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

A Randomized Phase 2, Double-blind, Placebo-controlled, Multi-center Study Comparing Pemetrexed in Combination With TH-302 vs. Pemetrexed in Combination With Placebo as Second-line Chemotherapy for Advanced Non-Squamous, Non-Small Cell Lung Cancer

The purpose of this study is to determine whether TH-302 in combination with pemetrexed is safe and effective in the treatment of 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