The purpose of this study is to determine whether S-1 is effective as 2nd line therapy in slowing tumor activity in patients with advanced non-small cell lung cancer. The study is also looking at the safety of S-1.

Advanced non-small cell lung cancer is relatively unresponsive to chemotherapy. This is true for the nucleoside analogue gemcitabine, with a response rate of approximately 10%, as well as for 5-fluorouracil (5-FU). Even when gemcitabine is combined with other chemotherapeutic drugs or biological agents, the overall tumor response rate remains basically unchanged. S-1 is a new generation oral fluoropyrimidine that combines Tegafur (5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione [FT]), an oral prodrug of 5-FU, with two modulators, Gimeracil (5-chloro-2,4-dihydroxypyridine [CDHP]), which inhibits 5-FU degradation by dihydropyrimidine dehydrogenase (DPD) inhibition, and Oteracil potassium (Oxo), which inhibits 5-FU phosphorylation in the digestive tract. This combination of 3 compounds is designed to achieve enhanced antitumor activity while decreasing gastrointestinal toxicity.

This is an open-label, multicenter, single-arm, 3-stage, Phase 2 study evaluating the efficacy and safety of single agent S-1 as 2nd line therapy for patients with advanced NSCLC. The 3 stages of this study correspond to a futility stage (stage 1), a decision stage (stage 2), and a stage for improvement of precision of ORR (stage 3).

Inclusion Criteria:

• 1. Has given written informed consent. 2. Has histologically and/or cytologically proven unresectable or recurrent NSCLC stage IIIB with pleural effusion or pericardial effusion, or stage IV (mixed forms with small cell lung cancer are excluded).

  3. Has received prior 1st line chemotherapy combination (platinum or non-platinum-based) treatment and has not received any 2nd line therapy.

  4. Has measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, ie, has at least one measurable lesion. A measurable lesion is one that can be accurately measured in at least one dimension with the longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm using spiral Computed Tomography (CT) scan.

  5. Is able to take medications orally. 6. Is ≥ 18 years of age. 7. Has an ECOG performance status 0 or 1. 8. Has adequate organ function as defined by the following criteria:

  1. AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN; if liver function abnormalities are due to underlying liver metastasis AST (SGOT) and ALT (SGPT) ≤ 5 x ULN.

  2. Total serum bilirubin of ≤ 1.5 x ULN.

  3. Absolute granulocyte count of ≥ 1,500/mm3.

  4. Platelet count ≥ 100,000/mm3.

  5. Hemoglobin of ≥ 9.0 g/dL.

  6. Calculated creatinine clearance (CrCl) ≥ 60 mL/min (Cockcroft-Gault formula). 9. Is willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

     Exclusion Criteria:

• 1. Has had treatment with any of the following within the specified time frame prior to study drug administration:

  1. Any investigational agent either concurrently or within the past 30 days.

  2. Any prior 1st line treatment with S-1 for NSCLC.

  3. Previous therapy for NSCLC within the past 21 days, including any chemotherapy, immunotherapy, biologic or hormonal therapy (6 weeks for nitrosureas or mitomycin C).

  4. Radiotherapy within the prior 2 weeks.

  5. Any radiation therapy to a target lesion within the past 3 months, unless there was evidence of PD after radiotherapy (and this target lesion must not be the only site of measurable disease).

  6. Current enrollment in another clinical study with an investigational agent. Patients participating in surveys or observational studies are eligible to participate in this study.

     2. Has a serious illness or medical condition(s) including, but not limited to, the following:

  1. Other active malignancies.

  2. Symptomatic brain metastasis not controlled by corticosteroids.

  3. Leptomeningeal metastasis.

  4. Myocardial infarction within the last 6 months, severe/unstable angina, congestive heart failure New York Heart Association (NYHA) class III or IV.

  5. Chronic nausea, vomiting, and/or diarrhea.

  6. Psychiatric disorder that may interfere with consent and/or protocol compliance.

  7. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.

  8. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this study.

     3. Is receiving concomitant treatment with drugs interacting with S-1. The following drugs are prohibited because there may be an interaction with S-1:

  1. Sorivudine, uracil, cimetidine, folinic acid, and dipyridamole (may enhance S-1 activity).

  2. Allopurinol (may diminish S-1 activity).

  3. Phenytoin (S-1 may enhance phenytoin activity).

  4. Flucytosine, a fluorinated pyrimidine antifungal agent (may enhance S-1 activity).

     4. Is a pregnant or lactating female. 5. With reproductive potential and refuses to use an adequate means of contraception (including male patients).