. Serum pregnancy test will be obtained on all women of childbearing age at screening; a urine pregnancy test will be performed on 
Day 0 if the result of a serum pregnancy test within 72 hours before administration of panitumumab-IRDye800 is not available. 
12. Blood will also be obtained as needed to evaluate any abnormal lab values experienced after study drug infusion.  Blood will not 
be taken at Day of Discharge if it is within the window of their Day 15 visit.  
13. Lymphoseek will be administered locally on the day before surgery.  Directly after injection, lymphoscintigraphy will be 
performed to identify the drainage pattern of the tracer and to identify hot spots (ie, sentinel nodes).  SPECT/CT imaging will be 
performed to determine the anatomical location of the hot spots.  
14. Concurrent medications will be reported at screening, Day 0 and Day 15, and in-between if any medication is given to treat 
adverse events or serious adverse events that in the assessment of the PI are possibly, probably or definitely related to a study 
procedure.  
15. See Section 7.5.1 for adverse events monitoring and reporting. 
9.2  
Study Procedures  
The following evaluations and procedures will be performed: 
9.2.1 Screening/Pre-Treatment (Within 30 days of treatment start) 
 Obtain written informed consent 
 Medical history including current medications 
 Physical examination 
 Performance Status 
 ECG 
 Vital signs (blood pressure, heart rate, respiratory rate, temperature) 
 Height and weight 
 Chemistries (standard basic metabolic profile with magnesium and phosphorus) 
 CBC and platelets 
 Serum pregnancy test for women of childbearing potential  
 Assessment for concomitant medications 
 Collect data from any standard-of-care information, including, but not limited to 
MRI, and PET/CT, performed prior to surgery 
9.2.2 Day 0 
 Prior to Infusion of panitumumab-IRDye800 
o Physical Examination (within 21 days) 
o Performance Status (within21 days) 

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o Vital signs (blood pressure, heart rate, respiratory rate, temperature) 
o Chemistries (standard basic metabolic profile with magnesium and phosphorus, 
within 21 days) 
(may skip if previous assessment within 14 days) 
o Pregnancy test for women of childbearing potential - a urine pregnancy test will 
be performed on Day 0 if the result of a serum pregnancy test within 72 hours 
before administration of panitumumab-IRDye800 is not available 
o Blood sample for panitumumab-IRDye800 antibody pharmacokinetics 
o Blood sample for future assessment of immunogenicity  
 IV infusion of panitumumab-IRDye800 over 15 (± 5) minutes  
o Vital signs immediately following panitumumab-IRDye800 infusion (+ 5 mins) 
(blood pressure;  heart rate;  respiratory rate;  temperature) 
 Observation for 30 (± 10) minutes 
 At the end of the observation period (ie, 30 (± 10) minutes after the end of 
panitumumab-IRDye800 infusion) 
o Vital signs (blood pressure, heart rate, respiratory rate, temperature) 
o Blood sample for panitumamab-IRDye800 antibody pharmacokinetics 
o 
Assessment for concomitant medications 
o 
Assessment for adverse events 
9.2.3 Day 0 to -4 (Day before Surgery) – for Cohort 1 only 
 Vital signs (blood pressure, heart rate, respiratory rate, temperature) 
 Blood sample for panitumumab-IRDye800 antibody pharmacokinetics 
 Local Lymphoseek injection  
 Preoperative LN mapping using lymphoscintigraphy and SPECT/CT imaging  
 Assessment for adverse events 
 Assessment for concomitant medications 
9.2.4   Day 1 to 5 (Day of Surgery) 
 Vital signs prior to surgery (blood pressure, heart rate, respiratory rate, temperature) 
 Serum magnesium and phosphorus  
 Blood sample for panitumumab-IRDye800 antibody pharmacokinetics 
 Scheduled routine surgical resection based on standard-of-care histopathology 
 Intraoperative imaging (fluorescence signal detection) 
 Intraoperative gamma tracing (radioactive signal detection) (Cohort 1 only) 

