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 non-squamous, non-small celllung cancer (NSCLC), including any of the following subtypes*:

  • Adenocarcinoma
  • Large cell
  • Bronchioloalveolar
  • NSCLC not otherwise specified

• Advanced disease, as defined by any of the following:

  • Stage IV (M1a or M1b)* disease based on the TNM staging system
  • Recurrent disease after prior radiotherapy or surgery

• Measurable disease, as defined by RECIST (PET and the PET portion of PET/CT are not acceptable methods of evaluation for response)

  • No prior radiotherapy to the only area of measurable disease unless there is progression of disease documented by physical examination, imaging tests, or pathology in this region

• 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 tumor progression in the brain

  • Patients must undergo head CT scan or MRI within 4 weeks prior to randomization for evaluation
  • At least 6 weeks since prior craniotomy and ≥ 4 weeks since prior radiotherapy
• ECOG performance status 0-1
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Total bilirubin normal
• Serum creatinine ≤ 1.5 times upper limit of normal (ULN)
• Fasting blood glucose normal (fasting < 120 mg/dL or below ULN)
• AST and ALT ≤ 3 times ULN
• Alkaline phosphatase ≤ 3 times ULN
• Urine protein by dipstick ≤ 1+ (within 2 weeks of randomization) OR urine protein:creatinine < 1.0
• INR < 1.5 or PTT normal
• Neuropathy ≤ CTCAE grade 1
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study treatment
• No prior allergic reaction to compounds of chemical or biological composition similar to those of cixutumumab
• No known hypersensitivity to any component of bevacizumab

• No poorly controlled diabetes mellitus

  • History of diabetes mellitus allowed, provided blood glucose is within normal range

• No history of other invasive malignancies unless there is no active disease and all treatment has been completed > 3 years prior to study

  • Patients with history of in-situ malignancies and curatively resected nonmelanomatous skin cancer are allowed
  • Patients with a history of breast cancer (without evidence of disease for ≥ 3 years) who recently completed adjuvant hormonal therapy < 3 years from the date of registration are eligible
• No history of thrombotic or hemorrhagic disorders
• No history of bleeding diathesis or coagulopathy
• No bleeding ≥ grade 2 (CTCAE version 3) requiring intervention within the past 4weeks
• No history of gross hemoptysis (defined as > ½ teaspoon of bright red blood)
• No history of hypertensive crisis or hypertensive encephalopathy
• History of hypertension allowed provided it is well-controlled (< 150/90 mm Hg) by stable anti-hypertensive therapy

• None of the following conditions within the past 6 months:

  • Abdominal fistula
  • Gastrointestinal perforation
  • Intra-abdominal abscess
  • Myocardial infarction
  • Stroke
  • Any CNS cerebrovascular ischemia
  • New York Heart Association class II-IV congestive heart failure or severe heart failure
  • Unstable or symptomatic angina pectoris
  • Significant vascular disease
  • Symptomatic peripheral vascular disease
• No ongoing, serious cardiac arrhythmia requiring medication
• No ongoing, active infection or fever
• No co-existing medical condition, psychiatric illness or limitations that would interfere with compliance of study requirements
• No serious non-healing wound, ulcer, bone fracture within the past 4 weeks
• No other concurrent anticancer therapy (e.g., biologic agents, chemotherapy, or radiotherapy)
• No prior chemotherapy or biologic or molecular targeted therapy for advanced NSCLC
• No prior cixutumumab or another IGF-IR inhibitor
• At least 3 weeks since prior radiotherapy and recovered
• More than 1 year since prior chemotherapy and/or biological or molecular targeted therapy as part of initial potentially curative therapy (i.e., one regimen of induction and/or adjuvant and/or concurrent chemoradiotherapy)
• More than 4 weeks since prior and no concurrent major surgical procedure
• More than 7 days since prior minor surgical procedure
• More than 1 week since prior and no concurrent daily treatment with acetylsalicylic acid (> 325 mg/day) or other non-steroidalanti-inflammatory agents
• More than 1 week since prior and no concurrent dipyridamole (Persantine), ticlopidine (Ticlid),clopidogrel (Plavix), and/or cilostazol (Pletal)
• No concurrent therapeutic anticoagulation, except prophylactic anticoagulation of venous access device
• No concurrent combination antiretroviral therapy in HIV-positive patients