Cetuximab in Combination With TS-1 and Cisplatin as First-line Treatment of Advanced Gastric Adenocarcinoma

Inclusion Criteria:

1. Written informed consent which was approved by the Institutional Review Board (IRB) of the site before any trial-related activities are carried out
2. Age ≥ 20 years
3. Histologically confirmed adenocarcinoma of the stomach or GEJ (adenocarcinomas of the esophagogastric junction types I to III according to Siewert's classification)
4. Archived tumor material sample for at least subsequent standardized epidermal growth factor receptor (EGFR) expression and Kirsten-rat sarcoma (KRAS) mutation assessments Investigators must make sure in advance that appropriate archived tumor material is available from a potentially eligible subject, and that a sample can be shipped to a central repository if the subject agrees to participate.
5. Unresectable advanced (M0) or unresectable metastatic (M1) disease For unresectable advanced disease (M0), at least one measurable locoregional lymph node or other measurable extraluminal tumor lesion ≥ 20 mm (independent of whether measured by conventional techniques or spiral computed tomography [CT] scan) must be documented.
6. At least one radiographically documented measurable lesion in a previously non-irradiated area according to the RECIST version 1.0, i.e., this lesion must be adequately measurable in at least one dimension (longest diameter [LD] to be recorded) as ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan. Primary tumor site will be considered as a non-measurable lesion only.
7. Eastern Cooperative Oncology Group - performance status (ECOG-PS) 0 to 1
8. Estimated life expectancy > 12 weeks
9. Medically accepted contraception (in patients with conception potential)
10. Glomerular filtration rate (GFR) ≥ 60 mL/min (estimated by the Cockcroft-Gault formula)
11. Aspartate Aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN) and Alanine Aminotransferase (ALT) ≤ 2.5 x ULN (or AST ≤ 5.0 x ULN and ALT ≤ 5.0 x ULN in patients with liver metastasis)
12. Bilirubin ≤ 3 x ULN
13. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
14. Platelets ≥ 100 x 10^9/L
15. Hemoglobin ≥ 9.0 g/dL (without transfusions)
16. Sodium and potassium within normal limits or ≤ 10% above or below (supplementation permitted)
17. Japanese (with Japanese citizenship)

Exclusion Criteria:

1. Prior chemotherapy. However previous (neo-)adjuvant (radio-)chemotherapy allowed if finished > 1 year prior to start of trial treatment and no more than 300 mg/m^2 cisplatin has been administered
2. Prior treatment with an antibody or molecule targeting EGFR- and/or vascular endothelial growth factor (VEGF) receptor-related signaling pathways
3. Brain metastasis and/or leptomeningeal disease (known or suspected)
4. Radiotherapy (except localized radiotherapy for pain relief), major surgery, or any investigational drug in the 30 days before the start of trial treatment
5. Concurrent chronic systemic immune or hormone therapy not indicated in this trial protocol except for physiologic replacement
6. Clinically relevant coronary artery disease (New York Heart Association [NYHA] functional angina classification III/IV), congestive heart failure (NYHA III/IV), clinically relevant cardiomyopathy, history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia
7. Known Human Immunodeficiency Virus (HIV) infection, active or chronic carrier of hepatitis B virus (HBV) (HBV antigen positive or HBV deoxyribonucleic acid (DNA) positive) or hepatitis C virus (HCV) (HCV antibody positive)
8. Chronic diarrhea or short bowel syndrome

9. Presence of any contraindication to treatment with cetuximab and SP including:

   • Known hypersensitivity to S-1, fluorouracil, cisplatin, cetuximab or to any of the excipients of these drugs
   • Known dihydropyrimidine dehydrogenase deficiency
   • Hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
   • Current treatment with sorivudine or its chemically related analogues, such as brivudine
   • Continuous treatment with flucytosine (based on the S-1 package insert)
   • Symptomatic peripheral neuropathy of Grade ≥ 2 and/or ototoxicity of Grade ≥ 2 according to National Cancer Institute - Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 3.0, except if due to trauma or mechanical impairment due to tumor mass
10. Pregnancy or lactation period
11. Concurrent treatment with a non-permitted drug (any other chemotherapy, systemic anticancer therapy or immunotherapy)
12. Previous malignancy other than gastric cancer in the last 5 years except basal cell cancer of the skin, preinvasive cancer of the cervix, and carcinoma in situ of the digestive tract
13. Medical or psychological conditions that would not permit the patient to complete the trial or sign the Informed Consent Form (ICF)
14. Legal incapacity or limited legal capacity