Paclitaxel, Carboplatin, and Bevacizumab With or Without Cixutumumab in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer

Inclusion Criteria:

* Histologically or cytologically confirmed with non-squamous, non-small cell lung cancer (NSCLC)
* Advanced NSCLC defined as either recurrent disease after prior radiation or surgery or stage IV (M1a or M1b) based on the TNM staging system (American Joint Committee on Cancer \[AJCC\] 2009)
* Measurable disease as defined by the revised Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). All sites of disease (of target and non-target disease sites) must be obtained within 4 weeks prior to randomization
* A head computed tomography (CT) or magnetic resonance imaging (MRI) required within 4 weeks prior to randomization
* Prior radiation therapy (RT) is allowed if it has been completed 3 weeks prior to randomization and patient has recovered from any adverse events related to RT
* Brain metastases are allowed, provided they have been treated with surgery and/or radiotherapy, the patient is neurologically stable, and repeat brain imaging shows no progression in the brain; at least 6 weeks should have elapsed from the time of craniotomy and at least 4 weeks from radiotherapy
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Absolute neutrophil count (ANC) ≥ 1500/mm³
* Platelet count ≥ 100,000/mm³
* Total bilirubin within institutional upper limit of normal (ULN)
* Serum creatinine ≤ 1.5 x ULN
* Fasting blood glucose within normal range (fasting \< 120 mg/dL or below ULN)
* Alkaline phosphatase (ALP) ≤ 3 x ULN
* Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN
* Urine dipstick must be ≤ 0-1+ within 2 weeks (14 days) of randomization; if urine dipstick result is \> 1+, a calculation of urine protein creatinine (UPC) ratio is required; patients must have a UPC ratio \< 1.0 to participate in the study
* Neuropathy, if present at baseline, must be ≤ Common Terminology Criteria for Adverse Events (CTCAE) grade 1
* Patients with a history of hypertension must be well-controlled (≤ 150/90) on a stable regimen of anti-hypertensive therapy
* Women of childbearing potential and sexually active males should use an accepted and effective method of contraception while on treatment and for 3 months thereafter

Exclusion Criteria:

* Prior chemotherapy or biologic/molecular targeted therapy for advanced NSCLC. Prior chemotherapy and/or biological/molecular targeted therapy as part of initial potentially curative therapy (one regimen of induction and/or adjuvant and/or concurrent chemoradiotherapy) was allowed provided it had been completed 1 year or more prior to randomization
* Prior treatment with IMC-A12 or another insulin-like growth factor 1 receptor (IGF-1R) inhibitor
* Patients on therapeutic anticoagulation; patient's international normalized ratio (INR) must be ≤ 1.5 or partial thromboplastin time (PTT) ≤ upper limits of normal within 2 weeks prior to randomization to be eligible; prophylactic anticoagulation of venous access devices is allowed provided the above criteria have been met
* Prior allergic reaction to compounds of chemical or biologic composition similar to those of IMC-A12
* Hypersensitivity to any component of bevacizumab
* Poorly controlled diabetes mellitus
* History of other invasive malignancies unless there is no active disease and all treatment has been completed ≥ 3 years prior to randomization; patients with history of in-situ malignancies and curatively resected nonmelanomatous skin cancer are eligible
* History of thrombotic or hemorrhagic disorders
* History of bleeding diathesis or coagulopathy
* ≥ grade 2 bleeding or any bleeding requiring intervention within 4 weeks prior to randomization
* History of gross hemoptysis (defined as ≥ 1/2 teaspoon of bright red blood)
* Any of the following within 6 months prior to randomization:

  * Abdominal fistula
  * Gastrointestinal perforation
  * Intra-abdominal abscess
  * Previous myocardial infarction
  * History of any central nervous system (CNS) cerebrovascular ischemia
  * New York Heart Association (NYHA) \> class II congestive heart failure or severe heart failure
  * Unstable or symptomatic angina pectoris
  * History of stroke
  * Significant vascular disease
  * Symptomatic peripheral vascular disease
* Ongoing, serious cardiac arrhythmia requiring medication at time of randomization
* Ongoing, active infection or ongoing fever at the time of randomization or any co-existing medical condition, psychiatric illness or limitations that would interfere with compliance of study requirements
* History of hypertensive crisis or hypertensive encephalopathy
* Any of the following within 4 weeks prior to randomization: a serious non-healing wound, ulcer, bone fracture, or major surgical procedure
* Anticipated major surgical procedure(s) during the course of the study
* Receiving daily treatment with aspirin (\> 325 mg/day) or non-steroidal anti-inflammatory agents (NSAIDs) known to inhibit platelet function for chronic conditions; patients must not be receiving treatment with dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix), and/or cilostazol (Pletal); if patient was receiving any of the following: aspirin (\> 325 mg/day), NSAID, and/or anti-platelet drugs, patient must have discontinued its use ≥ 1 week prior to randomization
* Pregnant or breast-feeding
* Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy