Anti-HER2 Therapy in Patients of HER2 Positive Metastatic Carcinoma of Digestive System

Inclusion Criteria:

* Signed informed consent.
* Male and female patients aged from 18 to 75 years
* Histologically confirmed Colorectal cancer,Esophagus squamous cell carcinoma, biliary tract cancer, and digestive system tumor beyond CRC and GC\&GEJA with the following specifications:

  * genetic testing conformed KRAS/NRAS/BRAF all wild type for colorectal cancer
  * Detection of a carcinoma with HER2 3+ (IHC) or HER2 2+ (IHC) with amplification proven by fluorescence in situ hybridization(FISH), silver in situ hybridization（SISH） or chromogenic in situ hybridization（CISH） using gastric cancer criteria by an accredited local pathologist.
  * Relapse or metastatic diseases, at least one measurable lesion according to RECIST 1.1, anticipated survival ≥ 12 weeks.
  * ECOG Performance status 0-1.
  * Patients who failed at least first line systemic therapy.
  * Adequate organ function as determined by the following laboratory results:
  * Absolute neutrophil count ≥1500 cells/mm3,
  * Platelet count ≥ 90,000 cells/mm3,
  * Hemoglobin ≥9.0 g/dL
  * Total bilirubin ≤ 1.5 upper limit of normal (ULN).
  * serum glutamate oxaloacetate transaminase(SGOT,AST), serum glutamate pyruvate transaminase(SGPT,ALT) \< 2.5 ULN without liver metastases; \< 5 ULN with liver metastases.
  * serum creatinine \< 1.5
  * ULN OR creatinine clearance ≥ 40 mL/ min.
* If able to reproduce, patients must be willing to use highly effective methods of contraception during treatment and for 7 months after the end of treatment.

Exclusion Criteria:

* Known hypersensitivity against treatment regimen.
* Baseline left ventricular ejection fraction(LVEF) \< 50% (measured by echocardiography or MUGA).
* Previous anti-her treatment.
* Immune therapy, biological therapy or any participation in clinical trial in previous two weeks.
* Surgery and not recovered in previous three weeks
* Clinical evidence of brain metastases, or uncontrolled epilepsy.
* Serious uncontrolled systemic intercurrent illness, e.g. infections or poorly controlled diabetes.
* Other malignancy within the last 5 years, except for carcinoma in situ of the cervix, or basal cell carcinoma.
* Clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, New York Heart Association(NYHA) III-IV; poorly controlled hypertension (systolic BP \> 180 mmHg or diastolic BP \> 100 mmHg); clinically significant valvular heart disease; unstable angina pectoris, myocardial infarction or high risk uncontrollable arrhythmias.
* Long term or high dose corticosteroids administration ( inhalation or short term oral administration for antiemesis and orexigenic is allowed)
* Patients of legally incapacity or of medical and ethical reasons not fit for study.
* Pregnant or lactating, or intending to become pregnant during the study.
* Jaundice, ascites, and / or alkaline phosphatase ≥3 × ULN; and / or ≥3 grade (CTC-AE) of persistent proteinuria, urinary protein / creatinine ratio\> 3.5g / 24 hours or renal failure need blood or peritoneal dialysis.
* Presence of \> grade 2(CTC-AE) persistent infection; unhealed wounds, ulcer or fracture, or patients with a history of organ transplant.
* Evidence of coagulation disorders. Like presence ≥grade 3 (CTC-AE) bleeding events.
* Known HIV or hepatitis B virus(HBV), hepatitis C virus(HCV) infection.
* Any \> grade 1 unresolved toxicity due to previous treatment (CTC-AE), except for alopecia, anemia and hypothyroidism).
* Not suitable for the study evaluated by investigators
* Known dihydropyrimidine dehydrogenase (DPD) deficiency.
* History of exposure to the following cumulative doses of anthracyclines:

  * Doxorubicin \> 500 mg/m2 OR Epirubicin \> 720 mg/m2.

    * If another anthracycline or more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin.