Conditions: Head and Neck Cancer Squamous Cell Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
This clinical trial is for participants with head and neck squamous cell carcinoma who are scheduled to have their tumor surgically removed. The study involves obtaining baseline tissue from a clinical biopsy or research biopsy and measurement of circulating tumor cells before surgery to determine whether AXL protein expression pre-treatment correlates to clinical outcomes (change in tumor size) after two doses of cetuximab. The importance of this study is to describe if AXL expression can be used as a biomarker to predict clinical response to cetuximab (CTX) treatment.

Detailed description:
This is a window of opportunity trial evaluating the hypothesis that AXL levels correlate with clinical response to cetuximab in head and neck patients. Patients with head and neck squamous cell carcinoma who are scheduled to undergo surgical resection of their tumor and are candidates for cetuximab chemotherapy are eligible to participate.

Primary:

1\. To test the hypothesis that low AXL correlates with clinical response to cetuximab in head and neck cancer patients

Secondary:

1\. To further describe the safety of pre-operative administration of cetuximab

Correlative:

1. To correlate AXL expression with change in Ki67 following cetuximab in Head and Neck Cancer (HNC) patients
2. To examine other putative markers of cetuximab sensitivity such as HER3 and change in circulating tumor cells
3. To establish the first panel of patient-derived xenografts from patients with known sensitivity or resistance to cetuximab

Following informed consent, tumor tissue from the research biopsy and a blood draw for circulating tumor cells will be obtained. The participant will then receive two weekly doses of pre-operative cetuximab during the interval between diagnostic biopsy and surgery (\~14 days), ensuring that no delay in standard of care (SOC) will occur.

For dose #1, participants will receive cetuximab 400 mg/m2 via intravenous infusion over 2 hours (maximum infusion rate 10 mg/min) as per the standard of care loading regimen for cetuximab monotherapy.

For dose #2, participants will receive cetuximab 250 mg/m2 via intravenous infusion over 1 hour (maximum infusion rate 10 mg/min) as per the standard of care dosing regimen for cetuximab monotherapy.

At the time of surgery, another blood draw will be obtained for analysis of circulating tumor cells, and a portion of the resected tumor will be obtained for study analysis.

Correlative studies will include the measurement of proteins hypothesized to be involved in cetuximab resistance such as AXL, Ki67, EGFR, and HER3 expression from both the biopsy and the surgical specimen. Blood will be analyzed for correlative analysis of circulating tumor cells. Tissue from the research biopsy will be utilized for participant-derived xenograft (PDX) development.

Arms:
arm 1: Two weekly doses of pre-operative cetuximab during the interval between diagnostic HNSCC biopsy and surgery (\~14 days), ensuring that no delay in standard of care (SOC) will occur. For dose #1, participants will receive cetuximab 400 mg/m2 via intravenous infusion over 2 hours (maximum infusion rate 10 mg/min) as per the standard of care loading regimen for cetuximab monotherapy. For dose #2, participants will receive cetuximab 250 mg/m2 via intravenous infusion over 1 hour (maximum infusion rate 10 mg/min) as per the standard of care dosing regimen for cetuximab monotherapy.

Interventions: intervention 1: Cetuximab
Intervention descriptions: intervention 1: Monoclonal antibody against epidermal growth factor receptor (EGFR)

Protocol document:
Prot_SAP_000.pdf: 
A Window of Opportunity Trial of Cetuximab in Patients with HNSCC 
Protocol UW18098 
6/26/2020 
 
 
 
 
A Window of Opportunity Trial of Cetuximab in 
Patients with Head and Neck Squamous Cell 
Carcinoma (HNSCC) 
NIDCR Protocol Numbers: 17-033-E; 17-034-E 
NIDCR Grant Number: P50 DE026787 
Principal Investigators: 
Justine Yang Bruce, MD 
Randall J. Kimple, MD, PhD 
NIDCR Program Official: Chiayeng Wang, PhD 
NIDCR Medical Monitor: Kevin McBryde, MD 
IND/IDE Sponsor: Not applicable 
 
 
 
 
 
 
 
 
 
 
NCT03769311 
 
 
 


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STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Conference on 
Harmonisation guidelines for Good Clinical Practice (ICH E6), the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46), and the NIDCR 
Clinical Terms of Award. All personnel involved in the conduct of this study have 
completed human subjects protection training. 


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SIGNATURE PAGE 
The signatures below constitute the approval of this protocol and the attachments, and 
provide the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
 
Principal Investigators or Clinical Site Investigators: Justine Yang Bruce, MD and 
Randall J. Kimple, MD, PhD 
 
 
Signed: 
Date: 
 
 
Name: Justine Yang Bruce, MD 
 
Title: Associate Professor, Department of Medicine, University of 
Wisconsin School of Medicine and Public Health 
 
 
 
 
 
Signed: 
Date: 
 
 
Name: Randall J. Kimple, MD, PhD 
 
Title: Associate Professor, Department of Human Oncology, University of 
Wisconsin School of Medicine and Public Health 


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TABLE OF CONTENTS  
 
PAGE 
STATEMENT OF COMPLIANCE ............................................................................................................. 2 
SIGNATURE PAGE ................................................................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................................. 4 
LIST OF ABBREVIATIONS ....................................................................................................................... 7 
PROTOCOL SUMMARY ......................................................................................................................... 10 
1 
KEY ROLES AND CONTACT INFORMATION .......................................................................... 13 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ......... 17 
2.1 
Rationale ............................................................................................................................. 22 
2.2 
Potential Risks and Benefits ............................................................................................. 23 
2.2.1 Potential Risks ....................................................................................................... 23 
2.2.2 Potential Benefits .................................................................................................. 24 
3 
OBJECTIVES .................................................................................................................................. 24 
3.1 
Study Objectives ................................................................................................................ 24 
3.2 
Study Outcome Measures ................................................................................................ 24 
3.2.1 Primary Endpoint .................................................................................................. 24 
3.2.2 Secondary Endpoint ............................................................................................. 25 
3.2.3 Exploratory Endpoints .......................................................................................... 25 
4 
STUDY DESIGN ............................................................................................................................. 25 
4.1 
Substudies (if applicable) .................................................................................................. 27 
5 
STUDY ENROLLMENT AND WITHDRAWAL ............................................................................ 27 
5.1 
Subject Inclusion Criteria .................................................................................................. 28 
5.2 
Subject Exclusion Criteria ................................................................................................. 29 
5.3 
Strategies for Recruitment and Retention ...................................................................... 30 
5.3.1 Subject Remuneration ....................................................................................................... 30 
5.4 
Treatment Assignment Procedures ................................................................................. 31 
5.5 
Subject Withdrawal ............................................................................................................ 31 
5.5.1 Reasons for Withdrawal ....................................................................................... 31 
5.5.2 Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention ............................................................................................................ 31 
5.6 
Premature Termination or Suspension of Study ............................................................ 32 
6 
STUDY INTERVENTION ............................................................................................................... 32 
6.1 
Study Product Description ................................................................................................ 32 
6.1.1 Acquisition .............................................................................................................. 33 
6.1.2 Formulation, Packaging, and Labeling .............................................................. 33 
6.1.3 Product Storage and Stability .............................................................................. 33 
6.2 
Dosage, Preparation and Administration of Study Product ......................................... 33 
6.2.1 Potential adverse events and precautions ........................................................ 35 
6.3 
Modification of Study Product Administration for a Subject ......................................... 37 
6.4 
Accountability Procedures for the Study Product .......................................................... 38 
6.5 
Assessment of Subject Compliance with Study Product Administration .................... 38 


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6.6 
Concomitant Medications/Treatments ............................................................................. 38 
7 
STUDY SCHEDULE ....................................................................................................................... 38 
7.1 
Screening / Baseline Visit (Day -28 to -1) ...................................................................... 39 
7.2 
Intermediate Visits ............................................................................................................. 40 
7.3 
Final Study Visit .................................................................................................................. 42 
7.4 
Withdrawal Visit .................................................................................................................. 42 
7.5 
Unscheduled Visit .............................................................................................................. 42 
8 
STUDY PROCEDURES /EVALUATIONS................................................................................... 43 
8.1 
Study Procedures/Evaluations ......................................................................................... 43 
8.2 
Laboratory Procedures/Evaluations ................................................................................ 44 
8.2.1 Clinical Laboratory Evaluations ........................................................................... 44 
8.2.2 Special Assays or Procedures ............................................................................ 44 
8.2.3 Specimen Preparation, Handling, and Storage ................................................ 45 
8.2.4 Specimen Shipment ............................................................................................. 46 
9 
ASSESSMENT OF SAFETY ......................................................................................................... 47 
9.1 
Specification of Safety Parameters ................................................................................. 47 
9.1.1 Unanticipated Problems ....................................................................................... 48 
9.1.2 Adverse Events ..................................................................................................... 48 
9.1.3 Serious Adverse Events....................................................................................... 48 
9.2 
Time Period and Frequency for Event Assessment and Follow-Up ........................... 49 
9.3 
Characteristics of an Adverse Event ............................................................................... 49 
9.3.1 Relationship to Study Intervention ...................................................................... 49 
9.3.2 Expectedness of SAEs ......................................................................................... 50 
9.3.3 Severity of Event ................................................................................................... 50 
9.4 
Reporting Procedures ....................................................................................................... 50 
9.4.1 Unanticipated Problem Reporting to IRB and NIDCR ..................................... 55 
9.4.2 Serious Adverse Event Reporting to NIDCR .................................................... 56 
9.4.3 Reporting of SAEs and AEs to FDA ................................................................... 57 
9.4.4 Events of Special Interest (if applicable) ........................................................... 57 
9.4.5 Reporting of Pregnancy ....................................................................................... 57 
9.5 
Halting Rules ...................................................................................................................... 57 
10 
STUDY OVERSIGHT ..................................................................................................................... 58 
11 
CLINICAL SITE MONITORING .................................................................................................... 59 
12 
STATISTICAL CONSIDERATIONS ............................................................................................. 60 
12.1 
Study Hypotheses .............................................................................................................. 60 
12.2 
Sample Size Considerations ............................................................................................ 60 
12.3 
Planned Interim Analyses (if applicable) ........................................................................ 61 
12.4 
Final Analysis Plan ............................................................................................................ 61 
13 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ...................... 61 
14 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 62 
14.1 
Monitoring, Auditing, and Data Quality Control and Assurance Measures by 
Study Team......................................................................................................................... 62 
15 
ETHICS/PROTECTION OF HUMAN SUBJECTS ..................................................................... 63 


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15.1 
Ethical Standard ................................................................................................................. 63 
15.2 
Institutional Review Board ................................................................................................ 63 
15.3 
Informed Consent Process ............................................................................................... 63 
15.4 
Exclusion of Women, Minorities, and Children (Special Populations) ........................ 64 
15.5 
Subject Confidentiality ....................................................................................................... 64 
15.6 
Future Use of Stored Specimens and Other Identifiable Data .................................... 65 
16 
DATA HANDLING AND RECORD KEEPING ............................................................................ 65 
16.1 
Data Management Responsibilities ................................................................................. 66 
16.2 
Data Capture Methods ...................................................................................................... 66 
16.3 
Types of Data ..................................................................................................................... 66 
16.4 
Schedule and Content of Reports ................................................................................... 66 
16.5 
Study Records Retention .................................................................................................. 66 
16.6 
Protocol Deviations ............................................................................................................ 67 
17 
PUBLICATION/DATA SHARING POLICY .................................................................................. 67 
18 
LITERATURE REFERENCES ...................................................................................................... 68 
APPENDICES ........................................................................................................................................... 73 
APPENDIX A: SCHEDULE OF EVENTS ............................................................................................. 74 


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LIST OF ABBREVIATIONS 
 
 
 
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
AE 
Adverse Event/Adverse Experience 
ANC 
absolute neutrophil count 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CBC 
complete blood cell count 
CCND-1 
cyclin D1 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
cm 
Centimeter 
CNS 
Central nervous system 
CRC 
Clinical Research Committee (CRC) 
CRF 
case report form 
CT 
computed tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CTX 
cetuximab 
CTXR 
cetuximab resistant 
CTXS 
cetuximab sensitive 
CVA 
cerebrovascular accident 
dL 
Deciliter 
DLT 
dose limiting toxicity 
DOT 
Disease Oriented Team 
DSMC 
Data Safety Monitoring Committee 
DSMS 
Data and Safety Monitoring System 
eCRF 
electronic case report form 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 


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FGFR 
fibroblast growth factor receptor 
GCP 
Good Clinical Practice 
HCl 
hydrochloric acid 
HER 
human epidermal growth factor receptor 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HNSCC 
head and neck squamous cell carcinoma 
HPV 
human papillomavirus 
hr 
Hour 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IUD 
Intra uterine device 
IV 
Intravenous 
kg 
Kilogram 
lb 
Pound 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mm3 
cubic millimeters 
MRI 
magnetic resonance imaging 
mTOR 
mechanistic target of rapamycin 
NCI 
National Cancer Institute 
NDC 
National Drug Code 
NIDCR 
National Institute of Dental and Craniofacial Research 
NIH 
National Institutes of Health 
NS 
Normal saline 
OHRP 
Office for Human Research Protections 
OS 
overall survival 
PDX 
patient-derived xenograft 
PI 
Principal Investigator 
PHI 
Protected Health Information 


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PI3K 
phosphatidylinositol 3-kinase 
PSR 
Protocol Summary Report 
PTEN 
phosphatase and tensin homolog 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RTK 
receptor tyrosine kinase 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SCC 
squamous cell carcinoma 
SFK 
Src Family Kinase 
SOC 
standard of care 
SOP 
Standard Operating Procedure 
ULN 
upper limit of normal 
UP 
unanticipated problem 
UPIRSO 
unanticipated problems involving risk to subjects or others 
US 
United States 
USP 
United States Pharmacopeia 
UW 
University of Wisconsin 
UWCCC 
University of Wisconsin Carbone Cancer Center 
WHO 
World Health Organization 
WOCP 
women of childbearing potential 
wt 
Weight 


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PROTOCOL SUMMARY 
 
Title: 
A window of opportunity trial of cetuximab in patients with head and 
neck squamous cell carcinoma (HNSCC): examining the role of 
receptor tyrosine kinase AXL in HNSCC therapy resistance 
Précis: 
This is a window of opportunity trial evaluating the hypothesis that 
AXL levels correlate with clinical response to cetuximab in head and 
neck patients. Patients with head and neck squamous cell carcinoma 
who are scheduled to undergo surgical resection of their tumor and 
are candidates for cetuximab chemotherapy are eligible to 
participate. 
 
 
Objectives: 
Primary: 
1. To test the hypothesis that low AXL correlates with clinical 
response to cetuximab in head and neck cancer patients 
 
 
Secondary: 
1. To further describe the safety of pre-operative administration 
of cetuximab 
 
Correlative: 
1. To correlate AXL expression with change in Ki67 following 
cetuximab in HNC patients 
2. To examine other putative markers of cetuximab sensitivity 
such as HER3 and change in circulating tumor cells 
3. To establish the first panel of patient-derived xenografts from 
patients with known sensitivity or resistance to cetuximab 
 
 
Population: 
36 adult patients (≥ 18 years) of either sex and of any race or 
ethnicity, who have a biopsy proven, squamous cell carcinoma of the 
head and neck, are candidates for pre-operative therapy with 
cetuximab, and are scheduled for resection of the tumor. 
Patients with advanced cutaneous head and neck squamous cell 
carcinoma are excluded. 
 
