A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
Phase: NA
Conditions: Recurrent Skin Cancer, Squamous Cell Carcinoma of the Skin
Sponsor: Rutgers, The State University of New Jersey

Protocol Version:  07/01/2015
CINJ#: 091303
Rutgers, The State University of New Jersey
195 Little Albany Street
New Brunswick, NJ 08903-2681
cinj.org
p. 732-235-2465
Title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of 
Skin (SCCS)
Principal Investigator: Janice Mehnert, M.D.    
Rutgers Cancer Institute of New Jersey
195 Little Albany Street
New Brunswick, NJ 08903
Telephone: (732) 235-6031, FAX: (732) 235-8808
Email: mehnerja@rutgers.edu
Rutgers Cancer Institute of New Jersey
Rutgers Cancer Institute of New Jersey 
Operations Center
Biostatistical Center
Office of Human Research Services
Biometrics Division
195 Little Albany Street
120 Albany Street, 5th Floor
New Brunswick, NJ 08903 
New Brunswick, NJ 08903
Telephone: (732) 235-8675
            Telephone: (732) 235-6791
FAX: (732) 235-7690
FAX: (732) 235-7350
Supported by: Rutgers Cancer Institute of New Jersey through Precision Medicine 
CONFIDENTIAL
This document is confidential and the property of the Rutgers Cancer Institute of New Jersey.  No part of it may be 
transmitted, reproduced, published, or used without prior written authorization from the study sponsor.
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Official Title: 
A Pilot Study of Neoadjuvant Cetuximab in Advanced 
Squamous Cell Carcinomas of 
Skin (SCCS) 
NCT number: 
NCT02324608 
Document Type: 
Protocol and Statistical Analysis Plan 
Date of the 
Document: 
01/24/2020 

Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
- 2 -
TABLE OF CONTENTS
1.
PURPOSE/SPECIFIC OBJECTIVES .......................................................................................................................4
2.
BACKGROUND AND SIGNIFICANCE ..................................................................................................................4
2.1 SUPPORTING DATA AND RATIONALE ...........................................................................................................................4
3.
PARTICIPATING INSTITUTIONS..........................................................................................................................8
4.
EXPERIMENTAL DESIGN AND METHODS........................................................................................................8
5.
PATIENT SELECTION CRITERIA.........................................................................................................................9
5.2 EXCLUSION CRITERIA ..................................................................................................................................................9
5.3 INCLUSION OF WOMEN AND MINORITIES...................................................................................................................10
5.4 PARTICIPATION OF CHILDREN....................................................................................................................................10
5.5 SOURCES OR METHODS OF RECRUITMENT.................................................................................................................10
5.6 STUDY ENROLLMENT PROCEDURES...........................................................................................................................10
6.
STUDY PARAMETERS ...........................................................................................................................................10
7.
TREATMENT PLAN ................................................................................................................................................12
8.
TOXICITY MONITORING AND ADVERSE EVENT REPORTING ...............................................................21
8.1 ADVERSE EVENT REPORTING REQUIREMENTS...........................................................................................................22
8.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAES) ..................................................................................................23
8.3 DEFINITION OF RELATED............................................................................................................................................23
8.4 DEFINITION OF UNEXPECTED .....................................................................................................................................23
10.
REMOVAL OF PATIENTS FROM STUDY/OFF STUDY CRITERIA...........................................................24
11.
LABORATORY EVALUATIONS AND PROCEDURES/CORRELATIVE AND PHARMACOKINETIC 
STUDIES.............................................................................................................................................................................24
12.
PHARMACEUTICAL INFORMATION..............................................................................................................26
13.
DATA COLLECTION AND RECORDS TO BE KEPT .....................................................................................27
13.1 CASE REPORT FORMS...............................................................................................................................................27
13.2 DATA SUBMISSION TIMELINE AND FORMS...............................................................................................................27
13.3 RESEARCH CHARTS..................................................................................................................................................27
13.4 REPORTS...................................................................................................................................................................27
14.
DATA AND SAFETY MONITORING..................................................................................................................28
15.
STATISTICAL CONSIDERATIONS....................................................................................................................28
16.2 POTENTIAL RISKS ......................................................................................................................................................28
16.3 CONSENT PROCEDURES ..............................................................................................................................................29
16.4 POTENTIAL BENEFITS.................................................................................................................................................29
THE BENEFITS OF PARTICIPATING IN THIS STUDY MAY BE IMPROVEMENT IN A PATIENT'S CANCER EITHER AS A MEASURE OF 
DISEASE ACTIVITY OR QUALITY OF LIFE IMPROVEMENTS. ........................................................................................................29
16.5 RISK-BENEFIT RATIO .................................................................................................................................................29
16.6 GENDER AND MINORITIES...........................................................................................................................................29
REFERENCES...................................................................................................................................................................30
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
- 3 -
LIST OF ABBREVIATIONS   
 (examples of some commonly used abbreviations, include any used in protocol)
AE
Adverse Event
ANC
Absolute neutrophil count
BUN
BRS
Blood urea nitrogen
Biospecimen Repository Service
CBC
Complete blood count
CINJOG
Cancer Institute of New Jersey Oncology Group
CT
computer tomography
CR
Complete response
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
DSMP
Data Safety Monitoring Plan
ECG
Electrocardiogram
FDA
Food and Drug Administration
HHS
Department of Health and Human Services
IRB
Institutional Review Board
kg
kilograms
mL
milliliters
mcg/g
MRI
Micrograms
Magnetic Resonance Imaging
NCI
National Cancer Institute
NIH
National Institutes of Health
OHRS
Office of Human Research Services
OHRP
Office of Human Research Protection
PBMC
Peripheral blood mononuclear cells
PD
Progressive disease
PET
Positron Emission Tomography
PHI
Protected health information
PI
Principal Investigator
PR
Partial response
RWJUH
Robert Wood Johnson University Hospital
SAE
Serious adverse event
SD
Stable disease
sCr
Serum creatinine
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
ULN
Upper limit of normal
1. Purpose/Specific Objectives
The purpose of this protocol is to serve as a pilot study for neoadjuvant cetuximab in potentially 
resectable, advanced squamous cell carcinoma.  The primary hypothesis is that cetuximab used in 
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
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the neoadjuvant setting for locally advanced squamous cell carcinomas is both safe and well 
tolerated and that its use may enhance the treatment of advanced cases of SCCS when delivered 
preoperatively. The overall treatment strategy expressed in the protocol is to treat locally 
advanced/unresectable squamous cell carcinomas with 8 weeks of neoadjuvant cetuximab, and 
monitor patients for disease response, adverse events, and overall safety. Potentially, patients may be 
able to go on to surgical resection if adequate disease response is achieved. The hope is that the data 
derived from this study will lead to a large randomized trial testing the efficacy of this approach in 
this disease, which has few available treatment options. 
1.1 Primary Objective(s)
The co-primary endpoints are to 
a) assess the response rate of cetuximab by RECIST criteria in patients with advanced SCCS and, b) 
to assess whether neoadjuvant cetuximab given in this patient population is both safe and feasible. 
1.2 Secondary Objective(s)
1.2.1 To measure the progression free and overall survival of patients with advanced SCCS who 
receive neoadjuvant cetuximab.
1.2.3 To determine the conversion to resectability of patients treated with neoadjuvant cetuximab 
and capture changes in reconstructive options rendered possible by neoadjuvant treatment.
1.2.3 Molecular correlates. All patients must have a biopsy of the locoregional disease (primary site 
or neck lymph nodes), and of the skin prior to therapy. Patients will also have tissue harvested at 
surgery that will undergo molecular analysis, or a second post treatment biopsy if surgery is not 
feasible. Our goals in the molecular analysis are to explore the following possibilities:
-Analyze the relationship of known DNA mutations in tumor per the FoundationOneTM  
genomic profile, and correlate to clinical endpoints such as clinical benefit and conversion to 
resectability to discover potential markers of response and/or resistance.
-Measure the downstream activation of signaling pathways without a known driver, including the 
EGFR pathway.
-Determine if tumor shrinkage with cetuximab is associated with increased apoptosis as 
evidenced by activated caspase-3, in pre- and post- treatment tumor tissues.
-Determine whether cetuximab results in increased ADCC in post-, compared with pre-treatment 
tumor tissues.
 
2. Background and Significance
2.1 Supporting Data and Rationale
Nonmelanoma skin cancers are the most common malignancies among Caucasians. 
Squamous cell carcinoma (SCC) of the skin is an increasingly common diagnosis, and is the second 
most common type of skin cancer worldwide (Alam and Ratner 2001). Specifically, results from a 
population based study performed in the United States using governmental data on skin cancer 
procedures and related office visits estimated the number of new skin cancer diagnoses to be over 
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
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3.5 million in 2006 (Rogers, Weinstock et al. 2010). Regardless of the true incidence, it is known 
that the number of cases has consistently risen over the past 20 years. This observation can be related 
to improved detection of skin cancer, increased UV and tanning bed exposure, and the aging of the 
U.S. population, since the incidence of SCCS increases dramatically with age (Bauman, Eaton et al. 
2007). It follows, then, that with a 10% decrease in stratospheric ozone annually and the continued 
growth of the aging U.S. population, the number of metastatic squamous cancers arising from a skin 
primary is certain to continue increasing annually for the foreseeable future. These cancers also 
plague patients who are recipients of solid organ transplants, historically a difficult population of 
patients for the delivery of cytotoxic systemic therapies. 
It should be noted that SCC and its precursor lesions can carry a significant morbidity 
associated with diagnosis, with an opportunity for recurrence, local or distant metastases, treatment 
related complications, and increased risk for development of secondary cancers (Wassberg, Thorn et 
al. 1999). Most often, these lesions are localized and amenable to surgery.  Larger and more invasive 
lesions often require multimodality care, but relatively little has been done to investigate a 
generalized management plan for these situations (Gaffney, Soyer et al. 2013). As a result, there is a 
lack of high-level data on systemic treatment options for cutaneous SCC unamenable to resection.  A 
10-year cohort study involving 985 patients with SCC found a 3.7% risk of metastasis and 2.1% risk 
of disease-specific death (Schmults, Karia et al. 2013). Published case reports have demonstrated 
responses with platinum-based chemotherapy with occasional complete responses noted in this 
patient population (Lawson, Otto et al. 2008, Nakamura, Okuyama et al. 2013). There are no 
prospective phase III studies available, and only one prospective phase II study regarding the use of 
platinum-based chemotherapy in this population. Cisplatin, either as a single agent or combined with 
5-FU, has occasionally produced useful responses, but again, data supporting efficacy is limited. In 
the only phase II study of biochemotherapy with interferon alfa, cis-retinoic acid and cisplatin, 35 
patients were assessed for response, 11 of which had distant metastases (Shin, Glisson et al. 2002). 
One of the 11 patients experienced a complete response. Twelve patients with only regional lymph 
node metastases were treated and 3 had either a partial (2) or complete (1) response. This lends some 
credence to a cisplatin-based regimen. Other studies are retrospective and most are anecdotal 
(Weinberg, Ogle et al. 2007, Cranmer, Engelhardt et al. 2010). In summary, historically, advanced 
SCCS is incredibly challenging to treat given its presence in a patient population which often has 
multiple comorbidities. In addition, the absence of randomized clinical trials that would provide 
guidelines for therapy further complicates this clinical situation. These facts underscore that this 
population of patients represents an unmet medical need that is likely to grow as the elderly 
U.S. patient population increases and as such, is a ripe area for clinical investigation. 
 
One potential novel treatment option includes targeting the epidermal growth factor receptor 
which is highly expressed in many epithelial tumors, including squamous cell carcinomas of the skin 
(DeConti 2012). The epidermal growth factor receptor (EGFR) has also been implicated in SCC 
development, specifically, it has been shown to be involved in UV-induced skin carcinogenesis 
(Gaffney, Soyer et al. 2013). Additional evidence in support of a relevant role of EGFR expression 
in these cancers includes a retrospective study, which demonstrated that primary cutaneous SCC of 
the head and neck that subsequently metastasized were more likely to overexpress EGFR than those 
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
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that did not (Bonner, Harari et al. 2006). Accordingly, the development of anti-EGFR drugs has been 
pursued for use in various malignancies. 
One such new EGFR-directed therapy is cetuximab, a monoclonal antibody that 
competitively inhibits EGFR (Gaffney, Soyer et al. 2013). Its mechanism of action is likely dual, in 
that it competitively inhibits natural EGFR ligands, preventing EGFR phosphorylation and it elicits 
antibody-dependent cell cytotoxicity (ADCC) (Fan, Masui et al. 1993, Lopez-Albaitero and Ferris 
2007). It has been approved in the treatment of SCC of the head and neck, in combination with 
radiation and/or platinum-based chemotherapy (Gaffney, Soyer et al. 2013). A randomized 
controlled trial by Bonner et al. in advanced oropharynx, hypopharynx, and larynx SCC of external 
beam radiation therapy + cetuximab versus EBRT alone revealed an improvement in 5 year overall 
survival for the cetuximab arm from 36.4% to 45.6% (Bonner, Harari et al. 2006). Cetuximab has 
also been used in EGFR-expressing, KRAS wild-type metastatic colorectal cancers in combination 
with chemotherapy regimens (Gaffney, Soyer et al. 2013). Additionally, studies demonstrating the 
efficacy of Cetuximab in recurrent squamous cell carcinomas have been promising (Bauman, Eaton 
et al. 2007). Data regarding use of cetuximab in advanced SCCS is scarce and consists of a few case 
series reports and one phase II trial (Nadiminti, Shao et al. 2013). The largest of these studies was 
published by Maubec et al, who reported the use of cetuximab as first line therapy for unresectable 
squamous cell carcinoma of the skin expressing EGFR in a phase II nonrandomized setting.  The 
trial accrued 36 poor-prognosis patients and demonstrated an overall disease control rate of 69% 
(Maubec, Petrow et al. 2011). Additionally, a prospective study looking at cetuximab with or 
without systemic chemotherapy in patients with locally recurrent or unresectable disease 
demonstrated clinical improvement in pain, tumor ulcer, and bleeding compared to pretreatment 
symptoms. Treatment with cetuximab was generally well tolerated with the main side effect being 
skin rash (Nadiminti, Shao et al. 2013). Multiple published case and retrospective reports have 
documented tumor responses in patients with SCCS treated with cetuximab (Bauman, Eaton et al. 
2007, Suen, Bressler et al. 2007, Miller, Sherman et al. 2010, Kim, Eleff et al. 2011, Kalapurakal, 
Malone et al. 2012), with one from our institution demonstrating an impressive complete response in 
an elderly patient with squamous disease (Kim, Eleff et al. 2011) (Figure 1).  
Figure 1. Images of a clinical complete response to cetuximab in a 92 year old man. Images from 
left: Patient prior to cetuximab (photo and CT), six weeks after cetuximab. Cetuximab was 
administered weekly from July to October 2008. The clinical CR lasted until patient’s last follow up 
in 2009 (7 months). 
 
