Three-Arm Randomized Phase II Study of Carboplatin and Paclitaxel in Combination With Cetuximab, IMC-A12 or Both in Patients With Advanced Non-Small Cell Lung Cancer Who Will Not Receive Bevacizumab-Based Therapy

Inclusion Criteria:

- Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)

- Stage IIIB disease

- T4, NX with nodule in ipsilateral lung lobe allowed provided patient is not
a candidate for combined chemotherapy and radiotherapy

- Stage IV disease (includes M1a and M1b)

- Measurable disease as defined by RECIST criteria

- Ineligible for or refused treatment with bevacizumab

- No small cell lung cancer or mixed small cell and NSCLC

- No untreated or symptomatic CNS metastases

- Patients with a history of CNS metastases that are definitively treated, stable,
and controlled are eligible provided the following criteria are met:

- Definitive therapy (surgery and/or radiotherapy) has been administered

- Not planning to undergo additional treatment for brain metastases

- Clinically stable

- Off corticosteroids or on a stable dose of corticosteroids for ≥ 14 days
before study entry

- ECOG performance status 0-1

- Leukocytes > 3,000/mm^3

- ANC > 1,500/mm^3

- Hemoglobin > 9 g/dL

- Platelet count > 100,000/mm^3

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST < 3 times ULN (< 5 times ULN if elevations due to liver metastases)

- Creatinine < 1.5 times ULN OR creatinine clearance > 60 mL/min

- Fasting serum glucose < 120 mg/dL

- PTT ≤ 1.2 times ULN and INR ≤ 1.5 (unless patient is on anticoagulation therapy)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 3 months after the
last dose of cixutumumab

- No poorly controlled diabetes mellitus

- Patients with a history of diabetes mellitus are eligible provided their blood
glucose is within normal range and they are on a stable dietary or therapeutic
regimen for this condition

- No peripheral neuropathy > grade 1 as per CTCAE v 4.0

- No history of or suspected interstitial pneumonitis or pulmonary fibrosis on imaging

- No significant uncontrolled cardiac disease within the past 6 months, including any
of the following:

- Uncontrolled hypertension (BP > 150/100 mm Hg)

- Unstable angina

- Recent myocardial infarction

- Uncontrolled congestive heart failure

- Cardiomyopathy with decreased ejection fraction

- No arterial thrombosis, pulmonary embolus, deep vein thrombosis, or hemorrhagic
disorders within the past 28 days

- No other prior or concurrent malignancy, except for the following:

- Curatively treated malignancy with no known active disease for ≥ 3 years AND is
considered to be at low risk for recurrence by the treating physician

- Adequately treated nonmelanoma skin cancer or lentigo maligna with no evidence
of disease

- Adequately treated cervical carcinoma in situ with no evidence of disease

- Prostatic intraepithelial neoplasia with no evidence of prostate cancer

- No history of any medical or psychiatric condition, addictive disorder, or laboratory
abnormality that, in the opinion of the investigator, may increase the risks
associated with study participation or study treatments or may interfere with the
conduct of the study or interpretation of study results

- No history of allergic reactions attributed to compounds of similar chemical or
biological composition to cixutumumab

- Concurrent therapeutic anticoagulation allowed provided there is no bleeding and
patient is on a stable dose of anticoagulation therapy (e.g., Warfarin with an INR of
2-3) for > 2 weeks prior to study entry

- No prior agents targeting the EGFR or IGFR pathways

- No prior therapy for advanced NSCLC, except for surgery and/or radiotherapy

- No prior systemic therapy, including bevacizumab for advanced stage NSCLC

- At least 21 days since prior radiotherapy

- More than 4 weeks since prior major surgery or hormonal therapy (other than hormone
replacement therapy) and recovered

- More than 1 year since prior neoadjuvant or adjuvant chemotherapy