A Safety and Efficacy Study in Patients With Gastric Cancer

Study Overview
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Brief Summary
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This is an open-label, international, two-arm, parallel, randomized, Phase 3 study evaluating the efficacy and safety of S-1/cisplatin versus 5-FU/cisplatin in patients with advanced gastric cancer previously untreated with chemotherapy for advanced disease. Patients will be randomly assigned (1:1) to S-1/cisplatin (experimental arm) or 5-FU/cisplatin (control arm). Patients will be stratified by number of metastatic sites (one vs. more than one), locally advanced or metastatic disease, prior adjuvant therapy (yes or no), measurable or non-measurable disease, and center.

Official Title
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An Open-Label Multicenter, Randomized, Phase 3 Study of S-1 in Combination With Cisplatin Against 5-Fu in Combination W/ Cisplatin in Patients W/ Advanced Gastric Cancer Previously Untreated W/ Chemotherapy for Advanced Disease

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: S-1/Cisplatin
* Drug: 5-FU/cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A patient must meet all of the following inclusion criteria to be eligible for enrollment in this study: Has given written informed consent Has histologically confirmed, unresectable, locally advanced (Stage IV) or metastatic gastric cancer, including adenocarcinoma of the gastro-esophageal junction Has measurable or evaluable but non-measurable disease, defined as follows: Measurable Disease - Patients with measurable disease as defined by RECIST criteria, i.e., the presence of 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. Locally recurrent disease (other than primary) is accepted if there is at least one measurable lesion (i.e. peritoneal mass, lymph node, etc.) Evaluable but Non-measurable Disease - Patients with all lesions below the limits defined above for measureable disease (i.e., longest diameter < 20 mm with conventional techniques or < 10 mm with spiral CT) excluding those patients with only a primary lesion and/or with only non-evaluable cancer such as bone metastases, ascites, pleural or pericardia effusions, lymphangitic carcinomatosis of the skin or lung, previously irradiated lesions not in progression, or peritoneal carcinomatosis < 10 mm in diameter with conventional imaging techniques. No prior palliative chemotherapy is permitted. Adjuvant and /or neo-adjuvant chemotherapy is permitted if more than 12 months have elapsed between the end of adjuvant or neo-adjuvant therapy and first recurrence. This does not qualify as 1st line therapy. Is able to take medications orally Is >_ 18 years of age Is at least 3 weeks from prior major surgery Is at least 4 weeks from prior radiotherapy Has a ECOG performance status 0 to 1 Has adequate organ function as defined by the following criteria: 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 Total serum bilirubin of <_ 1.5 x ULN Absolute granulocyte count of >_ 1,500/mm (i.e. >_ 1.5 x 10/L by International Units (IU) Platelet count >_ 100,000/mm (IU: >_ 100 x 10/L Hemoglobin value of >_ 9.0 g/dL Calculated creatinine clearance >_ 60 mL/min (Cockcroft-Gault formula) Is willing and able to comply with scheduled visits, treatment plans, laboratory tests and other study procedures Exclusion Criteria: Exclude a patient from this study if he/she does not fulfill the inclusion criteria, or if any of the following conditions are observed: Has had a treatment with any of the following within the specified timeframe prior to study drug administration: Any prior palliative chemotherapy or any previous therapy for malignancy, including any chemotherapy, immunotherapy, biologic or hormonal therapy, within the past 5 years. Adjuvant or neo-adjuvant therapy within the past 12 months Concurrent treatment with any investigational anti-cancer agent Prior cisplatin as neo-adjuvant and /or adjuvant chemotherapy with cumulative dose > 300 mg/m > 25% of marrow-bearing bone radiated Concurrent treatment with an investigational agent or within 30 days from randomization Concurrent enrollment in another clinical study Has a serious illness or medical condition(s) including, but not limited to the following: Known brain or leptomeningeal metastases Uncontrolled ascites requiring drainage at least twice a week Other malignancies within the past 5 years, except adequately treated carcinoma-in-situ of the cervix or non-melanoma skin cancer Myocardial infarction within the last 6 months, severe/unstable angina, congestive heart failure New York Heart Association (NYHA) class III or IV Chronic nausea, vomiting or diarrhea Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS-related illness Psychiatric disorder that may interfere with consent and/or protocol compliance Known neuropathy, Grade 2 or higher 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 judgement of the Investigator would make the patient inappropriate for entry into this study Is receiving concomitant treatment with drugs interacting with S-1. The following drugs are prohibited because there may be an interaction with S-1: Sorivudine, uracil, cimetidine, folinic acid, and dipyridamole (may enhance S-1 activity) Allopurinol (may diminish S-1 activity Phenytoin (S-1 may enhance phenytoin activity) Flucytosine, a fluorinated pyrimidine antifungal agent (may enhance S-1 activity) Is receiving concomitant treatment with drugs interacting with 5-FU: Sorivudine, uracil, cimetidine, folinic acid, and dipyridamole(may enhance 5-FU activity) Allopurinol (may diminish 5-FU activity) Phenytoin (5-FU may enhance phenytoin activity) Is receiving concomitant treatment with drugs interacting with cisplatin: Phenytoin (cisplatin may diminish phenytoin activity) Aminoglycosides (should be avoided within 8 days after cisplatin administration) Ethyol (may diminish cisplatin activity Is a pregnant or lactating female Has known hypersensitivity to 5-FU or cisplatin Patients with reproductive potential who refuse to use an adequate means of contraception (including male patients)