 
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
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Despite the fact that cetuximab has clear activity in cutaneous SCC, the exact mechanism of 
action in this disease is not clear. Cetuximab is a chimeric monoclonal antibody of the 
immunoglobulin G1 class, which binds with high affinity to the extracellular domain of the human 
EGFR. As the affinity of cetuximab for EGFR is approximately 5 to 10 fold higher than that of the 
endogenous ligands, it blocks the binding of these ligands to the extracellular domain of the receptor 
as well as ligand dimerization, resulting in inhibition of the receptor function and signaling 
(Markovic and Chung 2012). Furthermore, cetuximab induces the internalization of EGFR, which 
can lead to downregulation of EGFR (Figure 2). Binding to EGFR blocks phosphorylation and 
activation of receptor-associated kinases, resulting in inhibition of cell growth leading to apoptosis 
(Kirkwood, Butterfield et al. 2012). However, despite overexpression of EGFR in 80-90% of head 
and neck cancers, clinical activity remains limited to 10-20%.   In addition, unlike in non small cell 
lung cancer, activating mutations in EGFR are rare in squamous carcinomas arising in the head and 
neck, and in limited analyses done to date, also in squamous carcinomas arising in the skin (Chung, 
Ely et al. 2006).  
It is possible that in squamous cancers of the skin, a tumor type prone to a heavy mutation 
burden given its exposure to and dependence upon UV radiation for initiation, driver mutations may 
play a lesser role in tumor development and maintenance, or are as of yet, undiscovered. In this 
disease, cetuximab may be exerting antitumor activity through other mechanisms. For instance, as a 
chimeric IgG1 type monoclonal antibody, cetuximab may initiate antitumor responses through 
targeting of cytotoxic immune effector cells towards EGFR expressing tumor cells (antibody 
dependent cell-mediated cytotoxicity) (Vermorken, Mesia et al. 2008, Martinelli, De Palma et al. 
2009, Srivastava, Lee et al. 2013). This mechanism has recently been implicated in squamous 
malignancies of the head and neck. 
In summary, cetuximab exhibits antitumor activity in advanced cases of squamous carcinoma 
of the skin, a population that represents a major unmet need with few proven treatment options.  Our 
planned study will assess the ability of cetuximab to shrink locally advanced or aggressive tumors 
prior to surgery, measuring tumor response rate as a co-primary endpoint, and will investigate 
whether the delivery of this medication could possibly result in improved surgical reconstructive 
options. This trial will provide a unique window of opportunity to investigate the antitumor activity 
of cetuximab in patients with aggressive or recurrent squamous skin cancers who are candidates for 
neoadjuvant cetuximab. This trial will also allow us to assess the safety and feasibility of cetuximab 
in this patient population, which historically is of greater age and has more comorbid conditions than 
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
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patients with other advanced squamous tumors, such as locally advanced squamous tumors of the 
head and neck. 
An important strength of this study is the use of serial biopsies to allow us to investigate the 
mechanism of action of cetuximab and to discover potential predictors of response and/or resistance 
that can be validated in future trials.  Our mechanistic studies will focus on 1) apoptosis and 2) 
ADCC as possible mechanisms of cell death. Pre-and post-treatment tissues will be assayed for 
evidence of increased caspase-3 as an indication of apoptosis and for evidence of ADCC.  We will 
also measure changes in protein or mRNA production in response to cetuximab that may lead us to 
discover potential mechanisms of response or resistance. For instance, as we are also investigating in 
protocol CINJ# 031204, there is evidence that EGFR and IGF-1R interact on multiple levels, either 
through a direct association between the two receptors, by mediating the availability of each others 
ligands, or indirectly, via common interaction partners such as G protein coupled receptors (GPCR) 
or downstream signaling molecules, a cross-talk that may play a role in resistance to EGFR 
inhibitors.  We will be able to explore protein expression of EGFR and IGFR pathway members in 
pre-and –post treatment tumor samples. Finally, we will utilize the FoundationOne genomic profile 
to assess the relationship of known DNA mutations with clinical endpoints such as clinical benefit 
and conversion to resectability.  It is known that mutations in the TP53 tumor suppressor gene are 
very common in SCCs (Brash, Rudolph et al. 1991) and occur early in skin cancer development in 
keratinocytes (Jonason, Kunala et al. 1996, McGregor, Berkhout et al. 1997). Inactivation of 
CDKN2A and activating RAS mutations have also been described (Boukamp 2005). It is not clear, 
however, if these events are the main drivers of tumor initiation and maintenance, or if other 
potentially targetable genomic gains or losses occur which may be responsible. Our analysis will 
provide preliminary information that may shape personalization of treatment for these patients and 
optimize patient selection for therapy in the future. Of great use will also be the banked tumors that 
will be collected and stored as part of this study, an extremely useful resource for testing alternative 
hypotheses as additional information becomes available. 
Figure 12 From Chen LF, Cohen E, Grandis JR. New Strategies in Head and Neck Cancer: 
Understanding Resistance to Epidermal Growth Factor Receptor Inhibitors. Clin Cancer Res 
2010;16:2489- 2495.
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
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3. Participating Institutions 
This protocol will be available at the Rutgers Cancer institute of New Jersey/RWJUH in New 
Brunswick and Hamilton Campuses. All biopsies and subsequent surgery will be performed at these 
facilities. 
4. Experimental Design and Methods 
4.1 Duration of Study
20 patients are planned to be enrolled. The patients will be under active treatment with cetuximab 
monotherapy for approximately 8 weeks. Afterwards, they will be assessed for disease response and 
determination of whether the lesion is potentially resectable will be made.  We expect that patients 
will be accrued within 24 months and that followup time will average 18-24 months per patient. 
5. Patient Selection Criteria
5.1 Inclusion Criteria 
A patient is eligible for enrollment if all of the following inclusion criteria are met.
5.1.1  Patients  must have untreated or relapsed SCCS that is considered to be aggressive and 
locally advanced by the following criteria: tumors 2 cm or more, tumors invading deep 
tissues such as muscle, cartilage or bone; tumors showing perineural invasion, and/or tumors 
metastatic to loco-regional lymph nodes. Patients may have had prior surgical interventions 
or been treated with investigational agents with residual or recurrent disease. 
5.1.2 Patients must give informed consent. 
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
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Protocol Version: 07/01/2015
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5.1.3. Patients must agree to pre- and post- treatment biopsies. 
5.1.4 Patients must have an ECOG performance status ≤2 (Appendix B). 
5.1.5 Estimated life expectancy of at least 12 weeks. 
5.1.6 Negative pregnancy test 
5.2 Exclusion Criteria
A patient will not be eligible for this study if any of the following exclusion criteria are met.
  
5.2.1 Second primary malignancy only if treatment would interfere with the patient’s 
participation in this trial in the opinion of the treating physician. Clear exceptions are 1) 
patient had a second primary malignancy but has been treated and disease free for at least 3 
years, 2) in situ carcinoma (e.g. in situ carcinoma of the cervix) and, 3) additional skin 
cancers that have been definitively treated by surgery and/or radiation. Patients with chronic 
lymphocytic leukemia will be allowed if their blood counts are within acceptable 
hematologic parameters and if they are not currently requiring cytotoxic or biologic 
anticancer treatment (supportive treatment such as IVIG is permitted). 
5.2.2   Patients with distant organ metastases will not be included in this study. 
5.2.3 Serious concomitant systemic disorders (including active infections) that would 
compromise the safety of the patient or compromise the patient’s ability to complete the 
study, at the discretion of the investigator. 
5.2.4   Age <18 years. 
5.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic  
composition to cetuximab or other agents used in the study. 
5.2.6 Women who are pregnant, due to the teratogenic effects of radiation therapy and 
chemotherapy on the unborn fetus. Women of childbearing age must agree to undergo a 
pregnancy test prior to therapy and to use adequate contraception (hormonal or barrier  
method of birth control; abstinence) prior to study entry, for the duration of study 
participation and for 6 months after. Should a woman become pregnant or suspect she is 
pregnant while  participating in this study, she should inform her treating physician 
immediately. Menopausal status is  defined by one or more of the following:
Successful hysterectomy, bilateral tubal ligation or bilateral oophorecatomy OR
Amenorrhea > 12 consecutive months without another cause or for women with irregular 
menstrual periods and taking hormone replacement therapy (HRT), a documented serum 
follicle stimulating hormone (FSH) level >35 mIU/mL
5.2.7 Presence of the following grade 3-4 electrolyte abnormalities (CTCAE, v. 4.0):
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
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Protocol Version: 07/01/2015
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
Serum calcium (ionized or adjusted for albumin) < 8 mg/dl (1.75 mmol/L) or > 12.5 
mg/dl (> 3.1 mmol/L) despite intervention to normalize levels

