The purpose of this study is to determine if the combination of two new drugs pemetrexed (Alimta) and bevacizumab (Avastin) can increase the effectiveness of treatment for head and neck cancer. Currently pemetrexed is approved by the Food and Drug Administration (FDA) for another type of cancer, mesothelioma, but it is not approved for head and neck cancer.

Main objectives of this study are to 1) evaluate the time to progression (primary endpoint) with the combination of pemetrexed and bevacizumab in recurrent or metastatic head and neck cancer; 2) evaluate the objective response rate, duration of response, overall survival, and toxicities associated with the above therapy and 3) collect tumor tissue from previous diagnostic procedures and blood specimens prospectively, before and after therapy, for future correlative studies.

Inclusion Criteria:

1. Metastatic or locally recurrent squamous cell carcinoma of the head and neck. Patients with local recurrence will be considered incurable by means of locoregional therapy, as judged by the investigator.

2. Cytologically or histologically confirmed squamous cell carcinoma. Nasopharyngeal carcinoma of histologic subtype WHO II and III will be excluded.

3. Unidimensional measurable disease (RECIST criteria). If the only site of measurable disease is in a previously irradiated area, the patient must have documented progression of disease in this area.

4. ECOG performance status 0-1.

5. Full recovered from the effects of any prior surgery, or radiation therapy. A minimum time period of 3 weeks will elapse between the completion of extensive radiation therapy for recurrent/metastatic disease and enrollment in the study

6. Laboratory values:

   ANC ³ 1500/mm³. Platelets ³ 100,000/mm³. Total Bilirubin within normal institutional limits.

7. Transaminases (AST and ALT) < 3 x ULN. Creatinine clearance 45 ml/min or higher calculated using the Cockcroft-Gault formula.

8. Urine protein to creatinine (UPC) ratio of ≤ 1.0 on spot urine urinalysis.

9. Age > 18 years and capacity to give informed consent.

Exclusion Criteria:

1. Prior chemotherapy or biologic therapy for recurrent/metastatic head and neck cancer.
2. Prior pemetrexed, bevacizumab, or other antiangiogenesis agents at any time.
3. Presence of tumors that invaded major vessels.
4. 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
5. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to study enrollment.
6. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to registration. Serious non-healing wound, ulcer, or bone fracture.
7. History of brain metastasis or seizures.
8. Prior malignancy, with the exception of curatively treated squamous cell or basal carcinoma of the skin or in situ cervical cancer, unless there is a 5-year disease-free interval.
9. Pre-existing peripheral neuropathy > grade 2.
10. Myocardial infarction or stroke in the last 6 months. Unstable angina; Heart Association (NYHA) Grade II or greater congestive heart failure; Clinically significant peripheral vascular disease; CNS cerebrovascular ischemia within the last 6 months; active serious infection; other coexisting medical condition that would preclude full compliance with the study
11. Bleeding diathesis or coagulopathy.
12. Therapeutic anticoagulation (prophylactic use of warfarin 1 mg per day is allowed) or INR greater than 1.5 at registration
13. History of gross hemoptysis (defined as bright red blood of a ½ teaspoon or more).
14. Uncontrolled hypertension (>150/100)
15. Pregnant or lactating.
16. Use of NSAIDs within 5 days of protocol therapy.