Radiation, Cetuximab and Pemetrexed With or Without Bevacizumab in Locally Advanced Head and Neck Cancer

Inclusion Criteria:

* All patients must have pathologically confirmed AJCC 6th edition (see Appendix) stage III or IV (M0) squamous cell carcinoma or undifferentiated or poorly differentiated carcinoma of the oropharynx, larynx, or hypopharynx with no evidence of distant metastasis. Biopsy sampling of primary tumor with pathology report documentation of confirmed diagnostic tissue type is required. Patients should be evaluated by a Radiation Oncologist, Medical Oncologist and Otolaryngologist prior to enrolling on study.
* No prior treatment for head and neck cancer. Limited, organ-preserving surgery is allowed
* ECOG performance status 0-1
* Unidimensionally measurable disease is not required. However, patients should require treatment with full dose radiotherapy (not postoperative)
* Age greater or equal to 18 years
* Absolute neutrophil count greater or equal to 1500/µl, Platelet count greater or equal to 100,000/µl
* Creatinine clearance 45 ml/min or higher calculated using the Cockcroft-Gault formula
* Total bilirubin within normal limits and AST/ALT less than 3 times the upper limit of normal
* Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio. For UPC ratio \>0.5, 24-hour urine protein should be obtained and the level must be \<1000mg for patients to be eligible
* 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
* Patients should be willing and able to take folic acid and vitamin B12 supplementation and should interrupt aspirin or other non-steroidal anti-inflammatory agents for a 5-day period
* The use of anti-platelet agents(e.g. dipyridamole (Persatine), ticlopidine (Ticlid), clopidogrel (Plavix)) is allowed only if patient is not receiving aspirin or NSAID's known to inhibit platelet function.
* Patients who meet the following criteria will be excluded due to the possibility of increased risk for tumor bleeding with bevacizumab therapy:

  * active bleeding due to head and neck cancer of more than ½ teaspoon of bright red blood per episode or history of persistent bleeding due to SCCHN that required major intervention (surgery or embolization) to be controlled.
  * history of gross hemoptysis (bright red blood of .05 teaspoon or more per episode of coughing) less than or equal to 3 months prior to enrollment
  * history of coagulopathy or hemorrhagic disorders
* Patients should not be on therapeutic anticoagulation (prophylactic use of warfarin 1 mg per day is allowed) and INR should be \< 1.5 at registration.
* Patients with a prior history of squamous cell or basal carcinoma of the skin or in situ cervical cancer must have been curatively treated. Patients with a history of other prior malignancy must have been treated with curative intent and must have remained disease-free for 5 years post diagnosis
* Patients with history of hypertension must be well-controlled upon study entry (≤150/90) on a stable regimen of anti-hypertensive therapy. Patients should not have any prior history of hypertensive crisis or hypertensive encephalopathy.
* No major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment, or anticipation of need for major surgical procedure during the course of the study. Prior surgical therapy will consist only of incisional or excisional biopsy and organ sparing procedures such as debulking of airway compromising tumors or neck dissection in a patient with an existing primary tumor. Any non-biopsy procedure must have taken place \>4 weeks but \<3 months of initiating protocol treatment. No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to registration. No serious non-healing wound, ulcer, or bone fracture.
* No unstable angina or myocardial infarction within the previous 6 months; no symptomatic congestive heart failure; no serious cardiac arrhythmia requiring medication; no clinically significant peripheral vascular disease; no history of aortic dissection; no history of any CNS cerebrovascular ischemia or stroke within the last 6 months; no active serious infection. All patients will have a baseline EKG. If abnormalities consistent with active coronary artery disease are detected, the patient will be referred to a cardiologist for appropriate evaluation and management prior to treatment on study
* For patients who have baseline clinically significant pleural or peritoneal effusions (on the basis of symptoms or clinical examination) before initiation of protocol therapy, consideration should be given to draining the effusion prior to starting therapy due the potential of increased toxicity with pemetrexed in that setting
* Submission of archival tumor samples, unstained slides or blocks, for correlative studies is strongly encouraged, but not required for subject participation if tissue is not readily available or quantity is not sufficient for release per submitting pathologist.

Exclusion Criteria:

* Patients who are receiving any other investigational agents.
* Ineligible will be patients with uncontrolled intercurrent illness including, but not limited to,ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
* Patients should not have prior history of a serious reaction to a monoclonal antibody. Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies are not eligible.
* Women must not be pregnant or breast feeding because chemotherapy may be harmful to the fetus or the nursing infant. Pregnant women are excluded from this study because chemotherapy and/or bevacizumab have the potential for teratogenic or abortifacient effects.
* HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible drug interactions with study drugs. Appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated.