Phase II Trial of Bevacizumab in Combination With Pemetrexed as Second Line Therapy in Patients With Stable Brain Metastases From Non-small Cell Lung Cancer (NSCLC)(Excluding Squamous Cell Carcinoma)

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)

- 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