Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients With Adenocarcinoma.

Inclusion Criteria:

Patients must have Histologically or cytologically confirmed non-squamous cell, non small cell carcinoma of the lung.

Patient must have measurable stage IV disease (includes M1a, M1b stages or recurrent disease) (according to the 7th edition of the TNM classification system). However, patients with T4NX disease (stage III B) with nodule(s) in ipsilateral lung lobe are not eligible, because such patients were not included in historical controls.

Patients be age \>18 years.

Patients must have a Life Expectancy of greater than 12 weeks.

Patients must have an ECOG performance status 0 or 1 (Karnofsky \> 70%; see Appendix A).

Patients must have normal organ and marrow function as defined below, within one week prior to randomization:

* absolute neutrophil count \>1,500/mcL
* platelets \> 100,000/mcL
* total bilirubin: within normal institutional limits
* AST(SGOT)/ALT(SGPT) \< 2.5 X institutional upper limit of normal
* creatinine ≤ 1.5 X institutional upper limit of normal
* urine dipstick for proteinuria of \< less than 1+. If urine dipstick is \> 1+ then a 24 hour urine for protein must demonstrate \< 500 mg of protein in 24 hours to allow participation in the study.

Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Patients must have an INR \< 1.5 and a PTT no greater than upper limits of normal within 1 week prior to randomization.

Patients with a history of hypertension must be well-controlled (\<150sytolic/\<100diastolic) on a stable regimen of anti-hypertensive therapy.

Patients must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Patients with a history of gross hemoptysis (defined as bright red blood of ½ teaspoon or more) will be excluded from this trial.

Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements.

Patients with a history of thrombotic or hemorrhagic disorders.

Patients receiving chronic daily treatment with aspirin (\> 325 mg/day) or nonsteroidal anti-inflammatory agents known to inhibit platelet function. Treatment with dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and/or cilostazol (Pletal)is also not allowed.

Patients receiving therapeutic anticoagulation. Prophylactic anticoagulation of venous access devices is allowed provided Section 3.10 is met. Caution should be taken on treating patients with low dose heparin or low molecular weight heparin for DVT prophylaxis during treatment with bevacizumab as there may be an increased risk of bleeding.

Prior use of chemotherapy.

Patients receiving immunotherapy, hormonal-therapy and or radiotherapy within 2 weeks prior to entering the study. Note: Those who have not recovered from adverse events due to these agents administered will be considered ineligible.

Patients receiving any other investigational agents.

Patients with a serious non-healing wound ulcer, or bone fracture, or major surgical procedure within 21 days prior to starting treatment.

Patients with uncontrolled brain metastasis. Note: Patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks, and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin and paclitaxel or other agents used in the study are excluded.

Women that are pregnant or breastfeeding Note: Pregnant women are excluded from this study because the agents used in this study may be teratogenic to a fetus. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with paclitaxel, breastfeeding women are also excluded from this study.

Patients that are HIV-positive on combination antiretroviral therapy due to the potential for lethal infections when treated with marrow-suppressive therapy.