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

TH-302 is designed to target the hypoxic regions of tumors which are generally located
distant from tumor vessels. Pemetrexed has poor tissue penetration and targets the regions
of tumors that are located in proximity to the tumor vessels. The presence of hypoxia in
solid tumors is associated with a more malignant phenotype and resistance to chemotherapy.
The hypoxia-activated prodrug, TH-302, is designed to selectively target the hypoxic
microenvironment. There is evidence supporting the presence of hypoxia in NSCLC lesions
based on a hypoxia PET study. Combining pemetrexed with TH-302 may enable the targeting of
both the normoxic and hypoxic regions of NSCLC lesions.

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