Clinical trial NCT01979211
Conditions: Head and Neck Cancer
Keywords: head and neck cancer
Sponsor: University of Cincinnati
Start date: 2013-10-01; Completion date: 2022-01-19
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The standard treatment of surgery followed by radiation therapy can stop tumors from growing in the head and neck region in most patients. However, the cancer can recur or can spread to other parts of the body. Cetuximab is a drug that may delay or prevent tumor growth by blocking certain cellular chemical pathways that lead to tumor development. It was approved by the United States Food and Drug Administration (FDA) in 2006 for the treatment of head and neck cancer.

The purpose of this study is to determine how easily cetuximab can be added to treatment with radiation therapy in patients with cutaneous cancer of the head and neck. This study will also look at how well cetuximab added to radiation therapy works over time and how well this treatment is tolerated.

Detailed description:
This is a Phase II trial to characterize the feasibility of treating patients with locally advanced cutaneous squamous cell carcinomas of the head and neck with post-operative radiotherapy and cetuximab. Cetuximab has previously been given safely in conjunction with head and neck radiotherapy for mucosal squamous cell carcinoma in multiple phase III trials, and so Phase I data is not necessary here.

Arms: arm 1: Cetuximab 400 mg/m2 IV over 120 minutes loading dose \> 4 days prior to initiation of radiation; Cetuximab 250 mg/m2 IV over 60 minutes weekly weeks 2-7 concurrent with Radiation therapy 60-66 Gy in 2 Gy daily fractions
Interventions: intervention 1: Cetuximab intervention 2: Radiation Therapy
Intervention descriptions: intervention 1: 400 mg/m2 IV over 120 minutes week 1; 250 mg/m2 IV over 60 minutes weekly weeks 2-7 intervention 2: Radiation Therapy 60-66 Gy in 2 Gy fractions starting week 2 of Cetuximab

Protocol documents:
Prot_SAP_000.pdf: 
UCHN-12-001 
Page 0 of 38 
03APR2018 
SUMMARY OF CHANGES – Protocol 
 
For Protocol Amendment # to: Phase II Trial of Post-operative Concurrent Radiation 
and Cetuximab for Locally Advanced Cutaneous Squamous Cell Carcinoma of the 
Head and Neck 
 
UCCI Protocol #: UCHN-12-001 
IRB Protocol #: 2013-3193 (UC) 
 
UCCI Version Date: 03APR2018 
Original Protocol Date: 21NOV2013 
 
 
I. Brief Table of Changes: 
 
# 
Section 
Change 
1. 
1.6 
Added that tissue may be collected from pathology 
2. 
2.3 
Added tertiary objective to match protocol 
3. 
4.2.2 
Deleted unnecessary test/EKG 
4. 
5.0 
Changed registration into OnCore 
5. 
7.2 
Clarification in subsequent dosing 
6. 
7.2.1 
Change in premedication wording 
7. 
8.1 
Added pathology as source and added Univ of Mich 
8. 
11 
Changed reporting requirements as well as data collection 
9.  
12 
Added Study Calendar 
10. 
All 
Update font and layout; update investigators 
 
 
 
II. Detailed Table of Changes: 
Section 
Old Language 
New Language 
Rationale 
for 
Change 
1.6 
We plan to harvest and 
store tissue samples at the 
time of surgery through the 
Head and Neck Tumor 
Bank already in place 
We plan to harvest and 
store tissue samples at 
the time of surgery 
through the Head and 
Neck Tumor Bank 
already in place when 
possible.  Otherwise, 
tissues may be 
requested from 
pathology. 
Adding 
that 
tissue 
may 
be 
collected 
from pathology allows 
for the use of pre-
existing 
tissue 
samples. 
 
2.3 
 
To quantify EGFR 
phosphorylation 
patterns and immune 
The 
process 
for 
buccal 
swabs 
was 
already 
within 
the 
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markers in the tumor-
adjacent normal 
tissue from buccal 
swabs obtained pre-
treatment, post-
loading dose of 
cetuximab and during 
RT. 
 
protocol.  Here we 
clarified the tertiary 
objective 
4.2.2 
EKG within 8 weeks prior 
to start of treatment 
deleted 
Unnecessary 
per 
Hemonc (Dr Worden) 
5.0 
Patients are registered by 
contacting the University of 
Cincinnati Clinical Trials 
Office at 513-584-7698. 
Patients are registered 
and enrolled in OnCore 
at 
the 
University 
of 
Cincinnati by the clinical 
coordinators. 
For 
University of Michigan 
patients, 
a 
unique 
number will be assigned 
by 
the 
University 
of 
Michigan team who will 
notify the University of 
Cincinnati Clinical Trials 
Office at 513-584-7698 
so that the patient may 
be entered into OnCore.   
Added 
clarity 
that 
OnCore will be used 
for patient registration 
and enrollment which 
is in-line with current 
practices at UCCI.  
 
7.2 
Cetuximab 
weeks 
2 
through 7 or 8 (concurrent 
with 
RT 
depending 
on 
standard 
of 
care 
RT): 
Patients 
will 
receive 
cetuximab, 
250 
mg/m2, 
intravenously (i.v.) over 60 
minutes 
on 
a 
weekly 
schedule. The infusion rate 
of cetuximab must never 
exceed 
5 
mL/min. 
Cetuximab will be given 
once a week prior to RT for 
a 
total 
of 
6-7 
doses 
concurrent with radiation 
therapy.  
In cases of delay in the 
completion 
of 
radiation 
therapy, 
then 
the 
concurrent 
doses 
of 
cetuximab may continue 
beyond week 8 without 
dose 
interruption 
until 
Cetuximab 
weeks 
2 
through 
7 
or 
8 
(concurrent 
with 
RT 
depending on standard 
of care RT): Patients will 
receive cetuximab, 250 
mg/m2, 
intravenously 
(i.v.) 
over 
60-120 
minutes on a weekly 
schedule. Cetuximab will 
be given ceconcurrent 
with radiation therapy.  
In cases of delay in the 
completion of radiation 
therapy, 
then 
the 
concurrent 
doses 
of 
cetuximab may continue 
beyond week 8 without 
dose interruption until 
radiation 
therapy 
is 
completed. The total of 
number 
of 
cetuximab 
doses should not exceed 
Clarification 
in 
subsequent dosing 
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radiation 
therapy 
is 
completed. The total of 
number 
of 
cetuximab 
doses should not exceed 
11. 
 
11. 
 
7.2.1 
All 
patients 
will 
be 
premedicated 
with 
diphenhydramine 
hydrochloride, 50 mg, (or 
an 
equivalent 
antihistamine) by i.v. 30-
60 minutes prior to the 
first dose of cetuximab in 
an effort to prevent an 
infusion reaction. At the 
discretion of the treating 
physician, dexamethasone, 
20 mg, and an H2 blocker 
also may be administered 
i.v. 
Premedications 
are 
recommended 
prior 
to 
subsequent doses, but at 
the 
Investigator’s 
discretion, the dose of 
diphenhydramine 
or 
dexamethasone may be 
reduced. 
Premedications are 
recommended and per 
discretion of the treating 
physician. 
Allowing for individual 
local 
standard 
between  UC and UM 
7.3.3 
 
Updated table for 
clarification of cetuximab 
dosing modification 
 
8.1 
 
Added pathology as 
source and added 
University of Michigan 
 
 
8.2 
 
Added clarification 
regarding hypothesis for 
buccal swabs 
 
11 
 
Changed reporting 
requirements as well as 
data collection 
 
12 
 
Added Study Calendar 
 
All 
 
Update font and layout; 
update investigators 
 
 
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Phase II Trial of Post-operative Concurrent Radiation and Cetuximab for Locally 
Advanced Cutaneous Squamous Cell Carcinoma of the Head and Neck 
 
 
University of Cincinnati PI: 
Vinita Takiar,  MD 
Assistant Professor 
Department of Radiation Oncology 
University of Cincinnati 
 
University of Michigan PI: 
Michelle Mierzwa MD 
Assistant Professor 
Department of Radiation Oncology 
University of Michigan 
 
 
Statistician: 
Changchun Xie, PhD 
Assistant Professor 
Department of Epidemiology and Biostatistics 
University of Cincinnati 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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UCHN-12-001 
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Roadmap  
Eligibility:  cutaneous squamous cell carcinoma with invasion of any skeletal muscle, 
cartilage, bone or lymph nodes of the head and neck after resection 
 
 
 
 
 
 
`e3wqq 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1: 
 
Cetuximab 400mg/m2 
Surgery 
 
 Day 8 - 55:  
 Weekly Cetuximab 
250mg/m2 (x7-8 doses) 
+ 
RT 60-66 Gy 
Enrollment 
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Table of Contents 
 
Protocol Roadmap  
 
 
 
 
 
 
2 
 
1.  
Background  
 
 
 
 
 
 
5 
1.1 
Locally advanced cutaneous cancer 
 
 
 
5 
1.2 
Study Design 
 
 
 
 
 
 
5 
1.3 
Epidermal Growth Factor Receptor 
 
 
 
5 
1.4 
Cetuximab 
 
 
 
 
 
 
 
6 
1.5 
Safety of Cetuximab in SCCHN Clinical Studies 
 
7 
1.6 
Translational Science 
 
 
 
 
 
10 
1.7 
Quality of Life and Functional Assessments 
 
 
10 
 
2. 
Objectives 
 
 
 
 
 
 
 
12 
2.1 
Primary Objectives  
 
 
 
 
 
12 
2.2 
Secondary Objectives 
 
 
 
 
 
12 
2.3 
Tertiary Objectives  
 
 
 
 
 
12 
 
3.0 
Patient Selection 
 
 
 
 
 
 
12 
3.1 
Conditions for Patient Eligibility 
 
 
 
 
12 
3.2 
Conditions for Patient Ineligibility  
 
 
 
13 
 
4. 
Pretreatment Evaluations/Management  
 
 
15 
4.1 
Required Evaluations/Management 
 
 
 
