Study of Pemetrexed and Bevacizumab in Patients With 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.