A Study in Non-Small Cell Lung Cancer

Inclusion Criteria:

• The patient has histologically or cytologically confirmed, nonsquamous (adenocarcinoma/large cell or other) NSCLC.
• The patient has Stage IV disease at the time of study entry.
• Patients with treated brain metastases are eligible if they are clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 14 days prior to randomization, or after surgical resection performed at least 28 days prior to randomization. The patient may have no evidence of Grade 1 (or greater) Central Nervous System (CNS) hemorrhage based on pretreatment scans(performed within 21 days before randomization).
• The patient has measurable or nonmeasurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 guidelines.
• The patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
• If prior adjuvant or neoadjuvant chemotherapy, the last dose of adjuvant or neoadjuvant treatment was administered at least 6 months prior to randomization.
• The patient has adequate bone marrow reserve, and renal and hepatic function
• The patient has fasting serum glucose less than or equal to 125 mg/dL, and hemoglobin A1C less than or equal to 6%.
• Females with reproductive potential: Must have a negative serum or urine pregnancy test within 7 days prior to the first dose of any study drug.
• Males and females with reproductive potential: Must agree to use medically approved contraceptive precautions during the study and for 6 months following the last dose of any study drug.
• The patient has the ability to understand and the willingness to sign a written informed consent form.
• Previous radiation therapy is allowed to less than 25% of the bone marrow, but should have been limited and must not have included whole pelvis radiation.
• The patient has archived tumor tissue available for analysis (can be either primary tumor or metastases).
• The patient has an estimated life expectancy of at least 12 weeks.

Exclusion Criteria:

• Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
• Patients who have squamous histology.
• The patient's tumor fully or partially contains Small Cell Lung Cancer (SCLC).
• The patient has leptomeningeal disease.
• The patient is currently or has previously received chemotherapy for advanced (Stage IV) NSCLC.
• The patient has a history of treatment with other agents targeting the Insulin-like or Epidermal Growth factor receptors.
• Patients who have received prior Pemetrexed treatment.
• The patient has a known allergy/history of hypersensitivity reaction to any of the treatment components.
• The patient has diabetes mellitus as defined by being treated with glucose lowering medications in the past 3 months prior to enrollment.
• The patient has an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics, symptomatic congestive heart failure, uncontrolled hypertension, clinically significant cardiac arrhythmia,or psychiatric/social situations that would limit compliance with study requirements.
• The patient has an ongoing or active infection requiring parenteral antibiotic, antifungal, or antiviral therapy.
• The patient has undergone major surgery within 28 days prior to randomization.
• The patient has received a prior autologous or allogeneic organ or tissue transplantation.
• The patient is pregnant or lactating.
• The patient has a history of another primary cancer, with the exception of the following: curatively resected nonmelanomatous skin cancer, curatively treated carcinoma in situ, or other primary solid tumor treated with curative intent and no known active disease present and no treatment administered during the last 5 years.
• The patient has superior vena cava syndrome contraindicating hydration.
• The patient has current clinically-relevant coronary artery disease (New York Heart Association III or IV) or uncontrolled congestive heart failure.
• The patient has any Grade 2 (or greater) peripheral neuropathy.
• The patient has clinically significant third-space fluid collections, for example, ascites or pleural effusions that cannot be controlled by drainage or other procedures prior to study entry.
• The patient is unable to interrupt aspirin or other nonsteroidal anti-inflammatory agents, other than an aspirin dose less than or equal to 1.3 grams per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
• The patient is unwilling or unable to take premedications (folic acid, vitamin B12, or corticosteroids) required by the pemetrexed label.
• The patient has received a recent (within 30 days of enrollment) or is receiving concurrent yellow fever vaccination.