15 
4.2 
Highly Recommended Evaluations/Management 
 
15 
 
5.0 
Registration Procedures 
 
 
 
 
 
15 
 
6. 
Radiation Therapy  
 
 
 
 
 
15 
6.1 
Dose Specifications  
 
 
 
 
 
15 
6.2 
Technical Factors 
 
 
 
 
 
 
15 
6.3 
Localization, Simulation, and Immobilization 
 
 
16 
6.4 
Target and Normal Tissue Volume Definitions  
 
16 
6.5 
Treatment Planning and Delivery  
 
 
 
18 
6.6 
Compliance Criteria  
 
 
 
 
 
19 
6.7 
RT Quality Assurance Reviews 
 
 
 
 
19 
6.8 
Radiation Therapy Adverse Events 
 
 
 
19 
 
7. 
Drug Therapy 
 
 
 
 
 
 
20 
7.1 
Cetuximab Initial Dose 
 
 
 
 
 
21 
7.2 
Cetuximab Subsequent Doses 
 
 
 
 
21 
7.3 
Cetuximab Dose Modifications 
 
 
 
 
26 
7.4 
Adverse Events 
 
 
 
 
 
 
28 
 
8. 
Tissue/Specimen Submission 
 
 
 
 
29 
 
9. 
Patient Assessments 
 
 
 
 
 
29 
9.1 
Study Parameters  
 
 
 
 
 
29 
9.2 
Evaluation during Radiotherapy  
 
 
 
29 
9.3 
Evaluation in Follow-up 
 
 
 
 
 
29 
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9.4 
Outcomes Criteria  
 
 
 
 
 
30 
9.5 
Quality of Life and Functional Assessments 
 
 
30 
 
9.6 
Criteria for Discontinuation of Protocol Treatment 
 
31 
 
10.  
Statistical Considerations  
 
 
 
 
32 
 
 
11. 
Data and Safety Monitoring 
 
 
 
 
33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.1 Locally Advanced Cutaneous Cancer  
Cutaneous squamous cell carcinomas are very common malignant neoplasms in the 
United States, frequently associated with sun exposure and fair complexions.  Other risk 
factors include advanced age and acquired immunosuppression after solid organ 
transplantation or treatment for leukemia/lymphoma.   
 
Squamous cell carcinomas of the skin are considered aggressive non-melanoma skin 
cancers.  Cutaneous squamous cell carcinomas of the head and neck (CSCCHN) occur 
commonly, and this is reflected in the AJCC seventh edition 2010 staging, which created 
new staging for non-melanoma skin cancer staging that correlates with the head and neck 
mucosal staging1.   
 
Within CSCCHN, poor prognosis has been associated with involvement of the parotid 
gland, advancing cervical nodal metastases, immunosuppression, and bony involvement.  
Overall survival at 2 years in retrospective studies2-3, was 70-80% for N1 parotid and/or 
neck involvement, whereas it was 25-50% for N2-3 patients. It has been reported that 
immunocompromised patients have a 7.2 fold increased risk of local recurrence and a 5.3 
fold increased risk of any recurrence after treatment for CSCCHN.  Mortality is also 
increased with skin cancer; skin cancer was the fourth most common cause of death in a 
reported renal transplant cohort 4.  Additionally, single institution series have reported that 
histopathology of CSCC in immunocompromised patients is more aggressive, with tumor 
size being less important 5.  The 2010 AJCC staging manual documents increased local 
failure rates for tumors with invasion of skeletal muscle or cartilage.   
 
CSCCHN is most commonly managed with primary surgery, although very locally 
advanced lesions can be palliated with primary radiotherapy.  After radical resection, 
indications for post-operative radiotherapy include positive surgical margins, perineural 
invasion, positive lymph nodes, invasion of bone or cartilage and extensive skeletal muscle 
infiltration.  Despite surgery and post-operative radiotherapy, approximately 25% patients 
will experience loco-regional failure, 25% will develop distant metastases and the 2 year 
overall survival is several large series is reported to be 40-55%6 7 8.  In our experience at 
the University of Cincinnati, loco-regional control with surgery and post-operative 
radiotherapy alone has been 68% (unpublished).  
 
While these numbers could certainly be improved upon, there have been no prospective 
trials to date looking at the addition of chemotherapy or targeted therapies to radiotherapy 
in this setting.   
 
1.2 Study Design 
 
Postoperative RT alone is the current standard of care for patients with locally advanced 
cutaneous malignancies of the head and neck, with suboptimal outcome.  The goal of this 
trial is prospectively study the addition of concurrent cetuximab to radiotherapy for locally 
advanced CSCCHN in the post-operative setting for CSCCHN.   
 
1.3 Epidermal Growth Factor Receptor (EGFR) 
 
In mucosal SCCHN, a recent important area of advance has been the study of epidermal 
growth factor receptor (EGFR).  EGFR is expressed at very high levels in the majority of 
human mucosal head and neck squamous cell carcinoma (SCCHN). Furthermore, pre-
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clinical data indicate that it is not merely a ‘bystander’ but is intimately associated with the 
malignant phenotype of SCCHN. EGFR activation in response to a ligand (e.g., EGF or 
TGF-alpha) results in phosphorylation of its intracytoplasmic tyrosine kinase domain, 
leading to a cascade of signal transduction within the cell. This ultimately leads to DNA 
synthesis, cell proliferation, anti-apoptosis, and transcription of growth factors such as pro-
angiogenic molecules. Blockade of this pathway is an effective anti-neoplastic strategy; 
furthermore, EGFR blockade appears to result in radiosensitization. This hypothesis was 
proven in a randomized trial by Bonner, et al. (2006)9. In that study, patients with locally 
advanced, non-operative mucosal SCCHN were randomized to RT alone or RT with 
weekly cetuximab.  Local-regional control and survival were significantly improved with 
cetuximab. 2-year locoregional control was increased significantly with cetuximab by 9% 
(from 41 to 50%), and this translated into an overall survival advantage at 5 years.  5-year 
overall survival was 45% for RT/cetuximab, compared with 36% for RT alone. Interestingly, 
the development of > grade 2 rash associated with cetuximab was associated with 
significantly improved overall survival. 
 
1.4 Cetuximab 
Cetuximab is a humanized monoclonal antibody against the EGFR receptor. In the Bonner 
study of cetuximab and radiotherapy for locally advanced non-operative mucosal SCCHN 
described above, cetuximab appeared to have little toxicity when given concurrently with 
radiotherapy for mucosal SCCHN and 93% of patients received the prescribed cetuximab 
dose [Bonner 2006]. Furthermore, the Bonner study showed no evidence that cetuximab 
increased the rate of ≥ Grade 3 mucositis or dysphagia, no evidence of an increased rate 
of late effects, and no evidence of a worsening of QOL relative to RT alone.  
 
The Bonner study is not the only data in support of cetuximab as a valuable treatment 
against mucosal head and neck cancer. Cetuximab is currently under investigation in the 
post-operative setting for mucosal intermediate risk SCCHN in RTOG 0920.  In platinum-
refractory recurrent/metastatic mucosal SCCHN, single agent cetuximab has a response 
rate of approximately 11%10,  providing further clinical evidence that it is working via a 
pathway (or pathways) distinct from DNA damaging agents such as platins or RT. In first-
line therapy for recurrent/metastatic SCCHN, the addition of cetuximab to 5- FU/platinum 
significantly improved overall survival 11. 
 
In locally advanced unresectable CSCCHN, cetuximab has been investigated as a single 
agent, demonstrating 69% disease control rate at 6 weeks by RECIST criteria12.  Seventy-
eight percent of patients developed grade 2 acneiform rash, which was associated with 
prolonged disease free survival. To date, cetuximab has not been investigated 
concurrently with radiotherapy in the setting of cutaneous malignancy.  
 
Based upon the data described above, we propose testing concurrent cetuximab with 
postoperative RT for those patients who have a high risk of recurrence as results with 
radiotherapy alone are suboptimal. We will compare the results of the current study with 
historical results using the current standard of care for these patients (RT alone).  
 
1.5 Safety of Cetuximab in SCCHN Clinical Studies 
Cetuximab has been evaluated in 208 patients with locally or regionally advanced SCCHN 
who received cetuximab in combination with radiation and as monotherapy in 103 patients 
with recurrent or metastatic SCCHN. Of the 103 patients receiving cetuximab 
monotherapy, 53 continued to a second phase with the combination of cetuximab plus 
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chemotherapy. Patients receiving cetuximab plus radiation therapy received a median of 8 
doses (range 1-11 infusions). The population had a median age of 56; 81% were male and 
84% Caucasian. Patients receiving cetuximab monotherapy, received a median of 11 
doses (range 1-45 infusions). The population had a median age of 57; 82% were male and 
100% Caucasian. The most serious adverse reactions associated with cetuximab in 
combination with radiation therapy in patients with head and neck cancer were: infusion 
reaction (3%); cardiopulmonary arrest (2%); dermatologic toxicity (2.5%); mucositis (6%); 
radiation dermatitis (3%);confusion (2%);diarrhea (2%). 
 
Fourteen (7%) patients receiving cetuximab plus radiation therapy and 5 (5%) patients 
receiving cetuximab monotherapy, discontinued treatment primarily because of adverse 
events. The most common adverse events seen in 208 patients receiving cetuximab in 
combination with radiation therapy were acneiform rash (87%), mucositis (86%), radiation 
dermatitis (86%), weight loss (84%), xerostomia (72%), dysphagia (65%), asthenia (56%), 
nausea (49%), constipation (35%), and vomiting (29%). 
The most common adverse events seen in 103 patients receiving cetuximab monotherapy 
were acneiform rash (76%), asthenia (45%), pain (28%), fever (27%), and weight loss 
(27%). 
 
The data in the table below are based on the experience of 208 patients with 
locoregionally advanced SCCHN treated with cetuximab plus radiation therapy compared 
to 212 patients treated with radiation therapy alone (Cetuximab [Erbitux™] package insert, 
2006). 
 