Magnesium < 1.4 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
5.2.8 Prior radiation therapy is not an exclusion however, patient must have documented 
progression at the radiation site. 
5.3 Inclusion of Women and Minorities
Women and minorities are welcome to participate.
5.4 Participation of Children
Children younger than 18 years of age are not eligible for this trial. SCCS of the skin is 
exceedingly rare in this population, and it is not expected that subjects of this age group will be 
eligible.
5.5 Sources or Methods of Recruitment
Patients will be recruited mostly from the Rutgers Cancer Institute of New Jersey/RWJUH and 
from physicians participating in the Cancer Institute Oncology Group (CINJOG).
5.6 Study Enrollment Procedures 
A copy of the institution’s IRB-approved informed consent document and written justification for 
any changes made to the informed consent for this protocol must be on file at the Rutgers Cancer 
Institute of New Jersey’s Office of Human Research Services (OHRS) before any participating 
institution may enter patients. The CINJOG institution consent form must be reviewed and approved 
by OHRS Regulatory Affairs and all documents must be received (i.e., IRB approved 
documentation, IRB approved consent form, etc.).
To register eligible patients on this study, each site will contact OHRS. Contact information will be 
provided at the time of site activation. The signed and dated eligibility checklist, completed signature 
page of the consent form and additional source documents if requested by OHRS will need to be 
provided. Once OHRS verifies eligibility, a unique patient study number will be issued. The patient 
will not be identified by name. This is the point that the patient is considered on study. Patients must 
not start protocol treatment prior to registration.
If a patient does not receive any protocol therapy, baseline data will be collected and submitted on 
the pre-study and follow-up electronic case report forms (eCRF). The reason for not starting protocol 
therapy will be documented in the “follow-up eCRF”. Case report form completion instructions and 
training will be provided to each participating institution prior to study activation at the participating 
institution.
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
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6. Study Parameters 
Evaluations
Pre-
cetuximab
Weekly during 
neoadjuvant 
cetuximab
Post-
cetuximab 
(Week 9)
At surgery or 
prior to RT7
30 days 
after 
surgery 
or XRT
Follow ups 
every 3 
months 
after 
surgery or 
XRT for 2 
years
After 
locoregional 
or distant 
failure
History, 
physical exam 
and tumor site 
assessment 
X1
(within 14 days 
of treatment)
X6
X7 
X1
X1
X1
Photo of tumor 
and/or rash at 
head, neck, 
upper torso put 
into EMR
X
(within 14 days 
of treatment)
X6
X7
Incisional/core 
biopsy of 
primary tumor 
and loco-
regional lymph 
nodes if 
involved
X8
(within 30 days 
of treatment)
X8
(any time 
during this 
interval)
X
(within 30 
days of 
relapse)
Biopsy of skin
X8
(within 30 days 
of treatment)
X8
(any time 
during this 
interval)
X
(within 30 
days of 
relapse)
CBC, 
differential, 
platelets
X
(within 14 days 
of treatment)
X
X
X
Serum 
Chemistries2
X 
(within 14 days 
of treatment)
X
X
X
X
X
Liver 
Enzymes3
X 
(within 14 days 
of treatment)
X
X
X
Pregnancy 
Test4
X
(within 14 days 
of treatment)
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
- 13 -
Radiographic 
Assessments5
X5
(within 30 days 
of treatment)
X5
X
X5
*A +/- 2 day window is allowed for all study assessments indicated on this trial except treatment for which a 
+/- 1 day window is allowed. 
1. To include toxicity assessment, ECOG performance status, weight
2. Includes: Electrolytes, including serum magnesium, potassium, Calcium, BUN, Creatinine, 
Glucose, 
3. Includes: Total and Direct. Bilirubin, AST/ALT, Alkaline Phosphatase, Albumin, Total 
Protein.
4. Women 18-55 who have not undergone menopause must have urine pregnancy test within 14 
days of enrollment.
5. Tumor assessments as indicated by investigator, i.e. PET/CT, CT neck, chest/abdomen and 
pelvis or MRI of neck as needed to be obtained no more than 1 month prior to cetuximab; 
then per standard of care, in general, every three months after conclusion of surgery or XRT. 
6. Every 7 days
7. Includes evaluation by surgery and radiation oncology for optimal local therapy. Surgery will 
assess optimal timing of rebiopsy during their evaluation of patient once neoadjuvant therapy 
is complete.
8. See section 11
7. Treatment Plan
7.1 General Considerations The experimental aspect of this protocol is in the use of neoadjuvant 
cetuximab monotherapy in these patients with locally advanced or recurrent SCCS. Once treatment 
response to cetuximab monotherapy is established, the determination of patient tolerance to the 
selected dose and disease response/potential resectability of the lesion will be determined. 
7.2 Sequence of treatment
7.2.1 Prior to neoadjuvant cetuximab
Patients will be staged using imaging to delineate the extent of disease. Initial biopsy 
specimen (preferably a core biopsy as opposed to a FNA) will be procured from the 
primary cutaneous site. If the patient is found to have regional lymph node involvement, 
core biopsy of accessible node will also be obtained.  Samples will be used for 
confirmation of diagnosis as well as DNA and RNA genotyping. These specimens will be 
flash frozen and brought that same day to the Biospecimen Repository Service (BRS).
7.2.2 Neoadjuvant Cetuximab
Patients who agree and are eligible for this protocol will initially receive 8 weeks of 
neoadjuvant cetuximab. The initial dose of cetuximab will be 400 mg/m2 IV, followed by 
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
- 14 -
weekly doses of cetuximab 250 mg/m2 IV to complete 8 total weeks of treatment.  Even if 
a patient is found to have a cetuximab related folliculitis, they will complete the scheduled 
8 weeks of neoadjuvant cetuximab.
7.2.3 Assessing for response during and after neoadjuvant cetuximab
Response to cetuximab will be assessed by RECIST criteria. 
7.2.3.1 Response by RECIST criteria
After 8 weeks of Cetuximab has been completed, the patient will have a restaging CT 
scan with IV contrast for comparison to the first CT scan performed prior to neoadjuvant 
cetuximab. CT response will be evaluated using RECIST criteria for partial response 
versus progressive or stable disease ( Eisenhauer et al. 2009). The RECIST criteria will be 
applied to the combination of primary site and associated neck lymphadenopathy.
RECIST Criteria
Complete Response (CR)
Disappearance of all target lesions
Partial Response (PR)
At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, 
taking as reference the baseline sum LD.
Progressive Disease (PD)
At least a 20% increase in the sum of the 
LD of target lesions, taking as reference 
the smallest sum LD recorded since the 
treatment started or the appearance of 
one or more new lesions.
Stable disease (SD)
Neither sufficient shrinkage to qualify 
for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest 
sum LD since the treatment started.
7.2.4 Repeat Bx after neoadjuvant cetuximab. 
After 8 weeks of neoadjuvant cetuximab, tissue will either be harvested at surgery, or if 
the patient is not a surgical candidate, a biopsy specimen (preferably a core biopsy as 
opposed to a FNA) will be procured from the primary site or accessible lymph node. As 
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
- 15 -
this tissue will be used for DNA and RNA sequencing, tissue that is fresh and sufficient 
in quantity is required. These specimens will be flash frozen and brought that same day to 
the BRS. 
7.3 Study Agent (Cetuximab)
Cetuximab is an anti-EGFR receptor humanized chimeric monoclonal antibody. It is supplied as 100 
mg/50 mL, single-use vial or a 200 mg/100 mL, single-use vial. For more information on this agent, 
refer to the FDA approved Package Insert.
7.3.1 Dose Calculation
Doses will be calculated on day 1 of each cycle using the patient’s actual weight in the 
determination of body surface area. A variance of 10% of the calculated total dose will be allowed.
BSA (m2) =square root of ((height inches) x (weight lbs) /3131)
7.3.2 Treatment Administration
During neoadjuvant cetuximab, the initial dose is 400 mg/m
2 administered as a 120 minute 
intravenous infusion (maximum infusion rate 10 mg/min). The subsequent weekly doses are 250 
mg/m
2 infused over 60 minutes (maximum infusion rate 10 mg/min). If a weight change of ≥ 10% 
occurs, the cetuximab dose should be adjusted.
Cetuximab should not be delivered as an intravenous push or bolus. Administer via infusion pump or 
syringe pump. Do not exceed an infusion 
rate of 10 mg/min. Administer through a low protein 
binding 0.22- micrometer in-line filter. Parenteral drug products should 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. Do not shake or dilute.
7.3.3 Dose Modifications or Escalations
7.3.3.1 Cetuximab related Folliculitis
Patients will concomitantly be assessed for the presence of cetuximab related folliculitis given the 
published correlation of folliculitis with clinical benefit (Bonner 2006). After MD visits, the patient 
will be assessed for the development of folliculitis characteristic of EGFR inhibition. Though the 
rash associated with EGFR inhibition appears similar to acne vulgaris and is commonly referred to 
as acne, acne-like, or acneiform, these terms are technically inaccurate. EGFR-associated rash is 
dominated by pustules that contain an intrafollicular collection of neutrophils—the hallmarks of an 
infectious folliculitis. Per Perez-Soler, the typical EGFR associated rash has a clinical presentation 
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
- 16 -
characterized by pustular/popular appearance, usually involving the face, head, and upper torso, and 
often accompanied by pruritus, dry skin, and erythema (Perez-Soler, Zou et al. 2011).
In previous reports, the criteria used for significant EGFR associated rash has most commonly been 
grade 2+ on the CTCAE 4.0 criteria listed below. 
CTCAE 4.0 Criteria 
1
2
3
4
Pruritus/itching
Mildor localized
Intense 
or 
widespread
Intense 
or 
widespread and 
interfering with 
ADL
_
Rash/Desquamation
Macular 
or 
papular eruption 
or 
erythema 
without 
associated 
symptoms
Macular 
or 
papular 
eruption 
or 
erythema with 
pruritus 
or 
other 
associated 
symptoms; 
localized 
desquamation 
or other lesions 
covering <
50% of body 
surface 
area 
(BSA)
Severe, 
generalized 
erythroderma 
or 
macular, 
papular 
or 
vesicular 
eruption; 
desquamation 
covering
> 50% BSA
Generalized, 
exfoliative, ulcerative, 
or bullous dermatitis
Rash/Acneiform
Intervention not 
indicated
Intervention 
not indicated
Associated 
with 
pain, 
disfigurement, 
ulceration, 
or 
desquamation
_
Nail Changes
Discoloration; 
Ridging 
(koilonychias); 
pitting
Partial 
or 
complete 
loss 
of nail(s); pain 
in nail bed(s)
Interfering with 
ADL
_
Pro20140000555
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
- 17 -
7.3.3.2 Infusion Reactions
Serious infusion reactions occurred with the administration of Cetuximab in approximately 3% of 
patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Reduce the infusion rate 
by 50% for NCI CTCAE Grade 1 or 2 and non-serious NCI CTCAE Grades 3–4 infusion reactions. 
Once the infusion rate has been decreased due to an infusion reaction, it will remain decreased for all 
subsequent infusions. If the subject has a second infusion reaction at the slower infusion rate, the 
infusion should be stopped, and the subject should receive no further cetuximab treatment. 
Immediately and permanently discontinue cetuximab for serious infusion reactions that are life 
threatening and/or require hospitalization. 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.
Serious infusion reactions, requiring immediate, permanent discontinuation of cetuximab included 
rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of 
consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTCAE Grades 3 and 4) 
infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 
patient. Approximately 90% of severe infusion reactions occurred with the first infusion despite 
premedication with antihistamines.
Monitor patients for 1 hour following Cetuximab infusions in a setting with resuscitation equipment 
and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous 
antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in 
patients requiring treatment for infusion reactions. Immediately and permanently discontinue 
Cetuximab in patients with serious infusion reactions.
Infusion reactions may be managed per the following table:
Adverse Event Grade
Treatment Guidelines
Grade 1: 
Transient flushing or rash; drug fever < 38° C 
(< 100° F)
For mild infusion reactions manifesting only as 
delayed drug fever, consider administering 
prophylactic antihistamine medications for 
subsequent doses. Maintain the cetuximab 
dose, but slow the infusion rate by 50%. 
Acetaminophen 
or 
a 
non-steroidal 
anti- 
inflammatory 
drug 
(NSAID) 
may 
be 
administered prior to subsequent cetuximab 
infusions, if not otherwise contraindicated in 
subjects.
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
- 18 -
Grade 2:
Rash; flushing; urticaria; dyspnea; drug fever 
≥ 38 C ( ≥ 100° F)
For moderate infusion reactions manifesting 
only as delayed drug fever, slow the infusion 
rate for cetuximab by 50% and consider 
administering antihistamine medications and/or 
steroidal medications. Maintain the cetuximab 
dose. Acetaminophen or a non-steroidal anti-
inflammatory 
drug 
(NSAID) 
may 
be 
administered prior to subsequent cetuximab 
infusions, if not otherwise contraindicated in 
subjects.
Grade 3:
Symptomatic bronchospasm with or without 
urticaria; parenteral medication(s) indicated; 
allergy related edema/angioedema; hypotension
Severe infusion reactions require immediate 
interruption of cetuximab infusion and 
permanent discontinuation from further 
treatment 
with 
cetuximab. 
Appropriate 
medical 
therapy 
including 
epinephrine, 
corticosteroids, 
diphenhydramine, 
bronchodilators, 
and 
oxygen 
should 
be 
available for use in the treatment of such 
reactions. 
Subjects 
should 
be 
carefully 
observed until the complete resolution of all 
signs and symptoms.
Grade 4:
Anaphylaxis
NO FURTHER STUDY DRUG THERAPY. 
Life threatening infusion reactions require 
immediate interruption of cetuximab infusion 
and permanent discontinuation from further 
treatment with cetuximab. Appropriate medical 
therapy including epinephrine, corticosteroids, 
diphenhydramine, bronchodilators, and oxygen 
should be available for use in the treatment of 
such reactions. Subjects should be carefully 
observed until the complete resolution of all 
signs and symptoms.
7.3.3.3 Rash: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, 
paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, 
cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients 
receiving Cetuximab therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving 
Cetuximab in clinical trials. Severe acneiform rash occurred in 1–17% of patients.
Pro20140000555
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
- 19 -
Acneform 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. 
Monitor patients receiving Cetuximab for dermatologic toxicities and infectious sequelae. Instruct 
patients to limit sun exposure during Cetuximab therapy.
Rash occurring with Cetuximab administration may be graded according to the following table from 
CTCAE 4.0.
1
2
3
4
Pruritus/itching
Mild or localized; 
topical 
intervention 
indicated
Intense 
or 
widespread; 
intermittent; skin 
changes 
from 
scratching 
(e.g., 
edema, 
papulation, 
excoriations, 
lichenification, 
oozing/crusts); 
oral intervention 
indicated; 
limiting 
instrumental 
ADL
Intense 
or 
widespread; 
constant; 
limiting 
self care ADL or 
sleep; 
oral 
corticosteroid 
or 
immunosuppressive 
therapy indicated
_
Purpura
Combined area of 
lesions covering 
<10% BSA
Combined area of 
lesions covering 
10 - 30% BSA; 
bleeding 
with 
trauma
Combined area of 
lesions covering
>30% 
spontaneous 
bleeding
BSA;
_
Rash/acneiform
Papules 
and/or 
pustules covering 
<10% 
BSA, 
which 
may 
or 
may 
not 
be 
associated 
with 
symptoms 
of 
pruritus 
or 
tenderness
Papules 
and/or 
pustules covering 
10 - 30% BSA, 
which 
may 
or 
may 
not 
be 
associated 
with 
symptoms 
of 
pruritus 
or 
tenderness; 
associated 
with 
psychosocial 
impact; 
limiting 
Papules 
and/or 
pustules 
covering 
>30% BSA, which 
may or may not be 
associated 
with 
symptoms of pruritus 
or 
tenderness; 
limiting 
self 
care 
ADL; 
associated 
with 
local 
superinfection 
with 
oral 
antibiotics 
Papules and/or 
pustules 
covering 
any 
% BSA, which 
may or may 
not 
be 
associated 
with 
symptoms 
of 
pruritus 
or 
tenderness and 
are associated 
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
- 20 -
instrumental 
ADL
indicated
with extensive 
superinfection 
with 
IV 
antibiotics 
indicated; life- 
threatening 
consequences
Rash/maculo-
papular
Macules/papules 
covering 
<10% 
BSA 
with 
or 
without 
symptoms 
(e.g., 
pruritus, burning, 
tightness)
Macules/papules 
covering 
10 
- 
30% BSA with or 
without 
symptoms 
(e.g., 
pruritus, burning, 
tightness); 
limiting 
instrumental 
ADL
Macules/papules 
covering >30% BSA 
with 
or 
without 
associated 
symptoms; limiting 
self care ADL
Nail 
Discoloration
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; intervention 
not indicated
_
_
_
Nail Loss
Asymptomatic 
separation of the 
nail bed from the 
nail plate or nail 
loss
Symptomatic 
separation of the 
nail bed from the 
nail plate or nail 
loss; 
limiting 
instrumental 
ADL
_
_
Nail Ridging
Asymptomatic; 
clinical 
or 
diagnostic 
observations 
only; intervention 
not indicated
_
_
_
Cetuximab dose should be modified per the following table in case of severe (grade 3/4) rash:
Occurrence of Severe (Grade3/4) acneiform Cetuximab modification
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
- 21 -
rash
1st Occurrence
Delay infusion 1 to 2 weeks. If there is 
improvement, continue cetuximab at at 250 
mg/m2. If there is no improvement, discontinue 
cetuximab.
2nd Occurrence
Delay infusion 1 to 2 weeks. If there is 
improvement, continue cetuximab at at 200 
mg/m2. If there is no improvement, discontinue 
cetuximab.
3rd Occurrence
Delay infusion 1 to 2 weeks. If there is 
improvement, continue cetuximab at at 150 
mg/m2. If there is no improvement, discontinue 
cetuximab.
4th Occurrence
Discontinue cetuximab
For the occurrence of grade 1 or 2 rash, see supportive care guidelines in section 7.4.5.1.
7.3.4 Dose modifications for other toxicity: due to lack of evidence that cetuximab contributes to 
these toxicities, cetuximab dose will not be altered for renal failure, fatigue, nausea/vomiting.
7.3.4.1 Hematologic Toxicity
Cetuximab will not be dose reduced or held for hematologic adverse events, such as neutropenia, 
neutropenic fever, or thrombocytopenia.
7.3.4.2 Non-Hematologic Toxicity 
7.3.4.3 Pulmonary Toxicity
Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving 
Cetuximab in clinical trials. Interrupt Cetuximab for acute onset or worsening of pulmonary 
symptoms. Permanently discontinue Cetuximab for confirmed ILD.
7.3.4.4 Dermatologic Toxicity
Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial 
inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, 
blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving 
Cetuximab therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Cetuximab in 
clinical trials. Severe acneform 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. Monitor patients 
receiving Cetuximab for dermatologic toxicities and infectious sequelae. Instruct patients to limit 
sun exposure during Cetuximab therapy.
Pro20140000555
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
- 22 -
7.3.4.5 Hypomagnesemia and Electrolyte Abnormalities
In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) 
receiving Cetuximab and was severe (NCI CTCAE Grades 3 and 4) in 6–17%. The onset of 
hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after 
initiation of Cetuximab. Periodically monitor patients for hypomagnesemia, hypocalcemia, and 
hypokalemia, during and for at least 8 weeks following the completion of Cetuximab. Replete 
electrolytes as necessary.
7.4.3 Concomitant Medications
There are no concomitant medications that are contraindicated with cetuximab.
7.3.6 Supportive Care Guidelines
7.3.6.1 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:
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.
Antihistamines: Benadryl or Atarax may be helpful to control itching.
Topical Steroids: The benefit of topical steroids is unclear. Topical hydrocortisone cream 
will be provided for pruritis not relieved with antihistamine use.
Retinoids: No data to support use. Use is not advised. They will not be used 
prophylactically.
Benzoyl peroxide: Should NOT be usedas it 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.
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
- 23 -
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.
7.3.6 Adherence/Compliance
Patients will receive weekly cetuximab per their medical oncologist. They should adhere to their 
oncologist’s recommendations (based on the protocol) regarding administration of cetuximab. 
Failure to do so may result in removal from the study.
8. Toxicity Monitoring and Adverse Event Reporting
All patients who receive one dose of protocol therapy will be evaluable for assessment of 
toxicity.  Prior to each cycle the treating physician will fully assess the patient’s condition with 
respect to possible treatment related toxicities.  All adverse events, whether observed by the 
physician or reported by the patient, occurring during the active portion of therapy, or up to 30 
days after the last dose of treatment will be graded by a numerical score according to the NCI’s 
Common 
Terminology 
Criteria 
for 
Adverse 
Events 
(CTCAE), 
Version 
4.0 
(http://ctep.cancer.gov/reporting/ctc.html) and recorded in the patient’s medical record. For the 
purposes of reporting laboratory abnormalities, only Grade 3-4 adverse events will be recorded 
on the adverse event CRF pages.  Grade 1-2 laboratory abnormalities will not be recorded on the 
adverse event CRF pages.  Information entered on the adverse event CRF pages will include: 

