A Randomized Phase 2 Trial of TAS-114 in Combination With S-1 Versus S-1

This is a randomized, open-label, Phase 2 study of TAS-114 administered in combination with S-1, to investigate the efficacy, safety and tolerability of the TAS-114/S-1 regimen in patients with advanced or metastatic NSCLC.

The study will be conducted internationally in 2 regions: Asian \[Japan\] and Western \[Europe and US\]. Patients will be randomized into TAS-114/S-1 arm versus S-1 control arm in a 1:1 ratio.

Randomization will take place once the consented patient has completed all the necessary baseline procedures and is deemed eligible for study entry. Treatment assignment will be done centrally using a dynamic allocation method (biased coin) via an interactive voice/web response system (IXRS) stratified by:

* Geographical region (Region 1: Asian \[Japan\]; Region 2: Western \[Europe and US\])
* Histological subtypes (nonsquamous cell carcinoma \[including mixed\] and squamous cell carcinoma)

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥ 18 years old (≥ 20 years old in Japan);
2. Histologically diagnosed or cytologically proven advanced or metastatic NSCLC patients, either Stage IIIB/Stage IV disease (according to Version 7 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology), or recurrent disease following radiation therapy or surgical resection;
3. Patients who had received at least 2 prior therapies for advanced or metastatic disease condition, including platinum doublet and pemetrexed, docetaxel, or immunotherapy, and were refractory to or unable to tolerate their last prior therapy
4. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria (Version 1.1, 2009);
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;
6. Predicted life expectancy of at least 3 months;
7. Able to take medications orally;
8. Adequate organ function
9. Women of childbearing potential (WOCBP) must have a negative pregnancy test (urine or serum) within 7 days prior to starting the study drug. Both males and females must agree to use effective birth control during the study (prior to the first dose and for 6 months after the last dose) if conception is possible during this interval.
10. Willing and able to comply with required scheduled visits and study procedures.

Exclusion Criteria:

1. Treatment with any of the following within the specified time frame prior to the study drug administration:

   * Major surgery within prior 4 weeks and minor surgery within 7 days;
   * Radiotherapy for extended field within prior 4 weeks or limited field within prior 2 weeks;
   * Any anticancer therapy or investigational agent within prior 3 weeks.
2. A serious illness or medical condition
3. Concomitant treatment with the following drugs that may interact with S-1:

   Sorivudine, brivudine, uracil, eniluracil, folinate/folinic acid, Cimetidine, dipyridamole, and nitroimidazoles, including metronidazole and misonidazoleMethotrexate, Clozapine,Allopurinol,Phenytoin,Flucytosine, a fluorinated pyrimidine antifungal agent,Coumarin-derivative anticoagulant
4. Known hypersensitivity to S-1 or its metabolites (eg, 5-FU);
5. Previous use of TAS-114, S-1, and 5-FU drugs;
6. A pregnant or lactating female or possibly pregnant women, or men or women wishing to have children during the study period;
7. A judgment of the investigator that the patient is inappropriate for study participation.