Safety and Efficacy of Radiation/Cetuximab Plus EGFR Antisense DNA for Head and Neck Squamous Cell Carcinoma

3.1 Eligibility Criteria * First stage Patients with current AJCC edition stage IVA-IVC or recurrent or metastatic head and neck cancer will be eligible. Patients with M1 disease must have asymptomatic or low volume distant metastasis and require palliation for local and regional disease * Second stage (phase II part) Patients with current AJCC edition stage III-IVB (T1-T4, N1-3M0) head and neck cancer, except WHO type II and III nasopharyngeal cancer, including unknown primary tumors. * Histologically or cytologically confirmed diagnosis of squamous cell carcinoma or variants or poorly differentiated carcinoma. * Unidimensionally measurable disease (RECIST criteria). * ECOG Performance Status of 0-2 * In the second stage of the study, therapy will be administered with a curative intent and patients should not have recurrent disease or distant metastasis. * Primary tumor and/or lymphadenopathy should be technically suitable for intratumoral injections. The Otolaryngologist specialist on the head and neck team will determine this feasibility. * Participating patients should agree to undergo a tumor biopsy at baseline as well as approximately 2 weeks later as specified in study schema. * Prior treatment * First stage: any prior treatment, except prior therapy which specifically and directly targets the EGFR pathway, administered within the last 6 months. No prior radiation therapy to the head and neck. * Second stage: no prior chemotherapy, biologic/molecular targeted therapy (including any prior therapy which specifically and directly targets the EGFR pathway), or radiotherapy for head and neck cancer. * Prior surgical therapy will consist only of incisional or excisional biopsy, including tonsillectomy, and organ sparing procedures, including neck dissection. Any non-biopsy surgical procedure for head and neck cancer must have taken place at least one month before initiating protocol treatment, at the treating physician's discretion. * Patients must have organ and marrow function as defined below: Absolute neutrophil count \>/=1,000/µL Platelets \>/=75,000/µL Hemoglobin \>/= 10 g/dL Total bilirubin \<2 x upper normal institutional limits Creatinine clearance \> 20 mL/min * Age of \>/= 18 years * Because radiation therapy is known to be teratogenic and EFGR inhibitors may have teratogenic potential, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation, and for 3 months after completing study treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. * Informed consent must be obtained from all patients prior to beginning therapy. Patients should have the ability to understand and the willingness to sign a written informed consent document. 3.2 Exclusion Criteria * Severe renal insufficiency (creatinine clearance \< 20 mL/min) * Treatment with anticoagulants, except when used to maintain the patency of a central venous line, or INR \>1.5, or PTT ratio \>1.5. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements. Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, uncontrolled congestive heart failure. * Patients may not be receiving any other investigational agents. * No history of prior malignancy, with the exception of curatively treated squamous cell or basal carcinoma of the skin or in situ cervical cancer, DCIS or LCIS of the breast, localized early stage prostate cancer, or malignancy that has been treated with a curative intent with a 3-year disease-free survival. * Pregnant women are excluded from this study because cetuximab, EGFR AS, and radiation have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cetuximab and EGFR AS, breastfeeding should be discontinued if the mother is treated with cetuximab. The effects of cetuximab and EGFR AS on the developing human fetus at the recommended therapeutic dose are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while in this study, she should inform her treating physician immediately. * HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible drug interactions with cetuximab. Appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated. . HIV status of the patient will be obtained from the patient's history via discussion with the investigator. HIV testing is not required. * Prior severe infusion reaction to a monoclonal antibody. * Patients who are not informed of and are not willing to comply with the investigational nature of the study and have not signed a written informed consent in accordance with institutional and good clinical practice guidelines. * Phase 2 ONLY (second stage) - Subjects with M1 disease will be excluded.