Diffuse Gastric and Esophagogastric Junction Cancer S-1 Trial

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of S-1 and Cisplatin compared to 5-FU and Cisplatin in treatment of patients with metastatic diffuse gastric and gastro-esophageal junction cancer previously untreated with chemotherapy.

Detailed Description
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This is an open-label, international, Phase 3 study evaluating the efficacy and safety of the S-1/cisplatin regimen versus the 5-FU/cisplatin regimen in chemotherapy-naïve patients with metastatic diffuse gastric carcinoma including carcinoma of the gastro-esophageal junction. Patients will be randomly assigned to S-1/cisplatin (experimental regimen, Arm A) or 5-FU/cisplatin (control regimen, Arm B).

Official Title
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An Open-Label, Multicenter, Randomized, Phase 3 Study of S-1 and Cisplatin Compared With 5-FU and Cisplatin in Patients With Metastatic Diffuse Gastric Cancer Previously Untreated With Chemotherapy

Conditions
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Metastatic Diffuse Gastric Cancer Including Carcinoma of the Gastro-esophageal Junction

Intervention / Treatment
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* Drug: S-1 (Tegafur+Gimeracil+Oteracil) /cisplatin (investigational arm)
* Drug: Fluorouracil/cisplatin (control arm)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has given written Informed Consent. Histologically confirmed, unresectable, metastatic diffuse gastric cancer including carcinoma of the gastro-esophageal junction. No prior chemotherapy for gastric cancer except adjuvant and/or neo-adjuvant chemotherapy more than 12 months ago. Life expectancy of at least 3 months. Able to take medications orally. Eastern Cooperative Oncology Group performance status 0 to 1. Adequate organ function (bone marrow, kidney and liver). Exclusion Criteria: Certain type(s) of non-measurable lesion(s), if the only one(s). Certain serious illness or medical condition(s). Lost greater than or equal to 10% of body weight in the 3 months proceeding signing the Informed Consent Form. Treatment with drugs interacting with S-1, 5-FU, or cisplatin. Pregnant or lactating female. Known hypersensitivity to fluoropyrimidines or cisplatin. Other protocol-defined inclusion/exclusion criteria may apply.

