Phase 2 Trial of Bevacizumab in Combination With Pemetrexed

Inclusion Criteria: * Advanced stage NSCLC excluding squamous cell histology with measurable or evaluable disease. * Stable brain metastases required, no longer requiring active therapy such as steroid medications, which have been previously treated with radiation or surgery or both and have been documented to be stable on repeat imaging done at least one month after completion of therapy. * Prior therapy with one standard doublet front-line regimen for NSCLC (platinum containing) * Life expectancy of at least 3 months * ECOG Performance status 0-1 * Age 18 or higher * Use of effective means of contraception (men and women) in subjects of child-bearing potential * Ability/willingness to comply with vitamin supplementation including vitamin B 12 and folic acid started at least 1 week before first dose of pemetrexed and continued for at least 3 weeks after last dose * Ability/willingness to take dexamethasone the day before, of and after pemetrexed administration * Drainage of any clinically significant effusion * Ability to sign informed consent Exclusion Criteria: * Treatment with more than one prior chemotherapy regimen (unless one regimen was stopped for toxicity reasons with a different regimen replacement regimen started immediately and patient completed only 4-6 total cycles of first-line treatment. One prior regimen (up to 4 cycles) of neoadjuvant or adjuvant therapy for early stage disease will also be allowed. * Prior treatment with pemetrexed or bevacizumab * Prior chemotherapy within 28 days (6 weeks for BCNU, CCNU or mitomycin-C) * Current, recent (within 4 weeks of the first infusion of this study), or planned participation in any other experimental drug study * Concomitant chemotherapy, radiotherapy or investigational agents * Uncontrolled effusion (large pleural or peritoneal effusion or small/moderate effusion which requires drainage for symptom management) * Evidence of bleeding diathesis or coagulopathy * Use of anti-coagulant agents including warfarin, heparin, aspirin, NSAIDs * Pregnant (positive pregnancy test) or lactating women * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study * Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to day 0 * Urine protein:creatinine ratio greater than or equal to 1.0 at screening * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0 * Serious, non-healing wound, ulcer, or bone fracture * Lung carcinoma of squamous cell histology or any histology in close proximity to a major vessel, or with significant cavitation as assessed by treating investigator in consultation with an attending radiologist * History of hemoptysis (bright red blood of 1/2 teaspoon or more) * Neutrophils \< 1.5 x 10\^9/ L * Hemoglobin \<10.0 g/dl * Platelets \<100 x 10\^9/ L * Serum glutamic oxaloacetic transaminase (SGOT/ AST) or serum glutamic pyruvic transaminase (SGPT/ ALT) \> 2.5 times upper limits of normal * Creatinine \> 1.5 times upper limits of normal * Significant co-morbidities including: * Blood pressure of greater than 150/100 mmHg * Unstable angina * New York Heart Association (NYHA) Grade II or greater congestive heart failure * History of myocardial infarction within 6 months * History of stroke within 6 months * Clinically significant peripheral vascular disease * Inability to comply with study and/or follow-up procedures