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 Pathological evaluations – tissue assessments of the pathological tissues by optical 
scanning after clinical assessment by pathologist but prior to permanent fixation of 
the tissue  
 Assessment for adverse events 
 Assessment for concomitant medication 
9.2.5   Day of Discharge  
 Physical examination  
 Vital signs  
 Performance Status 
 Blood sample for panitumumab-IRDye800 antibody pharmacokinetics 
 Assessment for adverse events 
 Assessment for concomitant medications 
9.2.6    Day 15 (± 4 days) 
 Physical examination  
 Vital signs (blood pressure, heart rate, respiratory rate, temperature) 
 Performance Status  
 Serum magnesium and phosphorus; any other blood tests as needed to assess for any 
ongoing abnormalities, per PIs discretion 
 CBC and platelets 
 Blood sample for future assessment of immunogenicity 
 Blood sample for panitumumab-IRDye800 antibody pharmacokinetics 
 Assessment for adverse events 
 Assessment for concomitant medications 
9.2.7 Day 30 (± 4 days) 
 Investigator or study staff will contact the subject by telephone or review of 
electronic medical record data to collect any additional adverse events that are 
attributable to the study and/or concomitant medications. 

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9.3  
Description of Evaluations / Procedures  
9.3.1 Laboratory Evaluations:  Blood specimens will be collected for CBC; platelets; 
basic metabolic profile; magnesium and phosphorus; and serum pregnancy if 
necessary.  Blood will be taken for fluorescent-labeled antibody pharmacokinetics 
and blood will be obtained and banked for future analysis of immunogenicity 
against the study drug as requested by the FDA in pre-IND conversations.  
9.3.2 Physical Examinations:  A physical examination will be conducted to include 
review of all major systems prior to enrollment to study.  Standard head and neck 
examination and system-oriented physical examination will be conducted on other 
visits. 
9.3.3 Medical History:  A complete medical history including age; sex; race; current 
medications; any current or previous medical conditions; any previous surgeries; 
smoking history; alcohol use will be done at screening. 
9.3.4 Vital Signs:  Vital signs including blood pressure; heart rate; respiratory rate; and 
temperature will be collected at each clinic visit.  Height and weight will be 
collected at screening. 
9.3.5 Cardiac Monitoring:  An ECG will be obtained during the screening period.  
A previous ECG that was obtained as part of standard of care may be used as the 
baseline ECG if obtained within 21 days prior to of infusion.  QT/QTc interval will 
be assessed at screening.  
10. 
MEASUREMENTS 
10.1  Primary Outcome Measure 
The primary objective of the study is to determine if near-infrared fluorescence imaging of 
panitumumab-IRDye800 can identify metastatic disease in regional neck LNs of subjects with 
HNSCC. 
The primary endpoint is:  The number and location of panitumumab-IRDye800 positive LNs 
that are also tumor-positive at (histo-)pathology. 
10.2  Secondary Outcome Measure 
The secondary objective of the study is to determine if panitumumab-IRDye800 can identify 
LNs with the same accuracy as Lymphoseek.  
The secondary endpoint is:  The number and location of Lymphoseek positive LNs that are also 
tumor-positive at (histo-)pathology.  Comparison of the number and location of Lymphoseek 
positive LNs that are also tumor-positive at (histo-)pathology vs the number and location of 
panitumumab-IRDye800 positive LNs that are also tumor-positive at (histo-)pathology. 
11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (eg, advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes 

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made to the protocol will be submitted as a modification and will be approved by the IRB prior 
to implementation.  The PD will disseminate the protocol amendment information to all 
participating investigators. 
The protocol and any significant amendments will be submitted to FDA.  The PD is responsible 
for informing the Sponsor of protocol amendments. 
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study.  The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  This may include annual 
review of the following types of documents participating in the study:  regulatory binders, case 
report forms, eligibility checklists, and source documents.  In addition, the DSMC will regularly 
(monthly) review any DLTs, serious adverse events, and protocol deviations associated with the 
research to ensure the protection of human subjects.  Results of the DSMC audit will be 
communicated to the IRB and the appropriate regulatory authorities at the time of continuing 
review, or in an expedited fashion, as needed. 
11.3 
Data Management Plan 
The PD, or designees noted in the Delegation of Authority Log, will maintain adequate and 
accurate participant case histories with observations and other data pertinent to the study.  
Original source documents will be transcribed to Case Report Forms (CRFs).  Source documents 
include hospital records, clinical charts, laboratory and pharmacy records, and recorded 
electronic data.  Case report forms will be developed using the OnCore database system and 
maintained by the study team.  CRFs will be kept in a locked office, only accessible to the 
research team.   
12. 
STATISTICAL CONSIDERATIONS 
12.1 
Statistical Design 
12.1.1.  Primary Objective and Endpoint 
The primary objective of the study is to determine if near-infrared fluorescence imaging of 
panitumumab-IRDye800 can identify metastatic disease in regional neck LNs of subjects with 
HNSCC. 
The primary endpoint is:  The number and location of panitumumab-IRDye800 positive LNs 
that are also tumor-positive at (histo-)pathology. 
To answer the primary objective, we will calculate the sensitivity and specificity of the 
intraoperative 
findings 
on 
whether 
the 
LN 
is 
fluorescent 
(ie, presence 
of 
panitumumab-IRDye800) to the histopathological (gold standard) status of the LNs.  
We will use the matched pair Durkalski’s test (80), accounting for the cluster-correlation within 
subject, for all sensitivity and specificity comparisons (primary and secondary) using the 
clust.bin.pair package (81) in the R statistical software (84).  Significance for both primary and 
secondary analyses will be assessed at the 0.05 level and to assess uncertainty, 95% confidence 
intervals will be provided for all estimates.  

