Study of TH-302 or Placebo in Combination With Pemetrexed in Patients With Non-squamous Non-small Cell Lung Cancer

Inclusion Criteria: * Men and women ≥ 18 years of age. * Histologically or cytologically confirmed stage IIIB or IV NSCLC with non-squamous histology * Recurrent or progressive disease after one prior platinum-based non-pemetrexed chemotherapy treatment for advanced disease with or without maintenance * Neoadjuvant/adjuvant cytotoxic chemotherapy initiated \< 12 months prior to study randomization will be counted as one prior treatment * Neoadjuvant/adjuvant cytotoxic chemotherapy initiated ≥ 12 months prior to study randomization will not be counted as one prior chemotherapy treatment * Use of targeted agents (e.g., monoclonal antibodies or kinase inhibitors) will not be counted as a prior chemotherapy treatment * Patients with known EGFR-activating mutations or ALK rearrangements should have received treatment with a targeted kinase inhibitor (e.g., erlotinib, crizotinib) and no longer be considered as a candidate for such treatment * Measurable disease according to RECIST 1.1 * ECOG performance status 0-1 * Resolution to Grade ≤ 1 Adverse Events, of all clinically significant toxic effects of prior therapy * Adequate hematologic, hepatic, cardiac, and renal function * Female patients of childbearing potential must have a negative serum or urine pregnancy test, whichever is considered standard by the institution Exclusion Criteria: * Diagnosis of small cell carcinoma of the lung, squamous cell carcinoma of the lung or NSCLC NOS * Prior therapy with pemetrexed * Inability or unwillingness to take folic acid, vitamin B12 supplementation or corticosteroids * Inability to discontinue non-steroidal anti-inflammatory drugs for 5 days (long half-life) or for 2 days (short half-life, if CrCL \<80 mL/min) before pemetrexed dosing and until 2 days after pemetrexed dosing * Leptomeningeal disease or any untreated or symptomatic brain metastases, unless the following criteria are met: * brain metastases are stable and have been previously treated with either whole-brain radiotherapy or gamma-knife surgery * steroids are currently not required and more than 14 days since last steroid treatment * Symptomatic pleural effusion (\> CTCAE Grade 1 dyspnea) that is not amenable to drainage * Treatment with other systemic anticancer therapy within 4 weeks prior to the first dose of study medication * Treatment with full field radiation therapy within 4 weeks or limited field radiation therapy within 2 weeks prior to the first dose of study medication * Major surgery within 4 weeks or minor surgery within 2 weeks prior the first dose of study medication * Elective or a planned major surgery while on study treatment * Radiation therapy to greater than 25% of the bone marrow * Clinically significant active infection (e.g. tuberculosis, viral hepatitis, HIV) * Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct * Concurrent active malignancy other than adequately treated basal cell or squamous cell carcinoma of the skin or pre-invasive carcinoma of the cervix. * Pregnant or breast feeding * Patients who are taking medications that prolong QT interval and have a risk of Torsades de Pointes (Appendix F) or who have a history of long QT syndrome * Patients who are taking medications that are strong inducers or inhibitors of CYP3A4