Phase: 
Window of Opportunity Study 
Number of Sites: 
1 


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Description of 
Intervention: 
 
Following informed consent, tumor tissue from the research biopsy 
and a blood draw for circulating tumor cells will be obtained. The 
patient will then receive two weekly doses of pre-operative 
cetuximab during the interval between diagnostic biopsy and surgery 
ensuring that no delay in standard of care (SOC) will occur. 
For dose #1, patients will receive cetuximab 400 mg/m2 via 
intravenous infusion over 2 hours (maximum infusion rate 10 
mg/min) as per the standard of care loading regimen for cetuximab 
monotherapy.1 
For dose #2, patients will receive cetuximab 250 mg/m2 via 
intravenous infusion over 1 hour (maximum infusion rate 10 mg/min) 
as per the standard of care dosing regimen for cetuximab 
monotherapy.1 
At the time of surgery, another blood draw will be obtained for 
analysis of circulating tumor cells, and a portion of the resected 
tumor will be obtained for study analysis. 
Correlative studies will include the measurement of proteins 
hypothesized to be involved in cetuximab resistance such as AXL, 
Ki67, EGFR, and HER3 expression from both the biopsy and the 
surgical specimen. Blood will be analyzed for correlative analysis of 
circulating tumor cells. Tissue from the research biopsy will be 
utilized for patient-derived xenograft (PDX) development. 
 
Study Duration: 
30 months 
 
Subject Participation 
Duration: 
Estimated Time to 
Complete 
Enrollment: 
13-16 months 
 
18 months 


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Schematic of Study Design: 
The primary objective of this window of opportunity study is to test the hypothesis that 
low AXL expression correlates with clinical response to cetuximab in head and neck 
cancer patients. The secondary objective of this study is to further describe the safety of 
pre-operative administration of cetuximab. It is estimated that from the time of 
diagnosis/consult to resection of tumor is approximately 4-6 weeks. There is no 
absolute timeframe for study procedures to occur, although all protocol activities must 
be completed prior to resection. 
 
 
This is a window of opportunity trial to study AXL and CTX in HNSCC patients. HNSCC 
patients who will undergo surgery will be identified. The tumor will be measured by the 
treating physician. A research biopsy will be taken and scored for Ki67 and proteins 
hypothesized to be involved in CTX resistance, such as AXL, EGFR and HER3. A 
section of the biopsy will be used for PDX development. A blood draw will be taken for 
circulating tumor cell analysis. Patients will receive two doses of cetuximab. Safety will 
be evaluated and blood will be collected for quantification of circulating tumor cells prior 
to resection. Remnant tissue from the resected tumor will be stained for Ki67 and 
compared to pre-treatment tumors. It will also be analyzed for proteins hypothesized to 
be involved in CTX resistance, such as AXL, EGFR and HER3. Patients will have blood 
draws for circulating tumor cells at 3 follow up timepoints: one month post-surgery, 3 
months post definitive care and 12 months post definitive care. Patients will then 
continue on to standard of care. 


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1 
KEY ROLES AND CONTACT INFORMATION 
 
Principal 
Investigator: 
 
 
 
 
 
 
 
 
NIDCR Medical 
Monitor: 
NIDCR Program 
Official: 
Clinical Site 
Investigators: 
Justine Yang Bruce, MD 
University of Wisconsin Carbone Cancer Center 
WIMR Room 3019 
1111 Highland Avenue 
Madison, WI 53705 
Phone: (608) 262-4961 
jybruce@medicine.wisc.edu 
 
Randall J. Kimple, MD, PhD 
University of Wisconsin Carbone Cancer Center 
WIMR Room 3107 
1111 Highland Avenue 
Madison, WI 53705 
Phone: (608) 265-9156 
rkimple@humonc.wisc.edu 
Kevin McBryde, MD 
 
Chiayeng Wang, PhD 
 
Justine Yang Bruce, MD 
University of Wisconsin Carbone Cancer Center 
WIMR Room 3019 
1111 Highland Avenue 
Madison, WI 53705 
Phone: (608) 262-4961 
jybruce@medicine.wisc.edu 
 
Randall J. Kimple, MD, PhD 
University of Wisconsin Carbone Cancer Center 
WIMR Room 3107 
1111 Highland Avenue 
Madison, WI 53705 
Phone: (608) 265-9156 
rkimple@humonc.wisc.edu 
 
Institutions: 
University of Wisconsin-Madison 
Contact Person/Local Investigator: 
Justine Yang Bruce, MD 
University of Wisconsin Carbone Cancer Center 
1111 Highland Avenue, WIMR 3109 
Madison, WI 53705 
Phone: (608) 262-4961 
jybruce@medicine.wisc.edu 


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Other Key 
Personnel: 
Co-Investigators 
Clinical 
 
Greg Hartig, MD 
Department of Surgery 
Division of Otolaryngology-Head & Neck Surgery 
University of Wisconsin School of Medicine and Public Health 
600 Highland Avenue, MC 7375 
Madison, WI 53792 
Phone: (608) 265-8207 
hartig@surgery.wisc.edu 
 
Timothy M. McCulloch, MD 
Department of Surgery 
Division of Otolaryngology-Head & Neck Surgery 
University of Wisconsin School of Medicine and Public Health 
600 Highland Avenue, MC 7375 
Madison, WI 53792 
Phone: (608) 263-0192 
mccull@surgery.wisc.edu 
 
Tiffany Glazer, MD 
Department of Surgery 
Division of Otolaryngology-Head & Neck Surgery 
University of Wisconsin School of Medicine and Public Health 
600 Highland Avenue, MC 7375 
Madison, WI 53792 
Phone: (608) 265-8504 
glazer@surgery.wisc.edu 
Aaron Wieland, MD 
Department of Surgery 
Division of Otolaryngology-Head & Neck Surgery 
University of Wisconsin School of Medicine and Public Health 
600 Highland Avenue, MC 7375 
Madison, WI 53792 
Phone: (608) 262-2876 
wieland@surgery.wisc.edu 


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Seth Dailey, MD 
Department of Surgery 
Division of Otolaryngology-Head & Neck Surgery 
University of Wisconsin School of Medicine and Public Health 
600 Highland Avenue, MC 7375 
Madison, WI 53792-3284 
Phone: (608) 265-8207 
dailey@surgery.wisc.edu 
 
Paul Harari, MD 
Department of Human Oncology 
University of Wisconsin School of Medicine and Public Health 
K4/336, Clinical Science Center 
600 Highland Avenue, MC 3674 
Madison, WI 53792 
Phone: (608) 263-5009 
harari@humonc.wisc.edu 
 
Scientific 
Deric Wheeler, PhD 
Department of Human Oncology 
University of Wisconsin School of Medicine and Public Health 
WIMR Room 3159 
1111 Highland Avenue 
Madison, WI 53705 
Phone: (608) 263-3611 
dlwheeler@wisc.edu 
 
Seungpyo Hong, PhD 
Pharmaceutical Sciences Division 
University of Wisconsin School of Pharmacy 
Rennebohm Hall 
777 Highland Avenue 
Madison, WI 53705 
Seungpyo.hong@wisc.edu 


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Biostatisticians 
Menggang Yu, PhD 
University of Wisconsin 
Department of Biostatistics and Medical Informatics 
K6/436 Clinical Science Center 
600 Highland Avenue 
Madison, WI 53792 
Phone: (608) 261-1988 
meyu@biostat.wisc.edu 


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2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
Head and neck squamous cell carcinoma, and identification of potentially 
actionable mutations 
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer 
worldwide with over 600,000 new cases diagnosed annually.2 In the United States 
alone, in 2017, there were approximately 63,000 newly diagnosed HNSCC, with roughly 
13,300 deaths.3 
 
Head and neck cancer is a complex heterogeneous disease that arises from various 
sites including the oral cavity, tongue, pharynx, larynx and salivary glands. Over 90% of 
tumors that originate in the oropharyngolaryngeal axis are squamous cell carcinoma 
(SCC). Treatment for HNSCC patients includes surgery, radiation and chemotherapy in 
various combinations. Cure rates have improved only marginally over the last 30 years.4 
Typically, local or regional disease recurs in 30% of patients, and distant metastases 
appear in 25% of patients. The 5-year overall survival rate is 40%.5 Despite the ability to 
cure localized and locally advanced disease, there is a significant unmet need for 
treatment of patients who undergo surgical resection of their head and neck cancer. 
 
To identify molecular driver mutations in head and neck squamous cell carcinoma, the 
Cancer Genome Atlas Research Network profiled 279 HNSCC tumors and identified a 
series of mutations and amplifications. However, only a handful of identified oncogenes 
in head and neck squamous cell carcinoma are immediately targetable with agents in 
clinical development, namely epidermal growth factor receptor (EGFR), fibroblast 
growth factor receptor (FGFR), MET, cyclin D1 (CCND1) and phosphatidylinositol 3- 
kinase (PI3K) CA13.6 The identification of these novel mutations and their ability to be 
effectively targeted expands the potential future treatment armamentarium for patients 
with head and neck squamous cell carcinoma, but the role they play in cetuximab 
resistance is unknown. 
 
Cetuximab 
In 2006, the FDA approved cetuximab, a monoclonal antibody against the EGFR, in the 
treatment of HNSCC. The addition of cetuximab to standard radiation improves absolute 
survival rates for newly diagnosed head and neck squamous cell carcinoma patients by 
approximately 10%7,8 and is also valuable in the metastatic/recurrent setting where 
approximately 36% of patients experience response to cetuximab based combination 
therapy (vs. 20% to standard therapy).9 
 
Although cetuximab offers a significant advance for many patients with head and neck 
squamous cell carcinoma, nearly two-thirds of EGFR expressing patients do not 
respond to cetuximab-based therapy. The response rate to cetuximab alone for patients 
with metastatic head and neck squamous cell carcinoma is only 10-20%, highlighting 
the need for improved treatments.10,11 Virtually all patients who initially respond 
eventually become refractory to cetuximab. Intrinsic and acquired resistance to 
cetuximab is therefore a significant clinical problem in the treatment of HNSCC.12 


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Enhancing the effectiveness and survival impact of cetuximab would be highly valuable 
for the head and neck squamous cell cancer patient population. 
 
Primary head and neck tumor sites and cetuximab usage 
FDA approval has been issued for cetuximab (CTX) in the following settings: 
i) 
locally or regionally advanced squamous cell carcinoma of the head and neck 
in combination with radiation therapy, 
ii) 
recurrent locoregional disease or metastatic squamous cell carcinoma of the 
head and neck in combination with platinum-based therapy with 5-fluorouracil 
(5-FU), and 
iii) 
recurrent or metastatic squamous cell carcinoma of the head and neck 
progressing after platinum-based therapy. 
 
Cetuximab is approved for squamous cell carcinomas of all head and neck sites. This 
approval includes usage in the adjuvant, recurrent or metastatic settings. In the 
landmark study of cetuximab in combination with concurrent radiotherapy for treatment 
in the locoregional setting, 424 patients were randomized. Sites of primary tumor 
represented by those 424 patients included oropharynx, hypopharynx, and larynx. A 
predominance of oropharyngeal primaries was enrolled with 56% of patients 
randomized to the concurrent cetuximab plus radiotherapy arm having oropharyngeal 
primaries. Sixty three percent (63%) of patients within the radiotherapy monotherapy 
arm had oropharyngeal primaries.8 
 
In the EXTREME trial that led to approval of cetuximab in combination with 5-FU and 
platinum chemotherapy, 442 patients were enrolled with primary tumor sites including 
the oral cavity, oropharynx, hypopharynx, larynx, and a category of “other” unspecified 
squamous cell carcinomas of the head and neck. Again, the predominant primary tumor 
site was the oropharynx with 36% of patients randomized to chemotherapy plus 
cetuximab having primary oropharyngeal cancer. Thirty one percent (31%) of patients 
randomized to chemotherapy without cetuximab had an oropharyngeal primary. 
Squamous cell carcinomas originating from “other” head and neck sites accounted for 4 
and 10% of primary tumors within the chemotherapy plus cetuximab and chemotherapy 
alone arms respectively.9 
 
In the single-arm phase II study leading to approval of cetuximab monotherapy after 
platinum failure in the recurrent or metastatic setting, 103 patients were enrolled. Of 
those patients, pharyngeal primaries were again the most commonly enrolled, 
accounting for 38% of enrolled patients. Laryngeal primaries accounted for 20%. 
Primary paranasal sinus cancers accounted for 3%, while “other” and “unclassifiable” 
sites accounted for the remaining 39% of enrollment.10 Other trials studying 1-3 weeks 
of anti-EGFR therapy demonstrated a significant decrease in tumor size in operable 
head and neck squamous cell carcinoma.13,14 


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Evidence for the usage of cetuximab in advanced cutaneous squamous cell carcinomas 
is lacking overall. As such, treatment of advanced cutaneous carcinomas will be 
excluded from this study. 
 
Mechanisms of resistance 
As the only molecular targeting agent approved in 
head and neck cancer therapy, detailed 
understanding of how head and neck squamous cell 
cancers become refractory to cetuximab therapy is 
central to further refining the impact of this promising 
molecular agent and its clinical efficacy. Furthermore, 
development of biomarkers leading to the 
identification of patients who will be responsive to 
cetuximab therapy is of high significance. 
 
Resistance to cetuximab has been explored, and 
several mechanisms of resistance have been 
reported including: altered angiogenesis,15-17 
increased EGFR activity,18 increased expression of 
human epidermal growth factor receptor (HER) family 
ligands,19,20 decreased EGFR degradation,18,21 
epithelial to mesenchymal shift,22 phosphatase and 
tensin homolog (PTEN) degradation,23 a role for the 
nuclear EGFR signaling network20 and activation of 
HER3.18,24-29 Some tumors are intrinsically resistant 
to CTX and demonstrate no response to even the first 
dose of drug.10 The mechanism of resistance is not 
known. Treatment of two doses of CTX has not been 
shown to lead to clinical resistance to therapy. 
HER3 is a member of the EGFR family of receptor 
tyrosine kinases (RTKs) and is unique in the absence 
of intrinsic kinase activity. Despite this lack of kinase 
activity, HER3 is phosphorylated by hetero- 
dimerization with other family members.30 HER3 has 
multiple binding sites in the cytoplasmic tail for the 
regulatory subunit of phosphatidylinositol 3-kinase (PI3K) to be recruited and thus 
transmit signals to the PI3K/Akt/ mechanistic target of rapamycin (mTOR) survival 
pathway.31,32 Recent work by several laboratories, has found a strong role for HER3 
activity in therapeutic resistance.24-30,33 (Figure 1) 
 
To identify drivers of CTX resistance in HNSCC, University of Wisconsin (UW) 
investigators have utilized HNSCC human tumor specimens, patient-derived xenografts 
(PDXs) and a series of acquired and intrinsically resistant in vitro and in vivo model 


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systems.18,33-37 Investigation of these models to isolate molecular mechanisms of 
cetuximab resistance has generated several significant findings. 
 