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Descriptive statistics for continuous characteristics (eg, size of the tumor compartment) will 
include mean, standard deviation, median, interquartile range, minimum, and maximum values.  
Frequencies and percentages will be used to summarize categorical data.  Graphical tools such as 
heat maps, histograms, and boxplots will be used to assess distributional properties of continuous 
variables. 
12.1.2.  Secondary Objective and Endpoint 
The secondary objective of the study is to determine if panitumumab-IRDye800 can identify 
LNs with the same efficiency as Lymphoseek.  
The secondary endpoint is:  The number and location of Lymphoseek positive LNs that are also 
tumor-positive at (histo-)pathology. 
To answer the secondary objective:  We will determine if the LN tracer Lymphoseek can 
identify metastatic disease in regional neck LNs of subjects with HNSCC.  Similar to the primary 
analysis, we will calculate the specificity and sensitivity of Lymphoseek for metastatic LN 
identification, using histology as the gold standard, and compare these to neck dissection with 
Durkalski’s test.  Since false negatives are of particular concern, we will calculate the odds of 
obtaining a false negative using panitumumab-IRDye800 relative to the odds of obtaining a false 
negative using Lymphoseek-based SNB. 
12.1.3.  Sample Size Justification and Power Considerations  
We expect to enroll 10 T1/T2 node-negative subjects and 10 subjects with T1-4 and LN 
metastasis.  Based on the data on LN collection from our current IRB-35064 study, we expect 
that 50% of subjects will undergo a bilateral neck dissection, meaning we would have a total of 
30 necks.  Assuming an average of 20 LN harvested per neck we would have a total of 600 LNs.  
Based on previous findings from our IRB-35064 study, we expect approximately 30-40% of 
subjects (6 to 8 of 20) will have metastatic LNs with an overall prevalence of 5 to 10% of the 
total number of harvested LNs (30 to 60 of 600) being tumor-positive. 
Since this is a Phase 2 study, power considerations are limited but even so, we have excellent 
power to detect differences in specificity.  Although we will use Durkalski’s test to compare 
sensitivities and specificities, we estimated power by first determining the effective sample size 
(ESS), adjusting for the correlation of LNs within person, and then estimated power using 
McNemar’s test on this ESS.  We assumed an intra-class correlation of 0.005, yielding an 
effective sample size of 524 LNs.  With and effective sample size of 524, a prevalence of 7.5%, a 
significance level of 0.05, and a 0.25 proportion of discordant pairs, we have greater than 99% 
power to detect a 0.1 difference in specificities, assuming the lower specificity is 0.8.  Similarly, 
we have greater than 78% power to detect a 0.2 difference in sensitivity with the one-sided 
McNemar test.  This assumes the proportion of discordant pairs is 0.25 and the lower sensitivity 
is 0.75. 
13. 
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APPENDIX A:  Participant Eligibility Checklist  
A Participant Eligibility Checklist will be completed in its entirety for each subject prior to 
registration.  The completed, signed, and dated checklist will be retained in the subject’s study 
file and the study’s Regulatory Binder.  
The study coordinator, treating physician and an independent reviewer will verify that the 
participant’s eligibility is accurate, complete, and legible in source records.  A description of the 
eligibility verification process should be included in the EPIC or other Electronic Medical 
Record progress note.  
Protocol Title: 
A Phase 2 Study Evaluating Panitumumab-IRDye800 vs. Sentinel Node Biopsy 
and (Selective) Neck Dissection for Metastatic Lymph Node Identification in 
Patients with Head and Neck Cancer 
Protocol Number: 
IRB-43013 
Principal Investigator: Fred Baik, MD 
I.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
II.  Study Information: 
SRC-approved 
 IRB-approved 
 Contract signed 
 