Specific type and duration of reaction (i.e., start and stop dates, resolution).

Severity/grade. 

Relationship to study drug (causality, attribution).

Management of the event, if treated with medication and other actions taken to 
alleviate the clinical event.

Whether or not it was considered a SAE. 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
will be recorded as an adverse event if the frequency, intensity, or the character of the condition 
worsens during the study period.
8.1 Adverse Event Reporting Requirements 
An adverse experience is defined as any unintended or abnormal clinical observation that is not 
of benefit to the patient.  Either the condition was not present prior to exposure to the study 
therapy, or it has worsened in intensity or frequency following exposure to the study therapy.  
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
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All “unexpected” (defined below) and/or “serious” (defined below) adverse events occurring 
during the active portion of therapy, or up to 30 days after the last dose of treatment, will be 
reported to the OHRS at (732) 235-7577 or (732) 235-8675. Events will be promptly reported, in 
writing, to the local IRB in accordance with IRB policy.  If a death occurs the IRB will be 
notified within 24-hours of initial receipt of information.  All other SAEs must be reported to the 
IRB within three to ten days of initial receipt of information. Written follow-up reports are 
required when additional information is needed to fully characterize the event. Copies of each 
report sent to the IRB will be kept in the study regulatory file.
In addition to reporting to the local IRB, reporting to external bodies such as industry and/or the 
FDA may be necessary. The Oncology group affiliates site will report all SAEs to the OHRS will 
be responsible for forwarding SAE reports to the IRB and FDA.
Reporting SAEs using commercially available drugs:
In addition, any unexpected (not listed in the package insert) serious adverse events that are 
associated (definitely, probably or possibly related) with the use of cetuximab must be reported 
to the FDA within 10 business days using a FDA Form MedWatch 3500 form 
http://www.fda.gov/medwatch/safety/3500.pdf (fax # 1-800-FDA-0178).
8.2 Definition of Serious Adverse Events (SAEs)
A serious adverse event (experience) is one occurring at any dose level that results in any of the 
following outcomes:  

Death

Life-threatening- immediate risk of death from the reaction.

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity.

Results in a congenital anomaly/birth defect.