Tissue analysis of a head and neck squamous cell carcinoma patient cohort (n=63) 
identified that the receptor tyrosine kinase AXL was overexpressed in both human 
papillomavirus (HPV) positive and HPV-negative head and neck squamous cell 
carcinoma tumors and was significantly associated with higher pathologic grade, distant 
metastases, and shorter relapse free survival.37 Cetuximab-resistant head and neck 
squamous cell carcinoma patient-derived xenografts, relative to cetuximab-sensitive 
(CTXS) tumors, expressed significantly elevated levels of total and activated AXL.35,37 
HPV status does not predict CTX response.38 
 
Models (in vitro and de novo (in vivo)) of acquired resistance showed increased 
expression and activity of AXL.35,37,39 Models of intrinsically resistant HNSCC lines 
showed increased AXL expression and activity.35,37 Genetic ablation or therapeutic 
inhibition (antibody or small molecule inhibitors) of AXL led to increased sensitivity to 
cetuximab, both in vitro and in vivo.35,37 Overexpression of AXL in cetuximab sensitive 
HNSCC lines rendered them resistant, whereas a kinase dead AXL retained 
sensitivity.35 Proteomic analysis within cetuximab resistant models indicated a strong 
linkage between AXL, Src Family Kinase (SFK) and HER3 activity; a novel pathway 
leading to therapeutic escape from cetuximab therapy driven by AXL in HNSCC (data 
not shown). 
 
To correlate AXL expression with clinical response to CTX, we will use both change in 
tumor dimensions as measured by treating physician and change in Ki67 expression (% 
cells with Ki67 staining). Ki67 staining has been used successfully in HNSCC (and other 
tumor types) window trials as a surrogate marker of response to cetuximab and to 
assess the pharmacodynamic effects of novel targeting agents and can serve as a 
surrogate for clinical response.14,40-50 
 
Circulating Tumor Cells as a predictive biomarker for HNSCC 
Circulating tumor cells are tumor cells that detach from the primary tumor or metastasis 
and circulate in the bloodstream of a cancer patient. Circulating tumor cells are 
extremely rare and are heterogeneous,51 presenting a tremendous challenge for 
efficient, clinically significant detection of circulating tumor cells. 
 
Advances in biomedical engineering have led to the development of capture devices for 
circulating tumor cells. Some of the most promising devices generally combine 
immunocytochemical capture with microfluidic devices to capture circulating tumor cells. 
CellSearch is the only FDA-approved system for clinical use (metastatic breast, 
prostate, and colorectal cancer). In these diseases, the presence and the number of 
circulating tumor cells have been shown to be prognostic for development of metastatic 
disease.52 


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However, the clinical use of circulating tumor cells has been limited due to low 
sensitivity of current circulating tumor cell capture technology. For example, the only 
reports of circulating tumor cells in HNSCC involved CellSearch, and they were only 
able to detect circulating tumor cells in 1 out of 3 patients.53 Hence, there has been 
strong interest in the development of more sensitive devices to capture and evaluate 
circulating tumor cells as predictive biomarkers for cancer treatment. 
 
Highly Sensitive CTC Capture Assay 
Utilizing several biomimetic technologies at the University of Wisconsin (UW), we have 
developed a novel and highly sensitive assay to capture circulating tumor cells, as 
illustrated in Fig. 2. First, it has a biomimetic surface that induces cell rolling. The 
biofunctional surface is engineered by immobilizing selectins which can engage cell 
surface receptors to induce cell rolling.54 The cell rolling effect slows down the velocity 
of tumor cells and in turn improves capture specificity.54 
 
Another unique feature of this device is application of nanotechnology to cell capturing. 
By utilizing a flexible dendrimer nanoparticle, the device enables multivalent binding 
between antibody-functionalized dendrimers and tumor cells.55 Multivalent binding can 
improve binding affinity by as much as 106 times, thus improving sensitivity to capture 
circulating tumor cells.56 
 
Lastly, the circulating tumor cells assay can incorporate multiple antibody ligands for 
tumor cell capture.56 This enables the capture of circulating tumor cells with different 
surface biomarkers, such as cells that have undergone epithelial-mesenchymal 
transition. 
 
In prior work at the University of Wisconsin, the surfaces of the highly sensitive assay 
captured a high number of circulating tumor cells (221 circulating tumor cells per mL of 
blood, ranging from 36 to 1,135) from all 27 patients recruited57, which is significant 
considering that CellSearch could only detect circulating tumor cells from 1 of every 
three HNSCC patients.53 Importantly, when the UW results were compared to the 
previously reported clinical data from similar groups of cancer patients with comparable 
or worse cancer stages using CellSearch,53,58-60 the UW surfaces apparently achieved 
three orders of magnitude higher counts of circulating tumor cells than CellSearch 
(1,613 vs. 4.7 circulating tumor cells in 7.5 mL of blood). One can argue that the cells 
we captured could be non-circulating tumor cells; however, the UW device captured 
only 2.1 circulating tumor cells (could be epithelial cells) per mL from healthy donors’ 
blood (n=8), mitigating the concern of potential false-positive detection. 


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Flowing cells: RBCs 
 
Flow direction 
 
 
Rolling cells: CTCs and leukocytes 
 
 
 
 
 
Trapped CTC 
 
Microfluidic channel surface coated with micro-patterned domains 
 
Fig 2. A schematic diagram of CTC capture on a 
micropatterned surface using iterative cell rolling (E-selectin: 
red) and multivalent stationary adhesion (antibody: green). The 
inset diagram represents immobilized antibody molecules (e.g. 
aEpCAM, aPD-L1, and aEGFR) through a flexible polymer 
nanolinker (dendrimer and PEG: blue) by which the multivalent 
effect can be achieved through locally concentrated antibodies. 
 
 
 
Overall Goal and Importance of the Study 
This clinical trial seeks to obtain baseline tissue from a research biopsy and circulating 
tumor cells to determine whether AXL expression pre- treatment correlates to clinical 
outcomes after two doses of cetuximab. The importance of this study is to describe if 
AXL expression can be used as a biomarker to predict clinical response to cetuximab 
treatment. 
 
2.1 
Rationale 
Despite the broad advancement of molecularly targeted therapies across the 
oncology spectrum, cetuximab remains the only approved molecular targeted 
drug for the treatment of patients with head and neck squamous cell carcinoma. 
Cetuximab improves 5-year overall survival when combined with radiation in 
the curative treatment setting from 36.4% with radiation therapy alone to 45.6% 
with the combination.7,8 When combined with chemotherapy in the 
metastatic/recurrent setting, cetuximab improves overall survival by 2.7 
months.9 This survival impact is modest, however, and the response rate to 
cetuximab alone for patients with metastatic head and neck squamous cell 
carcinoma is only about 10-20%, highlighting the need for improved 
treatments.10,11 Enhancing the effectiveness and survival impact of cetuximab 
would be highly valuable for the head and neck squamous cell carcinoma 
patient population. 
 
Preliminary data35,37 suggest a role for AXL in cetuximab resistance in HNSCC, 
and the potential for AXL to serve as a functional biomarker for cetuximab 
response in humans. Targeting AXL has the potential to re-sensitize tumors to 
cetuximab therapy. 
Circulating tumor cell (rolling and trapped) 
Leukocyte (White blood cell) 
Red blood cell 
E-selectin coated region 
Antibody coated microdomains 
Antibody (aEpCAM, aHER, aEGFR, etc.) 
Poly(amidoamine) dendrimer 
Poly(ethylene glycol) linker 


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In this study, we propose a window of opportunity trial to evaluate levels of AXL 
in tumors pre- CTX treatment and compare that to the clinical response and 
changes in the size of the primary tumor mass or lymph nodes. Study 
participants will be treated with two doses of cetuximab given intravenously as 
per the standard of care regimen, except that the cetuximab will be 
administered during the interval between diagnostic biopsy and surgery instead 
of post-surgery. For dose #1, patients will receive a loading dose of cetuximab 
400 mg/m2 via intravenous infusion over 2 hours as per the standard of care 
loading dose regimen for cetuximab monotherapy. For dose #2, patients will 
receive cetuximab 250 mg/m2 via intravenous infusion over 1 hour as per the 
standard of care regimen for cetuximab monotherapy. 
 
We plan to use a portion of the pre-cetuximab treatment tumor samples to 
study correlative objectives of the role of AXL in cetuximab resistance and to 
create the first cohort of patient derived xenografts with known sensitivity or 
resistance to cetuximab treatment. These will be used to evaluate if targeting 
AXL in cetuximab resistant patient-derived xenografts will re-sensitize the tumor 
to cetuximab. In addition, blood samples will be collected to evaluate whether 
circulating tumor cells, among other biomarkers, correlate with response to 
treatment. 
 
We hypothesize that low AXL correlates with clinical response to CTX in 
HNSCC. Furthermore, we hypothesize that circulating tumor cells correlate with 
response to treatment and that the AXL/HER3 circuit can be used as a 
biomarker to predict cetuximab resistance in HNSCC. 
 
2.2 
Potential Risks and Benefits 
2.2.1 
Potential Risks 
Cetuximab-related risks include infusion reactions, acneiform rash, and in rare 
cases cardiopulmonary arrest and or interstitial lung disease (see details in 
section 6.2.1.) Other risks include those related to the research biopsy 
(bleeding and infection at the site where the needle is inserted, brief pain during 
the procedure) and blood draws (bruising, swelling at the injection site, 
dizziness and lightheadedness), as well as loss of confidentiality. Other study- 
related procedures that may introduce “risks” to study participants include: 
 
1) 
Urine/serum pregnancy tests; 
2) 
Premedication with diphenhydramine/acetaminophen prior to Cetuximab 
infusions; 
3) 
Potential medications used to treat Cetuximab-related rashes 
(Hydrocortisone, Doxycycline, Clindamycin); 
4) 
Risks of developing and/or correction of electrolyte disturbances due to 
Cetuximab infusion 


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2.2.2 
Potential Benefits 
There may be clinical benefit to the two administrations of cetuximab prior to 
surgery. Preliminary preclinical data35,37 suggest a role for AXL in cetuximab 
resistance in head and neck squamous cell carcinoma. AXL may potentially 
serve as a functional biomarker for cetuximab response in humans. Targeting 
AXL has the potential to resensitize tumors to cetuximab therapy. Treatment 
with two doses of cetuximab may offer clinical benefit including decreasing the 
tumor volume of the cancer to allow for easier resection at the time of surgery. 
Other benefits may include a predictive response that may determine sensitivity 
of a patient’s cancer to systemic treatment. 
 
3 
OBJECTIVES 
 
3.1 
Study Objectives 
 
Primary: To evaluate the hypothesis that low AXL correlates with clinical 
response to cetuximab in head and neck cancer patients 
 
Secondary: To further describe the safety of pre-operative administration of 
cetuximab 
 
Correlative: 
1. To correlate AXL expression with change in Ki67 following cetuximab in 
HNC patients 
2. To examine other putative markers of cetuximab sensitivity such as HER3 
and change in circulating tumor cells and other biomarkers 
3. To establish the first panel of patient-derived xenografts from patients with 
known sensitivity or resistance to cetuximab 
 
 
3.2 
Study Outcome Measures 
3.2.1 
Primary Endpoint 
The objective response rate (ORR) measured by clinical examination and 
clinical measurements at the time of diagnosis and within 48 hours prior to 
surgery 
This objective is to compare levels of AXL prior to CTX treatment to the 
clinical response and changes in the size of the primary tumor mass or 
lymph nodes. Patients will have their squamous cell carcinoma (either 
primary site or nodal metastases) measured in centimeters by the clinical 


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team via clinical measurement at two timepoints: 1) the time of diagnosis 
(pre- CTX) and 2) after treatment with 2 doses of cetuximab and within 48 
hours prior to surgery (post-CTX). 
 
3.2.2 
Secondary Endpoint 
The rate of hospital re-admissions for wound care or surgical complications 
attributed to cetuximab (such as fistula or deep cellulitis) within 28 days after 
surgery 
 
Although the use of cetuximab pre-operatively has been studied in a pre- 
operative trial14, this clinical trial will expand upon this information to further 
evaluate any other complications during surgery due to pre-operative 
cetuximab. We will also plan a descriptive analysis of all AEs and SAEs 
associated with pre-operative cetuximab. 
 
3.2.3 
Exploratory Endpoints 
3.2.3.1 Change in Ki67 from pre- versus post-cetuximab treated tumors and its 
correlation with levels of AXL expression pre-cetuximab treatment 
3.2.3.2 Correlation of measures of putative markers of cetuximab sensitivity, 
including protein, RNA, circulating tumor cells with cetuximab response, 
measured by Ki67 
 
3.2.3.3 
Establishment of patient-derived xenografts with known 
sensitivity/resistance to cetuximab 
 
4 
STUDY DESIGN 
This clinical trial is a single-site, single arm, open label, window of opportunity study for 
patients with squamous cell carcinoma of the head and neck. Subjects (targeted N=36) 
are patients who have biopsy-proven, squamous cell carcinoma of the head and neck, 
excluding advanced cutaneous head and neck squamous cell carcinoma, who are 
anticipated to undergo surgical resection of the tumor, and who are candidates for 
cetuximab pre-operative therapy. Patients with newly diagnosed cancer or those who 
present with recurrent disease are eligible for this trial. All patients will undergo a 
research biopsy (in clinic or at the time of panendoscopy—not standard of care) and a 
staging workup with cross-sectional imaging of the neck (standard of care). 
 
Research-related Biopsies and Blood Draws 


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Research-related procedures include a separate research biopsy of the tumor at the 
time of the diagnostic biopsy for analysis of Ki67, putative markers of CTX sensitivity, 
and research-related blood draws for collection of circulating tumor cells at five 
timepoints: screening visit, within 24 hours prior to surgery, and at follow-up visits: 
approximately 1 month post-surgery, as well as approximately 3 and 12 months post 
definitive care. The tissue obtained for research biopsy will be placed in culture media 
or saline and provided to the biologic correlate study team. If pathology confirms a 
diagnosis other than HNSCC, the patient will be removed from the study, and the 
research biopsy tissue will be released to the University of Wisconsin Translational 
Science BioCore (TSB) Biobank. If the clinical biopsy is inconclusive, the research 
tissue will be released back to University of Wisconsin Surgical Pathology department to 
aid in a clinical diagnosis. The research-related blood draws will be given directly to the 
biologic correlate study team for quantification of circulating tumor cells and/or other 
biomarkers. 
 
Cetuximab Administration in the Pre-operative Setting 
Cetuximab is an FDA approved chemotherapy agent for the treatment of (a) locally or 
regionally advanced squamous cell carcinoma of the head and neck in combination with 
radiation therapy, (b) recurrent locoregional disease or metastatic squamous cell 
carcinoma of the head and neck in combination with platinum-based therapy with 5-FU, 
and (c) recurrent or metastatic squamous cell carcinoma of the head and neck 
progressing after platinum-based therapy. Treatment with cetuximab prior to surgical 
resection is considered the investigational portion of this study, as neoadjuvant 
cetuximab is not considered standard of care. However, treatment with cetuximab as a 
monotherapy may offer a benefit to patients as cetuximab is a known and approved 
chemotherapy agent for the treatment of head and neck cancer. In patients with 
recurrent and/or metastatic HNSCC with progression on platinum-based chemotherapy, 
those patients who were treated with cetuximab monotherapy had overall response 
rates from 10-13% and disease control rates from 46-56%.61 Although surgical resection 
will offer definitive treatment for local HNSCC, use of neoadjuvant cetuximab may offer 
disease response such as shrinkage of the tumor that may offer improved surgical 
resection. 
Cetuximab will be given twice via IV infusions at pre-specified doses within a 14-day 
period between the time of their biopsy confirming their cancer and their scheduled 
surgery. Given that the standard of care time interval between diagnosis/consult and 
curative surgical resection is approximately 4-6 weeks at the University of Wisconsin, 
treatment with pre-operative cetuximab is not anticipated to delay curative surgical 
resection. No dose reductions of cetuximab are allowed although the rate of infusion of 
the drug can be reduced at the discretion of the investigator as per the standard of care 
infusion rate modifications noted in the FDA prescribing information of cetuximab. 
 
