This is a multicenter, non-randomized, Phase II study of patients with previously untreated NSCLC not amenable to radiotherapy or surgical treatment. The planned enrollment for this trial is 78 patients (including a 10% rate for inevaluable patients). There will be a total of 39 patients in each cohort (Cohorts A and B).

The trial will include a lead-in phase for each cohort to assess safety. In Cohort A, 10 patients will receive ixabepilone 30 mg/m2 and carboplatin AUC = 6 intravenously (IV) on Day 1 of one 21-day treatment cycle. If no unexpected toxicities occur, Cohort A will open to enrollment. Enrollment for Cohort A will be done in two stages (after the lead-in portion is completed). The first stage for Cohort A will enroll a total of 22 patients (this will include the 10 patients from the lead-in phase). If there are at least 3 responses during stage 1, enrollment for stage 2 will proceed. For stage 2 of the study, 17 additional patients will be enrolled (for a total of 39 patients in Cohort A). During stage 1 and stage 2, patients in Cohort A will receive treatment with ixabepilone 30 mg/m2 and carboplatin AUC = 6 intravenously (IV) on Day 1 of each 21-day treatment cycle. Treatment will continue until disease progression or unacceptable toxicity occurs.

After the lead-in phase for Cohort A is completed, a similar lead-in portion, also consisting of 10 patients, will be done for Cohort B. Patients in Cohort B will receive ixabepilone 30 mg/m2, carboplatin AUC = 6 intravenously (IV), and bevacizumab 15 mg/kg on Day 1 of one 21-day treatment cycle. If no unexpected toxicities occur in this group, Cohort B will open to enrollment. Enrollment for Cohort B will also be done in two stages (after the lead-in portion is completed). The first stage for Cohort B will enroll a total of 22 patients (this will include the 10 patients from the lead-in phase). If there are at least 3 responses during stage 1, enrollment for stage 2 will proceed. For stage 2 of the study, 17 additional patients will be enrolled (for a total of 39 patients in Cohort B). During stage 1 and stage 2, patients in Cohort B will receive treatment with ixabepilone 30 mg/m2, carboplatin AUC = 6 intravenously (IV), and bevacizumab 15 mg/kg on Day 1 of each 21-day treatment cycle. Treatment will continue until disease progression or unacceptable toxicity occurs.

Unexpected toxicities include any grade 4 hematologic toxicity or grade 3/4 non hematologic toxicity that does not reverse within 7 days in more than 2 patients.

Eligible patients will receive ixabepilone, carboplatin, and bevacizumab (bevacizumab will be administered to patients in Cohort B only) at 21-day intervals. Patients will be re evaluated every 6 weeks using computerized tomography (CT) scans. Response to therapy will be assigned using Response Evaluation Criteria in Solid Tumors (RECIST) (Therasse et al. 2000) (see Section 7). Patients who have objective response or stable disease will continue treatment for 6 cycles, until the time of tumor progression or intolerable treatment-related side effects. Patients in Cohort B without progressive disease will be eligible to receive bevacizumab monotherapy for 6 additional cycles, or until undue toxicity or tumor progression occurs.

Inclusion Criteria:

1. Histologically confirmed non-small-cell bronchogenic carcinoma (squamous carcinoma, adenocarcinoma, or large cell carcinoma). Cytologic specimens obtained by brushings, washings, or needle aspiration of the defined lesion are acceptable. Mixed tumors with small-cell anaplastic elements are not eligible.

2. Patients who have newly diagnosed unresectable stage III or IV disease are eligible. Patients with stage III disease should be ineligible for combined modality therapy

3. Patients must not have received any prior antineoplastic chemotherapy for metastatic lung cancer prior to study entry.

4. Patients who have had previous radiotherapy as definitive therapy for locally advanced non-small-cell are eligible as long as the recurrence is outside the original radiation port. Radiation therapy must have been completed greater than 4 weeks prior to registration.

5. Male or female patients >=18 years of age.

6. Life expectancy of at least 3 months.

7. ECOG performance status of <=1.

8. Measurable disease by RECIST criteria (see Section 7).

9. Laboratory values as follows:

   • ANC >=1500/mm3 (7 days prior to treatment);
   • Hemoglobin >=8 g/dL;
   • Platelets >=100,000 mm3 (7 days prior to treatment)
   • Bilirubin <=1 x ULN for institution
   • AST/SGOT <=2.5 x ULN or <=5.0 x ULN in patients with liver metastases and
   • ALT/SGPT <=2.5 x ULN or <=5.0 x ULN in patients with liver metastases
   • Creatinine <=2.0 mg/dL or
   • Calculated (measured) GFR >=40 mL/min
   • PT/INR and PTT <=1.5 x ULN

10. Peripheral neuropathy <= grade 1.

Exclusion Criteria:

1. A history of cardiac disease as defined by malignant hypertension, unstable angina, congestive heart failure of > grade 2 per New York Heart Association (NYHA) criteria (see Appendix B), myocardial infarction within the previous 6 months, or symptomatic cardiac arrhythmias.
2. Metastatic brain or meningeal tumors.
3. Uncontrolled intercurrent illness.
4. Chemotherapy, investigational drug therapy, or major surgery ≤ 4 weeks prior to starting study drug, or patients who have not recovered from side effects of previous therapy.
5. Patient is <=5 years free of another primary malignancy, except if the other primary malignancy is not currently clinically significant or requiring active intervention, or if the other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ.

Exclusion Criteria for Enrollment on Bevacizumab (Cohort B):

1. Patients with squamous cell histology NSCLC.

2. Patients who have had a major surgical procedure (not including mediastinoscopy), open biopsy, or significant traumatic injury within 1 month of beginning bevacizumab.

3. Patients who have had primary thoracic radiation within 3 months of beginning bevacizumab.

4. Fine needle aspiration, core biopsy, mediastinoscopy or other minor surgical procedure within 7 days of beginning bevacizumab.

5. Patients receiving thrombolytic therapy within 10 days of starting bevacizumab.

6. Patients with serious non-healing wound, ulcer, or bone fracture.

7. Patients with evidence of bleeding diathesis or coagulopathy.

8. Patients with history of hemoptysis (defined as bright red blood of ½ teaspoon or more per episode) within 3 months prior to study enrollment.

9. Patients with proteinuria at screening, as demonstrated by either:

   • Urine protein : creatinine (UPC) ratio >=1.0 or
   • Urine dipstick for protein >=2+ (patients discovered to have >=2+ proteinuria on dipstick at baseline should undergo a 24-hour urine collection, and must demonstrate <1 g of protein in 24 hours to be eligible).

10. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to beginning bevacizumab.