Monoclonal antibodies, such as cetuximab and bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab may stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving cetuximab together with paclitaxel, carboplatin, and bevacizumab may kill more tumor cells. This phase II trial is studying how well giving cetuximab together with paclitaxel, carboplatin, and bevacizumab works in treating patients with advanced non-small cell lung cancer

PRIMARY OBJECTIVES:

I. To evaluate the frequency and severity of hemorrhage toxicities in patients with advanced non-small cell lung cancer treated with the combination of carboplatin, paclitaxel, cetuximab and bevacizumab followed by therapy with cetuximab and bevacizumab.

SECONDARY OBJECTIVES:

I. To evaluate progression-free and overall survival, response rate (confirmed plus unconfirmed, complete plus partial), and frequency and severity of non-hemorrhage toxicities in this group of patients treated with this regimen.

II. To perform molecular correlative studies on patient tissue to investigate in an exploratory manner potential predictors of efficacy.

OUTLINE: This is a multicenter study.

INDUCTION THERAPY: Patients receive cetuximab IV over 1-2 hours on days 1, 8, and 15 and paclitaxel IV over 3 hours, carboplatin IV over 30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive cetuximab IV over 1 hour on days 1, 8, and 15 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 1 year and then every 6 months for up to 3 years.

Inclusion Criteria:

• Patients must have histologically or cytologically proven newly diagnosed selected stage IIIB (T4 lesion due to malignant pleural effusion) or stage IV, advanced primary non-small cell lung cancer (adenocarcinoma, large cell carcinoma, or unspecified) or recurrent disease after previous surgery and/or irradiation; patients with tumors having squamous cell components > 50% are not eligible
• Patients with known brain metastases are not eligible; all patients must have a pretreatment CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to registration
• Patients may have measurable or non-measurable disease documented by CT, MRI, X-ray or physical exam; measurable disease must be assessed within 28 days prior to registration; pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease; non-measurable disease must be assessed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (Form #848)
• Patients must not have received any prior systemic chemotherapy or biologic therapy for non-small cell lung cancer; patients must not have received any adjuvant therapy for non-small cell lung cancer
• Prior radiation is permitted; however, at least three weeks must have elapsed since the completion of prior radiation therapy and patients must have recovered from all associated toxicities at time of registration; measurable or non-measurable disease must be outside the previous radiation field or a new lesion must be present
• At least four weeks must have elapsed since surgery (thoracic or other major surgeries) and patients must have recovered from all associated toxicities at the time of registration; measurable disease must be present outside the area of surgical resection; there must be no anticipation of need for major surgical procedures during protocol treatment
• Patients must not have received prior cetuximab, ZD1839, erlotinib or other investigational agents that target the EGFR pathway; patients must not have received prior VEGF-related agents; patients must not have received prior chimerized or murine monoclonal antibody therapy or have documented presence of human anti-mouse antibodies (HAMA)
• ANC >= 1,500/mcl
• Platelet count >= 100,000/mcl
• Hemoglobin >= 9 mg/dl
• Patients must have a serum creatinine =< institutional upper limit of normal (IULN) AND calculated or measured creatinine clearance >= 50 cc/min using the Cockroft-Gault Formula
• Urine protein must be screened by urine analysis for Urine Protein Creatinine (UPC) ratio; for UPC ratio > 0.5, 24-hour urine protein must be obtained and the level must be < 1,000 mg for patient enrollment
• Serum bilirubin =< 2 x IULN
• Either SGOT or SGPT =< 2 x IULN (if both SGOT and SGPT are done, both must be =< 2 x IULN)
• International Normalized Ratio (INR) =< 1.5; patients must not be taking full-dose anticoagulation therapy; patients may be enrolled initially if they are on low-dose warfarin (i.e., 1 mg daily)
• All patients must have a Zubrod performance status of 0 - 1
• Correlative science studies: institutions must have received IRB approval of S9925 (the Lung Cancer Specimen Repository); patients must be offered participation in S9925; with the patient's consent, blood, plasma and tissue will be submitted for testing via S9925; patients must be registered separately to S9925 in order for institutions to receive credit for specimen submissions
• Patients must not have had hemoptysis >= 1/2 teaspoon within 3 months prior to registration
• Patients must not have >= grade 2 symptomatic neuropathy-sensory (National Cancer Institute [NCI] Common Terminology Criteria Version 3.0)
• Patients must not have documented evidence of acute hepatitis or have an active or uncontrolled infection
• Patients must not have the following: history (within past 6 months) of CVA, myocardial infarction or unstable angina; uncontrolled hypertension; New York Heart Association grade 2 or greater congestive heart failure; serious cardiac arrhythmia requiring medication; or clinically significant peripheral vascular disease
• Patients must not have had an open biopsy or significant traumatic injury within 28 days prior to registration; patients must not have had a core biopsy within 7 days prior to registration
• Patients must not have serious or non-healing wound, ulcer or bone fracture
• Patients must not have history of abdominal fistula, gastrointestinal perforation or intraabdominal abscess within 28 days prior to registration
• Patients must have no known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies
• Patients must not have evidence of bleeding diathesis or coagulopathy
• Patients must be willing to provide prior smoking history as required on the S0536 Prestudy Form (Form #54655)
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years
• Pregnant or nursing women are not eligible for this trial; women/men of reproductive potential must not participate unless they have agreed to use an effective contraceptive method during protocol treatment and for at least 6 months following completion of bevacizumab treatment
• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
• At the time of patient registration, the treating institution's name and ID number must be provided to the Data Operations Center in Seattle in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered into the data base