Second Line Chemotherapy for S-1 Refractory Advanced Gastric Cancer

Randomized Phase II/III Trial of Second Line Chemotherapy Comparing CPT-11 Monotherapy Versus S-1/CPT-11 Combination for S-1 Refractory Gastric Cancer

The purpose of this study is compare overall survival of the test arm (CPT-11/S-1 combination) to the control arm (CPT-11 alone) in the subjects with S-1 refractory advanced gastric cancer.

Standard chemotherapy for advanced gastric cancer (AGC) in the US is Cisplatin/5-FU (CF) or docetaxel/CF (DCF), is in Europe epirubicin/CF (ECF) or epirubicin/oxaliplatin/ capecitabine (EOX). Until 2006, there was no evidence of standard chemotherapy for AGC in Japan. In 2007, by the results of JCOG9912 trial (5-FU alone vs. CPT-11/CDDP vs S-1) and SPIRITS trial (S-1 alone vs. S-1/CDDP), S-1/CDDP is regarded as a new standard regimen in Japan. In 2008, by the results of TOP-002 trial (s-1 alone vs. S-1/CPT-11), S-1/CPT-11 could not show the superiority to S-1 alone. One of the other phase III trials, JACCRO GC-03 trial (S-1 alone vs. S-1/docetaxel, NCT00287768) is now ongoing. However, the position of CPT-11 in the treatment of AGC will be regarded as a second-line.

In Japan there is a controversy for the treatment of S-1 refractory gastric cancer. The controversy is continuing S-1 (like FOLFOX to FOLFIRI) or not as a second-line. After the successful adjuvant S-1 results (ACTS-GC trial), the same problem will occur in the patients who are recurrent from adjuvant S-1.

Then, we conducted a phase II/III trial of CPT-11 with or without S-1 in the treatment of first-line S-1 refractory AGC.

Inclusion Criteria:

• Histologically proven inoperable advanced gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) or relapse gastric adenocarcinoma
• Subjects must be able to take orally
• Subjects must be confirmed to be PD status by picture diagnosis after first-line chemotherapy using S-1 alone, S-1 + Cisplatinum or S-1 + taxane, except S-1 + CPT-11
• Within 4 weeks from the diagnosis of PD
• Total dosage of S-1 at the first-line is over 2,240mg/m2 in S-1 alone treatment, 1,680mg/m2 in the S-1 combination
• ECOG performance status ≤ 1
• Follow up Age 20 or over
• Life expectancy estimated more than 12 weeks
• Hgb ≥ 8 g/dL, WBC 4,000-12,000/mm3, ANC ≥ 2,000/mm3, platelets ≥ 100,000/mm3
• Creatinine ≤ upper normal limit (UNL)
• Total bilirubin ≤ 1.5 X UNL
• Written informed consent

Exclusion Criteria:

• S-1 + CPT-11 was employed as a first-line
• Any other cytotoxic agents therapy, immuno-therapy, radiation-therapy
• After S-1 adjuvant
• Suspended cases by adverse events by S-1 or S-1 combination
• Excessive amounts of ascites require drainage
• Known brain metastases
• History of hypersensitivity to fluoropyrimidines and CPT-11
• Pregnancy or lactation women, or women with suspected pregnancy or men with willing to get pregnant
• Active double cancer
• Gastrointestinal bleeding
• Any subject judged by the investigator to be unfit for any reason to participate in the study