Maintenance Treatment With S-1 in Gastric Cancer Patients

Study Overview
=================
Brief Summary
-----------------
Gastric cancer remains the third leading cause of cancer-related death worldwide and is especially frequent in East Asia. Fluoropyrimidines are the backbone of first-line chemotherapy for advanced gastric cancer (AGC), and S-1 provides new option with its simplicity and convenience. 5-Fluorouracil (5-FU) was the only efficacious treatment for AGC before the nineties of the 20th century, and afterwards with the discovery of chemotherapy such as cisplatin, oxaliplatin, S-1 and capecitabine, response rate as well as survival had been improved greatly. Most of AGC will progress after first-line treatment; therefore, seeking an efficient and low toxic maintaining regimen to prolong progression-free survival (PFS) becomes a hot topic in oncologic field. Some clinical researches demonstrated maintenance treatment for advanced colorectal cancer (CRC) and lung cancer. The investigators had conducted a phase III clinical trial that demonstrated capecitabine maintenance versus observation prolonged PFS significantly after first-line chemotherapy with FOLFOX or XELOX regimens in advanced CRC. In AGC, several retrospective studies revealed patients receiving 5-FU/leucovorin(LV), capecitabine, or trastuzumab maintaining therapy experienced significantly longer PFS than that stopped chemotherapy after first-line chemotherapy. Some one-arm phase II clinical trials found 5-FU/LV, capecitabine, S-1, capecitabine plus bevacirumab, or capecitabine plus bevacirumab plus trastuzumab maintenance seemed to yield sound PFS and good tolerance. However, there were no randomized controlled clinical trials for maintenance treatment of these regimens in AGC, except that a phase II Chinese randomized controlled trial of Uracil and Tegafur (UFT) versus observation experienced early termination. Above all, so far, there is no data to demonstrate that regular 2-6 months of chemotherapy followed by maintenance treatment could prolong PFS and OS for AGC. S-1 is effective for gastric cancer, and was approved as palliative treatment for advanced gastric cancer and adjuvant treatment; in addition, with its relative less frequency of side effects and convenient oral administration, S-1 as maintenance regimen could be prone to be accepted by patients. Therefore, the current study is designed to investigate that S-1 as maintenance treatment after first-line palliative chemotherapy could improve PFS and OS for patients with advanced gastric cancer through a perspective randomized clinical study.

Detailed Description
-----------------
Patients with AGC who achieved objective response or stable disease after 2-6 months of first-line chemotherapy were randomly assigned to one of two groups, to receive either S-1 (40 mg for BSA<1.25 m2, 50 mg for 1.25≤BSA<1.50 m2 and 60 mg for BSA≥1.50 m2 b.i.d. on days 1-14, q3w) as maintenance therapy or observation. The treatment will continue until disease progression or unacceptable toxicity.

Official Title
-----------------
Maintenance Treatment With S-1 Versus Observation After First-line Chemotherapy in Patients With Advanced Gastric Cancer: a Randomized Phase II Study

Conditions
-----------------
Gastric Cancer Stage IV, Cancer of Stomach

Intervention / Treatment
-----------------
* Drug: S-1 maintenance
* Other: Observation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age older than 18 years Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 At least one measurable lesion according to the Response Evaluation Criteria in Solid Tumor (RECIST version 1.0) Histologically confirmed gastric cancer with inoperable locally advanced or recurrent and/or metastatic disease, not amenable to curative therapy No previous chemotherapy for metastatic GC was allowed, the interval after the end of adjuvant/neoadjuvant chemotherapy beyond 6 months was allowable Life expectancy of at least 3 months Adequate hematologic, hepatic and renal function. Neutrophil count ≥ 1.5 × 109/L; platelet count ≥ 100 × 109/L; Serum bilirubin ≤ 1.5 × upper limit of normal (ULN), AST or ALT ≤ 2.5 × ULN (or ≤ 5 × ULN in patients with liver metastases), alkaline phosphatase ≤ 2.5 × ULN (or ≤ 5 × ULN in patients with liver metastases, or ≤ 10 × ULN in patients with bone but no liver metastases); serum creatinine ≤ 1.5 × ULN；and albumin ≥ 25 g/L Patients who achieved objective response or stable disease after 2-6 month first-line chemotherapy The first-line chemotherapy regimens were doublets including platinum (cisplatin or oxaliplatin) plus fluoropyrimidine (5-FU, capecitabine, or S-1) Signed informed consent Exclusion Criteria: Known hypersensitivity to platinum (cisplatin or oxaliplatin) or fluoropyrimidine (5-FU, capecitabine, or S-1) History or clinical evidence of brain metastases Previous chemotherapy for metastatic disease Positive serum pregnancy test in women of childbearing potential Subjects with reproductive potential not willing to use an effective method of contraception Received any investigational drug treatment within 4 weeks of start of study treatment Other prior malignancies in the past 5 years Unresolved bowel obstruction or malabsorption syndrome

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 maintenance group<br>S-1 maintenance | Drug: S-1 maintenance<br>* S-1 maintenance till disease progression or untolerable toxicities, in oral doses of 40 mg (BSA<1.25 m2), 50 mg (1.25≤BSA<1.50 m2) and 60 mg (BSA≥1.50 m2) b.i.d. on days 1-14 for each 21-day cycle.<br>* Other names: S-1 monotherapy maintenance;|
| Other: Observation group<br>Observation without anti-tumor treatment | Other: Observation<br>* Observation without anti-tumor treatment<br>* Other names: Observation without anti-tumor treatment;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maintenance progression-free survival (PFS) | The Kaplan-Meier survival from randomization to maintenance or observation until the date of first documented progression or date of death from any cause, whichever came first. | from date of randomization to maintenance or observation until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression-free survival from induction treatment (PFS2) | The Kaplan-Meier survival from induction treatment (the initiation date of first-line chemotherapy) until the date of first documented progression or date of death from any cause after maintenance treatment or observation, whichever came first | from induction treatment (the initiation date of first-line chemotherapy) until the date of first documented progression or date of death from any cause after maintenance treatment or observation, whichever came first, assessed up to 2 years | 
| overall survival (OS) | The Kaplan-Meier survival from induction treatment (the initiation date of first-line chemotherapy) until death from any cause or the last follow-up date. | from induction treatment (the initiation date of first-line chemotherapy) until death from any cause or the last follow-up date, assessed up to 2 years. | 
| toxicity relevant to S-1 maintenance/observation | any toxicities occurring during the treatment of S-1 maintenance/observation | from date of randomization to maintenance or observation until the date of first documented progression or unaccepted toxicities, assessed up to 30 days after the last oral administration of S-1. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
S-1, Advanced Gastric Cancer, Maintenance, First-line treatment