Surgical Resection 


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The surgical resection is considered standard of care therapy for this study population. 
Patients will undergo definitive standard of care surgery within 4 weeks of the first 
protocol dose of cetuximab. 
Specimens from the tumor resection will be transferred to pathology in culture media or 
saline per standard operating procedures. The biologic correlate study team will wait for 
the pathology team to access the specimen in the gross room and then will be given a 
portion of tissue that will not be required for diagnosis (i.e., remnant). The study team 
will then process and embed that fresh tissue to an FFPE block for downstream studies. 
Alternatively, the biologic correlate study team will request 20 x 5 µm unstained FFPE 
slides from the diagnostic tissue after surgical pathology clinical review is complete. 
 
Post-Surgical Assessment 
Patients will be assessed for post-surgical complications (readmission, wound healing, 
infection) at 1 month +/- 2 weeks post-surgery. Complications will be categorized as 
related, probably related, possibility related, unlikely related, or unrelated to cetuximab. 
 
Post-surgical adjuvant therapy will be delivered based on standard of care therapy as 
per recommendations of the University of Wisconsin Multidisciplinary Head and Neck 
Oncology Tumor Board. Receiving the two doses of cetuximab in the pre-operative 
setting will not be grounds for exclusion of cetuximab use at a later point. Such usages 
would include concurrent chemoradiotherapy,8 palliative combination chemotherapy9 
and/or palliative monotherapy with cetuximab.10 
 
Distant metastatic disease and/or unresectable recurrent locoregional disease will be 
managed as per the institutional standard of care. 
 
Expected duration of subject participation is approximately 13 to 16 months. The time to 
complete study enrollment is estimated to be 18 months. The time to complete the study 
analysis is estimated to be 30 months (from time of first patient enrolled to the time of 
last patient completed treatment). 
 
 
4.1 
Substudies (if applicable) 
Not applicable. 
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
This study is anticipated to enroll a target sample size of 36 subjects. We estimate 
approximately 100 subjects will be screened to reach the target enrollment. 


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5.1 
Subject Inclusion Criteria 
Adult men and women and members of all races and ethnic groups are eligible 
for this trial. Persons with impaired decision-making capacities will not be 
eligible for enrollment in this study. Eligibility criteria will be assessed via clinical 
labs, review of medical records as well as self-reporting. Subjects will be 
recruited from the University of Wisconsin Hospital and Clinics. 
 
Step 1 registration will occur when subject has signed consent and consent has 
been registered (added) to ONCORE.: 
• Age > 18 years 
• Informed consent: patients must be informed of the investigational nature of 
the study and must be able to sign a written informed consent. 
• Inclusion criteria for research biopsy (screen) 
o Patients must have suspected or known clinical presentation of head 
and neck squamous cell carcinoma or a recurrence of head and neck 
squamous cell carcinoma after initial therapy. For newly suspected head 
and neck cancer, the procedure will obtain tissue for both standard of 
care biopsy and additional tissue for research. 
o Participants must have sufficient tumor volume (approximately 10 cc) to 
accommodate at minimum 2-3 core samples for the research biopsy. 
This will be approximated based on clinical evidence, such as physician 
visualization or palpitation. 
o Patients are required to consent to the TSB Biobank protocol (2016- 
0934) as part of this study. 
o Surgical management must be the chosen modality for management of 
the head and neck squamous cell cancer. 
■ 
Other therapeutic modalities may follow, but surgery must be the 
choice for first therapy rendered. 
 
For Step 2 enrollment on this study an individual must meet all criteria for Step 
1 and the following criteria: 
• Inclusion criteria for cetuximab treatment: 
o Patients must have a biopsy proven, squamous cell carcinoma of the 
head and neck, excluding advanced cutaneous head and neck 
squamous cell carcinoma. 
o ECOG performance status £ 1 
o Women of childbearing potential (WOCP) must not be pregnant 
(confirmed by a negative urine/serum pregnancy test within 7 days of 
cetuximab treatment). In addition, a medically acceptable method of birth 
control must be used such as an oral, implantable, injectable, or 
transdermal hormonal contraceptive, an intrauterine device (IUD), use of 
a double barrier method (condoms, sponge, diaphragm, or vaginal ring 


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with spermicidal jellies or cream), or total abstinence during the study 
participation and for 6 months after last dose of study drug. Women who 
are postmenopausal for at least 1 year or surgically sterile (bilateral tubal 
ligation, bilateral oophorectomy, or hysterectomy) are not considered to 
be WOCP. 
• Men who are not surgically or medically sterile must agree to use an 
acceptable method of contraception. Male patients with female sexual 
partners who are pregnant, possibly pregnant, or who could become 
pregnant must agree to use condoms during the study and for 6 months 
post study drug. Total abstinence for the same study period is an 
acceptable alternative. 
• Patients with other concomitant malignancies are allowed to participate on 
the clinical trial as long as the surgical resection of the head and neck 
squamous cell carcinoma is clinically indicated. 
• Patients with metastatic disease are allowed to participate on the clinical 
trial as long as the surgical resection of the head and neck squamous cell 
carcinoma is clinically indicated. 
• 
5.2 
Subject Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from 
participation in this study: 
• Diagnosis of nasopharyngeal carcinoma, advanced cutaneous squamous 
cell carcinoma of the head & neck, and salivary gland tumors 
• Other concurrent severe and/or uncontrolled concomitant medical 
conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that 
could cause unacceptable safety risks or compromise compliance with the 
protocol 
• Prior chemotherapy, radiotherapy, or major surgery within 8 weeks of study 
enrollment or those who have not recovered (to grade ≤ 1 or baseline) from 
clinically significant adverse events due to agents administered more than 8 
weeks earlier (alopecia and fatigue excluded). Clinical significance to be 
determined by the study investigator 
• Prior cetuximab therapy is allowed so long as administered ³ 8 weeks ago. 
• History of allergic reactions attributed to compounds of chemical or biologic 
composition similar to those of cetuximab 
• Pregnancy, breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the screening visit through 6 
months after the last dose of trial treatment 
• Ongoing or active infection, including active tuberculosis or known infection 
with the human immunodeficiency virus (HIV). Patients with chronic, stable 
infections such as hepatitis C with an undetectable viral load, or HIV 


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infection on highly active antiretroviral therapy with undetectable viral load 
are allowed on the clinical trial. 
• Ongoing treatment with other investigational agents. 
• Any of the following cardiac conditions: 
o uncontrolled or poorly-controlled arrhythmia or uncontrolled cardiac 
insufficiency 
o uncontrolled or poorly-controlled hypertension (>180 mmHg systolic or > 
130 mmHg diastolic) 
• Any of the following conditions: 
o serious or non-healing wound, ulcer, or bone fracture 
o history of abdominal fistula, gastrointestinal perforation, or intra- 
abdominal abscess within 28 days of study enrollment 
o history of cerebrovascular accident (CVA) or transient ischemic attack 
within 12 months prior to study enrollment 
o history of myocardial infarction, ventricular arrhythmia, stable/unstable 
angina, symptomatic congestive heart failure, coronary/peripheral artery 
bypass graft or stenting or other significant cardiac disease within 6 
months prior to study enrollment 
o history of arterial or venous thrombosis/thromboembolic event, including 
pulmonary embolism within 6 months of study enrollment 
o any condition requiring the use of immunosuppression, excluding 
rheumatologic conditions treated with stable doses of corticosteroids 
o Use of herbal supplements (St. John’s Wort, gingko biloba, etc.) within 
one week of cetuximab treatment 
 
For patients who do not meet eligibility criteria for Step 2 of the study, the tissue 
from the research biopsy will be released to the TSB Biobank or back to 
surgical pathology if needed for a clinical diagnosis. 
 
5.3 
Strategies for Recruitment and Retention 
The most common method that will be used to recruit subjects is through pre- 
screening of medical records for patients of a study physician. Members of the 
study team will preview the schedules of the study physicians to determine the 
gross eligibility of upcoming patients. When a patient may meet gross eligibility, 
study team members will notify the physician. At the patient’s next clinic visit, 
the physician may then include a discussion about study participation with the 
patient. 
 
5.3.1 
Subject Remuneration 
Subjects are eligible to receive up to $200 for participating in this study to offset the 
barriers of the extra research procedures and visits. Participants will be 
provided remuneration in the amount of $100 after the research biopsy, and 
$50 after each CTX administration. 


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5.4 
Treatment Assignment Procedures 
Not applicable. This is a single arm Window of Opportunity study. 
 
5.5 
Subject Withdrawal 
Subjects may withdraw voluntarily from the study or the investigator may 
terminate a subject's participation. 
5.5.1 
Reasons for Withdrawal 
In addition to discontinuation from therapy related to toxicities as outlined in the 
Halting Rules of Section 9.5, a subject will also be discontinued from protocol 
therapy and followed up per protocol under the following circumstances: 
• 
Documented disease progression 
• 
The treating physician thinks a change of therapy would be in the best 
interest of the subject. 
• 
The subject requests to discontinue protocol therapy, whether due to 
unacceptable toxicity or for other reasons. 
o If a subject decides to prematurely discontinue protocol therapy 
(“refuses treatment”), the subject should be asked if he or she may still 
be contacted for further scheduled study assessments. The outcome of 
that discussion should be documented in both the medical records and 
in the electronic case report form (eCRF). 
• 
A female subject becomes pregnant. 
• 
The subject meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation. 
 
Subjects will be removed from protocol therapy and the site investigator notified 
when any of the criteria listed above apply. The reason for discontinuation of 
protocol therapy will be documented on the eCRF. 
 
5.5.2 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention 
If a subject decides to withdraw from the study (and not just from protocol 
therapy) all efforts should be made to complete and report study assessments 
as thoroughly as possible. The study team should contact the subject or a 
responsible relative by telephone to establish as completely as possible the 
reason for the study withdrawal. A complete final evaluation at the time of the 
subject’s study withdrawal should be made with an explanation of why the 


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subject is withdrawing from the study. If the reason for removal of a subject 
from the study is an adverse event, it will be recorded on the eCRF. 
 
If a subject is unevaluable for safety and efficacy endpoints (i.e., lacks 
molecular/correlative studies, and creation of PDXs, subject has not received 
both cetuximab doses in their entirety and/or has not had surgical resection of 
the tumor), then the subject will be replaced at the discretion of the principal 
investigator. 
 
5.6 
Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study 
suspension or termination, will be provided by the suspending or terminating 
party to NIDCR and regulatory authorities. If the study is prematurely 
terminated or suspended, the principal investigator will promptly inform the IRB 
and will provide the reason(s) for the termination or suspension. 
 
Circumstances that may warrant termination include, but are not limited to: 
 
• Determination of unexpected, significant, or unacceptable risk to subjects 
• Insufficient adherence to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination of futility 
 
6 
STUDY INTERVENTION 
 
6.1 
Study Product Description 
Cetuximab (Erbitux®) is a Monoclonal Antibody/Epidermal Growth Factor 
Receptor (EGFR) Inhibitor. It is indicated for the treatment of: 
 
• locally or regionally advanced squamous cell carcinoma of the head and 
neck (SCCHN) in combination with radiation therapy; 
• recurrent locoregional disease or metastatic squamous cell carcinoma of the 
head and neck in combination with platinum-based therapy with 5-FU; and 
• recurrent or metastatic squamous cell carcinoma of the head and neck 
progressing after platinum-based therapy. 
See Package Insert for further information. 


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6.1.1 
Acquisition 
Commercial Cetuximab will be utilized in this study. Cetuximab will be prepared 
and administered per UWHC pharmacy and hospital guidelines. 
 
See Package Insert for further information. 
 
6.1.2 
Formulation, Packaging, and Labeling 
Erbitux is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a 
small amount of easily visible, white, amorphous cetuximab particulates. 
Erbitux is supplied at a concentration of 2 mg/mL in either 100 mg (50 mL) or 
200 mg (100 mL), single-use vials. Cetuximab is formulated in a solution with 
no preservatives, which contains 8.48 mg/mL sodium chloride, 1.88 mg/mL 
sodium phosphate dibasic heptahydrate, 0.41 mg/mL sodium phosphate 
monobasic monohydrate, and Water for Injection, USP. 
 
Cetuximab is supplied at a concentration of 2 mg/mL as a 100 mg/50 mL, 
single-use vial or as a 200 mg/100 mL, single-use vial as a sterile, injectable 
liquid containing no preservatives. 
 
Cetuximab can be supplied to two dosage forms: 
• A 100 mg/50 mL, single-use vial, individually packaged in a carton (NDC 
66733-948-23) 
• A 200 mg/100 mL, single-use vial, individually packaged in a carton (NDC 
66733-958-23) 
 
6.1.3 
Product Storage and Stability 
Product vials will be stored under refrigeration at 2º C to 8º C (36º F to 46º F). 
Product will not be frozen. Increased particulate formation may occur at 
temperatures at or below 0º C. This product contains no preservatives. 
Preparations of Erbitux in infusion containers are chemically and physically 
stable for up to 12 hours at 2º C to 8º C (36º F to 46º F) and up to 8 hours at 
controlled room temperature (20º C to 25º C; 68º F to 77º F). Any remaining 
solution will be discarded in the infusion container after 8 hours at controlled 
room temperature or after 12 hours at 2º to 8º C. Any unused portion of the vial 
will be discarded. 
 
6.2 
Dosage, Preparation and Administration of Study Product 
 
Cetuximab Preparation 
Cetuximab will not be administered as an intravenous push or bolus. It will only 
be administered via infusion pump or syringe pump. The infusion rate will not 
exceed 10 mg/min. 


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Cetuximab will be administered through a low protein binding 0.22-micrometer 
in-line filter. 
 
Parenteral drug products will be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
The solution should be clear and colorless and may contain a small amount of 
easily visible, white, amorphous, cetuximab particulates. The solution is not to 
be shaken or diluted. 
 
Cetuximab Administration Guidelines 
Treatment with cetuximab will occur during the period between initial diagnosis 
and surgical resection. The standard of care (SOC) commonly utilizes 
approximately 4 weeks after diagnosis for preoperative scheduling and medical 
optimization. As such, this clinical trial does not delay standard of care curative 
treatment for head and neck cancer. 
 
Prior to administration of cetuximab, subjects will be premedicated with 
diphenhydramine and acetaminophen as described in Section 6.6. 
 
For Dose #1, subjects will be treated with cetuximab 400 mg/m2 via intravenous 
infusion over 2 hours (maximum infusion rate 10 mg/min) as per the standard of 
care loading regimen for cetuximab monotherapy.1 
 
For Dose #2, subjects will be treated with cetuximab 250 mg/m2 via intravenous 
infusion over 1 hour (maximum infusion rate 10 mg/min) as per the standard of 
care dosing regimen for cetuximab monotherapy.1 
See section 6.6 for concomitant medication as cetuximab pretreatment. 
Cetuximab Administration Monitoring 
• Vitals signs will be monitored every 15 minutes for the first hour, and then 
every 30 minutes until cetuximab infusion is complete for the first infusion as 
per the University of Wisconsin Hospital and Clinic guidelines. The nurse 
should remain with the patient for the first 15 minutes of drug administration 
for the first and second dose of cetuximab administration as per the 
University of Wisconsin Hospital and Clinics guidelines 
• Hypersensitivity reaction to cetuximab can occur. For first and second dose, 
patient should be treated in a location to optimize emergency care. 
• For the first dose of cetuximab, the subject must remain in the treatment 
area for 60 minutes following the completion of the cetuximab as per the 
University of Wisconsin Hospital and Clinics guidelines. 
 
Supportive Care 


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Optimal patient care is to be given to all patients. 
 
6.2.1 
Potential adverse events and precautions 
 
Infusion Reactions 
Serious infusion reactions can occur during cetuximab administration. Serious 
infusion reactions include rapid onset of airway obstruction (bronchospasm, 
stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial 
infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion 
reactions occurred in 2–5% of patients in prior clinical studies with a fatal 
outcome in 1 patient [Cetuximab FDA prescribing information].8,10,62,63 
 
Approximately 90% of severe infusion reactions occurred with the first infusion 
despite premedication with antihistamines. Thus, patients must be monitored 
for at least 1 hour following cetuximab infusions in a setting with resuscitation 
equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, 
corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). For 
any subjects who experience an infusion reaction, longer monitoring may be 
necessary and is appropriate to confirm resolution of the event. 
 
In the event of an infusion reaction, 
• For NCI CTC grade 1, grade 2, and non-serious grade 3 infusion 
reaction, cetuximab will be temporarily held with administration of 
emergency medications as appropriate by the treating physician. 
Upon resolution of the infusion reaction, subjects may be 
rechallenged with cetuximab at a reduced infusion rate. 
• For serious grade 3 and all grade 4 infusion reactions, cetuximab will 
be permanently discontinued. 
• All subjects should receive appropriate medical intervention as 
appropriate by the treating physician 
• Emergency medications to be available in the event of an infusion 
reaction include: 
■ 
Diphenhydramine 25-50 mg IV 
■ 
Dexamethasone 4-10 mg IV 
■ 
Albuterol nebulization solution 2.5 mg/3ml 
 
Cardiopulmonary Arrest 
Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 
patients treated with radiation therapy and cetuximab as compared to none of 
212 patients treated with radiation therapy alone.8 Three patients with prior 
history of coronary artery disease died at home, with myocardial infarction as 
the presumed cause of death. One of these patients had arrhythmia and one 
had congestive heart failure. Death occurred 27, 32, and 43 days after the last 


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dose of cetuximab. One patient with no prior history of coronary artery disease 
died one day after the last dose of cetuximab. In Study 2, fatal cardiac 
disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with 
EU-approved cetuximab and platinum-based therapy with 5-FU as compared 
to 4 (2%) of 215 patients treated with chemotherapy alone.9 Five of these 7 
patients in the chemotherapy plus cetuximab arm received concomitant 
cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the 
chemotherapy-alone arm received cisplatin. Cardiopulmonary arrest and/or 
sudden death has been observed in a small percentage of patients during the 
trials that have led to approval of cetuximab, resulting in the issuance of an 
FDA black box warning.1 
 
During cetuximab treatment and after completion of cetuximab treatment, 
subjects will have close monitoring of serum electrolytes, including serum 
magnesium, potassium, and calcium. 
 
Development of cardiopulmonary arrest will result in permanent 
discontinuation of cetuximab. 
 
Pulmonary Toxicity 
Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 
(<0.5%) patients receiving cetuximab in colorectal cancer and head and neck 
cancer.8,10,63 
• Subjects who develop acute onset pulmonary symptoms should have the 
cetuximab withheld and be evaluated by the treating physician. 
• Subjects who have confirmed interstitial lung disease after treatment with 
cetuximab will be permanently discontinued from cetuximab treatment. 
 
Dermatologic Toxicity 
Dermatologic toxicities, including acneiform rash, skin drying and fissuring, 
paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, 
abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative 
keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in 
patients receiving cetuximab therapy. Acneiform rash occurred in 76–88% of 
1373 patients receiving cetuximab.8,10,62,63 Severe acneiform rash occurred in 
1–17% of patients. Acneiform rash usually developed within the first two 
weeks of therapy and resolved in a majority of the patients after cessation of 
treatment, although in nearly half, the event continued beyond 28 days. 
 
• Study subjects will be monitored for dermatologic toxicities and infectious 
sequelae. 
• Subjects will be instructed to limit sun exposure during cetuximab treatment 
• Severe (NCI CTC Grade 3 or 4) acneiform rash will result in discontinuation 
of cetuximab therapy.1 


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• Intolerable grade 2 rash, despite maximum supportive care, will result in 
discontinuation. 
• NCI CTC Grade 1 or 2 rash is to be treated with one or more of the 
following medications at the treating physician’s discretion, based upon 
supportive care evidence.64 Potential medications that can be used for the 
treatment of cetuximab-related rash may include, but are not limited to, the 
following: 
■ 
Hydrocortisone 1 to 2.5% lotion 
■ 
Doxycycline 100 mg bid 
■ 
Clindamycin 1% lotion 
 
Hypomagnesemia and Electrolyte Abnormalities 
• Periodic monitoring for hypomagnesemia, hypocalcemia, and hypokalemia 
will be performed during and after completion of cetuximab. All 
abnormalities will be noted in the patient’s medical record. The treating 
clinician will determine if the abnormality is clinically significant. Repletion 
of electrolyte deficits will be performed as per discretion of the treating 
physician. 
 
Assessment of Research Biopsy Site 
• Assessment of the research biopsy site will be monitored by treating 
physician until resolution. 
 
6.3 
Modification of Study Product Administration for a Subject 
Dose Delays/Dose Modifications 
• No dose modifications will be planned. Please refer to section 6.2.1 
(subsection, Infusion Reactions) for more information regarding infusion rate 
decreases in the setting of infusion reaction. 
• Dose delays secondary to intolerance (such as infusion reactions) are 
permitted. Subjects can be rechallenged with cetuximab within 3 days but 
will otherwise be discontinued from the study. 
• Expected adverse events that would delay cetuximab infusion: 
- 
Grade 3 or higher nausea, vomiting, diarrhea, stomatitis, or rash 
uncontrolled despite maximal medical management due to a toxicity that 
is considered at least PROBABLY related to study treatment 
- 
Any other Grade 3 or higher non-hematologic toxicity, except grade 3 
fatigue lasting >7 days, due to a toxicity that is considered at least 
PROBABLY related to study treatment 
- 
Grade 3 or 4 electrolyte abnormalities that are corrected within 48 hours 
will not be considered a serious adverse event. 


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6.4 
Accountability Procedures for the Study Product 
Cetuximab will be obtained and purchased as a commercial supply. The 
investigator or an approved representative (e.g. pharmacist) must maintain 
accurate records of dates and quantities of CTX dispensed under this study, 
and to whom study drug is dispensed. 
Cetuximab should be stored in a secure area according to local regulations. 
Cetuximab must be dispensed only from official study sites by authorized 
personnel according to local regulations. 
 
Drug Destruction 
Opened vials must be disposed of at the site as chemotherapy or biohazardous 
waste, provided documented procedures for destruction are in place. 
 
 
6.5 
Assessment of Subject Compliance with Study Product Administration 
Not applicable. 
 
6.6 
Concomitant Medications/Treatments 
Prior to cetuximab (CTX) administration, participants will be premedicated with 
two medications, taking place 30-60 minutes prior to treatment: 
• an H1 antagonist (50 mg of diphenhydramine) intravenously 
administered over 1 minute, taking place 30–60 minutes prior to the first 
dose; premedication will be administered for the subsequent cetuximab 
dose based upon clinical judgment and presence/severity of prior 
infusion reactions.1 
• Acetaminophen (650 mg orally) will be administered 30-60 minutes prior 
to chemotherapy as per University of Wisconsin Hospital and Clinics 
guidelines. 
 
 
 
 
7 
STUDY SCHEDULE 
See table in Appendix A. When calculating days of tests and measurements, the day a 
test or measurement is done is considered Day 0. Therefore, if a test were done on a 
Monday, the Monday one week later would be considered Day 7. 


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COVID-19 testing: Literature reports suggest that SARS-CoV-2 can be detected in the saliva of 
patients known to be infected with the virus. Therefore COVID-19 testing may be required per 
UWHC recommendations for aerosolizing procedures (research biopsy for correlative study). 
 
 
7.1 
Screening / Baseline Visit (Day -21 to 1) 
Study Visit 1 and 2 
• Informed consent/HIPAA authorization obtained prior to any research 
procedures. Subjects will also be required to sign biobanking consent for 
banking of residual study samples. (research-related) 
• Demographics (recorded for the study from medical records maintained as 
part of standard clinical care) 
• Medical history including prior therapies and pathology (recorded for the 
study from medical records maintained as part of standard clinical care) 
• Concomitant medications (recorded for the study from medical records 
maintained as part of standard clinical care) 
• Physical exam, height (screening only), weight (recorded for the study from 
medical records maintained as part of standard clinical care) 
• Vital signs (blood pressure, heart rate, temperature) (recorded for the study 
from medical records maintained as part of standard clinical care) 
• ECOG performance status (recorded for the study from medical records 
maintained as part of standard clinical care) 
• CBC with differential (recorded for the study from medical records 
maintained as part of standard clinical care) 
• Blood chemistries (sodium, potassium, chloride, bicarbonate, BUN 
creatinine, glucose, AST, ALT, Alk Phos, T. bili, calcium, magnesium, 
• T. protein and albumin (recorded for the study from medical records 
maintained as part of standard clinical care) 
• Within 7 days prior to initiation of cetuximab: Urine pregnancy test for 
women of childbearing potential (WOCP). If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. 
(standard clinical care for CTX administration) 
• Adverse event evaluation (standard clinical care for CTX administration) 
• Research biopsy for biological correlative studies 
• Research blood draw for analysis of circulating tumor cells/biomarkers 
• Measurement of tumor size via clinical assessement (research-related) 


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7.2 
Intermediate Visits 
Study Visit 3, Cetuximab Dose 1 
• Vital signs (blood pressure, heart rate, temperature) (recorded for the study 
from medical records maintained as part of standard clinical care for CTX 
administration) 
• Weight (recorded for the study from medical records maintained as part of 
standard clinical care for CTX administration) Only required if 
screening/baseline visit > 7 days prior to treatment. 
• CBC with differential (recorded for the study from medical records 
maintained as part of standard clinical care for CTX administration) Only 
required if screening labs > 7 days prior to treatment. 
• Blood chemistries (sodium, potassium, chloride, bicarbonate, BUN 
creatinine, glucose, AST, ALT, Alk Phos, T. bili, calcium, magnesium, T. 
protein and albumin) (recorded for the study from medical records 
maintained as part of standard clinical care for CTX administration). Only 
required if screening labs > 7 days prior to treatment. 
• Adverse event evaluation (standard clinical care for CTX administration) 
• Administration of cetuximab (research-related) 
 
 
Study Visit 4, Cetuximab Dose 2 (7 days +/- 3 days from Study Visit 3) 
• Vital signs (blood pressure only) (recorded for the study from medical 
records maintained as part of standard clinical care for CTX administration) 
• Blood Chemistry: Potassium, calcium and magnesium (recorded for the 
study from medical records maintained as part of standard clinical care for 
CTX administration) 
• Adverse event evaluation (standard clinical care for CTX administration) 
• Administration of cetuximab (research-related) 
 
 
Study Visit 5, Safety Evaluation (within 7 days prior to surgery) 
• Concomitant medications (recorded for the study from medical records 
maintained as part of standard clinical care for CTX administration) 
• Physical exam (recorded for the study from medical records maintained as 
part of standard clinical care for CTX administration) 
• Vital signs (blood pressure, heart rate, temperature) (recorded for the study 
from medical records maintained as part of standard clinical care for CTX 
administration) 
• Weight (recorded for the study from medical records maintained as part of 
standard clinical care for CTX administration) 


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• ECOG performance status (recorded for the study from medical records 
maintained as part of standard clinical care for CTX administration) 
• CBC with differential (recorded for the study from medical records 
maintained as part of standard clinical care for CTX administration) 
• Blood chemistries (chloride, bicarbonate, BUN creatinine, glucose, AST, 
ALT, Alk Phos, T. bili, calcium, magnesium, T. protein and albumin) 
(recorded for the study from medical records maintained as part of standard 
clinical care for CTX administration) 
• Adverse event evaluation (standard clinical care for CTX administration) 
• Measurement of tumor size via clinical assessment (research-related) 
 
 
SOC Surgery 
• Blood draw for pre-surgical measurement of circulating tumor 
cells/biomarkers in serum should be done within 1 day prior to surgery 
(Research procedure) 
• During surgery, a portion of the resected tumor which pathology will not 
need for diagnosis (remnant tissue) will be obtained for study analysis 
 
 
SOC Follow Up Visit 1, 1 month post-surgery (+/- 2 wk) 
• Blood draw for post-surgical measurement of circulating tumor 
cells/biomarkers in serum (Research procedure) 
• Concomitant medications (recorded for the study from medical records 
maintained as part of standard clinical care) 
• Physical exam (recorded for the study from medical records maintained as 
part of standard clinical care) 
• Vital signs (blood pressure, heart rate, temperature) (recorded for the study 
from medical records maintained as part of standard clinical care) 
• Weight (recorded for the study from medical records maintained as part of 
standard clinical care) 
• ECOG performance status (recorded for the study from medical records 
maintained as part of standard clinical care) 
• Serious adverse event evaluation (pertains to both research-related (section 
9.1) AND standard clinical care) 
 
SOC Follow Up Visit 2, 3 months post-definitive treatment* (+/- 4 wk) 
• Physical exam (recorded for the study from medical records maintained as 
part of standard clinical care) 


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• Vital signs (blood pressure, heart rate, temperature) (recorded for the study 
from medical records maintained as part of standard clinical care) 
• ECOG performance status (recorded for the study from medical records 
maintained as part of standard clinical care) 
• Neck Imaging (findings recorded for the study from medical records 
maintained as part of standard clinical care) 
• Blood draw for post-surgical measurement of circulating tumor 
cells/biomarkers in serum (research-related procedure) 
7.3 
Final Study Visit 
SOC Follow Up Visit 3, 12 months post-definitive treatment* (+/- 4 wk) 
• Physical exam (recorded for the study from medical records maintained as 
part of standard clinical care) 
• Vital signs (blood pressure, heart rate, temperature) (recorded for the study 
from medical records maintained as part of standard clinical care) 
• Weight (recorded for the study from medical records maintained as part of 
standard clinical care) 
• ECOG performance status (recorded for the study from medical records 
maintained as part of standard clinical care) 
• Neck Imaging (findings recorded for the study from medical records 
maintained as part of standard clinical care) 
• Blood draw for post-surgical measurement of circulating tumor 
cells/biomarkers in serum (research-related procedure) 
 
* Definitive therapy is defined as surgery alone, surgery + XRT or Surgery + 
chemoXRT 
 
 
7.4 
Withdrawal Visit 
If a subject decides to withdraw from the study (and not just from protocol 
therapy) all efforts should be made to complete and report study assessments 
as thoroughly as possible. The treating investigator should contact the subject 
or a responsible relative by telephone to establish as completely as possible 
the reason for the study withdrawal. A complete final evaluation at the time of 
the subject’s study withdrawal should be made with an explanation of why the 
subject is withdrawing from the study. If the reason for removal of a subject 
from the study is an adverse event, it will be recorded on the eCRF. 
 
7.5 
Unscheduled Visit 
If a study subject should need an unscheduled visit, the treating physician 
should document the reason for the unscheduled visit (preferably in a clinic 


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note in the patient’s chart). A complete description of the subject’s symptoms 
and appropriate physical examination should be performed. In addition, the 
treating physician should document any recommendations and treatment plan 
for the subject at the time of the clinic visit. This information will be recorded on 
the eCRF. 
 
