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