 
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Late Radiation Toxicity 
The overall incidence of late radiation toxicities (any grade) was higher in cetuximab in 
combination with radiation therapy compared with radiation therapy alone. The following 
sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), 
subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), 
esophagus (44% versus 35%), skin (42% versus 33%), brain (11% versus 9%), lung (11% 
versus 8%), spinal cord (4% versus 3%), and bone (4% versus 5%). The incidence of 
Grade 3 or 4 late radiation toxicities were generally similar between the radiation therapy 
alone and the cetuximab plus radiation treatment groups. 
 
 
Clinically Relevant Adverse Events Related to Cetuximab 
Pooled adverse event data are available for 2,127 patients treated with cetuximab alone or 
in combination with chemotherapy and/or radiation therapy  (21 ImClone studies, 9 Merck 
KgaA, 2 BMS, and 1 ECOG study). A total of 90.3% of the patients reported adverse 
events (AEs). Approximately two-thirds (64.8%) of patients reported at least one Grade 3 
or 4 event. Cetuximab-related AEs were observed in 1,817 patients (85.4%). The most 
common composite groupings of adverse events deemed related to cetuximab as reported 
by investigators in all cetuximab trials (N = 1,817) include acneiform rash (76.2%), acne-
like 
rash 
(72.4 
%), 
fatigue/malaise/lethargy 
(30.1%), 
nausea/vomiting 
(24%), 
mucositis/stomatitis (17.5 %), infusion-related symptoms (15.6%), diarrhea (15.4 %), and 
hypersensitivity reaction (5.3%). 
Acne-Like Rash 
In clinical studies of cetuximab, dermatologic toxicities, including acneiform rash, skin 
drying and fissuring, and inflammatory and infectious sequelae (e.g., blepharitis, cheilitis, 
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cellulitis, cyst) were reported. In patients with advanced colorectal cancer, acneiform rash 
was reported in 89% (686/774) of all treated patients, and was severe (grade 3 or 4) in 
11% (84/774) of these patients. Subsequent to the development of severe dermatologic 
toxicities, complications including S. aureus sepsis and abscesses requiring incision and 
drainage were reported. Non-suppurative acneiform rash described as “acne”, “rash”, 
“maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis” was observed in 
patients receiving cetuximab plus irinotecan or cetuximab monotherapy. One or more of 
the dermatological adverse events were reported in 88% (14% grade 3) of patients 
receiving cetuximab plus irinotecan and in 90% (8% grade 3) of patients receiving 
cetuximab monotherapy. Acneiform rash most commonly occurred on the face, upper 
chest, and back but could extend to the extremities and was characterized by multiple 
follicular- or pustular-appearing lesions. Skin drying and fissuring were common in some 
instances, and were associated with inflammatory and infectious sequelae (e.g., 
blepharitis, cellulitis, cyst). Two cases of S. aureus sepsis were reported. The onset of 
acneiform rash was generally within the first two weeks of therapy. Although in a majority 
of the patients the event resolved following cessation of treatment, in nearly half of the 
cases, the event continued beyond 28 days. 
 
Nail Disorder 
A related nail disorder, occurring in 14% of patients (0.4% Grade 3), is characterized as a 
paronychial inflammation with associated swelling of the lateral nail folds of the toes and 
fingers, with the great toes and thumbs as the most commonly affected digits. 
 
Infusion Reactions 
In clinical trials, severe, potentially fatal infusion reactions were reported, one leading to 
death. These events include the rapid onset of airway obstruction (bronchospasm, stridor, 
hoarseness), urticaria, and/or hypotension. In studies in advanced colorectal cancer, 
severe infusion reactions were observed in 3% of patients receiving cetuximab plus 
irinotecan and 2% of patients receiving cetuximab monotherapy. Grade 1 and 2 infusion 
reactions, including chills, fever, and dyspnea usually occurring on the first day of initial 
dosing, were observed in 16% of patients receiving cetuximab plus irinotecan and 19% of 
patients receiving cetuximab monotherapy. A 20-mg test dose was administered 
intravenously over 10 minutes prior to the initial dose to all patients in earlier studies. The 
test dose did not reliably identify patients at risk for severe allergic reactions. Severe 
infusion reactions occurred with the administration of cetuximab in approximately 3% of 
patients, rarely with fatal outcome (<1 in 1000). Approximately 90% of severe infusion 
reactions were associated with the first infusion of cetuximab despite the use of 
prophylactic antihistamines. These reactions were characterized by the rapid onset of 
airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and/or hypotension. 
 
Pulmonary Toxicity 
Interstitial lung disease (ILD) was reported in 3 of 774 (< 0.5%) patients with advanced 
colorectal cancer receiving cetuximab. Interstitial pneumonitis with non-cardiogenic 
pulmonary edema resulting in death was reported in one case. Two patients had pre-
existing fibrotic lung disease and experienced an acute exacerbation of their disease while 
receiving cetuximab in combination with irinotecan. In the clinical investigational program, 
an additional case of interstitial pneumonitis was reported in a patient with head and neck 
cancer treated with cetuximab and cisplatin. The onset of symptoms occurred between the 
fourth and eleventh doses of treatment in all reported cases. 
 
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1.6 Translational Science 
This study will aim to address future translational science questions related to EGFR and 
cetuximab in skin cancers.  We plan to harvest and store tissue samples at the time of 
surgery through the Head and Neck Tumor Bank already in place when possible.  
Otherwise, tissues may be requested from pathology. These samples may be used for 
future exploratory analysis of other molecular factors in CSCCHN. Presently, while much 
has been learned about the relationships among EGFR, cetuximab, and SCCHN, there is 
marked uncertainty regarding if and how this biological information should be used 
clinically in mucosal or cutaneous SCCHN.  
 
1.7 Quality of Life and Function Assessments 
It is now well established that cancer of the head and neck often has profoundly 
debilitating effects on quality of life (QOL), function, and performance. In a recently 
reported phase III trial of cetuximab and radiation therapy (RT) for mucosal head and neck 
squamous cell carcinoma (HNSCC), cetuximab did not significantly increase acute RT-
associated adverse effects (Bonner 2006). This study also found that addition of cetuximab 
to RT significantly improved locoregional control and increased overall survival without 
adversely affecting QOL (Curran 2007)13.  
 
1.7.1 Quality of Life (QOL) Assessments 
Quality of life will be assessed using two validated, multidimensional patient reported QOL 
measures including: the FACT HN and the Dermatology Life Quality Index (DLQI). Both of 
these QOL validated tools are currently being used by the RTOG in SCCHN trials, and the 
FACT HN is being used in the UCCI Prospective Head and Neck Oncology 
Comprehensive Database that is set to go live 1/1/13.   
The FACT-H&N is a multidimensional, patient self-report QOL instrument specifically 
designed and validated for use with head and neck cancer patients. The FACT-HN 
consists of a 27-item core scale (FACT-G) and is supplemented with a 12-item head and 
neck subscale targeting head and neck related symptoms and side effects14.  
The Dermatology Life Quality Index (DLQI) will be used to explore the impact of cetuximab 
induced rash on quality of life. It is expected that rash (acneiform; maculo-papular), pruritis, 
and other visible consequences associated with cetuximab-induced rash will have a 
significant negative impact quality of life15,16. The DLQI17 is designed to assess the impact 
of a wide range of skin disease on patient quality of life 18,19, and it is currently being used 
in RTOG 0920 to assess the impact of cetuximab-induced rash on QOL in mucosal 
SCCHN. The DLQI consists of 10 items and covers 6 domains including symptoms and 
feelings, daily activities, leisure, work and school, personal relationships, and treatment. 
Response categories include "not at all," "a little,"a lot," and "very much," with 
corresponding scores of 0, 1, 2, and 3 respectively; the response "not relevant" (and 
unanswered items) are scored as "0". A total score is calculated by summing the score of 
all items, resulting in a maximum score of 30 and a minimum score of 0. Scale scores are 
calculated for each domain. Higher scores indicate poorer HRQL (i.e., more impairment). 
The FACT HN and DLQI will be administered a baseline and at 3, 12, and 24 months after 
the start of radiation therapy.  
 
1.7.2 Timeframe of Assessments 
These patient-reported QOL and function measures and the clinician-assessed measures 
will be administered at baseline and at 3, 12, and 24 months from the start of radiation. 
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The 3- month QOL assessment was chosen to coincide with usual practice of seeing a 
head and patient 2-3 weeks after completion of radiation therapy. This assessment will 
provide the immediate impact of radiation therapy +/- cetuximab on QOL. The 12-month 
QOL assessment was chosen to coincide with usual practice of seeing a head and patient 
1 year after completion of radiation therapy. The Radiation Oncologists expect at this time 
that almost all acute toxicities related to radiation will be resolved, and they are interested 
in assessing the patient’s QOL at that time. These 2 assessment time points for patient 
reported outcomes are routinely used in RTOG and other head and neck studies. PRO 
assessment has been added at 24 months from RT completion.  That time point was 
chosen because 80 to 90% of the patients who will progress do so by 2 years. For patients 
who are disease free then, the issue, it is felt, 
becomes the long-term sequelae of the treatments. 
 
 
2.0 OBJECTIVES 
 
2.1 Primary Objective 
 
To assess the 2 – year locoregional control (LRC) of cetuximab and radiation therapy in 
high risk postoperative patients with cutaneous squamous cell carcinoma of the head and 
neck. 
 
2.2 Secondary Objectives 
 
To descriptively assess the impact of the addition of cetuximab to postoperative radiation 
therapy on the following: 
 2 year- disease-free survival (DFS) and 2 and 5 –year overall survival (OS); 
 
 
2.3 Tertiary Objectives  
To assess the impact of the addition of cetuximab to postoperative radiation therapy on the 
following: 
Patient-reported quality of life (QOL), swallowing, xerostomia, and skin toxicity based on 
head and neck specific instruments, including the Functional Assessment of Cancer 
Therapy-Head & Neck (FACT-HN) and the Dermatology Life Quality Index (DLQI); 
 
To quantify EGFR phosphorylation patterns and immune markers in the tumor-adjacent 
normal tissue from buccal swabs obtained pre-treatment, post-loading dose of cetuximab 
and during RT. 
 
