A Phase II Randomized Trial of Paclitaxel, Carboplatin, Bevacizumab With or Without IMC-A12 in Patients With Advanced Non-Squamous 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