Anti-HER2 Therapy in Patients of HER2 Positive Metastatic Carcinoma of Digestive System
Anti-HER2 Therapy in Patients of HER2 Positive Metastatic Carcinoma of Digestive System
To seek the efficacy signals of trastuzumab in combination with chemotherapy in pretreated
 patients of HER2 positive, relapse or metastatic carcinoma of digestive system as response
 rate (RR) determined by the Investigator using RECIST 1.1, and provide evidence for phase III
 clinical trial.
Human epidermal growth factor receptor 2, (HER2) is overexpressed /amplified in multiple
 carcinomas, for example, gastric cancer(GC), gastroesophageal junction
 adenocarcinoma(GEJA),and breast cancer.And HER2 is closely related to tumor proliferation
 &metastases.About 90% Chinese esophagus cancer are squamous cell origin. The reported HER2
 overexpression ranged from 5-30%, Beijing cancer hospital reported an 11% positive rate. The
 variety of HER2 positive rate may because of the absence of standard HER2 testing criteria.
 The current treatment for metastatic Esophageal squamous Cell Carcinoma (ESCC) is not
 satisfactory. Fluorouracil and platinum are considered as first line standard of care (SOC)
 with a 20-30% RR and 7-9 months overall survival (OS). In second line setting, there is no
 SOC in china. And the efficacy is not satisfactory. Esophageal adenocarcinoma has a higher
 HER2 positive rate of 14%, but no data reported of using trastuzumab in these patients in
 China. Biliary tract cancer (BTC), including intrahepatic/extrahepatic cholangiocarcinoma and
 Gallbladder cancer (GBC) is very aggressive, total 5y survival is less than 5% for
 unresectable patients. GBC is account for approximately 2/3 of BTC, and it's estimated the
 incidence in china is 52800 and the mortality is 40700 in 2015. Most patients are diagnosed
 in advanced stage and lose the opportunity of surgery. However, there is no SOC for
 unresectable BTC, gemcitabine plus platinum provided a 30% RR and 10 month OS. In second line
 treatment, no differences were seen between various experimental agents. The reported HER2
 positive rate range from 5.1% to 57% in biliary duct cancer and 4.7% to 64% in GBC.
 Researchers reported her2 amplification is related to tumor stage and lymph nodes metastasis
 in 221 BTC patients. Another study reported a 16.6% positive rate and worse prognosis with a
 sample size of 230 GBC patients. Meanwhile, HER2 pathway mutation rate reached 37%. All imply
 that BTC may be the potential anti HER therapy population. Besides, other digestive system
 tumor has low HER2 positive rate (Small intestinal cancer 0.9-3%; hepatocellular carcinoma
 2.4%; Pancreatic cancer 3%; etc.). However, the patient pool is large and has no SOC in
 second Line. Whether these HER2 + patients can gain benefit form anti- her treatment is worth
 investigating. In 2016 American Society of Clinical Oncology (ASCO), a study reported that
 using trastuzumab and pertuzumab combination, 35% metastatic colorectal cancer (CRC) and 50%
 BTC patients who heavily pretreated had objective response. However, china doesn't have
 studies for these patients. .

 The concurrent basket trial will explore the efficacy and safety of trastuzumab with
 chemotherapy in Chinese patients of pretreated, HER2 positive, relapse or 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.