Requires intervention to prevent one of the outcomes listed in this definition.
The definition of serious adverse event (experience) also includes important medical events.  
Medical and scientific judgment will be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  These events 
will usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization.
8.3 Definition of Related
There is a reasonable possibility that the drug caused the adverse experience.  That is, the event 
is judged by the investigator to be possibly, probably or definitely related to the treatment.  
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Protocol title: A Pilot Study of Neoadjuvant Cetuximab in Advanced Squamous Cell Carcinomas of Skin (SCCS)
PI: Janice Mehnert, MD
Protocol Version: 07/01/2015
CINJ#: 091303
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8.4 Definition of Unexpected
Any adverse drug experience and/or specificity, that is not included in the current investigator’s 
brochure and/or package insert. 
 9. Treatment Evaluation/Criteria for Response
For the purposes of this study, the response to neoadjuvant cetuximab is judged by 1) development 
of cetuximab related folliculitis as below and 2) response at the primary site or involved locoregional 
lymph nodes by CT using RECIST criteria.
Response and progression will be evaluated in this study using the international criteria proposed by 
the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Committee (Eisenhauer et al. 
2009)Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used in the RECIST criteria. Note: Lesions are either measurable or non- measurable using the 
criteria provided below. The term “evaluable” in reference to measurability will not be used because 
it does not provide additional meaning or accuracy.
In addition, patients will be evaluated weekly during neoadjuvant cetuximab to assess for grade of 
rash using CTCAE 4.0 criteria.
9.1 Evaluation of folliculitis
Folliculitis will be graded weekly following the initiation of neoadjuvant cetuximab per the criteria 
in section 7.3.3.1
9.2 Evaluation of CT response at primary site 
Measurable lesions are defined as those that can be accurately measured in at least one dimension as 
>10 mm with spiral CT scan. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). As all CT scans in this protocol will be performed using spiral CT, no 
lesions smaller than 10 mm will be used to assess for response.
Response will be graded per RECIST criteria:
Recist Criteria
Complete Response (CR)
Disappearance of all target lesions
Partial Response (PR)
At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, 
taking as reference the baseline sum LD.
Progressive Disease (PD)
At least a 20% increase in the sum of the 
LD of target lesions, taking as reference 
the smallest sum LD recorded since the 
treatment started or the appearance of 
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one or more new lesions.
Stable disease (SD)
Neither sufficient shrinkage to qualify 
for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest 
sum LD since the treatment started.
10. Removal of Patients from Study/Off Study Criteria
In the absence of treatment delays due to adverse events, treatment may continue until one of the 
following criteria applies:
a)  Intercurrent illness that prevents further administration of treatment, 
b)  Patient decides to withdraw from the study, 
c)  Noncompliance with treatment plan, 
d) General or specific changes in the patient's condition render the patient unacceptable 
for 
further treatment in the judgment of the investigator,
e) Protocol violation - any patient found to have entered this study in violation of the protocol 
might be discontinued from the study at the discretion of the Principal Investigator. 
11. Laboratory Evaluations and Procedures/Correlative and Pharmacokinetic Studies
11.1 An overview of the possible molecular investigations, and in order or priority include 
1. FoundationOne genomic profile from paraffin embedded tumor samples taken before 
cetuximab, before/at definitive local treatment and after progression
2. Analysis of ADCC and caspase by IHC
3. RNA sequencing of tumor samples before and after cetuximab
4. RNA sequencing of skin samples before and after cetuximab
5. DNA sequencing of tumor and skin samples before and after cetuximab
6. IHC analysis of EGFR downstream pathways that are illuminated by the above
The laboratory investigations are very comprehensive, ranging from partial DNA sequencing 
(FoundationOne™) in order to check for a battery of known DNA mutations related to cancer, to 
RNA sequencing on fresh tissue, which will shed light on how protein production is altered when the 
tumor is treated with cetuximab. FoundationOne™ is targeted DNA sequencing that is performed on 
paraffin embedded tumor samples. As a pan-cancer test, FoundationOne™ is designed to interrogate 
the entire coding sequence of 236 cancer-related genes (3,769 exons) plus 47 introns from 19 genes 
often rearranged or altered in cancer. These genes are known to be somatically altered in human 
solid cancers based on recent scientific and clinical literature.  ADCC and caspase will be examined 
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by IHC as in the laboratory, using paraffin embedded tissue from pre- and post- treatment samples. 
In addition, RNA sequencing will be performed on tumor samples from before and after neoadjuvant 
cetuximab, to investigate changes in protein production caused by cetuximab ie changes in protein 
production downstream in the EGFR pathway or completely alternate pathways that may be 
triggered by cetuximab. Western blot will also be utilized to look at changes in protein production in 
the EGFR pathway and other relevant signaling pathways. In addition, HPV status can be easily 
determined from RNA sequencing. Once the cDNA library is created by the Cancer Institute 
Functional Genomics (Curtis Krier and, Emmanuel Zachariah), analysis will be performed by 
bioinformatics. We will have experience with the procedures necessary to perform these analyses 
that are ongoing in protocol CINJ #091305. In addition, these complementary protocols will allow us 
to conduct parallel investigations in squamous tumors of the skin versus those of the head and neck, 
and to see if similar mechanisms are operative or if in fact these tumors are distinct biologic entities. 
11.2 Tissue to be collected
All patients must have a diagnosis of squamous cell carcinoma (SCC) of skin prior to entering into 
this protocol. This diagnosis is typically achieved by a biopsy from either the primary site or FNA 
from a neck lymph node. However, the scant amount of tissue obtainable from an FNA would not be 
adequate for the molecular biology aspect of this protocol, which include
1. Providing tissue to the pathology department so that they are able to confirm diagnosis of 
SCC in the tissue retrieved, which then will be sent to FoundationOne™ for DNA 
sequencing and analysis of genetic mutations. 
2. Providing frozen tumor to the Cancer Institute Functional Genomics Facility for RNA 
sequencing
3. Providing frozen tumor and skin tissue to be used in Western Blot analysis.
4. Providing FFPE tumor and skin tissue for use in IHC analysis. 
Thus, all patients on the protocol, prior to neoadjuvant cetuximab, will have an incisional/core 
biopsy from the primary site and a skin punch biopsy even though they already have a diagnosis of 
SCC. Incisional biopsy is favored over other types (core biopsy) for this biopsy because incisional 
biopsy has the best chance of supplying an adequate tumor sample. 
After neoadjuvant cetuximab, additional tissue will be obtained at surgery or if the patient is not a 
candidate for surgery, biopsy will be obtained prior to treatment with XRT or with further systemic 
therapy.  This tissue will only be used for RNA sequencing (and not sent to FoundationOne™ for 
DNA analysis), and thus a core biopsy may be employed here instead of incisional biopsy. A skin 
punch skin biopsy will also be performed after neoadjuvant cetuximab, preferably from a similar 
location as the first skin biopsy i.e. obtain two skin biopsies of neck and neck or right upper chest 
and right upper chest. If there is a locoregional/distant recurrence or persistence, a third incisional 
biopsy of locoregional/distant disease if possible and again paraffin-embedded sample will be sent to 
FoundationOne™ for analysis and fresh tissue may be obtained for RNA sequencing. 
11.3 Collection and Handling Procedures
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Collection and handling procedures will be performed at RWJUH, New Brunswick campus.
1. Prior to day of procedure, OHRS will be informed of the pending biopsies. 
Incisional or excisional biopsy will be obtained from the primary site and BRS notified. 
2. Tissues will be sent to RWJUH pathology and research specimens will be transported by 
BRS
3. At RWJUH pathology
a. Part of the tumor sample will be made into a paraffin embedded block, part of 
which they will use to confirm SCC, and the remainder of the paraffin embedded 
block will be sent to FoundationOneTM.
b. Part of the tumor sample will be put in dry ice and sent asap to the Cancer Institute 
Genomic Facility (Kurtis Crier). 
c. The skin sample will be logged in, put in dry ice and sent asap to Cancer Institute 
Genomic Facility. The skin sample does not require any pathologic diagnosis, and its 
purpose is solely to investigate etiology of the cetuximab folliculitis.
11.3.1 Handling of Fresh tissue at the Cancer Institute Functional Genomics Facility Clinical 
samples will be sent to:
Curtis Krier, Manager Functional Genomics Facility 