8 
STUDY PROCEDURES /EVALUATIONS 
 
8.1 
Study Procedures/Evaluations 
Criteria for Disease Assessment 
Assessment of Clinical Benefit Rate 
Response assessment of cetuximab on clinical lesions will be determined by 
quantitative measurement performed by the treating physician pre-treatment 
and at the time of surgery. Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 Committee65 criteria will be used to define clinical response prior 
to surgery. 
 
Assessment of Disease Recurrence 
Participants will be evaluated for evidence of recurrence on 2 occasions: 3 and 
12 months post-definitive treatment (recorded for the study from medical 
records maintained as part of standard clinical care). 
 
Given that all known disease will be surgically resected at the time of surgery, 
the only measure of relevance for this study will be recurrence of disease. 
Recurrence will be evaluated in this study using the new international criteria 
proposed by the RECIST 1.1 Committee.65 Note: Lesions are either 
measurable or non-measurable using the criteria provided below. 
 
Measurable Disease 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non- 
measurable as follows (per RECIST 1.1).65 
 
Tumor lesions: 
Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter in the plane of measurement is to be 
recorded) with a minimum size of: 
o 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
o 10 mm measurement by clinical exam (lesions which cannot be 
accurately measured or are <10mm should be recorded as non- 
measurable) 
o 20 mm by chest X-ray.as >20 mm with conventional techniques (CT, 
MRI, x-ray) or as >10 mm with spiral CT scan. All tumor measurements 


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must be recorded in millimeters (or decimal fractions of centimeters). To 
be considered pathologically enlarged and measurable, a lymph node 
must be ≥ 15 mm in short axis when assessed by CT scan. 
 
Malignant lymph nodes: 
To be considered pathologically enlarged and measurable, a lymph node must 
be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. The measurements will be 
recorded for the study from medical records maintained as part of standard 
clinical care. 
 
Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter 
<10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis) as well as 
truly non-measurable lesions. Lesions considered truly non-measurable 
include: leptomeningeal disease, ascites, pleural/pericardial effusions, 
inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
 
8.2 
Laboratory Procedures/Evaluations 
8.2.1 
Clinical Laboratory Evaluations 
All clinical labs and evaluations done in this study are performed as standard 
medical care. 
 
8.2.2 
Special Assays or Procedures 
Research Biopsy 
Collection of specimen: In order to participate in this study, the tumor must be 
large enough to allow for the correlative study endpoints to be achieved. The 
minimum amount of tissue to achieve this is 2-3 core samples from the 
research biopsy with a strong preference for a cut-forceps biopsy (minimum 
recommended size: 2 x 2 x 2mm). 
 
Remnant Tumor Tissue 
Collection of surgical specimen: All specimens will go directly to the UWHC 
pathology department for diagnosis and processing. The biologic correlate 
study team will wait for the pathology team to access the specimen in the gross 
room and then will be given a portion of tissue that will not be required for 
diagnosis (i.e., remnant). 
 
Circulating Tumor Cells/Biomarkers 


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Collection of specimen: We will collect blood for circulating tumor cell/or other 
biomarker identification at five timepoints: baseline, prior to surgical resection, 
one month post surgery, 3 and 12 months post definitive treatment. 
Approximately 10mL of blood will be collected in heparinized vaccutainers 
(green top) at each time point. 
 
Establishment of Patient-Derived Xenografts 
Collection of specimen: The research biopsy will also be used to establish 
patient-derived xenografts. 
 
Determination of putative biomarkers of CTX sensitivity 
Collection of specimen: the research biopsy will also be used for correlative 
analysis of putative biomarkers of CTX sensitivity. 
 
8.2.3 
Specimen Preparation, Handling, and Storage 
Research Biopsy 
Processing of specimen: The tissue obtained for research biopsy will be placed 
in culture media or saline, stored at room temperature and provided to the 
biologic correlate study team within 3 hours post-surgery. The samples will be 
identified with the research study number and “research biopsy”. The label will 
be stripped of all patient identifiers, such as MR number or dates. If squamous 
cell carcinoma is NOT confirmed, the tissue from the research biopsy will be 
relinquished to the TSB Biobank or surgical pathology based on clinical need. 
 
Approximately 1/3 of the research biopsy will be formalin fixed and paraffin 
embedded. The remaining tissue will be used directly in mice to establish the 
first panel of PDX from patients with known sensitivity or resistance to 
cetuximab. 
 
Tumor Tissue 
Processing of specimen: The study team will process and embed the fresh 
tissue obtained from the pathology department to an FFPE block for 
downstream studies. Alternatively, the biologic correlate study team will request 
20 x 5 µm unstained FFPE slides from the diagnostic tissue after surgical 
pathology clinical review is complete. The specimens will be labeled with the 
research study number, “surgical resection,” and section number, if applicable. 
The label will be stripped of all patient identifiers, such as the medical record 
number or dates. 
 
Research Tissue samples and PDXs within the context of this protocol will be 
maintained under the supervision of Dr. Randy Kimple located at: 
University of Wisconsin 
3107 WIMR 


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1111 Highland Avenue 
Madison WI 53705 
 
Circulating Tumor Cells/Biomarkers 
Processing of specimen: The samples will be picked up by a member of the 
biologic correlative study team and transported to Dr. Hong’s lab. Upon arrival 
at the lab, PHI patient identifiers will be stripped from the sample and 
relabeled. The samples will be labeled with the subject’s study ID number and 
coded time point (1- baseline, 2- pre-surgical resection, 3- one month post 
surgery, 4- three months post definitive-treatment, 5- twelve months post 
definitive treatment). Processing and storage of the circulating tumor cell 
samples within the context of this protocol will occur under the supervison of Dr. 
Seungpyo Hong’s lab located at: 
 
Pharmaceutical Sciences Division 
University of Wisconsin School of Pharmacy 
7234 Rennebohm Hall 
777 Highland Avenue 
Madison WI 53705 
 
Determination of putative biomarkers of CTX sensitivity 
The biologic correlate study team will formalin fix and paraffin embed (FFPE) 
approximately one third of the research biopsy tissue to be used to assess 
putative biomarkers of CTX sensitivity (e.g. total and phosphorylated AXL, 
EGFR and HER3 expression using immunohistochemistry assays). The FFPE 
research and surgical specimens will be used to establish the change in Ki67 
(ΔKi67). 
 
Correlations between the change in Ki67 index (ΔKi67) and AXL expression 
and HER3 expression in the research biopsy will be performed. Further 
correlation between other biomarkers and AXL expression will be performed. 
 
Determination of circulating tumor cells 
We hypothesize that changes in circulating tumor cells detected using the 
described head and neck cancer optimized capture approach (section 2) will 
correlate with response as determined by change in Ki67. Circulating tumor 
cells will be quantified at each time point. In addition, we plan to utilize captured 
circulating tumor cells to establish the first reported circulating tumor cell- 
derived head and neck cancer patient derived xenografts and to compare these 
PDXs to those established using standard techniques. 
 
8.2.4 
Specimen Shipment 
Not applicable. 


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9 
ASSESSMENT OF SAFETY 
 
9.1 
Specification of Safety Parameters 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse 
events are reported in a routine manner at scheduled times during a trial. 
Additionally, certain adverse events must be reported in an expedited manner 
to allow for optimal monitoring of patient safety and care. The first step is to 
identify the event using the Common Terminology Criteria for Adverse Events 
(CTCAE). The CTCAE document provides descriptive terminology for adverse 
event reporting. A grading (severity) scale is provided for each adverse event 
term. 
 
Adverse events, Serious adverse events and unanticipated problems will be 
recorded on the study eCRF’s and reported per section 9.4. Certain toxicities 
are known and can be expected. 
 
Cetuximab: 
Common: Change in nails, rash, itching, dry skin, acne, dehydration, 
weight loss, loss of appetite, sores in mouth which may cause difficulty 
swallowing, constipation, diarrhea, vomiting, nausea, difficulty sleeping, 
headache, tiredness, pain, fever, infection, especially when white blood cell 
count is low, cough, shortness of breath, hypomagnesemia, hypokalemia 
and hypocalcemia 
 
Occasional: Allergic reaction which may cause rash, low blood pressure, 
wheezing, shortness of breath, swelling of the face or throat, confusion, 
depression, worry, fainting, severe blood infection, blood clot which may 
cause swelling, pain, shortness of breath 
 
Rare: Scarring of the lungs, kidney damage which may require dialysis, 
cardiac arrest 
 
Additional risks from study procedures 
Biopsy 
Possible risks from a tissue biopsy include bleeding and infection. There 
can also be some degree of pain associated with the biopsy. 
 
Blood draw 
Possible risks include: pain, bleeding and/or bruising, feeling faint, infection 
with redness, irritation, and, more rarely, a blood clot in the vein at the site 
where the blood is drawn. 


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In addition to physical risks there is also the risk of “breach of 
confidentiality”. If this occurs, it will be reported as an unanticipated 
problem. 
 
9.1.1 
Unanticipated Problems 
The Office for Human Research Protections (OHRP) considers unanticipated 
problems involving risks to subjects or others to include, in general, any 
incident, experience, or outcome that meets all of the following criteria: 
• unexpected in terms of nature, severity, or frequency given (a) the 
research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population 
being studied; 
• related or possibly related to participation in the research (“possibly 
related” means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures 
involved in the research); and 
• suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized. 
 
 
9.1.2 
Adverse Events 
An adverse event is any untoward or unfavorable medical occurrence in a 
human subject, including any abnormal sign (for example, abnormal physical 
exam or laboratory finding), symptom, or disease, temporally associated with 
the subject’s participation in the research, whether or not considered related to 
the subject’s participation in the research. 
 
9.1.3 
Serious Adverse Events 
A serious adverse event (SAE) is one that meets one or more of the following 
criteria: 
• Results in death 
• Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred) 


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• Results in inpatient hospitalization or prolongation of existing 
hospitalization 
• Results in a persistent or significant disability or incapacity 
• Results in a congenital anomaly or birth defect 
• An important medical event that may not result in death, be life 
threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, the event may jeopardize 
the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
 
9.2 Time Period and Frequency for Event Assessment and Follow-Up 
Unanticipated problems will be recorded in the data collection system throughout 
the duration of the study. 
 
All AE’s will be recorded from the time of informed consent until 28 days past last 
dose of study drug or day of surgery, whichever is first. SAE’s will be recorded 
from the time of informed consent through 28 days past last dose of study drug or 
28 days post-surgery, whichever is later. Serious adverse events that occur more 
than 28 days after surgery and have an attribution of possibly, probably, or 
definitely related to cetuximab (or other research procedures such as biopsy or 
blood draws) require reporting per table 1. 
 
At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit. Events will be followed for outcome information until resolution 
or stabilization. 
 
9.3 Characteristics of an Adverse Event 
Any adverse event, inclusive of all related study procedures, will be examined 
(section 9.1). 
 
9.3.1 
Relationship to Study Intervention 
The causality, or attribution, of AEs refers to the relationship of the AE to the 
experimental intervention (drug/biologic). The investigator, using the following points, 
makes the assessment of whether there is a reasonable possibility of a causal 
relationship: 
1. Related (Possible, Probable, Definite) 
 
a. The event is known to occur with the study intervention. 
b. There is a temporal relationship between the intervention and event onset. 


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c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
 
a. There is no temporal relationship between the intervention and event 
onset. 
b. An alternate etiology has been established. 
 
Based on the aforementioned points, the PI assigns attribution of the adverse 
event to the study treatment. Attribution categories are as follows: 
• Definite: The AE is clearly related to the study treatment 
• Probably: The AE is likely related to the study treatment 
• Possible: The AE may be related to the study treatment 
• Unlikely: The AE is doubtfully related to the study treatment 
• Unrelated: The AE is clearly NOT related to the study treatment 
9.3.2 
Expectedness of SAEs 
Expected events are those that have been previously identified as resulting 
from administration of the intervention. An adverse event is considered 
unexpected, for expedited reporting purposes only, when either the type of 
event or the severity of the event is not listed in: 
• Current known adverse events listed in this protocol 
• Drug package insert (for commercially available agent) 
 
 
9.3.3 
Severity of Event 
This study will utilize version 5.0 of the CTCAE of the National Cancer Institute 
for toxicity and performance reporting. A copy of the CTCAE version 5.0 can be 
downloaded from the NCI website at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTC 
AE_v5_Quick_Reference_5x7.pdf. 
 
9.4 
Reporting Procedures 
Procedures for Recording Adverse Events 
• AEs will be recorded from time of informed consent until 28 days post 
discontinuation of study drug or day of surgery, whichever is first. 
• AEs will be recorded regardless of whether or not they are considered 
related to the study intervention. 
• AEs will be recorded in the subject’s medical record and in the research 
study records. 


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Reporting Requirements for Serious Adverse Events 
• All AEs considered related to study drug(s) or procedure will be followed until 
resolution to ≤ Grade 1 or baseline, deemed clinically insignificant, and/or 
until a new anti-cancer treatment starts, whichever occurs first. 
• At the 3 month and 12 month follow up visits, any AEs deemed by treating 
physician or study PI to be probably related to the research blood draw 
procedure will be recorded at time of visit and followed until resolution to 
≤ Grade 1 or baseline, deemed clinically insignificant. 
 
Procedures for Recording and Reporting Serious Adverse Events 
• SAEs will be reported from time of informed consent until 28 days after 
discontinuation of cetuximab or definitive surgery, whichever is later. 
• Any SAEs experienced after this 28-day period will only be reported if the 
investigator suspects a causal relationship (possibly, probably or definitely 
related) to the study treatment. 
• SAEs will be reported on the SAE Submission Form and entered in SAE tab 
in OnCore within 1 business day of discovery of the event. 
• SAEs include events related and unrelated to the study drug(s). 
• SAEs will be recorded in the subject’s medical record and on the appropriate 
study specific eCRF form within OnCore. 
• All SAEs, regardless of relation to study drug, will be followed until resolution 
to ≤ Grade 1 or baseline and/or deemed clinically insignificant and/or until a 
new anti-cancer treatment starts, whichever occurs first. 
• Recurrent episodes, complications, or progression of the initial SAE will be 
reported as follow-up to the original episode within 24 hours of the 
investigator receiving the follow-up information. 
 
Expedited Reporting of Serious Adverse Events 
Depending on the nature, severity, and attribution of the serious adverse event 
an SAE report will be phoned in, submitted in writing, or both according to Table 
1 below. All serious adverse events must also be reported to the UWCCC Data 
and Safety Monitoring Committee Chair. All serious adverse events must also 
be reported to the UW IRB (if applicable), and any sponsor/funding agency not 
already included in the list. 
 
Determine the reporting time line for the SAE in question by using the following 
table. 
 