III.  Inclusion/Exclusion Criteria 
Inclusion Criteria 
(From IRB-approved protocol) 
Yes No 
Supporting 
Documentation** 
1. Biopsy confirmed diagnosis of squamous cell carcinoma of 
the head and neck 
 
 
      
2. Subjects with recurrent disease or new primary will be 
allowed 
 
 
      
3. Planned standard of care surgery with curative intent for 
squamous cell carcinoma 
 
 
      
4. *SNB only cohort: Subjects diagnosed with a T1-T2 stage 
tumor, any subsite within the head and neck that is 
amenable to local sentinel node tracer injection and are 
scheduled to undergo surgical resection of the tumor, 
including a sentinel node biopsy  
 
 
      
5. *Neck dissection only cohort: Subjects diagnosed with any 
T stage, any subsite within the head and neck that are 
scheduled to undergo surgical resection, including a 
(modified) neck dissection 
 
 
      

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

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1 February 2021 
Appendix B – Imaging Devices Appendix 
Device name 
Manufacturer 
Commercially 
available? 
510(k) 
Non-significant 
risk? 
Serial No. of 
submission 
to 
 
Intraoperative near-infrared fluorescence imaging, in vivo 
Spy-Phi 
and/or 
PINPOINT– 
IR9000 
(Handheld/Endoscopic)  
Novadaq Inc. 
Yes (modified light 
source for our study) 
No 
Yes 
SN0008 
Explorer Air 
SurgVision 
Yes (modified light 
source for our study) 
No 
Yes 
SN0008 
PDE-NEO II and/or FIGS 
Hamamatsu Photonics K.K. 
Yes 
Yes 
Yes 
SN0012 
IMAGE1 + ICG Hopkins telescope and/or 
VITOM  
Karl Storz Endoscopes 
Yes 
Yes 
N.A. 
N.A. 
Vevo LAZR-X 
VisualSonics 
Yes (for preclinical 
imaging) 
No 
Yes 
In progress 
Firefly for da Vinci 
Intuitive Surgical Inc. 
Yes 
Yes 
N.A. 
N.A. 
 
Intraoperative near-infrared fluorescence imaging, ex vivo (back table) 
Spy-Phi 
and/or 
PINPOINT– 
IR9000 
(Handheld/Endoscopic)  
Novadaq Inc. 
Yes (modified light 
source for our study) 
No 
Yes 
SN0008 
Explorer Air 
SurgVision 
Yes (modified light 
source for our study) 
No 
Yes 
SN0008 
PDE-NEO II and/or FIGS 
Hamamatsu Photonics K.K. 
Yes 
Yes 
Yes 
SN0012 
IGP ELVIS v4 
LI-COR Biosciences 
No 
No 
Yes 
SN0012 
IMAGE1 + ICG Hopkins telescope and/or 
VITOM  
Karl Storz Endoscopes 
Yes 
Yes 
N.A. 
N.A. 
Vevo LAZR-X 
VisualSonics 
Yes (for preclinical 
imaging) 
No 
Yes 
In progress 
Firefly for da Vinci 
Intuitive Surgical Inc. 
Yes 
Yes 
N.A. 
N.A. 

IRB-43013 / ENT0065 
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Device name 
Manufacturer 
Commercially 
available? 
510(k) 
Non-significant 
risk? 
Serial No. of 
submission 
to 
 
 
Laboratory near-infrared fluorescence imaging, ex vivo 
Pearl Triology 
LI-COR Biosciences 
Yes 
N/A 
Odyssey CLx 
LI-COR Biosciences 
Yes 
IGP ELVIS v4 
LI-COR Biosciences 
No 
Leica fluorescence microscope 
Leica 
Yes 
Vevo LAZR-X 
VisualSonics 
Yes 
Dosimeter 
Pogue Laboratory 
No 
Stand-alone Firefly for da Vinci 
Intuitive Surgical Inc. 
Yes, on the robot