Combining Cyramza, ONIVYDE, and Lonsurf as a second-line treatment for metastatic gastric cancer

Inclusion Criteria:

1. histologically or cytologically confirmed metastatic gastric adenocarcinoma
2. patients have received only first line of systemic therapy, including recurrence during adjuvant therapy or within 6 months after the completion of adjuvant treatment.
3. ECOG(Eastern Cooperative Oncology Group) performance status 0 or 1
4. patients with HER2/neu-positive tumor must be exposure to Herceptin treatment
5. at least one measurable disease according to the RECIST version 1.1;
6. patients are aged 20 to 80 years;
7. patients have a life expectancy ≥ 3 months;
8. patients have adequate renal function with defined as serum creatinine ≤ 1.5 times the upper limit of normal (ULN) or Ccr ≥ 40 mL/min;
9. patients with adequate hepatic function as defined by a total bilirubin ≤1.5 times the ULN, and aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times the ULN or 5 times the ULN in the setting of liver metastases.
10. patients have adequate bone marrow function, defined as an absolute neutrophil count ≥ 1500/mm3, hemoglobin ≥9 g/dL, and platelet count ≥ 100,000/mm3 (transfusion or G-CSF support before enrollment is allowed)
11. patients have International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) \< 1.5 x ULN;
12. patients' urinary protein is ≤1+ on dipstick or routine urinalysis or a 24-hour urine collection for protein must demonstrate \<1000 mg of protein if urine dipstick or routine analysis is ≥ 2+;
13. patients with childbearing potential shall have effective contraception for both the patient and his or her partner during the study;
14. female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose of protocol therapy;
15. the ability to understand and willingness and to sign a written informed consent document.

Exclusion Criteria:

1. patient can't take oral drugs;
2. known hypersensitivity to irinotecan, fluoropyrimidine, or ramucirumab;
3. receipt of surgery within the past 4 weeks before study enrollment;
4. ≥ grade 2 diarrhea and ascites
5. concurrent severe infection with intravenous systemic antibiotics treatment;
6. patients have experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy;
7. patients have a prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation;
8. patients have:

   * cirrhosis at a level of Child-Pugh B (or worse) or
   * cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis;
9. patients have a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy;
10. patients have undergone major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to the first dose of protocol therapy. Patients have elective or planned major surgery to be performed during the course of the clinical trial;
11. patients have uncontrolled or poorly-controlled hypertension (\>160 mmHg systolic or \> 100 mmHg diastolic for \>4 weeks) despite standard medical management;
12. patients have experienced any grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy;
13. patients have a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to first dose of protocol therapy;
14. patients are receiving chronic antiplatelet therapy, including dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted;
15. previously received prior nal-IRI (ONIVYDE®) or TAS-102 (LONSURF®) or ramucirumab therapy
16. another previous malignancy diagnosed within the past 5 years except for non melanoma skin cancer or stage I cervical cancer;
17. pregnant or breast feeding women.