Multicenter, Open-Label, Randomized, Phase II Trial of Docetaxel, Carboplatin and Bevacizumab as First-Line Treatment, Followed by Bevacizumab Plus Pemetrexed Versus Pemetrexed Alone as Second Line Treatment of Stage IIIB or IV NSCLC

Inclusion Criteria:

- Age ≥ 18 years

- Histologically or cytologically confirmed stage IIIB with malignant pleural effusion
or stage IV NSCLC except squamous-cell carcinoma.

- Measurable disease defined by RECIST.

- Adequate organ function

- Peripheral neuropathy ≤ grade 1

- ECOG Performance Status 0-1

- Estimated survival of ≥ 12 weeks

- Provide written informed consent

Exclusion Criteria:

- Prior chemotherapy for advanced NSCLC

- Neoadjuvant or adjuvant treatment within 6 months of registration

- Prior radiation therapy within 3 weeks of registration. All side effects must have
resolved by registration

- Prior treatment with an investigational or marketed agent that acts by
antiangiogenesis mechanisms

- Large ( > 4 cm) centrally located lesions or large lesions in close proximity to
major blood vessels unless treated with palliative radiation

- Brain metastases or leptomeningeal disease, except for patients who have had a
resection and/or completed a course of cranial irradiation, have no worsening CNS
symptoms, and have discontinued all corticosteroids for that indication for at least
1 month prior to registration

- History of gross hemoptysis (defined as bright red blood of at least ½ teaspoon or
2.5 mL per episode) within 3 months of registration unless definitively treated with
surgery, radiation, arteriographic embolization, or endobronchial interventions at
least 4 weeks prior to registration

- Presence of cavitary lesion

- Presence of squamous histology (mixed tumors will be categorized by the predominant
cell type unless small cell elements are present, in which case the patient is
ineligible; sputum cytology alone is not acceptable)

- Major surgery, open biopsy or significant traumatic injury within 4 weeks of
registration or anticipation of need for major surgical procedure during the course
of the study

- Minor surgical procedures, fine needle aspirations or core biopsies within

1 week prior to registration

- Current, ongoing therapeutic anticoagulation with full-dose warfarin or its
equivalent

- Current or recent (within 10 days of the first dose of study treatment) use of
aspirin (at least 325 mg/day) or other NSAIDs with anti-platelet activity or
treatment with dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix),
or cilostazol (Pletal)

- History of prior malignancy within the past 3 years except for curatively treated
basal cell carcinoma of the skin, cervical intra-epithelial neoplasia, or treated
localized prostate cancer with a current PSA of < 1.0 mg/dL on two successive
evaluations, at least 3 months apart, with the most recent evaluation no more than 4
weeks prior to registration

- History of serious systemic disease

- Pregnancy or women who are breast-feeding. Women of child-bearing potential and
non-vasectomized men must agree to use effective methods of birth control during and
3 months following treatment period. Women of child- bearing potential must have a
negative pregnancy test.

- History of severe hypersensitivity reaction to docetaxel or any other drugs
formulated with polysorbate 80

- Any other medical condition, including mental illness or substance abuse, which in
the judgment of the investigator, is likely to interfere with a patient's ability to
provide informed consent, cooperate, and participate in the study, or to interfere
with the interpretation of the results

- Use of any investigational agent within 4 weeks prior to registration