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 |
| --- | --- |
| Experimental: S-1+Cisplatin<br>Participants received S-1 25 milligrams per meter square (mg/m^2) orally twice daily (BID) every 12 hours from Day 1 through Day 21, 1 hour before or after meal with a glass of water; followed by a 7-day rest period from Day 22 to Day 28 in a 28-day cycle. Participants received a single dose of cisplatin 75 mg/m^2 as a 1- to 3-hour intravenous (IV) infusion on Day 1 following the morning dose of S-1 for a maximum of 8 cycles (each cycle of 28 days). Participants received study medication until progression of disease (PD), adverse event (AE), withdrawal of consent, or other reason for discontinuation, whichever happened earlier. | Drug: S-1 (Tegafur+Gimeracil+Oteracil) /cisplatin (investigational arm)<br>* 25 mg/m² body surface area (BSA) orally 2 times daily from Days 1 through 21 followed by a 7 day rest period, plus cisplatin 75 mg/m2 BSA on Day 1 each 28 day cycle Number of Cycles: until progression or unacceptable toxicity develops. Treatment with cisplatin is limited to a maximum of 8 cycles.<br>* Other names: TS-1, Tegafur+Gimeracil+Oteracil;|
| Active Comparator: 5FU+Cisplatin<br>Participants received 5-Fluorouracil (5-FU) 800 mg/m^2 per 24 hours as continuous IV infusion over 120 hours from Day 1 through Day 5 followed by a 16-day rest period on Days 6 through 21 in a 21-day cycle. Participants received a single dose of cisplatin 80 mg/m^2 as a 1- to 3-hour IV infusion on Day 1 prior to the start of the 5-FU infusion on Day 1 for a maximum of 8 cycles (each cycle of 21 days). Participants received study medication until PD, AE, withdrawal of consent, or other reason for discontinuation, whichever happened earlier. | Drug: Fluorouracil/cisplatin (control arm)<br>* 5-FU: 800 mg/m2 BSA/24 hours by continuous intravenous infusion (CIV) from Days 1 through 5 plus cisplatin 80 mg/m2 BSA on Day 1 each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops. Treatment with cisplatin is limited to a maximum of 8 cycles.<br>* Other names: TS-1, Tegafur+Gimeracil+Oteracil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from randomization to the date of death for the ITT population. Participants who did not die were censored at the date last known to be alive. Analysis was performed by using Kaplan-Meier method. | From the date of randomization until disease progression or death, cut-off date: 15 August 2014 (approximately 40 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was defined as the time from date of randomization until date of radiological disease progression or death due to any cause. Disease Progression was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, where any of the 3 criteria have been met: 1) at least 20% increase in the sum of diameters of the target lesions, taking as reference the smallest sum on study, including the baseline sum, 2) Progression in no-target lesion(s), 3) appearance of new lesion(s) Participants who were alive with no PD were censored at the date of the last tumor assessment. Participants who received new anticancer therapy before disease progression were censored at the date of the last evaluable tumor assessment before new anticancer therapy was initiated. Analysis was performed by using Kaplan-Meier method. | From date of randomization until disease progression or death, cut-off date: 07 March 2014 (approximately 34.7 months) | 
| Time to Treatment Failure (TTF) | TTF was defined as the time from date of randomization until date of PD (clinical or radiologic), or permanent discontinuation of study treatment (S-1 or 5-FU), or death due to any cause. Participates who were still on study treatment at the time of the analysis were censored at the last date the participants was known to be on treatment. | From date of randomization until disease progression, cut-off date: 07 March 2014 (approximately 34.7 months) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE) | AE was defined as any untoward medical condition that occurs in a participants while participating in a clinical study and does not necessarily had to have a causal relationship with the use of the study medication. 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 or became serious during on-treatment period (from first dose of study medication up to 30 days of last study medication [maximum duration: 35.7 months]). | From first dose of study medication up to 30 days of last study medication (maximum duration: 35.7 months) | 
| Number of Participants With TEAEs With Severity Greater Than or Equal to (>=) Grade 3 | An AE was any untoward medical condition that occurred in a participants while participating in a clinical study and does not necessarily had to have a causal relationship with the use of the study medication. TEAEs were defined as AEs that developed or worsened or became serious during on-treatment period (from first dose of study medication up to 30 days of last study medication [maximum duration: 35.7 months]). | From first dose of study medication up to 30 days of last study medication (maximum duration: 35.7 months) | 
| Overall Response Rate (ORR): Percentage of Participants With Overall Response | ORR was defined as the percentage of participants with objective evidence of complete response (CR) or partial response (PR) based on the Investigator review of the images and application of Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as the disappearance of all target or non-target lesions. Any pathological lymph nodes for target lesions or all lymph nodes for non-target lesions were non-pathological morphologically that was reduced in size in short axis to less than (<) 10 millimeter (mm). PR was defined as target lesions with at least 30% decrease in the sum of diameters, taking baseline sum diameters as reference. | From date of first study medication until cut-off date: 07 March 2014 (approximately 34.7 months) | 
| Duration of Response (DR) | Duration of response was defined as the time (in months) from date of first confirmed response (CR or PR) to date of first progressive disease (PD) or death. Per the RECIST criteria, definitions were as follows: CR was defined as the disappearance of all target or non-target lesions. Any pathological lymph nodes for target lesions or all lymph nodes for non-target lesions were non-pathological morphologically that was reduced in size in short axis to <10 mm. Analysis was performed by using Kaplan-Meier method. | From date of first study medication until cut-off date: 07 March 2014 (approximately 34.7 months) | 
| Time to Tumor Response (TTR) | TTR was defined as the time (in months) from the date of randomization to the date of first observation of response (PR or CR) (whichever status was recorded first). TTR was assessed based on investigator assessment utilizing RECIST 1.1. CR was defined as the disappearance of all target or non-target lesions. Any pathological lymph nodes for target lesions or all lymph nodes for non-target lesions were non-pathological morphologically that was reduced in size in short axis to <10 mm. PR was defined as target lesions with at least 30% decrease in the sum of diameters, taking baseline sum diameters as reference. Analysis was performed by using Kaplan-Meier method. | From date of first study medication until cut-off date: 07 March 2014 (approximately 34.7 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric Cancer , S-1, Phase 3