 
3.0 PATIENT SELECTION 
 
3.1 Conditions for Patient Eligibility 
3.1.1  Pathologically (histologically) proven diagnosis of cutaneous squamous cell 
carcinoma of the head and neck; 
3.1.2  Pathologic invasion of skeletal muscle, cartilage, bone or lymph nodes (>N1), M0 
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including no distant metastases, based upon the following minimum diagnostic workup:  
3.1.2.1  General history and physical examination by a Radiation Oncologist and/or 
Medical Oncologist within 2 weeks prior to registration;  
3.1.2.2  Examination by an ENT or Head & Neck Surgeon, within 8 weeks prior to 
registration;  
3.1.2.3  Chest CT scan (with or without contrast) or CT/PET of chest (with or without 
contrast) within 8 weeks prior to registration.  
3.1.3  Gross total resection of the primary tumor with curative intent must be completed 
within 9 weeks of registration.  This may be a recurrent cutaneous squamous cell 
carcinoma of the skin, and patient is still eligible as long as all gross disease is currently 
resected.   
3.1.4  Zubrod performance status of 0-2 within 2 weeks prior to registration 
3.1.5  Age > 18;  
3.1.6  CBC/differential obtained within 4 weeks prior to registration on study, with adequate 
bone marrow function defined as follows:  
3.1.6.1  Absolute granulocyte count (AGC) > 1,500 cells/mm3;  
3.1.6.2  Platelets > 100,000 cells/mm3;  
3.1.6.3  Hemoglobin > 8.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb > 8.0 g/dl is acceptable).  
3.1.7 Adequate hepatic function, defined as follows: 
3.1.7.1  Total bilirubin < 2 x institutional ULN within 2 weeks prior to registration;  
3.1.7.2  AST or ALT < 3 x institutional ULN within 2 weeks prior to registration.  
3.1.8  Negative serum pregnancy test within 2 weeks prior to registration for women of 
childbearing potential;  
3.1.9  The following assessments are required within 2 weeks prior to the start of 
registration: Na, K, Cl, glucose, Ca, Mg, and albumin. Note: Patients with an initial 
magnesium < 0.5 mmol/L (1.2 mg/dl) may receive corrective magnesium supplementation 
but should continue to receive either prophylactic weekly infusion of magnesium and/or 
oral magnesium supplementation (e.g., magnesium oxide) at the investigator’s discretion.  
3.1.10  Women of childbearing potential and male participants who are sexually active 
must agree to use a medically effective means of birth control;  
3.1.11  Patients must provide study specific informed consent prior to study entry, 
including consent for optional tissue submission  
3.2 Conditions for Patient Ineligibility  
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3.2.1  Prior invasive malignancy unless disease free for a minimum of 3 years; noninvasive 
cancers (For example, carcinoma in situ of the breast, oral cavity, or cervix are all 
permissible) are permitted even if diagnosed and treated < 3 years ago. Prior basal cell 
carcinoma and squamous cell carcinoma of the skin is allowed.  Patients with a history of 
T1-2, N1, M0 resected differentiated thyroid carcinoma are considered eligible.   
3.2.2  Prior systemic chemotherapy or anti-EGF therapy for the study cancer or for a 
different prior cancer; 
3.2.3  Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields;  
3.2.4  Severe, active co-morbidity, defined as follows:  
3.2.4.1 Unstable angina and/or congestive heart failure requiring hospitalization within 6 
months prior to registration; 
3.2.4.2  Transmural myocardial infarction within 6 months prior to registration;  
3.2.4.3  Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration;  
3.2.4.4  Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of registration;  
3.2.4.5  Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires 
oxygen therapy or is thought to require oxygen therapy within 1 year prior to registration;  
3.2.4.6  Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, 
however, that laboratory tests for coagulation parameters are not required for entry into 
this protocol.  
3.2.4.7  Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC 
definition; note: HIV testing is not required for entry into this protocol. The need to exclude 
patients with AIDS from this protocol is necessary because the treatments involved in this 
protocol may be significantly immunosuppressive. Protocol-specific requirements may also 
exclude immuno-compromised patients.  
3.2.4.8 Grade 3-4 electrolyte abnormalities (CTCAE, v. 4.03):  
 
Serum calcium (ionized or adjusted for albumin) < 7 mg/dl (1.75 mmol/L) or > 
12.5 mg/dl (> 3.1 mmol/L) despite intervention to normalize levels;  
 
Glucose < 40 mg/dl (< 2.2 mmol/L) or > 250 mg/dl (> 14mmol/L);  
 
Magnesium < 0.9 mg/dl (< 0.4 mmol/L) or > 3 mg/dl (> 1.23 mmol/L) despite 
intervention to normalize levels;  
 
Potassium < 3.5 mmol/L or > 6 mmol/L despite intervention to normalize levels;  
 
Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels.  
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3.2.5  Pregnancy or women of childbearing potential and men who are sexually active and 
not willing/able to use medically acceptable forms of contraception; this exclusion is 
necessary because the treatment involved in this study may be significantly teratogenic.  
3.2.6  Prior allergic reaction to cetuximab.  
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT 
4.1 Required Evaluations/Management   
Baseline QOL and functional assessments prior to the start of treatment: the Functional 
Assessment of Cancer Therapy-Head & Neck (EORTC HN35); the Dermatology Life 
Quality Index (DLQI);  
4.2 Highly Recommended Evaluations/Management 
4.2.1  Evaluation for prophylactic gastrostomy tube placement (especially if the patient is > 
10% below ideal body weight) within 4 weeks prior to the start of treatment;  
4.2.2 Banking of tumor tissue and blood in the UCCI Head and Neck Tumor Bank is 
highly encouraged but not required for protocol enrollment. 
5.0 Registration Procedures 
Patients are registered and enrolled in OnCore at the University of Cincinnati by the clinical 
coordinators. For University of Michigan patients, a unique number will be assigned by the 
University of Michigan team who will notify the University of Cincinnati Clinical Trials Office 
at 513-584-7698 so that the patient may be entered into OnCore.   
6.0 RADIATION THERAPY  
Protocol treatment must begin within 3 weeks after registration. 
6.1  Dose Specifications  
The prescribed radiotherapy dose will be 60-66 Gy in 2 Gy once-daily fraction size (total of 
30-33 fractions). Radiotherapy should begin on a Monday, Tuesday or Wednesday. The 
daily dose of 2 Gy will be prescribed such that 95% of the PTV volume receives at least 
95% of prescribed dose. The spinal cord dose may not exceed 45 Gy to any volume larger 
than 0.03 cc. 
6.2  Technical Factors 
Treatment Planning/Delivery: Megavoltage energy photon beam irradiation is required, but 
may also include electron therapy as necessary to include superficial disease areas.  3D 
conformal or IMRT treatment planning may be may be used, and treatment verification 
films must be taken a least once weekly.   
6.3 Localization, Simulation, and Immobilization 
6.3.1  Patients must have an immobilization device (e.g., aquaplast mask) made prior to 
treatment planning CT scan.  
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6.3.2  All patients will undergo CT simulation for treatment planning. The treatment 
planning CT scan may be completed with or without IV contrast. The treatment planning 
CT scan must be performed with the immobilization device and in the treatment position. 
Slice thickness should be 0.3 cm or less.  
6.4 Target and Normal Tissue Volume Restrictions 
6.4.1 Definition of Target Volumes 
6.4.1.1 CTV60: This volume will receive 2 Gy per day. CTV60 will include the primary 
tumor bed (based on preoperative imaging, preoperative physical exam/endoscopy, 
operative findings, pathologic findings) plus the post-operative neck. This volume may 
include the skin. It is recognized that after surgery, there can be considerable distortion of 
normal anatomy. If possible, preoperative GTV(s) should be fused onto the postoperative 
radiation therapy planning CT scan, and appropriate margins added for microscopic 
spread (1.5-2 cm). 
CTV60 also will include the ipsilateral pathologically positive hemineck (if both sides of the 
neck are proven pathologically positive, CTV60 will include both sides). This generally 
means encompassing nodal levels 2a, 3, and 4 for all cases. Nodal levels 1, 2b, 5a, and 
5b are included in CTV60 in selected circumstances.  For questions, contact the Principal 
Investigator, Dr. Mierzwa. 
6.4.1.2  CTV56: This will include all other regions felt to be at risk for harboring 
microscopic cancer that do not meet the criteria for CTV60. For example, this would apply 
to the contralateral hemineck being irradiated electively for a midline primary cancer. This 
volume will receive approximately 1.85- 2 Gy per day.  
6.4.1.3  CTV66 Optional: This may be defined at the discretion of the treating radiation 
oncologist. This would include a region or regions felt to be at especially high risk for 
recurrence (e.g., an area of very close margin of resection or nodal extracapsular 
extension). This area will be receiving a daily fraction size of 2- 2.2 Gy and thus, the 
volume of CTV66 should be kept as small as possible.  
6.4.1.4  Planning Target Volumes (PTVs): In general, the PTV should not go outside of the 
skin surface; if it does exceed the skin surface, the application of bolus material over this 
portion of the PTV may be considered to treat skin to full dose.  
6.4.1.4.1  PTV Expansion The minimum CTV-to- PTV expansion is 3 mm (a larger 
expansion may be necessary for a target volume subject to significant intra-fraction 
variability, such as the non-immobilized oral tongue).  In general, the CTV-to-PTV 
expansion should not exceed 10 mm.  
6.4.2 Definition of Normal Tissues/Organs at Risk (OARs)- adapted from RTOG 1016 
6.4.2.1  Spinal Cord: The cord begins at the cranial-cervical junction (i.e., the top of the C1 
vertebral body). Superior to this is brainstem and inferior to this is cord. The inferior border 
of the spinal cord is at approximately T3-4 (i.e., just below the lowest slice level that has 
PTV on it). The spinal cord shall be defined based on the treatment planning CT scan. In 
addition, however, a Planning Risk Volume (PRV) spinal cord shall be defined. The 
PRVcord = cord + 5 mm in each dimension. This is irrespective of whether or not IGRT is 
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used.  
6.4.2.2  Brainstem: The inferior most portion of the brainstem is at the cranial-cervical 
junction where it meets the spinal cord. For the purposes of this study, the superior most 
portion of the brainstem is approximately at the level of the top of the posterior clinoid. The 
brainstem shall be defined based on the treatment planning CT scan. In addition, however, 
a Planning Risk Volume (PRV) brainstem shall be defined. The PRVbrainstem = brainstem 
+ 3 mm in each dimension.  
6.4.2.3  Lips and Oral Cavity: These should be contoured as 2 separate structures as the 
goal is to keep the lip dose much lower than the oral cavity dose. The definition of lips is 
self explanatory. The oral cavity will be defined as a composite structure consisting of the 
anterior 1⁄2 to 2/3 of the oral tongue/floor of mouth, buccal mucosa, and palate.  
6.4.2.4  Parotid Glands: Parotid glands will be defined based on the treatment planning CT 
scan.  
6.4.2.5  OARpharynx: This will be defined as the “uninvolved” posterior pharyngeal wall 
plus adjacent constrictor muscles. This extends from the superior constrictor region (the 
inferior pterygoid plates level) to the cricopharyngeal inlet (posterior cricoid cartilage level). 
This should not overlap the PTVs.  
6.4.2.6  Cervical Esophagus: This will be defined as a tubular structure that starts at the 
bottom of OARpharynx and extends to the thoracic inlet.  
6.4.2.7  Glottic/Supraglottic Larynx (GSL): Obviously, for patients who have had a total 
laryngectomy, this structure is not applicable. This will be defined as a “triangular prism 
shaped” volume that begins just inferior to the hyoid bone and extends to the cricoid 
cartilage inferiorly and extends from the anterior commissure to include the arytenoids. 
This includes the infrahyoid but not suprahyoid epiglottis.  
6.4.2.8  Mandible: This includes the entire boney structure of the mandible from TMJ 
through the symphysis. It is recognized that for oral cavity cancers, this may overlap with 
CTVs and PTVs.  
6.4.2.9  Unspecified Tissue Outside the Targets: This will be defined as tissue located 
between the skull base and thoracic inlet that is not included in either the target volumes or 
the normal tissues described above.  
6.5 Treatment Planning and Delivery 
Dose Prescription to PTVs 
 As described in Section 6.1, prescribed radiotherapy dose will be 60 Gy in 2 Gy once-daily 
fraction size. For inverse planning IMRT, the goal is for 95% of the PTV60 to receive 95% 
of 2 Gy with a minimum dose (cold spot) of no less than 56 Gy. It is recognized that 
portions of the PTV60 close to/within the skin may receive significantly less than 56 Gy. 
Bolus should be considered for these cutaneous areas deemed to be at risk for 
microscopic disease. Electron cones may also be employed to provide adequate dose to 
PTVs which emcompass cutaneous tissues.  
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For IMRT prioritization, PTV60 will be the highest priority target structure. PTV66 and 
PTV56, if applicable, will be ranked in the IMRT planning as lower priority than PTV60 
although higher priority than normal structures other than spinal cord and brain stem.  
6.5.4  Dose Constraints to Normal Structures  
Spinal Cord: The PRVcord (as defined in Section 6.4.2.1) should not exceed 45 Gy to any 
volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). The spinal cord PRV 
should not exceed 50 Gy to any volume in excess of 0.01 cc. In treatment planning, the 
spinal cord PRV should be given the highest priority.  
Brainstem: The PRVbrainstem (as defined in Section 6.4.2.2) should not exceed 50 Gy to 
any volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment 
planning, the PRVbrainstem should be given less priority than the PRVcord but more 
priority than the other critical structures listed below.  
Lips: Reduce the dose as much as possible unless lips involved with primary tumor. The 
mean dose should be < 20 Gy. The maximum dose will be < 30 Gy.  
Oral Cavity: Reduce the dose as much as possible. The mean dose should be < 30 Gy.  
Parotid Glands: In most cases, it will be easier to spare one parotid than the other. The 
treatment planning goal will be for this individual parotid gland to receive a mean dose of < 
26 Gy. Additional planning goals may include: 1) At least 50% of one parotid will receive < 
30 Gy; and/or 2) At least 20 cc of parotid tissue (from the combination of both glands) will 
receive < 20 Gy.  
OARpharynx: Reduce the dose as much as possible. Some recommended (but not 
mandatory) treatment goals include: 1) No more than 33% of the OARpharynx exceeds 50 
Gy; 2) Mean dose < 45 Gy; 3) No more than 15% of the OARpharynx exceeds 60 Gy.  
Cervical Esophagus: Reduce the dose as much as possible. For oral or oropharyngeal 
cancer, some recommended (but not mandatory) treatment goals include: 1) No more than 
33% of the esophagus exceeds 45 Gy; 2) Mean dose < 35 Gy; 3) No more than 15% of 
the esophagus exceeds 54 Gy. For larynx cancer, higher doses are expected and 
permitted. Some recommended doses (but not mandatory) treatment goals include: 1) No 
more than 33% of the esophagus exceeds 50 Gy; 2) Mean dose < 45 Gy; 3) No more than 
15% of the esophagus exceeds 60 Gy.  
Glottic and Supraglottic larynx (GSL): Reduce the dose as much as possible.  
Mandible: Reduce the dose as much as possible, hot spots within the mandible should be 
avoided. It is recommended that maximum dose within the mandible be < 66 Gy. For 
tumors that were not clinically or pathologically involving the mandible, the CTV should be 
contoured off the mandible. 
Unspecified Tissue Outside the Targets: For the typical case in which there is no CTV66, 
no more than 5% of unspecified tissue can receive greater than 58 Gy and no more than 
1% or 1cc of unspecified tissue can receive 64 Gy or more. When a boost is used to 
increase the dose to high risk regions to as much as 66 Gy, these numbers can be 
increased. In this case, no more than 5% of the unspecified dose should exceed the level 
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of the boost dose, and no more than 1% or 1 cc should exceed the boost dose value plus 
10%.  
6.6 Compliance Criteria 
Treatment breaks must be clearly indicated in the treatment record along with the 
reason(s) for the treatment break(s). Treatment breaks, if necessary, ideally should not 
exceed five treatment days at a time and ten treatment days total. Treatment breaks 
should be allowed only for resolution of severe acute toxicity and/or for intercurrent illness 
and not for social or logistical reasons. 
 
6.7  Radiation Therapy Adverse Events The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 
will be utilized for grading all adverse events.  Placement of a feeding tube should be 
recorded as should use of a feeding tube during and after treatment (e.g., greater than or 
less than 50% of nutrition by tube). Other common radiation adverse events include: 
fatigue, weight loss, regional alopecia, xerostomia, hoarseness, transient ear discomfort, 
and skin erythema and desquamation within the treatment fields. Less common long-term 
treatment adverse events include: hypothyroidism, loss of hearing, chronic swallowing 
dysfunction requiring permanent feeding tube, and skin/soft tissue fibrosis. Much less 
common radiation adverse events include: mandibular osteoradionecrosis, and cervical 
myelopathy (< 1% with restriction of spinal cord dose to max dose of 45 Gy). 
7.0 DRUG THERAPY 
 Protocol treatment must begin within 2 weeks after registration. 
7.1 Cetuximab Initial Dose (Prior to RT): Patients will receive an initial dose of cetuximab, 
400 mg/m2, intravenously (i.v.) over 120 minutes. No chemotherapy or radiation will be 
given this day, and the 400 mg/m2 initial dose of cetuximab will precede the first 250 
mg/m2 dose of cetuximab and the first radiation treatment by at least 5 days (the day of 
the loading dose is not included in these 5 days). The infusion rate of cetuximab must 
never exceed 5 mL/min. 
7.2 Cetuximab subsequent dosing 
Cetuximab weeks 2 through 7 or 8 (concurrent with RT depending on standard of care 
RT): Patients will receive cetuximab, 250 mg/m2, intravenously (i.v.) over 60 minutes on a 
weekly schedule. The infusion rate of cetuximab must never exceed 5 mL/min. Cetuximab 
will be given once a week prior to RT for a total of 6-7 doses concurrent with radiation 
therapy.  
In cases of delay in the completion of radiation therapy, then the concurrent doses of 
cetuximab may continue beyond week 8 without dose interruption until radiation therapy is 
completed. The total of number of cetuximab doses should not exceed 11. 
7.2.1 Safety 
CAUTION: 
Infusion 
reactions 
may 
occur 
during 
or 
following 
cetuximab 
administration. Most infusion reactions occur with the first infusion of cetuximab, 
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but some patients’ first infusion reactions have been reported following subsequent 
doses (a severe reaction occurred in one patient following the 8th dose). The 
infusion reaction may occur during the infusion or be delayed until any time after 
the infusion. Premedications are recommended and per discretion of the treating 
physician. 
The medical staff must closely observe patients for treatment-related adverse events, 
especially infusion reactions during the cetuximab infusion and during a post-infusion 
observation hour. For the initial cetuximab infusion, vital signs (blood pressure, heart rate, 
respiratory rate, and temperature) should be monitored prior to the administration of 
cetuximab, a half hour into the infusion, at the completion of the infusion, and 60 minutes 
post the infusion in an area with resuscitation equipment and other agents (epinephrine, 
prednisone equivalents, etc.) available. A nurse must be present in the immediate 
treatment area throughout the infusion and observation period. A physician must be in 
close proximity to the patient treatment area.  
For subsequent infusions, vital signs should be taken pre- and post-infusion. 
7.2.2  Formulation  Cetuximab is an anti-EGFR receptor humanized chimeric monoclonal 
antibody. Cetuximab is expressed in SP2/0 myeloma cell line, grown in large scale cell 
culture bioreactors, and purified to a high level purity using several purification steps 
including protein A chromatography, ion exchange chromatography, low pH treatment, and 
nanofiltration. Cetuximab is not known to be a vesicant. 
7.2.3  Safety Precautions Appropriate mask, protective clothing, eye protection, gloves 
and Class II vertical-laminar- airflow safety cabinets are recommended during preparation 
and handling.  
7.2.4  Preparation and Administration Cetuximab must not be administered as an i.v. 
push or bolus. Cetuximab must be administered with the use of a low protein binding 0.22-
micrometer in-line filter.  Cetuximab is supplied as a 50-mL, single-use vial containing 100 
mg of cetuximab at a concentration of 2 mg/mL in phosphate buffered saline. The solution 
should be clear and colorless and may contain a small amount of easily visible white 
amorphous cetuximab particulates.  Cetuximab can be administered via infusion pump or 
syringe pump.  
. Infusion Pump:  
 
Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike or other appropriate transfer device may be used).  
 
