The goal of this clinical research study is to learn if knowing biomarker status can help researchers find better treatment combinations for patients with advanced NSCLC.

Researchers want to use biomarker status to decide what drug (bevacizumab, or cixutumumab) to give in combination with carboplatin and pemetrexed. The safety of these drug combinations will also be studied.

The Study Drugs:

Carboplatin is designed to interfere with the growth of cancer cells by stopping cell division, which may cause the cells to die.

Pemetrexed is designed to block enzymes in the body that play a part in tumor growth.

Bevacizumab is designed to block the growth of blood vessels that supply nutrients necessary for tumor growth. This may prevent or slow down the growth of cancer cells.

Cixutumumab is a monoclonal antibody, which means that it attaches to specific targets on cancer cells. These targets are called IGF-1R and help the cancer cells grow and divide. Cixutumumab is designed to block these receptors on tumor cells that may cause tumors to grow.

Study Groups and Drug Administration (Combination Therapy):

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the roll of dice) to 1 of 3 groups. You will have an equal chance of being assigned to each group. Each cycle is 21 days (+/- 5 days).

• If you are in Group 1, you will receive carboplatin and pemetrexed on Day 1 of each cycle. Carboplatin will be given by vein over 10 minutes. Pemetrexed will be given by vein over 30 minutes.
• If you are in Group 2, you will receive bevacizumab, carboplatin, and pemetrexed on Day 1 of each cycle. Bevacizumab will be given by vein over about 90 minutes for the first dose, about 60 minutes for the second dose, and about 30 minutes for all other doses. Carboplatin will be given by vein over 10 minutes. Pemetrexed will be given by vein over 30 minutes.
• If you are in Group 3, you will receive cixutumumab, carboplatin, and pemetrexed on Day 1 of each cycle. Cixutumumab is given by vein over 60 minutes. Carboplatin will be given by vein over 10 minutes. Pemetrexed will be given by vein over 30 minutes.

Study Visits During Combination Therapy:

If you are in Group 3, before you begin receiving study drugs, you will have a hearing test.

On Day 1 (+/- 5 days) of Cycles 1, 2, and 4:

• You will have a physical exam, including measurement of your weight and vital signs.
• You will be asked about any drugs you may be taking and any side effects you may be having.
• Your performance status will be recorded.
• Blood (about 3 teaspoons) will be drawn for routine tests.
• If you are in Group 2, urine will be collected for routine tests.

On Days 8 and 15 of Cycle 1:

°If you are in Group 3, blood (about 1 teaspoon) will be drawn for routine tests.

On Day 1 of Cycle 3:

• You will have a physical exam, including measurement of your weight and vital signs.
• You will be asked about any drugs you may be taking and any side effects you may be having.
• Your performance status will be recorded.
• Blood (about 3 teaspoons) will be drawn for routine tests.
• You will have a CT scan and/or MRI scan of the chest (and abdomen if the doctor thinks it is needed) to check the status of the disease.
• You will have an MRI scan of the brain.
• You will have a chest x-ray to check the status of the disease.
• If you are in Group 2, urine will be collected for routine tests.

At any time your doctor thinks it may be needed, blood (about 1 teaspoon) will be drawn to check how well your blood clots.

Maintenance Therapy:

After you have completed 4 cycles of combination therapy, you may be eligible for maintenance therapy.

If you are in Group 1,you will receive pemetrexed by vein over 10 minutes on Day 1 (± 5 days) of every 21-day cycle.

If you are in Group 2, you will receive pemetrexed by vein over 10 minutes and bevacizumab over about 30 minutes on Day 1 (± 5 days) of every 21-day cycle.

If you are in Group 3, you will receive pemetrexed by vein over about 10 minutes and cixutumumab by vein over about 60 minutes on Day 1 (± 5 days) of every 21-day cycle.

Study Visits During Maintenance Therapy:

On Day 1 of each cycle:

• You will have a physical exam, including measurement of your weight and vital signs.
• You will be asked about any drugs you may be taking and any side effects you may be having.
• Your performance status will be recorded.
• Blood (about 3 teaspoons) will be drawn for routine tests.
• You will have a CT scan and/or MRI scan of the chest (and abdomen if the doctor thinks it is needed) to check the status of the disease.
• You will have an MRI scan of the brain.
• You will have a chest x-ray to check the status of the disease.
• If you are in Group 2, urine will be collected for routine tests.

Length of Study:

You may continue taking the study drug(s) for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse or intolerable side effects occur.

Your participation on the study will be over once you have completed the end-of-dosing visit and follow-up.

End-of-Dosing Visit:

When you go off study for any reason, you will have an end-of-dosing visit. The following tests and procedures will be performed:

• Your medical history will be recorded.
• You will have a complete physical exam, including measurement of your weight and vital signs.
• You will be asked about any drugs you may be taking and any side effects you may be having.
• Your performance status will be recorded.
• Blood (about 3 teaspoons) and urine will be collected for routine tests.
• You will have a CT scan and/or MRI of the chest (and abdomen if the doctor thinks it is needed) to check the status of the disease.
• You will have an MRI scan of the brain.
• You will have a chest x-ray.
• You will have an ECG.
• If you are in Group 3, you will have a hearing test.

Follow-Up:

You will have follow-up every 4 weeks after you are no longer taking the study drugs. You will be contacted at a clinic visit or by phone. You will be called every 3 months for up to 3 years and asked about any cancer treatments you may be receiving. This phone call should take about 10 minutes.

