Randomized Phase II Trial of Pemetrexed vs. Pemetrexed/Bevacizumab vs. Pemetrexed/Carboplatin/Bevacizumab in Patients With Stage IIIB/IV Non-Small-Cell Lung Cancer and ECOG Performance Status 2

Inclusion Criteria:

1. Patients must be >=18 years of age.

2. Non-squamous NSCLC (adenocarcinoma or large cell carcinoma). Mixed tumors with small
cell anaplastic elements are not eligible. Mixed tumors with squamous histology are
acceptable as long as the squamous element is not the dominant histology.

3. Unresectable stage IIIB or stage IV disease. Stage IIIB disease should be ineligible
for combined modality therapy (i.e., pleural effusions, pericardial effusions).

4. ECOG performance status of 2.

5. No prior systemic therapy for stage IIIB or stage IV lung cancer.

6. Life expectancy of at least 12 weeks.

7. Patients must have measurable disease per RECIST version 1.1 (see Section 8).

8. Laboratory values as follows:

- Absolute neutrophil count (ANC) ≥1500/μL

- Hemoglobin (Hgb) ≥10 g/dL

- Platelets ≥100,000/μL (≤7 days prior to treatment)

- AST or ALT and alkaline phosphatase (ALP) must be <2.5 x ULN, or <5 x ULN in
patients with liver metastases.

- Total bilirubin <1.5 x the institutional ULN

- Calculated creatinine clearance ≥45 mL/min

9. The ability to take folic acid, Vitamin B12, and dexamethasone according to protocol.

10. Women of childbearing potential must have a negative serum or urine pregnancy test
performed within 7 days prior to start of treatment. Women of childbearing potential
or men with partners of childbearing potential must use effective birth control
measures during treatment. If a woman becomes pregnant or suspects she is pregnant
while participating in this study, she must agree to inform her treating physician
immediately.

11. Patient must be accessible for treatment and follow-up.

12. Patients must be able to understand the investigational nature of this study and give
written informed consent prior to study entry.

Exclusion Criteria:

1. Squamous cell histology. Mixed tumors will be categorized by the predominant cell
type unless small cell elements are present, in which case the patient will be
ineligible; sputum cytology alone is unacceptable.

2. Patients with active brain metastases. Patients who have received radiation or
surgery for brain metastases are eligible if there is no evidence of central nervous
system (CNS) disease progression, and at least 2 weeks have elapsed since treatment.
Ideally, patients should not still require use of seizure medication or steroids.

3. Patients who have had major surgical procedure (not including mediastinoscopy), open
biopsy, or significant traumatic injury within 4 weeks of beginning treatment; or,
the anticipation of the need for major surgical procedure during the course of the
study.

4. Women who are pregnant or lactating.

5. Minor surgical procedures (with the exception of the placement of portacath or other
central venous access) must be completed at least 7 days prior to beginning protocol
treatment.

6. History of hypersensitivity to active or inactive excipients of any component of
treatment (pemetrexed, bevacizumab, and/or carboplatin).

7. Pulmonary carcinoid tumors.

8. Patients with proteinuria at screening as demonstrated by either:

- urine protein creatinine (UPC) ratio ≥1.0 at screening OR

- urine dipstick for proteinuria ≥2+ (patients discovered to have ≥2+ proteinuria
on dipstick urinalysis at baseline should undergo a 24 hour urine collection,
and must demonstrate ≤1 g of protein/24 hours to be eligible) (see Appendix B)

9. Patients with a serious non healing wound, active ulcer, or untreated bone fracture.

10. Patients with evidence of bleeding diathesis or significant coagulopathy (in the
absence of therapeutic anticoagulation).

11. Patients with history of hematemesis or hemoptysis (defined as having bright red
blood of ½ teaspoon or more per episode) within 1 month prior to study enrollment.

12. History of myocardial infarction or unstable angina within 6 months of beginning
treatment.

13. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg
and /or diastolic blood pressure >100 mmHg while on antihypertensive medications).

14. New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF)
(see Appendix C).

15. Serious cardiac arrhythmia requiring medication.

16. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or
recent peripheral arterial thrombosis) within 6 months prior to Day 1 of treatment.

17. History of stroke or transient ischemic attack ≤ 6 months prior to beginning
treatment.

18. Any prior history of hypertensive crisis or hypertensive encephalopathy.

19. History of abdominal fistula or gastrointestinal perforation ≤ 6 months prior to Day
1 of beginning treatment.

20. Concurrent severe, intercurrent illness including, but not limited to, ongoing or
active infection, or psychiatric illness/social situations that would limit
compliance with study requirements.

21. Mental condition that would prevent patient comprehension of the nature of, and risk
associated with, the study.

22. Use of any non-approved or investigational agent ≤ 30 days of administration of the
first dose of study drug. Patients may not receive any other investigational or
anti-cancer treatments while participating in this study.

23. Past or current history of neoplasm other than the entry diagnosis with the exception
of treated non-melanoma skin cancer or carcinoma in situ of the cervix, or other
cancers cured by local therapy alone and a DFS ≥5 years.