Fill cetuximab into a sterile evacuated container or bag such as glass containers, 
polyolefin bags (e.g., Baxter Intravia), ethylene vinyl acetate bags (e.g., 
Baxter Clintec), DEHP plasticized PVC bags (e.g., Abbott Lifecare), or PVC 
bags.  
 
Repeat procedure until the calculated volume has been put in to the container. 
Use a new needle for each vial.  
 
Administration must be through a low protein binding 0.22-micrometer in-line filter 
(placed as proximal to the patient as practical).  
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Affix the infusion line and prime it with normal saline before starting the infusion.  
 
Maximum infusion rate should not exceed 5 mL/min.  
 
Use 0.9% saline solution to flush line at the end of infusion.  
. Syringe Pump:  
 
Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike may be used).  
 
Place the syringe into the syringe driver of a syringe pump and set the rate.  
 
Administration must be through a low protein binding 0.22-micrometer in-line filter 
rated for syringe pump use (placed as proximal to the patient as practical).  
 
Connect up the infusion line and start the infusion after priming the line with 
cetuximab.  
 
Repeat procedure until the calculated volume has been infused.  
 
Use a new needle and filter for each vial.  
 
Maximum infusion rate should not exceed 5 mL/min.  
 
Use 0.9% saline solution to flush line at the end of infusion.  
. Cetuximab should be piggybacked to the patient’s infusion line. Following the cetuximab 
infusion, a one-hour observation period is recommended. 
. 7.2.5  Storage Requirements/Stability Store vials under refrigeration at 2 C to 8 C (36 F 
to 46 F). DO NOT FREEZE. Increased particulate formation may occur at 
temperatures at or below 0 C. This product contains no preservatives. Preparations 
of cetuximab in infusion containers are chemically and physically stable for up to 12 
hours at 2 C to 8 C (36 F to 46 F) and up to 8 hours at controlled room temperature 
(20 C to 25 C; 68 F to 77 F). Discard any remaining solution in the infusion 
container after 8 hours at controlled room temperature or after 12 hours at 2 to 8 C. 
Discard any unused portion of the vial. 
 
7.3.  Dose Modifications (adapted from RTOG 1016) 
Cetuximab Dose Levels 
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7.3.2  Cetuximab Dose Modifications for Hematologic Adverse Events 
Cetuximab will not be dose reduced or held for hematologic 
adverse events, such as neutropenia, neutropenic fever, or 
thrombocytopenia< 50 mL/min 
7.3.3  Cetuximab Dose Modifications for Non-Hematologic 
Adverse Events (adapted from RTOG 0920) 
 
 
 
Hypomagnesemia- Electrolyte repletion, principally magnesium, was necessary in some 
patients treated with cetuximab and in severe cases, intravenous replacement was 
required. The time to resolution of electrolyte abnormalities is not well known, hence 
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monitoring during and after cetuximab treatment is recommended: 
 
 
 
 
7.3.4 Management of Cetuximab Infusion Reactions (adapted from RTOG 1016) 
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If a patient has an infusion reaction, the infusion rate must be decreased.  If a second 
infusion reaction occurs at the reduced infusion rate, the cetuximab must be stopped. 
 
7.3.5 Cetuximab Special Instructions   If cetuximab is omitted for more than four 
consecutive infusions for adverse events due to cetuximab, or for an intercurrent illness 
(e.g., infection) requiring interruption of therapy, the subject should be discontinued from 
further cetuximab therapy. Cetuximab doses held due to toxicity should not be made up. If 
a cetuximab dose is missed for reasons unrelated to drug toxicity, then the missed dose 
may be made up at the discretion of the Medical Oncologist, at the next appropriate time 
point. If adverse events prevent the administration of cetuximab, the subject may continue 
to receive radiation therapy. 
7.3.5.1  Management of Cetuximab Infusion Reactions Severe or life threatening (grade 
3 or 4) infusion reactions require the immediate interruption of cetuximab therapy and 
permanent discontinuation from further treatment. Appropriate medical therapy including 
epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen 
should be available for use in the treatment of such reactions. Patients should be carefully 
observed until the complete resolution of all signs and symptoms.  In clinical trials, mild to 
moderate infusion reactions were managed by slowing the infusion rate of cetuximab and 
by continued use of antihistamine pre-medications (e.g., diphenhydramine) in subsequent 
doses. If the patient experiences a mild or moderate (grade 1 or 2) infusion reaction, the 
infusion rate should be permanently reduced by 50%. For grade 1 or 2 reactions 
manifesting only as delayed drug fever, see below.  Cetuximab should be immediately and 
permanently discontinued in patients who experience  severe (grade 3 or 4) infusion 
reactions.  
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7.3.5.2  Treatment of Isolated Drug Fever  In the event of isolated drug fever, the 
investigator must use clinical judgment to determine if the fever is related to the study drug 
or to an infectious etiology.  If a patient experiences isolated drug fever, for the next dose, 
pre-treat with acetaminophen or non-steroidal anti-inflammatory agent, repeat antipyretic 
dose 6 and 12 hours after cetuximab infusion. The infusion rate will remain unchanged for 
future doses.  If a patient experiences recurrent isolated drug fever following pre-
medication and post- dosing with an appropriate antipyretic, the infusion rate for 
subsequent dosing should be 50% of previous rate. If fever recurs following infusion rate 
change, the treating Medical Oncologist should assess the patient’s level of discomfort 
with the event and use clinical judgment to determine if the patient should receive further 
cetuximab.  
7.3.5.3  Cetuximab-related Rash  
Manifestations  Rash associated with EGFR-inhibitors is a relatively new dermatologic 
condition. It appears to be “acneiform” but it is NOT considered a form of acne; rather, it is 
a form of folliculitis. Skin changes may be manifested in a number of ways: erythema; 
follicle based papules, which may ulcerate; pain; itching; cosmetic disturbance; and/or nail 
disorders. The rash may become infected and transform into cellulitis.  
Grading of Cetuximab-induced Rash According to physician judgment, if a patient 
experiences grade 3 rash, cetuximab treatment adjustments should be made. In patients 
with mild and moderate skin adverse events, cetuximab should continue without 
adjustment. NOTE: Rash intensity (i.e., the size and number of papules or the level of 
discomfort and extent of erythema) may be an important consideration. However, the 
absolute number of lesions, without associated physical discomfort, does not 
necessarily constitute a basis for a dose reduction or delay.  
Skin and nail changes should be graded as follows, with dose modification for > grade 3 
changes.   
 
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adapted from RTOG 1016 
 
7.3.5.3.1 Drug Related Rash Management 
Patients developing dermatologic adverse events while receiving cetuximab should be 
monitored for the development of inflammatory or infectious sequelae, and appropriate 
treatment of these symptoms initiated. Below are suggestions for managing cetuximab- 
induced rash adapted from:  Perez-Soler R, Delord J, Halpern A, et al. HER1/EGFR 
inhibitor-associated rash: Future directions for management and investigation outcomes 
from the HER1/EGFR Inhibitor Rash Management Forum. The Oncologist. 10:345–356, 
2005. 
Antibiotics: The benefit of routine antibiotics in uncomplicated (uninfected) rash is 
unclear. Some clinicians have used oral minocycline (Minocin), mupirocin (Bactroban), or 
topical clindamycin (Cleocin). Rash complicated by cellulitis should be treated with 
appropriate antibiotics based on clinical judgment or microbial sensitivity analysis.  
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Antihistamines: Benadryl or Atarax may be helpful to control itching.  
Topical Steroids: The benefit of topical steroids is unclear.  
Retinoids: No data to support use. Use is not advised.  
Benzoyl peroxide: Should NOT be used--may aggravate rash.  
Makeup: Rash can be covered with makeup; this should not make it worse (use a 
dermatologist-approved cover-up, e.g., Dermablend, or any other type of foundation). 
Remove makeup with a skin-friendly liquid cleanser, e.g., Neutrogena, Dove, or Ivory Skin 
Cleansing Liqui-Gel.  
Moisturizers: Use emollients to prevent and alleviate the skin dryness, e.g., Neutrogena 
Norwegian Formula Hand Cream or Vaseline Intensive Care Advanced Healing Lotion.  
Sunlight: It is recommended that patients wear sunscreen and hats and limit sun 
exposure while receiving cetuximab as sunlight can exacerbate any skin reactions that 
may occur.  
Over-the-counter medications: Over-the-counter acne vulgaris medications (e.g., 
benzoyl peroxide) are not advised. This rash is not like acne vulgaris and these treatments 
could make it worse.  
7.4 Adverse Events  
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03. will be utilized for AE reporting. All 
serious adverse events will be reported to the IRB per institutional protocol.  
 