This is an investigational study. Carboplatin and pemetrexed are FDA approved and commercially available for the treatment of certain types of NSCLC. Bevacizumab is FDA approved and commercially available for treatment of certain types of colon or rectal cancer, NSCLC, and renal cell carcinoma. Cixutumumab is not FDA approved or commercially available. At this time, cixutumumab is only being used in research.

Up to 225 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. The patient has a diagnosis of pathologically confirmed nonsquamous (nonpredominant squamous) NSCLC by tumor biopsy and/or fine-needle aspiration. Mixed tumors will be categorized by the predominant cell type; if small cell elements are present, the patient is ineligible.
2. The patient has a diagnosis of either stage IIIB or stage IV NSCLC or has recurrent NSCLC and is not a candidate for curative treatment. Patients may not have had chemotherapy for the advanced setting.
3. The patient has measurable NSCLC.
4. The patient's Eastern Cooperative Oncology Group (ECOG) performance status is </=2 at study entry.
5. The patient should have tumor available for epidermal growth factor receptor (EGFR) mutations, ALK fusions and other molecular analyses. If there is no tissue then the patient has should have biopsy accessible tumor.
6. The patient has adequate hematologic function as defined by an absolute neutrophil count (ANC) >/= 1,500/mm^3, platelet count >/= 100,000/mm^3, white blood cell count (WBC) >/= 3,000/ mm^3, and hemoglobin >/= 9 g/dL.
7. The patient has adequate hepatic function as defined by a total bilirubin level </= 1.5 X the upper limit of normal (Serum bilirubin >/= 1.5x Upper Limit of Normal in the setting of known Gilbert's disease is allowed), and alkaline phosphatase, AST and ALT </= 2.5 X the upper limit of normal or </= 5.0 x ULN if liver metastases are present.
8. The patient has adequate renal function as defined as CrCl of at least 45ml/min.
9. If patient has brain metastasis, they must have been stable (treated and/or asymptomatic) and off steroids for at least 2 weeks.
10. The patient is >/= 18 years of age.
11. The patient has signed informed consent.
12. Pregnancy Test. Women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for six (6) months after discontinuation of the study drugs. Childbearing potential will be defined as women who have had menses within the past 12 months, who have not had tubal ligation, hysterectomy or bilateral oophorectomy. Should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately. The patient, if a man, agrees to use effective contraception or abstinence for the duration of study participation and for six (6) months after discontinuation of the study drugs.
13. The ability to interrupt the use of NSAIDS two days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Pemetrexed.

Exclusion Criteria:

1. The patient has received prior definitive therapy (chemotherapy, surgery, or radiotherapy) within 3 months of initiating study drug or within, 2 weeks of localized palliative radiotherapy. Patients treated with initial biologic therapy that progress are eligible (no drug within 4 weeks). Patients must have recovered from the acute toxic effects prior to Day 1 of Cycle 1 to grade </= 1 or baseline.
2. Patients may not have had prior chemotherapy for first line treatment for NSCLC Stage IIIB/IV. Patient with activating EGFR mutations could have been treated with an EGFR tyrosine kinase inhibitor. Similarly patient with ALK or ROS1 fusions could have had treatment with crizotinib or other ALK inhibitors. Patients may not have had prior biologic therapy with antibodies targeting VEGF,or insulin-like growth factor receptor (IGFR).
3. The patient has undergone prior thoracic or abdominal surgery within 30 days of study entry, excluding prior diagnostic biopsy.
4. The patient has a history of uncontrolled angina, arrhythmias, or congestive heart failure.
5. The patient has inadequately controlled hypertension (defined as systolic blood pressure > 140 and/or diastolic > 90 mm Hg on antihypertensive medications).
6. The patient has a history of stroke or transient ischemic attack within 6 months prior to Day 1 of Cycle 1.
7. The patient is unable or unwilling to take folic acid, vitamin B12 supplementation, or dexamethasone according to protocol.
8. The patient has neuropathy >/= grade 2.
9. The patient has a history of gastrointestinal fistula, perforation, or abscess, inflammatory bowel disease, or diverticulitis.
10. The patient is currently receiving ongoing treatment with full-dose warfarin or equivalent (that is, unfractionated and/or low molecular weight heparin).
11. The patient is pregnant.
12. The patient is breastfeeding.
13. Presence of significant third space fluid which cannot be controlled by drainage.
14. The patient's tumor harbors the EML4-ALK fusion gene.
15. Drug Specific Eligibility for Treatment Arms. Patients are excluded from the Bevacizumab arm if they have a history of hemoptysis (>/= ½ teaspoon of bright red blood per episode) within 3 months prior to randomization.
16. Drug Specific Eligibility for Treatment Arms. Patients are excluded from Bevacizumab arm if the Urine Protein Creatinine (UPC) ratio is not within the institutional normal limits.
17. Drug Specific Eligibility for Treatment Arms. Patients are excluded from the IMC-A12 containing arm if they have poorly controlled diabetes: HBA1C>8% or if the patient has abnormally elevated fasting serum glucose (defined >110% ULN).
18. Drug Specific Eligibility for Treatment Arms. Patients are excluded if they have known hypersensitivity to any of the drugs.

Through study completion, an average of 3 years

Patients who were evaluable for toxicity and grades 1-3 adverse events.