Table 1. Expedited Reporting Requirements for Adverse Events that Occur in 
Non-IND/IDE Studies Within 28 Days Post Surgical Intervention, 
 


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NOTE: Investigators MUST immediately report to the UWCCC DSMC, NIDCR (via 
Rho) and the IRB (if applicable) ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention. See below. 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death. 
2) A life-threatening adverse event. 
3) An adverse event that results in inpatient hospitalization or prolongation of 
existing hospitalization for ≥ 24 hours. 
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life 
threatening, or require hospitalization may be considered serious when, based 
upon medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition (FDA, ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria* MUST be 
immediately reported to the UWCCC within the timeframes detailed in the table 
below: 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour; 5 
Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar 
Days 
* Hospitalization for planned surgical resection does not require reporting* 
Expedited AE reporting timelines are defined as: 
• 24-Hour; 5 Calendar Days – The AE must initially be reported within 24 hours 
of learning of the AE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
• 10 Calendar Days – A complete expedited report on the AE must be 
submitted within 10 calendar days of learning of the AE. 
1 
 
Serious adverse events that occur more than 28 days after the surgery and have 
an attribution of possibly, probably, or definitely related to cetuximab (or other 
research procedures such as biopsy or blood draws) require reporting as follows: 


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SAE Requiring [24] Hour Reporting Occurs at UWCCC 
Report to the UWCCC DSMC: 
Reference the SAE SOP (Standard Operating Procedure) and the SAE Reporting 
Workflow for DOTs on the UWCCC website (http://kb.wisc.edu/uwccc) for specific 
instructions on how and what to report to the UWCCC for [24] hour initial and follow- 
up reports. A follow-up report is required to be submitted within 5 days of the 
initial [24] hour report. 
For this protocol, the following UWCCC entities are required to be notified: 
a. saenotify@uwcarbone.wisc.edu 
b. UWCCC PIs: Justine Yang Bruce, MD and Randall Kimple, MD, PhD 
c. UWCCC PM: Diana Trask 
d. Any other appropriate parties listed on the SAE Routing Form (for follow-up 
reports only) 
 
Report to the IRB 
Please refer to the document “Unanticipated Problems/Adverse Event Reporting 
Decision Guide” found on the UW Health Science IRB website: 
https://kb.wisc.edu/hsirbs/. SAEs must be reported to the IRB Chair/director 
within 10 calendar days. 
SAE Requiring [10] Calendar Day Reporting Occurs at UWCCC 
Report to the UWCCC DSMC: 
Reference the SAE SOP and the SAE Reporting Workflow for DOTs on the 
UWCCC website (http://kb.wisc.edu/uwccc) for specific instructions on how and 
what to report to the UWCCC for [10] calendar day reports. 
For this protocol, the following entities are required to be notified: 
a. saenotify@uwcarbone.wisc.edu 
b. UWCCC PIs: Justine Yang Bruce, MD and Randall Kimple, MD, PhD 
c. UWCCC PM: Diana Trask 
d. Any other appropriate parties listed on the SAE Routing Form (for follow-up 
reports only) 
 
Other Reportable Events 
Reporting timeframes begin when PI learns of the occurrence of the event. 
Refer to Table 2. 
Expedited 24-hour notification followed by complete report within 10 
calendar days for: 
• All Grade 4, and 5 SAEs 


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Table 2. Other Reportable Events Timeframe 
Event 
Definition 
Reporting 
Breach of 
confidentiality 
The exposure of any study information or 
communications directly related to a 
study subject to anyone not named as 
study staff or the release of a study 
subject’s identifiable information to study 
staff who were not specified to receive 
such information in the protocol or IRB 
application. 
Within 14 business days of 
knowledge of event 
Protocol 
deviation 
A deviation is an incident involving a 
departure from the IRB-approved 
protocol in the actual conduct of the 
study. Deviations may result from the 
action of the participant, investigator, or 
staff. 
See details below 
Major 
deviations 
Deviations are considered major when 
the unapproved change(s) in previously 
approved research activities, 
implemented without IRB approval, may 
potentially adversely affect subjects’ 
rights, safety, welfare, or willingness to 
continue participation, or affect the 
scientific design of the study and/or the 
integrity of the resultant data. 
Within 14 business days of 
knowledge of event 
Minor 
deviations 
Deviations are considered minor when 
the unapproved change(s) in previously 
approved research activities, 
implemented without IRB approval, do 
not adversely affect subjects or the 
integrity of the study data. 
Cumulative minor 
deviations are reported at 
the time of continuing 
review. 


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Table 2. Other Reportable Events Timeframe 
Event 
Definition 
Reporting 
Protocol 
violation 
An incident involving an intentional 
deviation from the IRB-approved protocol 
that was not implemented in response to 
an emergency situation and that may 
impact a subject’s rights, safety, and/or 
welfare, makes a substantial alteration to 
risks to subjects, or affects the scientific 
design of the study and/or the integrity of 
the resultant data. Violations may also 
be repeated deviations (major or minor) 
of the same nature. Violations can 
represent serious or continuing non- 
compliance with the federal regulations 
and guidelines for ethical conduct of 
human subject research. 
Within 14 business days of 
knowledge of event 
Protocol 
Exceptions 
A protocol exception is an IRB-approved 
deviation for a single subject or a small 
group of subjects but is not a permanent 
revision to the research protocol. 
Protocol exceptions must 
be approved by local IRB 
prior to implementation. 
 
9.4.1 
Unanticipated Problem Reporting to IRB and NIDCR 
Incidents or events that meet the OHRP criteria for unanticipated problems 
require the creation and completion of an unanticipated problem report form. 
OHRP recommends that investigators include the following information when 
reporting an adverse event, or any other incident, experience, or outcome as an 
unanticipated problem to the IRB: 
 
• appropriate identifying information for the research protocol, such as the 
title, investigator’s name, and the IRB project number; 
• a detailed description of the adverse event, incident, experience, or 
outcome; 
• an explanation of the basis for determining that the adverse event, 
incident, experience, or outcome represents an unanticipated problem; 
• a description of any changes to the protocol or other corrective actions 
that have been taken or are proposed in response to the unanticipated 
problem. 


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To satisfy the requirement for prompt reporting, unanticipated problems will be 
reported using the following timeline: 
 
• Unanticipated problems that are serious adverse events will be reported 
to the IRB and to NIDCR within 10 calendar days of the investigator 
becoming aware of the event. 
• Any other unanticipated problem will be reported to the IRB and to 
NIDCR within 10 calendar days of the investigator becoming aware of 
the problem. 
• All unanticipated problems should be reported to appropriate institutional 
officials (as required by an institution’s written reporting procedures), the 
supporting agency head (or designee), and OHRP within one month of 
the IRB’s receipt of the report of the problem from the investigator. 
All unanticipated problems will be reported to NIDCR’s centralized reporting 
system via Rho Product Safety: 
• Product Safety Fax Line (US): 1-888-746-3293 
• Product Safety Fax Line (International): 919-287-3998 
• Product Safety Email: rho_productsafety@rhoworld.com 
General questions about SAE reporting can be directed to the Rho Product 
Safety Help Line (available 8:00AM – 5:00PM Eastern Time): 
• US: 1-888-746-7231 
• International: 919-595-6486 
 
9.4.2 
Serious Adverse Event Reporting to NIDCR 
Any AE meeting the specified Serious Adverse Event criteria will be submitted 
on an SAE form to NIDCR’s centralized safety system via Rho Product Safety. 
This report may be sent by fax or email. Once submitted, Rho Product Safety 
will send a confirmation email to the investigator within 1 business day. The 
investigator should contact Rho Product Safety if this confirmation is not 
received. This process applies to both initial and follow-up SAE reports. 
SAE Reporting Contact Information: 
 
• Product Safety Fax Line (US): 1-888-746-3293 
• Product Safety Fax Line (International): 919-287-3998 
• Product Safety Email: rho_productsafety@rhoworld.com 


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General questions about SAE reporting can be directed to the Rho Product 
Safety Help Line (available 8:00AM – 5:00PM Eastern Time): 
 
• US: 1-888-746-7231 
• International: 919-595-6486 
The study clinician will complete a Serious Adverse Event Form and submit via 
fax or email within the following timelines: 
 
• All deaths and immediately life-threatening events, whether related or 
unrelated, will be recorded on the Serious Adverse Event Form and 
submitted to Product Safety within 24 hours of site awareness. 
• Serious adverse events other than death and immediately life- 
threatening events, regardless of relationship, will be reported by fax 
within 10 calendar days of site awareness. 
All SAEs will be followed until resolution or stabilization. 
 
9.4.3 
Reporting of SAEs and AEs to FDA 
Not applicable. 
 
9.4.4 
Events of Special Interest (if applicable) 
Not applicable. 
 
9.4.5 
Reporting of Pregnancy 
• Pregnancy will be reported from time of first study drug until 6 months 
after discontinuation of either study drug. 
• Pregnancy will be reported to UW via an unanticipated problem 
submission and the NIDCR medical monitor within 1 business day of 
discovery of the event. 
 
To ensure subject safety, each pregnancy in a subject on study treatment will 
be reported to UW and the NIDCR medical monitor within 1 business day of 
learning of its occurrence. The pregnancy will be followed to determine 
outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
 
9.5 
Halting Rules 
During the conduct of this study, subjects with adverse events and serious 
adverse events that are probably attributed to cetuximab will be evaluated and 


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analyzed weekly by the principal investigators. If >25% of subjects have serious 
adverse events that are probably related to pre-operative cetuximab treatment, 
then enrollment for the study will be suspended for further analysis. 
Subsequent review of serious, unexpected, and related AEs will be evaluated 
by the DSMC, IRB, and the NIDCR. The NIDCR and local regulatory authorities 
retain the authority to suspend additional enrollment and administration of 
cetuximab for the entire study, as applicable. 
 
10 
STUDY OVERSIGHT 
A summary of DSMC activities is as follows: 
• Reviews all clinical trials conducted at the UWCCC for subject safety, protocol 
compliance, and data integrity. 
• Reviews Adverse Events recorded by study team as described in section 9.4. 
• Reviews all Serious Adverse Events (SAE) requiring expedited reporting, as 
defined in the protocol, for all clinical trials conducted at the UWCCC, and studies 
conducted at external sites for which the UWCCC acts as an oversight body. 
• Reviews all reports generated through the UWCCC DSMS elements (Internal 
Audits, Quality Assurance Reviews, Response Reviews, Compliance Reviews, 
and Protocol Summary Reports) described in Section II of this document. 
• Notifies the protocol PI of DSMC decisions and, if applicable, any requirements for 
corrective action related to data or safety issues. 
• Notifies the Clinical Research Committee (CRC) of DSMC decisions and any 
correspondence from the DSMC to the protocol Principal Investigator. 
• Works in conjunction with the UW Health Sciences IRB in the review of relevant 
safety information as well as protocol deviations, non-compliance, and 
unanticipated problems reported by the UWCCC research staff. 
• Ensures that notification of SAEs requiring expedited reporting is provided to 
external sites participating in multi-institutional clinical trials coordinated by the 
UWCCC. 
 
Monitoring and Reporting Guidelines 
UWCCC quality assurance and monitoring activities are determined by study 
sponsorship and risk level of the protocol as determined by the PRMC. All protocols 
(including Intervention Trials, Non-Intervention Trials, Behavioral and Nutritional 
Studies, and trials conducted under a Training Grant) are evaluated by the PRMC at the 
time of committee review. UWCCC monitoring requirements for trials without an 
acceptable external DSMB are as follows: 
 
• 
Intermediate Monitoring 
Protocols subject to intermediate monitoring generally include UW Institutional 
Phase I/II and Phase II Trials. These protocols undergo review of subject safety 
at regularly scheduled DOT meetings where the results of each subject’s 


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treatment are discussed and the discussion is documented in the DOT meeting 
minutes. The discussion includes the number of subjects enrolled, significant 
toxicities, dose adjustments, and responses observed. Protocol Summary 
Reports are submitted on a bi-annual basis by the study team for review by the 
DSMC. 
 
Review and Oversight Requirements 
• Study Progress Review 
o Protocol Summary Reports (PSR) are required to be submitted to the DSMC 
in the timeframe determined by the risk level of the study (quarterly; semi- 
annually; or annually). The PSR provides a cumulative report of SAEs, as well 
as instances of noncompliance, protocol deviations, and unanticipated 
problems, toxicities and responses that have occurred on the protocol in the 
timeframe specified. PSRs for those protocols scheduled for review are 
reviewed at each DSMC meeting. 
o Protocol Summary Reports enable DSMC committee members to assess 
whether significant benefits or risks are occurring that would warrant study 
suspension or closure. This information is evaluated by the DSMC in 
conjunction with other reports of quality assurance activities (e.g., reports 
from Internal Audits, Quality Assurance Reviews, etc.) occurring since the 
prior review of the protocol by the DSMC. Additionally, the DSMC requires the 
study team to submit external DSMB or DSMC reports, external monitoring 
findings for industry-sponsored studies, and any other pertinent study-related 
information. 
o In the event that there is significant risk warranting study suspension or 
closure, the DSMC will notify the PI of the DSMC findings and ensure the 
appropriate action is taken for the protocol (e.g., suspension or closure). The 
DSMC ensures that the PI reports any temporary or permanent suspension of 
a clinical trial to the appropriate agencies. DSMC findings and requirements 
for follow-up action are submitted to the CRC. 
 
 
11 
CLINICAL SITE MONITORING 
Clinical site monitoring is conducted to ensure that the rights of human subjects are 
protected, that the study is implemented in accordance with the protocol and/or other 
operating procedures, and that the quality and integrity of study data and data collection 
methods are maintained. Monitoring for this study will be performed by NIDCR’s Clinical 
Research Operations and Management Support (CROMS) contractor. The monitor will 
evaluate study processes and documentation based on NIDCR standards and the 
International Conference on Harmonisation (ICH), E6: Good Clinical Practice guidelines 
(GCP). 


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Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by the CROMS contractor, in collaboration with the NIDCR Office of Clinical 
Trials and Operations Management (OCTOM) and the NIDCR Program Official. The 
CMP will specify the frequency of monitoring, monitoring procedures, the level of clinical 
site monitoring activities (e.g., the percentage of subject data to be reviewed), and the 
distribution of monitoring reports. Some monitoring activities may be performed 
remotely, while others will take place at the study site(s). Staff from the CROMS 
contractor will conduct monitoring activities and provide reports of the findings and 
associated action items in accordance with the details described in the CMP. 
Documentation of monitoring activities and findings will be provided to the site study 
team, the study PIs, OCTOM, and the NIDCR. The NIDCR reserves the right to conduct 
independent audits as necessary. 
 
12 
STATISTICAL CONSIDERATIONS 
 
12.1 
Study Hypotheses 
The primary objective of this window of opportunity trial is to test the 
hypotheses that elevated AXL and HER3 can predict cetuximab resistance 
(CTXR) in head and neck cancer patients. Following informed consent, tumor 
tissue from the pre-treatment/research biopsy will be obtained for further 
analysis. The participant will then receive two weekly doses of cetuximab 
during the interval between research biopsy and surgery, ensuring that no 
delay in standard of care (SOC) will occur. At the time of surgery, additional 
tumor tissue will be obtained for study analysis. 
 
Correlative studies will include the measurement of AXL and HER3 expression 
from the pre-treatment/research biopsy as well as collection of circulating tumor 
cells. Tissue from the pre-treatment/research biopsy will be utilized for patient- 
derived xenograft (PDX) development. 
 
12.2 
Sample Size Considerations 
We plan to enroll 36 HNSCC patients, powered on the basis of the primary 
study endpoint: the clinical response rate to cetuximab according to RECIST 
criteria in low AXL vs. high AXL patients (measured using VECTRA/inForm 
software). Previous data show that 1 in 3 patients respond to cetuximab, and 
about one-third (21/57 or 37%) of HNSCC patients have high AXL 
expression.37 This sample size is based on 90% power to detect a difference 
between a response rate of 20% in the high AXL (2+ or 3+) group vs. 65% in 
the low AXL (0 or 1) group, with an expected ratio of 2:1 low vs. high AXL 
expression participants. One-sided type I error was fixed at 5%. 
 
