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.