8.0 TISSUE/SPECIMEN SUBMISSION 
8.1  Tissue/Specimen Submission    
Tumor tissue and blood will be collected from all patients when possible.  Tumor tissue will 
be collected at the time of resection and will include specimens from the primary tumor and 
nodal disease as available.  All University of Cincinnati specimens will be maintained in the 
UCCI Tumor Bank per institutional protocol or will be requested from pathology.  All 
University of Michigan specimens will be maintained at University of Michigan. Tissue and 
blood submission is encouraged but not required for protocol enrollment. 
8.2  Buccal swab collection 
For University of Michigan patients ONLY, buccal swabs will be collected from the area 
within the anticipated radiation field pre-cetuximab (between days -7 to 0), after the first 
dose of cetuximab (between days 3 and 7), and during radiotherapy (between days 22 and 
30). Specimens will be collected as follows: After subject rinses his/her mouth with water, 
buccal cells (mucosal cells), will be scraped using sterile Cell Lifter (Manufacturer: 
CORNING LIFE SCIENCES PLASTIC 3008).  
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In order to obtain enough cells for analysis of proteins, cell lifer will be twirled 3-4 times 
gently. Total time will be about 20-30 seconds.  The cells will be collected from the cell 
lifter into 50 ml sterile collection tube containing ice cold 5 ml of sterile PBS with protease 
and phosphatase inhibitor. These collection tubes will be transported to research 
laboratory located in Med Sci I (Room # 4311) on ice as soon as possible.  The swabs will 
be transfer to freezer until testing. 
 
Objective of Study: 
1. Deep sequencing of DNA from normal and tumor specimen to identify driver 
oncogenes in given patient. 
2. Analyze pharmacodynamic changes in the normal tissue collected before and 
during (total 3 time points/patient) radiotherapy for driver molecules identified by 
DNA sequencing using high density immunoblotting. 
Correlate findings from objective 1 and 2 with clinical outcome in terms of toxicity and 
response 
 
9.0 PATIENT ASSESSMENTS 
9.1 Study Parameters:  
Gross total resection/surgical pathology (for post-operative patients) or biopsy (for 
definitive patients) must be completed within 7 weeks prior to registration.  
A general history & physical by a Radiation Oncologist and/or Medical Oncologist must be 
done within 2 weeks prior to registration, and an examination by an ENT or Head & Neck 
Surgeon must be done within 8 weeks prior to registration per routine standard of care.  
9.2 Evaluation During Radiotherapy 
A general history & physical by a Radiation Oncologist and/or Medical Oncologist must be 
done weekly per routine standard of care.  
Patients must have CBCw/diff, CMP, and Mg every other week during radiation therapy 
per routine standard of care for cetuximab administration. 
Biopsy of any lesion(s) suspicious for tumor recurrence is urged.  
9.3 Evaluation in Follow Up 
A history and physical by one of the following: a Radiation Oncologist, Medical Oncologist, 
an ENT, or a Head and Neck Surgeon must be performed at 1 and 3 months post-XRT, 
then q3 months for 2 years, every 6 months for 3 years, then annually for a total of 5 years. 
This is required for study entry and is chosen as it coincides with standard of care practice 
in follow-up for head and neck cancers.  This should include a complete head and neck 
and cutaneous exam and review of systems focusing on head and neck, cutaneous and 
pulmonary complaints.   
QOL and functional assessments (the Functional Assessment of Cancer Therapy-Head & 
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Neck (EORTC HN35); the Dermatology Life Quality Index (DLQI)) will be performed at 
Month 3, Month 12 and Month 24. 
Chest imaging will be performed as indicated clinically. 
Biopsy of any lesion(s) suspicious for tumor recurrence is at the discretion of the treating 
physician.  
9.4 Outcomes Criteria 
No evidence of disease (NED): All patients must have not measurable tumor following 
surgery. Local-Regional Relapse: Recurrent cancer in the tumor bed and/or neck not 
clearly attributable to a second primary neoplasm; both imaging and biopsy confirmation 
are recommended but not required. LRR will be further subdivided into three 
subcategories: 
In-Field Local-Regional Relapse- Review of the imaging of the local-regional relapse and 
the patient’s previous RT treatment data reveals that the “epicenter” of the local-regional 
relapse is within CTV60 and received an estimated dose of at least 50 Gy. 
Marginal Local-Regional Relapse- Review of the imaging of the local-regional relapse and 
the patient’s previous RT treatment data reveals that the “epicenter” of the local-regional 
relapse was “near” CTV60. This is defined as an estimated dose to this region that is 
between 20 and 50 Gy.  
Out-of-Field Local-Regional Relapse- Review of the imaging of the local-regional relapse 
and the patient’s previous RT treatment data reveals that the “epicenter” of the local-
regional relapse was not near CTV60 or CTV56 and received an estimated dose < 20 Gy.  
Distant Relapse: For clinical evidence of distant metastases (lung, bone, brain, etc.); 
biopsy is required. A solitary lung mass/nodule should be considered a second primary 
upper aerodigestive neoplasm unless proven otherwise. 
Second Primary Neoplasm: All second primary neoplasms will be biopsy proven with 
documentation of specific histology. Modified rigorous criteria for a second primary (below) 
have been adapted from the definition by Warren and Gates (1932). 
A distinct lesion separated from the primary tumor site by > 2 cm of normal epithelium; a 
new cancer with different histology; Any cancer, regardless of head and neck mucosal 
subsite, occurring 5 or more years after initial treatment; In the lung, new primary tumors, if 
squamous cell cancer, must have histologic findings of dysplasia or CIS. 
Second Primary Upper Aerodigestive Neoplasm: The emergence of a new, invasive 
malignancy in the upper aerodigestive tract as a second primary should be documented. 
These neoplasms include lung cancer, esophageal cancer (including GE junction cancer), 
or 2nd primary head and neck cancer that is clearly remote from the index cancer. 
9.5 Quality of Life and Functional Assessments 
The assessments will be completed prior to the start of cetuximab (baseline) and at 3, 12, 
and 24 months from the end of RT. 
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9.5.1 The Functional Assessment of Cancer Therapy-Head & Neck (FACT HN) is a 
multidimensional, patient-self report quality of life (QOL) instrument specifically designed 
and validated for use with head and neck patients. 
9.5.2  The Dermatology Life Quality Index (DLQI) consists of 10 items and covers 6 
domains including symptoms and feelings (e.g., felt itchy, sore, painful, embarrassed), 
daily activities, leisure, work and school, personal relationships, and treatment.  
9.6 Criteria for Discontinuation of Protocol Treatment 
Reasons for discontinuation of protocol treatment will include unacceptable toxicity, patient 
withdrawal of consent, progression of disease or development of a second primary 
malignancy. In the event that a patient discontinues protocol treatment, follow-up and data 
collection will continue as specified in the protocol.   
 
9.7 Off study criteria 
Reasons for patient discontinuation of study include completion of study follow-up, death 
or lost to withdrawal of patient consent (including patients lost to follow-up).  A patient may 
withdraw consent partially or fully at any time during the study.  Partial withdrawal of 
consent will be defined as patient refusal to continue protocol therapy while continuing to 
consent to follow-up on study.  Full withdrawal of consent will be defined as refusal of any 
further participation in the study.     
 
 
10.0 Statistical Considerations 
This is a Phase II trial to characterize the 2 year loco-regional control of patients with 
locally advanced cutaneous squamous cell carcinomas of the head and neck treated with 
post-operative radiotherapy and cetuximab.  Our secondary goal is to characterize the 
oncologic and quality of life outcomes associated with this treatment.  Cetuximab has 
previously been given safely in conjunction with head and neck radiotherapy for mucosal 
squamous cell carcinoma in multiple phase III trials, and so Phase I data is not necessary 
here.  Patients receiving at least 80% of the radiotherapy dose prescribed will be 
considered to have completed protocol therapy. Patients who complete therapy but 
become non-evaluable for toxicity before the post-treatment observation period ends will 
be counted as evaluable in the final analysis, and weighted in statistical analyses by the 
proportion of the 18-week toxicity observation period for which they were evaluable. 
 
Patient accrual is projected to be 20-25 cases per year based on current estimates of the 
number of patients with locally advanced CSCCHN diagnosed/treated annually at the 
University of Cincinnati and the University of Michigan. Otolaryngology billing records from 
University of Michigan suggest that 65-75 patients annually undergo resection of locally 
advanced cutaneous squamous cell carcinoma and all would be potential trial candidates.  
It is expected that this trial will be open to accrual for 24-36 months.   
 
This is a Simon 2-stage design with 40 patients in stage 1 and an additional 70 in stage 2. 
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The null hypothesis is 0.65 LRC at 2 years and the alternative is 0.78 LRC at 2 yrs.  An 
interim analysis will be performed after 40 patients are accrued and the first 20 patients 
have had 2 years of potential follow-up.  Kaplan-Meier estimates will be used to determine 
futility.  The trial may go on to accrue a total of 110 patients.  
 
The sample size of 110 patients begins with the hypothesis that the use of concurrent 
cetuximab and radiotherapy post-operatively improves 2 year loco-regional control (LRC) 
compared to radiotherapy alone. Using Simon’s optimal two stage design with locoregional 
control as the primary efficacy point, 2 year loco-regional control for patients with locally 
advanced CSCCHN has historically been 55-70 % with resection and post-operative 
radiotherapy alone at 2 years, with 5 year overall survival of approximately 40-55% and 
median survival of 20-25 months.  In the multi-center, randomized trial of mucosal SCCHN 
by Bonner et al., the additional of cetuximab to radiotherapy increased 2 yr LRC from 41 to 
50% and correspondingly increased 5 yr OS from 36 to 45%.  Based on these results, our 
target loco-regional control would be 78% based on the University of Cincinnati experience 
achieving 65% loco-regional control with post-operative RT alone. We would reject the null 
hypothesis if greater than if Kaplan Meier curves estimated greater than 72% loco-regional 
control.  
 Initial statistical design was formed with the help of Jareen Meizen-Derr, PhD, MPH in the 
Division of Biostatistics and Epidemiology at CCHMC.  Data collection would be completed 
by the UCCI Clinical Trials Office and data analysis would be completed by a 
biostatistician within the Department of Radiation Oncology.  Changchun Xie, PhD in the 
Dept of Epidemiology and Biostatistics will be the statistician analyzing data for this trial 
going forward at the University of Cincinnati. The trial will also be opened at the University 
of Michigan.  
Loco-regional control and overall survival will be estimated by the Kaplan-Meier method. 
 
