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

Study Overview
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Brief Summary
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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.

Detailed Description
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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)

Official Title
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A Randomized, Open-Label, Multi-Center, International Phase 2 Study of TAS-114 in Combination With S-1 in Patients With Advanced or Metastatic Non-Small Cell Lung Cancer

Conditions
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Advanced or Metastatic Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: TAS-114
* Drug: S-1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old (≥ 20 years old in Japan); 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; 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 Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria (Version 1.1, 2009); Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; Predicted life expectancy of at least 3 months; Able to take medications orally; Adequate organ function 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. Willing and able to comply with required scheduled visits and study procedures. Exclusion Criteria: 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. A serious illness or medical condition 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 Known hypersensitivity to S-1 or its metabolites (eg, 5-FU); Previous use of TAS-114, S-1, and 5-FU drugs; A pregnant or lactating female or possibly pregnant women, or men or women wishing to have children during the study period; A judgment of the investigator that the patient is inappropriate for study participation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: TAS-114 + S-1<br>Participants received 400 milligrams (mg) of TAS-114 tablets orally twice daily (BID) along with 30 milligrams per meter square (mg/m^2) of S-1 capsule BID for 2 weeks (Day 1 to 14), followed by 1 week recovery period (Day 15 to 21) in each 21 days cycle, until progressive disease (PD), occurrence of intolerable side effects, removal by the Investigator, or withdrawal of consent (maximum treatment duration: 51 weeks). | Drug: TAS-114<br>* TAS-114 was a modulator of 5-fluorouracil (5-FU).<br>Drug: S-1<br>* S-1 was designed to provide oral delivery of 5-FU and to reduce the rate of degradation of 5-FU in vivo.<br>|
| Active Comparator: S-1 (Monotherapy)<br>Participants received 30 mg/m^2 of S-1 capsules BID for 2 weeks (Day 1 to 14) followed by 1 week recovery period (Day 15 to 21) in each 21 days cycle, until progressive disease (PD), occurrence of intolerable side effects, removal by the Investigator, or withdrawal of consent (maximum treatment duration: 38 weeks). | Drug: S-1<br>* S-1 was designed to provide oral delivery of 5-FU and to reduce the rate of degradation of 5-FU in vivo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Based on Central Independent Review | Progression-free survival was defined as the time (in months) from the day of randomization to the start of radiologic disease progression or death (any cause), whichever occurred first. Response assessments were made based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). As per RECIST 1.1 criteria, progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). (Note: the appearance of one or more new lesions was also considered progressions). Participants who did not have disease progression or died were censored at the last known time that the participant was progression free. | From date of randomization or until date of disease progression or death whichever occurred first (approximately up to 13 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from the first dose of the study treatment to death from any cause. Participants who were alive at the end of study were censored at the last date the participant was known to be alive. OS was estimated from Kaplan-Meier method. | From date of randomization until death (approximately up to 15 months) | 
| Overall Response Rate (ORR) Based on Central Independent Review | ORR was defined as the percentage of participants with objective evidence of complete response (CR) or partial response (PR) per response evaluation criteria in solid tumors (RECIST) version 1.1. CR was defined as the disappearance of all target lesions and non-target lesions and normalization of tumor marker level. Any pathological and non-pathological lymph nodes must have reduction in short axis to less than (<) 10 mm. PR was defined as at least a 30 percent (%) decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum diameters. | From date of first dose of study drug to the date of first documentation of progression or death (approximately up to 13 months) | 
| Disease Control Rate (DCR) Based on Central Independent Review | DCR was defined as the percentage of participants with objective evidence CR, PR, or stable disease (SD). Based on the central review of tumor assessments per RECIST, version 1.1. CR was defined as disappearance of all target lesions. Reduction in any pathological lymph nodes in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the smallest sum diameters during study. | From date of first dose of study drug to the date of first documentation of progression or death (approximately up to 13 months) | 
| Duration of Response (DR) Based on Central Independent Review | DR was derived for participants with objective evidence of PR or CR. DR was defined as the time (in months) from the first documentation of response (CR or PR) to the first documentation of objective tumor progression or death due to any cause. Participants who were alive and progression-free as of the analysis cut-off date were censored at their last evaluable tumor response assessment before initiation of any new anticancer treatment. | From date of first response to the date of first documentation of progression or death (approximately up to 13 months) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was defined as any untoward medical condition that occurs in a participants while participating in a clinical study and does not necessarily have a causal relationship with the use of the study treatment. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs were defined as AEs that developed or worsened during the TEAE period which was defined as the period from the time of first dose of study treatment until 30 days after last dose of study treatment. AEs included both serious and non- serious adverse events. | From first dose of study drug up to 30 days after the last dose of study drug (approximately up to 13 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, phase 2 study, TAS-114, S-1