125 Paterson Street, CAB 7050
RWJMS
New Brunswick, NJ 08901
Phone 732 235 6426
12. Pharmaceutical Information
12.1 Investigational Agents
There are no investigational agents involved in this study.
12.2 Commercial Agents Product description: 
Cetuximab is a commercially available agent.. 
Preparation: Cetuximab® (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, preservative- free, injectable 
liquid. It should be prepared as for standard preparation as per the package insert. 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° C to 8° C. Discard any unused portion of the vial.
Route of administration:
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Premedicate with an H1 antagonist (eg, 50 mg of diphenhydramine) intravenously 30–60 minutes 
prior to the first dose; premedication should be administered for subsequent Cetuximab doses based 
upon clinical judgment and presence/severity of prior infusion reactions.
Administer 400 mg/m2 initial dose as a 120-minute intravenous infusion followed by 250 mg/m2 
weekly infused over 60 minutes. Reduce the infusion rate by 50% for NCI CTCAE Grade 1 or 2 
infusion reactions and non-serious NCI CTCAE Grades 3–4 infusion reactions. Permanently 
discontinue for serious infusion reactions. Withhold infusion for severe, persistent acneform rash. 
Reduce dose for recurrent, severe rash.
Expected toxicities: The most common adverse reactions (incidence ≥25%) are: cutaneous adverse 
reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. Refer to the 
package insert for a complete list of toxicities.
Drug Interactions: No known drug interactions with cetuximab.
13. Data Collection and Records to be Kept 
13.1 Case Report Forms
A subset of the National Cancer Institute (NCI) CRFs, in electronic format, will be utilized.   
Completion of the electronic CRFs (eCRFs) will be done in accordance with the instructions in a 
study specific data capture plan.  All eCRFs will be completed by clinical research coordinators 
of the OHRS. The eCRFs will be maintained in a confidential format in a secure database.
13.2 Data Submission Timeline and Forms
Completion of eCRFs will occur in accordance with NCI guidelines.  Baseline (pre-study) 
eCRFs (e.g., enrollment, medical history, concomitant medications, disease assessment, etc.) will 
be completed no later than 14 days after the start of treatment.   Treatment eCRFs (e.g., drug 
administration, adverse events, chemistries, etc.) will be completed no later than 14 days 
following each cycle of treatment.  Off-treatment information (e.g., follow-up, best response, 
etc.) will be completed no later than 14 days after the end of protocol treatment.
13.3 Research Charts
A research chart (i.e., shadow chart) is maintained at OHRS for each patient enrolled.  Copies of 
significant study source documents will be maintained in the research chart.  Examples of source 
document copies that will be maintained in the research chart include: signed informed consent 
form, documents that verify eligibility and treatment and documents that verify Grade 3-4 
adverse events and response. This information will be updated on a prospective basis and will be 
confidentially maintained at the OHRS.
13.4 Reports
Publications and annual reports for submission to the IRB will be written by the Rutgers Cancer 
Institute of New Jersey PI using the data captured on the e-CRFs. 
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14. Data and Safety Monitoring
Monitoring of this study will occur in accordance with the Cancer Institute’s NCI approved Data and 
Safety Monitoring Plan (DSMP).  An “initiation audit” will be conducted in accordance with the 
DSMP following enrollment of the first two (2) or three (3) patients.  Subsequent audits will occur 
on an annual basis prior to annual IRB continuing review, if the findings from the initiation audit 
were satisfactory.  More frequent audits of patient data and study conduct will occur if necessary.  
Prior audit findings and/or situations that may arise during the course of the study will determine the 
need for more frequent auditing.  All audit findings will be reported to the Cancer Institute’s Human 
Research Oversight Committee and the PI. 
15. Statistical Considerations
15.1 Primary Hypothesis
We hypothesize that the response rate to cetuximab is greater than 10%. 
15.2 Sample Size Justification
Sample size was justified based on the primary hypothesis. We expect the response rate is 30%. 
With 20 patients, the one-sided Binomial exact test at a significance level 0.05 (actual Type I error = 
4.32%) will achieve 76.2% power when true response rate is 30%. 
15.3 Methods for Randomization and Stratification
This is a safety/feasibility study. There will be no randomization.
15.4 Outcome Measures
The primary outcome is the response rate of cetuximab by RECIST criteria in patients with 
advanced SCCS.
The secondary outcomes include time to progression, time to death of patients with advanced SCCS 
who receive neoadjuvant cetuximab. Molecular correlates and tumor size will be also obtained.
15.5 Statistical Analysis
A one-sided Binomial exact test will be used to test the primary hypothesis. The estimation of 
progression-free survival and overall survival will be performed by the Kaplan-Meier product limit 
method. Descriptive statistics for all outcome measures will be provided. To evaluate the association 
between variables, either chi-square test (categorical vs. categorical) or two sample t-test (categorical 
vs. continuous) or correlation (continuous vs. continuous) will be used depending upon the types of 
variables in comparisson.
16. Human Subjects
16.1 Subject Population 
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The study population for this protocol is advanced squamous cell carcinoma of skin as defined in the 
eligibility criteria. 
16.2 Potential Risks
Potential risks to the patient secondary to cetuximab include the potential for hypersensitivity 
reaction, rash, hypomagnesemia, and pulmonary complications. These will be monitored as detailed 
in Sections 7.3.3. In terms of the individual’s cancer, there is a risk of treatment not being effective. 
Furthermore, if the drug is not effective, there is the possibility of disease progression.
16.3 Consent Procedures 
Informed consent must be obtained prior to commencing any research procedures.  The PI shall seek 
such consent only under such circumstances that provide the prospective patient opportunity to 
consider whether or not to participate and that minimizes the possibility of coercion or undue 
influence.  The information given to the patient, or the representative, shall be in a language 
understandable to the subject or representative.  The informed consent document may not include 
any exculpatory language through which the subject or representative is made to waive any of the 
subject’s legal rights or releases, or appears to release the investigator, the sponsor or the institution 
from liability for negligence.
16.4 Potential Benefits
The benefits of participating in this study may be improvement in a patient's cancer either as a 
measure of disease activity or quality of life improvements. 
16.5 Risk-Benefit Ratio
All risks and benefits of this treatment will be discussed with the patient prior to enrollment on this 
study. Along these lines, the basic principles of what we are hoping to accomplish with cetuximab 
followed by surgery will be explained. The potential risks detailed in Section 16.2 will be made clear 
as well, along with what measures are in place to minimize these risks. 
Alternative treatment will also be discussed. These options include beginning standard 
chemotherapy if applicable, therapy, monitoring off therapy, or enrolling in another clinical trial. 
Additionally, the importance of the knowledge gained through this study will be discussed with the 
patient. 
All told, with the combination of employing proper patient selection and study termination criteria, 
close clinical and lab follow-up (both of the cancer as well as other relevant body systems), and with 
the medical knowledge of cetuximab (as an FDA-approved medication, for oncologic medical 
purposes in head and neck and colon cancer) we believe that the potential benefits outweigh the risks 
of the trial..
16.6 Gender and Minorities 
This protocol is open to both men and women and all races. 
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17. Economic/Financial Considerations
There are no standards of care for patients with SCCS due to the lack of randomized studies in this 
population. However, phase II data for the use of cetuximab exist in this patient population and as 
such, this therapy is often widely available. Thus the treatment modalities of this protocol 
(cetuximab, surgery, radiation) will be paid per usual, by insurance or government agencies (charity 
care, medicare, Medicaid). Precertification of these modalities will occur prior to treatment on 
protocol. Funding will be sought for the pretreatment biopsies that are a mandatory part of this study. 
The additional investigational aspects of the study including, IHC, PCR, and RNA sequencing will 
be performed as funds allow, possibly financed through the Precision Medicine Group, or other 
grants. 
19. Publication of Research Findings
The policies and procedures of Rutgers Cancer Institute legal department (see: Investigator’s 
Handbook) will govern publication of the trial. It is expected that the results of this trial will be 
submitted for publication in a timely manner following the conclusion. The PI, and all co-authors 
prior to submission or use, must review any abstract or manuscript.
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