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: A<br>In Arm A, S-1 25 mg/m² was administered orally BID from Day 1 through Day 21 followed by a recovery period from Days 22 through Day 28. On Day 1, the morning dose of S-1 was administered before cisplatin 75 mg/m2 administration as a 1- to 3-hour IV infusion. This regimen was repeated every 4 weeks. S-1 was administered one hour before or one hour after a meal with a glass of water (approximately 100 mL). | Drug: S-1/Cisplatin<br>* In Arm A, S-1 25 mg/m2 was taken orally two times daily for 21 days followed by a 7-day recovery period. The patient was instructed to have nothing by mouth (NPO 1 hour prior to and 1 hour after S-1 administration. S-1 was taken with approximately 8 ounces of water and prior to cisplatin infusion on Day 1. Cisplatin 75 mg/m2 was administered as a 1- to 3-hour IV infusion after the morning dose of S-1 on Day 1 of each cycle. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment for cisplatin.<br>|
| Active Comparator: B<br>In Arm B, 5-FU 1000 mg/m2/24 hours was administered by continuous intravenous infusion (CIV) over 120 hours (on Days 1 through 5). This regimen was repeated every 4 weeks. 5-FU CIV followed cisplatin infusion on Day 1. All 5-FU used in this study was commercially available product. | Drug: 5-FU/cisplatin<br>* In Arm B, 5-FU 1000 mg/m2/24 hours was administered CIV on Days 1 through 5 following cisplatin 100 mg/m2 administered IV as a 1- to 3-hour infusion on Day 1. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment for cisplatin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Survival | Survival was defined as the time from the date of randomization to the time of death (from any cause) for each patient. | The cutoff date for survival analysis was 07 March 2008 (12 months after last patient randomized). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | The proportion of patients with objective evidence of complete response (CR) or partial response (PR) based on tumor response assessments. Per the Response Evaluation Criteria in Solid tumors (RECIST), CR was defined as the disappearance of all target lesions for at least 4 weeks, and PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions. | Data cutoff was 07 March 2008 (12 months after last patient randomized). | 
| Duration of Response (DR) | Duration of response was defined as the time 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 the disappearance of all target lesions for at least 4 weeks, PR was at least a 30% decrease in the sum of the longest diameter of target lesions, and PD was at least a 20% increase in the sum of the longest diameter of target lesions. | Data cutoff was 07 March 2008 (12 months after last patient was randomized). | 
| Progression-free Survival (PFS) | The time from randomization to date of first documented PD or date of death, whichever occurred first. | From date of randomization until date of first documented PD, date of death, or until data cutoff on 07 March 2008 (12 months after last patient randomized), whichever came first. | 
| Time to Treatment Failure (TTF) | The time from randomization to date of permanent discontinuation of S-1 or 5-FU, first documented PD, or death, whichever occurred first. | From date of randomization until date of permanent discontinuation of S-1 or 5-FU, first documented PD, death, or data cutoff on 07 March 2008 (12 months after last patient randomized), whichever came first. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric Cancer