For evaluation of safety endpoints, any participant that undergoes a research 
biopsy will be included. For evaluation of efficacy, molecular/correlative studies, 
and creation of PDXs, participants must receive both cetuximab doses in their 


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entirety and have surgical resection of the tumor. If a participant is unevaluable 
for these endpoints, then the patient will be replaced at the discretion of the 
principal investigator. 
 
 
12.3 
Planned Interim Analyses (if applicable) 
Not applicable. 
 
12.4 
Final Analysis Plan 
Analysis of Primary Endpoints 
The relationship between AXL expression as a continuous variable with clinical 
response will be analyzed using the Wilcoxon rank sum test. 
 
Analysis of Secondary Endpoints 
The safety of pre-operative cetuximab, as evaluated by hospital re-admissions 
for wound care or surgical complications attributed to cetuximab within 28 days 
after surgery, will be reported as a proportion including an exact 95% 
confidence interval. 
 
Analysis of Correlative Endpoints 
Summary statistics of the change in Ki67 (ΔKi67), as established by the 
surgical specimen, will be reported for the response to cetuximab endpoint. 
Correlation between ΔKi67 and putative biomarkers will be analyzed as a 
continuous variable and will be tested using Pearson’s correlation 
coefficient. Correlation between two biomarkers such as AXL and HER3 
expression as continuous variables will be investigated using Pearson’s 
correlation coefficient. 
 
Summary statistics will be used to report circulating tumor cells at each time 
point and the changes between time points. The association of change in 
circulating tumor cells with ΔKi67 (early response) will be explored graphically 
and with Pearson’s correlation coefficient. 
 
 
13 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Study staff will maintain appropriate medical and research records for this study, in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for 
the protection of confidentiality of subjects. Study staff will permit authorized 
representatives of NIDCR and regulatory agencies to examine (and when required by 
applicable law, to copy) research records for the purposes of quality assurance reviews, 
audits, and evaluation of the study safety, progress and data validity. 


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Source documents will include all records within the HealthLink Electronic Medical 
Records system such as hospital records, clinical and office charts, laboratory notes, 
memoranda, pharmacy dispensing records, copies or transcriptions certified after 
verification as being accurate and complete, photographs or digital photo files, x-rays, 
and subject files and records kept at the pharmacy, at the laboratories, and medico- 
technical departments involved in the clinical trial. In addition, protocol specific forms will 
be designed which require treating physician signature to serve as source documents. 
This may include forms such as toxicity forms with grading and attribution and tumor 
measurement forms. 
 
14 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
14.1 
Monitoring, Auditing, and Data Quality Control and Assurance Measures 
by Study Team. 
All personnel involved in FDA regulated clinical trial activities are required to complete 
the Human Subjects Training and Good Clinical Practice (GCP) via CITI every 3 years. 
Training is monitored at each IRB continuing review and with the submission of protocol 
amendments. 
 
At the protocol level, the Principal Investigators will assign and document protocol 
responsibilities based on study roles. Training on all IRB approved protocols (initial 
version and subsequent amendments) are documented for each person listed as key 
personnel on the University of Wisconsin Health Sciences IRB application. These 
documents are retained with the study regulatory files, and collection is coordinated by 
Human Oncology regulatory staff. 
 
Eligibility checklists are signed by the study coordinator and the treating physician prior 
to enrollment. Adverse event grading and attributions are assigned by physicians at 
clinic visits and will be signed by the physician at that time. 
 
A data report will be run quarterly to ensure study data is entered into the study 
database in a timely manner. After the report is run, the Research Program Manager 
will review and audit at least 25% of accrued cases since the last report was run. 
Auditing assistance will be provided by a study coordinator not involved in the cases 
being audited. Audits will include case review (Informed consent, eligibility, response, 
toxicity) and source document review. 
 
Other relevant UWCCC SOPs that would be followed include: 
 
• Adverse Event Assessment and Documentation_SOP 
• CTRP and ClinicalTrials.gov Reporting_SOP 
• Delegation of Authority Log_SOP 


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• DSMS Reporting Guidelines_SOP 
• Informed Consent Process_SOP 
• Maintaining a Regulatory File_SOP 
• OnCore Data Quality Assurance_SOP 
• Protocol Deviation_Guidance 
• Reportable Events_SOP 
• Reporting of Serious Adverse Events (SAEs) at UWCCC, 1SP, JC, 
And Affiliate Sites_SOP 
• Source Documentation_SOP 
• Study Close Out_SOP 
 
15 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
15.1 
Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with 
the principles set forth in The Belmont Report: Ethical Principles and Guidelines 
for the Protection of Human Subjects of Research, as drafted by the US 
National Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the 
ICH E6. 
15.2 
Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all subject 
materials will be submitted to the IRB for review and approval. Approval of both 
the protocol and the consent form must be obtained before any subject is 
enrolled. Any amendment to the protocol will require review and approval by 
the IRB before the changes are implemented in the study. 
 
15.3 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to 
participate in the study and continues throughout study participation. Extensive 
discussion of risks and possible benefits of study participation will be provided 
to subjects and their families, if applicable. A consent form describing in detail 
the study procedures and risks will be given to the subject. Persons who are 
not fluent in English and persons with impaired decision-making capacities will 
not be eligible for enrollment in this study. 
 
Consent forms will be IRB-approved, and the subject is required to read and 
review the document or have the document read to him or her. The investigator 


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or designee will explain the research study to the subject and answer any 
questions that may arise. The subject will sign the informed consent document 
prior to any study-related assessments or procedures. Subjects will be given 
the opportunity to discuss the study with their surrogates or think about it prior 
to agreeing to participate. They may withdraw consent at any time throughout 
the course of the study. A copy of the signed informed consent document will 
be given to subjects for their records. The rights and welfare of the subjects will 
be protected by emphasizing to them that the quality of their clinical care will 
not be adversely affected if they decline to participate in this study. 
 
 
The consent process will be documented in the clinical or research record. 
 
15.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
Children are excluded from this study because insufficient data are available in 
adults to judge potential risks in children. 
Individuals of any gender or racial/ethnic group may participate in this study. 
 
15.5 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the investigators, study staff, 
and the sponsor(s) and their agents. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to any study 
information relating to subjects. 
 
All members of the study team will be listed on the IRB application and are 
required to undergo annual HIPAA training to ensure responsible conduct 
regarding protected health information (PHI) in research. In addition, Human 
Subjects Training and Good Clinical Practice trainings are required every three 
years for members of the study team. 
 
The study protocol, documentation, data, and all other information generated 
will be held in strict confidence. No information concerning the study or the data 
will be released to any unauthorized third party without prior written approval of 
the sponsor. All PHI is stored securely on password protected servers. 
 
The study monitor or other authorized representatives of the sponsor may 
inspect all study documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or 
hospital) for the study subjects. The clinical study site will permit access to such 
records. 
 
To further protect the privacy of study participants, the Secretary, Health and 
Human Services (HHS), has issued a Certificate of Confidentiality (CoC) to all 


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researchers engaged in biomedical, behavioral, clinical, or other human 
subjects research funded wholly or in part by the federal government. 
Recipients of NIH funding for human subjects research are required to protect 
identifiable research information from forced disclosure per the terms of the NIH 
Policy (https://humansubjects.nih.gov/coc/index). As set forth in 45 CFR Part 
75.303(a) and NIHGPS Chapter 8.3, recipients conducting NIH-supported 
research covered by this Policy are required to establish and maintain effective 
internal controls (e.g., policies and procedures) that provide reasonable 
assurance that the award is managed in compliance with Federal statutes, 
regulations, and the terms and conditions of award. It is the NIH policy that 
investigators and others who have access to research records will not disclose 
identifying information except when the participant consents or in certain 
instances when federal, state, or local law or regulation requires disclosure. 
NIH expects investigators to inform research participants of the protections and 
the limits to protections provided by a Certificate issued by this Policy. 
15.6 
Future Use of Stored Specimens and Other Identifiable Data 
Residual samples will be relinquished to the TSB Biobank (2016-0934) for 
future exploratory analyses at the termination of this study. All subjects will 
have already signed a consent for the TSB Biobank protocol as part of the 
inclusion criteria. 
Any use of specimens outside the context of this protocol, including genetic 
testing, will only occur after IRB approval. 
 
 
 
16 
DATA HANDLING AND RECORD KEEPING 
This study will report clinical data using the UWCCC data management system utilizing 
study specific case report forms. Key study personnel are trained on the use of case 
report forms and will comply with protocol specific instructions for data collection. 
 
Patient demographics, patient specific study treatment calendars, adverse events and 
other information will be maintained with the UWCCC data management system. 
 
Participant data will be collected using protocol specific case report forms (CRFs). The 
CRFs will be approved by the study’s Principal Investigator and the study biostatistician 
prior to release for use. The Study Coordinator or designee will be responsible for 
registering the patient into the UWCCC data management system at time of study entry, 
completing CRFs based on the patient specific calendar, and updating the patient 
record until patient death or end of required study participation. 


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16.1 
Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study 
staff under the supervision of the investigator. All source documents and 
laboratory reports must be reviewed by the study team and data entry staff, 
who will ensure that they are accurate and complete. Unanticipated problems 
and adverse events must be reviewed by the investigator or designee. 
 
UWCCC Radiotherapy will serve as the Clinical Research Office for this trial. 
 
16.2 
Data Capture Methods 
Data will be collected through the web-based clinical research platform, 
OnCore (Forte Research), a system compliant with Good Clinical Practices and 
Federal Rules and Regulations. UWCCC personnel will coordinate and manage 
data for quality control assurance and integrity. All data will be collected and 
entered into OnCore by study site personnel. 
 
16.3 
Types of Data 
Patient demographics, patient medical history, patient specific study treatment 
calendars, adverse events, laboratory/pathology reports obtained during the 
course of treatment and afterwards, e.g., blood tests, biopsy results), findings 
from physical exams, and imaging scan reports/outcomes will be maintained 
with the UWCCC data management system. 
 
 
16.4 
Schedule and Content of Reports 
The UWCCC Protocol Review and Monitoring Committee (PRMC) determines 
the level of risk, thus the appropriate timelines for review of study documents, 
conduct and accrual. Protocol Safety Reports are run, reviewed and signed off 
by the study PI per the determined schedule. PSRs are then sent for review to 
the Data Safety Monitoring Committee (DSMC). A summary of the DSMC 
decisions for this study will be provided to the medical monitor at NIDCR 
according to the determined DSMC meeting schedule. 
 
Protocol Safety Reports include information such as accrual, adverse events, 
serious adverse events, and unanticipated problems. Annual review by the UW 
Health Sciences IRB will review accrual, reportable events, and study progress. 
A copy of the continuing review and supporting documents will be submitted to 
NIDCR at time of submission to the IRB. 
 
16.5 
Study Records Retention 
Shadow research charts with original consent forms and documents specifically 
created for this study will be maintained in the Department of Human Oncology 


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until the study is terminated. The records will then be sent to Wisconsin State 
Records Archiving facility for long term storage (10 years) and re-archived as 
needed. Study records will be maintained for at least three years from the date 
that the grant federal financial report (FFR) is submitted to the NIH. 
 
16.6 
Protocol Deviations 
Except in the case of a medical emergency, no protocol deviation is authorized. 
Changes to the protocol will be established by amendments by the Principal 
Investigator approved by the UW HS IRB. Protocol deviations may affect the 
conduct of the study from legal and ethical points of view and may influence the 
statistical analysis and pertinence of the study. Medical emergencies have to 
be handled in the patients’ best interest. The investigator has to contact the 
Sponsor to clarify if a patient may continue in the study when a protocol 
violation out of medical reasons has occurred. Protocol deviations that are not 
identifiable from the eCRF have to be recorded in a protocol deviation form. 
Protocol deviations will be evaluated at the data review meeting before 
database lock and will be described in the statistical analysis plan. 
 
It is the responsibility of the Principal Investigator to use continuous vigilance to 
identify and report deviations within 7 working days of identification of the 
protocol deviation, or within 7 working days of the scheduled protocol-required 
activity. All deviations must be addressed in study source documents and 
reported to NIDCR and to the UW HS IRB per their policies. The Principal 
Investigator is responsible for knowing and adhering to the reviewing IRB 
requirements. 
 
 
 
17 
PUBLICATION/DATA SHARING POLICY 
This study will comply with the NIH Public Access Policy, which ensures that the public 
has access to the published results of NIH funded research. It requires scientists to 
submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital 
archive PubMed Central upon acceptance for publication. 
 
The clinical trial will be registered on ClinicalTrials.gov, which is sponsored by the 
National Library of Medicine. 
 
The study investigators will have sole right to determine the content of the presented 
and published data. As PIs, Drs. Bruce and Kimple will retain a spot as both first and 
last author on all manuscripts, unless either elects to forgo this. Co-Is will have input 
into all remaining authorship spots. 


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APPENDICES 
A: SCHEDULE OF EVENTS 


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APPENDIX A: SCHEDULE OF EVENTS 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday one week later would 
be considered Day 7. 
 
Study Visit 1 
and 2 
Study 
Visit 3 
Study 
Visit 4 
Study 
Visit 5 
SOC 
SOC 
Follow up 1 
SOC 
Follow up 
2 
SOC 
Follow up 3 
Screening/ 
Baseline1 
Dose 
1 
Dose 
22, 
Safety 
Eval11 
Surgery 
1 mo post- 
op +/- 2 
wk 
3 mo 
post- 
definitiv 
e care10 
+/- 4 wk 
12 mo 
post- 
definitive 
care10 
+/- 4 wk 
REQUIRED ASSESSMENTS 
Informed consent 
X3 
Demographics 
X 
Medical History 
X 
Concurrent meds 
review 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
Vitals signs 
X 
X 
X13 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X4 
X 
X 
X 
X 
ECOG 
Performance status 
X 
X 
X 
X 
X 
CBC with diff 
X 
X4 
X 
Serum chemistry,5 
X 
X4 
X9 
X 
Pregnancy test for 
WOCP 
X6 
Adverse event 
evaluation7 
X 
X 
X 
X 
DISEASE ASSESSMENT 
Tumor 
measurements by 
clinical assessment 
X 
X 
Neck Imaging12 
X 
X 
TREATMENT 
Cetuximab 
X 
X 
CORRELATIVE STUDIES 
Tumor tissue from 
surgery 
X 
Blood collection 
for circulating 
tumor cells 
X 
X8 
X 
X 
X 
Research biopsy 
for biologic 
correlative studies 
X 
FOOTNOTES 
1. Pre-study tests to be done within 21 days of dose 1 cetuximab therapy. 


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2. Time between doses: 7 days (+/-3 days) 
3. Informed consent to be obtained within 28 days of starting treatment. 
4. If screening/baseline procedures are within 7 days prior to cetuximab dose 1, they don’t need to be repeated on day of dose 1. 
5. Serum chemistry should include: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, AST, ALT, alkaline 
phosphatase, total bilirubin, calcium, magnesium, protein, albumin. 
6. A negative serum/urine pregnancy test is required within 7 days prior to cetuximab dose 1. 
7. 
For subjects with unresolved treatment-related toxicity, follow as medically appropriate until resolution or stabilization. 
8. 
Pre-surgical blood draw for circulating tumor cells in serum should be done within 1 day prior to surgery. 
9. 
Prior to dose 2, required labs: magnesium, calcium and potassium 
10. Definitive therapy is defined as surgery alone, surgery + XRT or Surgery + chemoXRT 
11. Within 7 days prior to surgery, but as close as possible to surgery. 
12. May include any of the SOC imaging such as PET/CT, PET/MRI, CT or MRI 
13. Blood Pressure only