A Study to Evaluate the Efficacy and Safety of Trastuzumab in Combination With Capecitabine and Oxaliplatin as First-line Chemotherapy for Inoperable, Locally Advanced or Recurrent and/or Metastatic Gastric Cancer

Trastuzumab will be administered at a loading dose of 8 mg/kg (on day 1) followed by 6mg/kg i.v. infusion every 3 weeks.

Trastuzumab is to be continued until disease progression or intolerable toxicity.

Capecitabine (Xeloda) 2000mg/m2d, d1-14; q3w, until disease progression or intolerable toxicity.

Oxaliplatin 130mg/m2 d1; q3w, 6 cycles

Inclusion criteria

• Histologically confirmed adenocarcinoma of the stomach or gastro-oesophageal junction with inoperable locally advanced or recurrent and/or metastatic disease, not amenable to curative therapy.
• Measurable disease, according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.0), assessed using imaging techniques (CT or MRI).
• HER2 positive tumour (primary tumour or metastasis) as assessed by the central laboratory. (Both IHC and Dual SISH will be performed on all patients in the central laboratory.)
• ECOG Performance status 0, 1 or 2.
• Life expectancy of at least 3 months.
• Male or female. Age ≥ 18 years.
• Signed informed consent.

Exclusion criteria

• Previous chemotherapy for advanced/metastatic disease (prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has elapsed between completion of adjuvant/neoadjuvant therapy and enrolment into the study; the total dose of cisplatin should be less than 300mg/m2, adjuvant/neoadjuvant therapy with oxaplatin is not allowed).
• No prior use of EGFR-targeting drugs,such as Trastuzumab,lapatinib or other TKIs.
• Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome (e.g. patients with partial or total gastrectomy can enter the study, but not those with a jejunostomy probe).
• Patients with active (significant or uncontrolled) gastrointestinal bleeding.
• Residual relevant toxicity resulting from previous therapy (with the exception of alopecia), e.g. neurological toxicity ≥ grade 2 NCI-CTCAE 4.0.
• Other malignancy within the last 5 years, except for carcinoma in situ of the cervix, or basal cell carcinoma.
• Neutrophil count < 1.5 × 109/L, or hemoglobin < 90 g/L,or platelet count < 100 × 109/L.
• Serum bilirubin > 1.5 × upper limit of normal (ULN); or, AST or ALT > 2.5 × ULN(or > 5 × ULN in patients with liver metastases); or, alkaline phosphatase > 2.5 × ULN (or > 5 × ULN in patients with liver metastases, or > 10 × ULN in patients with bone but no liver metastases); or, albumin < 25 g/L.
• Creatinine clearance < 60 mL/min.
• History of documented congestive heart failure; angina pectoris requiring medication;evidence of transmural myocardial infarction on ECG; poorly controlled hypertension (systolic BP > 180 mmHg or diastolic BP > 100 mmHg); clinically significant valvular heart disease; or high risk uncontrollable arrhythmias.
• Baseline LVEF < 50% (measured by echocardiography or MUGA).
• Patients with dyspnoea at rest due to complications of advanced malignancy or other disease, or who require supportive oxygen therapy.
• Patients receiving chronic or high dose corticosteroid therapy. (Inhaled steroids and short courses of oral steroids for anti-emesis or as an appetite stimulant are allowed).
• Clinically significant hearing abnormality.
• Known dihydropyrimidine dehydrogenase (DPD) deficiency.
• History or clinical evidence of brain metastases.
• Serious uncontrolled systemic intercurrent illness, e.g. infections or poorly controlled diabetes.
• 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.
• Radiotherapy within 4 weeks of start of study treatment (2 week interval allowed if palliative radiotherapy given to bone metastastic site peripherally and patient recovered from any acute toxicity;prior adjuvant radiotherapy is allowed if complete at least 6 months ).
• Major surgery within 4 weeks of start of study treatment, without complete recovery.
• Patients with known active infection with HIV, HBV, or HCV.
• Known hypersensitivity to any of the study drugs.