Definitions of Endpoints 
2 year LRC will be defined as the absence of tumor appearance in the primary site or neck 
within 2 years, as assessed and documented through clinical exam and imaging 
completed q3 months by treating physicians during the follow-up period.   Loco-regional 
recurrence should be confimed by biopsy when possible, and the precise location 
documented (primary site versus neck).   
 
2 yr DFS will be defined as absence of loco-regional recurrence or the development of 
metastatic disease within 2 years, as assessed by q3 month clinical exam and annual 
chest imaging.  Distant metastases should be biopsied when possible, and a solitary 
spicualted lung nodule is considered a second primary neoplasm unless proven otherwise.  
2 and 5 year OS will be defined as the absence of death from any cause during those time 
periods.   
 
The QOL analysis is the change of QOL score on the FACT-HN and DLQI from baseline to 
the 3, 12 and 24-month intervals.  The mean summary score and standard deviation of 
these scales will be calculated and the mean change summarized for each time point.  
 
11. 
Data collection and Data and Safety Monitoring 
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Each site will be responsible for oversight of the trial as well as data and safety monitoring.  
See below for each site specifications. 
11.1 Data collection 
At the University of Cincinnati, patient data will be collected at time of study visits or 
through the electronic medical record and data will be stored securely within OnCore. The 
University of Michigan will utilize Velos.  
Per our data use agreement, de-identified study data may be shared between University of 
Cincinnati and University of Michigan.  
11.2 Data and Safety Monitoring  
UCCI: All cancer related therapeutic clinical trials conducted at the University of Cincinnati 
Cancer Institute (UCCI) require monitoring by a safety committee as part of their Data 
Safety and Monitoring Plan. The internal UCCI Data Safety Monitoring Board (DSMB) will 
monitor all investigator initiated studies. The DSMB is an independent group of experts 
who will advise the study investigators and report relevant findings to IRB or other 
appropriate authorities.  
  
Study parameters may vary depending on the type and risk of the study under evaluation. 
Each study will be evaluated at least twice a year.  The DSMB will focus on the analytic 
plan to include: hypothesis, primary objective, endpoints and will monitor study conduct 
including accrual, protocol required tests, IND, toxicities and efficacy. The DSMB will use 
case report forms, and data points to complete their safety assessment and make 
recommendations for a continued monitoring plan. All meetings are recorded by the DSMB 
Coordinator.  
  
DSMB initial study evaluation will occur after previous Protocol Review and Monitoring 
committee (PRMC) and Institutional Review Board (IRB) approval. If the DSMB 
recommends a study design amendment or the PI desires to amend the study, PRMC 
approval will be required.  
  
All serious adverse events will be reported immediately to the DSMB Chair and other 
members of the DSMB by the study sponsor or designee. The DSMB Chair or DSMB 
Administrator will notify the Study Sponsor (or sponsor designee) directly of any findings of 
a serious and immediate nature or recommendations to discontinue all or part of the trial. 
An Immediate Action report will be created and submitted to the UCCI CTO Regulatory 
Coordinator for appropriate dissemination to regulatory authorities. 
UM: This trial will be locally monitored in accordance with the NCI approved University of 
Michigan Comprehensive Cancer Center Data and Safety Monitoring Plan. 
 
The study team will meet quarterly or more frequently depending on the activity of the 
protocol. The discussion will include matters related to the safety of study participants 
(SAE/UaP reporting), validity and integrity of the data, enrollment rate relative to 
expectations, characteristics of participants, retention of participants, adherence to the 
protocol (potential or real protocol deviations) and data completeness. At these regular 
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meetings, the protocol specific Data and Safety Monitoring Report form will be completed 
and signed by the Principal Investigator or by one of the co-investigators. 
 
Data and Safety Monitoring Reports will be submitted to the University of Michigan 
Comprehensive Cancer Center Data and Safety Monitoring Committee on a quarterly 
basis for independent review. 
 
Data and Safety Monitoring Reports will be submitted to the coordinating center, UCCI, for 
overall review of study conduct.   
 
12. Study Calendar 
Screening labs should be completed within two weeks of starting treatment. Chest CT or 
PET/CT required within 8 weeks prior to registration. 
   
Day 
Screening 
Wk1  Wk2 
Wk3 
Wk4 
Wk5 
Wk6 
Wk7 
Wk8 
Follow-up 
Cetuximaba 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Radiationb 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Concurrent 
meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examc 
 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
 
Vital signs 
 
X 
 
 
 
 
 
 
X 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
 
X 
 
X 
 
Performance 
status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC w/diff, plts 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
CMP/Mg 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Pregnancy Testd 
 
X 
 
 
 
 
 
 
 
 
 
 
Radiologic 
evaluationd  
 
X 
 
 
 
 
 
 
 
 
Xe 
 
Adverse event 
evaluation 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
PD blood 
draws/Tissue 
collection 
 
Xf 
 
 
 
 
 
 
 
 
 
 
QOL 
 
X 
 
 
 
 
 
 
 
 
Xg 
a. 
On days when Cetuximab is given with RT, Cetuximab should be given prior to RT. Cetuximab should be given 1 week 
prior to beginning radiation and then every week during radiation for a total of 7-8 doses. There is a +/- 2 day window for 
cetuximab treatments. In cases of RT delay, cetuximab may continue beyond week 8 until radiation completed not to 
exceed 11 doses.  
b. 
M-F per standard of care 
c. 
To be performed by medical oncologist (or NP), radiation oncologist or ENT surgeon 
d. 
Serum pregnancy test (women of childbearing potential). 
e. 
CT chest or PET/CT at screening and then Chest Xray, or Chest CT or PET/CT  as clinically indciated 
f. 
optional  
g. 
Follow-up months 3, 12 and 24 
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References 
 
1 AJCC staging manual 2010 
 
2 O’Brien, CJ, McNeil, EB, McMahon, JD, et al (2002) Significance of clinical stage, extent of 
surgery and pathologi findings in metastatic cutaneous squamous cell carcinoma of the parotid 
gland.  Head Neck. 24:417-22. 
3 Audet, N, Palme, CE, Gullane, P. (2004) Cutaneous metastatic squamous cell carcinoma of the 
parotid: analysis and outcome.  Head Neck. 26: 727-32. 
 
4 Marcen, R, Pascual, J, Tato, AM, et al. (2003) Influence of immunosuppression on the prevalence 
of cancer after kidney transplatiation.  Transplant Proc. 35: 1714-6. 
 
5 Smith, KJ, Hamza, S, Skelton, H. (2004) Histologic features in primary cutaneous squamous cell 
carcinoma in immunocompromised patients focusing on organ trnasplanttation.  Dermatol Surg. 30: 
634-41. 
 
6 Hinerman, RW, Indelicato, DJ, Amdur, RJ, et al. Cutaneous Squamous Cell Carcinoma Metastatic 
to Parotid-Area Lymph Nodes.  Laryngoscope. 118:1989-96. 
7 Givi, B, Andersen, PE, Diggs, BS, et al. (2011) Outcome of patients treated surgically for lymph 
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8 Wang, JT, Palme, CE, Morgan, GJ, et al. (2011) Predictors of outcome in patients with metastatic 
cutaneous head and neck squamous cell carcinoma involving cervical lymph nodes. Head Neck, 
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9 Bonner, JA, Harari, PM, Giralt, J, et al. (2010) Radiotherapy plus cetuximab for locoregionally 
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between cetuximab-induced rash and survival. Lancet Oncol. 11:21-8. 
10 Vermorken JB, Trigo J, Hitt R, et al. (2007) Open-label, uncontrolled, multicenter phase II study 
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therapy. J Clin Oncol.; 25: 2171-7. 
11 Vermorken JB, Mesia R, Rivera F, et al. (2008) Platinum-based chemotherapy plus cetuximab in 
head and neck cancer. NEJM. 359(11):1116-27. 
12 Maubec, E, Petrow, P, Scheer-Senyarich, I (2011) Phase II study of cetuximab as first line single 
drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Onc. 29(25): 
3419-26. 
 
13 Curran D, Giralt J, Harari PM, et al. (2007) Quality of life in head and neck cancer patients after 
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14 Cella DF, Tulsky DS, Gray G, et al. (1993) The functional assessment of cancer therapy scale: 
Development and validation of the general measure. J Clin Oncol. 11(3):570-579. 
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15 Boone SL, Rademaker A, Liu D, et al (2007) Impact and management of skin toxicity associated 
with anti-epidermal growth factor receptor therapy: Survey results. Oncology. 72(3-4):152-9. 
16 Agero AL, Dusza SW, Benvenuto-Andrade C, et al. (2006) Dermatologic side effects associated 
with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol. 55(4):657-70. 
17 Finlay AY, Khan GK. (1994) Dermatology Life Quality Index (DLQI): A simple practical 
measure for routine clinical use. Clin Exp Dermatol. 19(3). 
18 Lewis V, Finlay AY. (2004) 10 years experience of the Dermatology Life Quality Index (DLQI). 
J Investig Dermatol Symp Proc. 9(2):169-80. 
19 Basra MK, Fenech R, Gatt RM, et al. (2008) The Dermatology Life Quality Index 1994-2007: A 
comprehensive review of validation data and clinical results. Br J Dermatol.  Sep 15 [Epub ahead of 
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