This pilot clinical trial studies the side effects and how well cetuximab before surgery works in treating patients with skin cancer that forms, grows, and spreads quickly and has spread from where it started to nearby tissue or lymph nodes. Monoclonal antibodies, such as cetuximab, may block tumor growth in different ways be targeting certain cells. Giving cetuximab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PRIMARY OBJECTIVES:

I. To assess the response rate of cetuximab by Response Evaluation Criteria in Solid Tumors (RECIST) criteria in patients with advanced squamous cell carcinoma of skin (SCCS).

II. To assess whether neoadjuvant cetuximab given in this patient population is both safe and feasible.

SECONDARY OBJECTIVES:

I. To measure the progression free and overall survival of patients with advanced SCCS who receive neoadjuvant cetuximab.

II. To determine the conversion to resectability of patients treated with neoadjuvant cetuximab and capture changes in reconstructive options rendered possible by neoadjuvant treatment.

III. Analyze the relationship of known deoxyribonucleic acid (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.

IV. Measure the downstream activation of signaling pathways without a known driver, including the epidermal growth factor receptor (EGFR) pathway.

V. Determine if tumor shrinkage with cetuximab is associated with increased apoptosis as evidenced by activated caspase-3, in pre- and post- treatment tumor tissues.

VI. Determine whether cetuximab results in increased antibody-dependent cell cytotoxicity (ADCC) in post-, compared with pre-treatment tumor tissues.

OUTLINE:

Patients receive cetuximab intravenously (IV) over 60-120 minutes once weekly for 8 weeks.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Inclusion Criteria:

• 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
• Patients must give informed consent
• Patients must agree to pre- and post-treatment biopsies
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Estimated life expectancy of at least 12 weeks
• Negative pregnancy test

Exclusion Criteria:

• 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 intravenous immunoglobulin [IVIG] is permitted)
• Patients with distant organ metastases will not be included in this study
• 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
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to cetuximab or other agents used in the study
• Women who are pregnant; 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
• 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
• Prior radiation therapy is not an exclusion however, patient must have documented progression at the radiation site

Up to 2 years after the last participant receives treatment.