Ramucirumab, Trastuzumab, Fluorouracil, Oxaliplatin, Capecitabine, and Cisplatin in Treating Patients with Stage IV HER2-Positive Gastroesophageal Junction or Gastric Cancer

Inclusion Criteria

• Patients must have pathologically or cytologically Memorial Sloan-Kettering Cancer Center (MSKCC) confirmed diagnosis of gastric or GEJ adenocarcinoma
• Patients must have stage IV gastric or GEJ adenocarcinoma with HER2 overexpression and/or amplification as determined by next generation sequencing assay, (immunohistochemistry [IHC] 3+) or fluorescent in situ hybridization (FISH+ is defined as HER2:chromosome 17 centromere probe [CEP17] ratio >= 2.0); MSKCC confirmation of HER2 status is not mandatory prior to enrollment and treatment on study; for patients with outside HER2 testing, if sufficient tissue is available HER2 testing will be repeated at MSKCC for purpose of analysis and will not impact the patient's eligibility
• Available archival tumor tissue should be submitted to MSKCC for integrated mutation profiling of actionable cancer targets (IMPACT) analysis, but will not be required prior to registration; note: if tissue is depleted, patient will still be eligible after discussion with the principal investigator (PI)
• Patients must have disease that can be evaluated radiographically, this may be measurable disease or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Patients may have received no prior chemotherapy for stage IV disease; patients may have received prior adjuvant therapy (chemotherapy and/or chemoradiation) if more than 6 months have elapsed between the end of adjuvant therapy and registration
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Peripheral neuropathy =< grade 1
• Total bilirubin =< 1.5 mg/dL (25.65 umol/L) (except patients with Gilbert's disease)
• Aspartate transaminase (AST) and alanine transaminase (ALT) =< 3.0 times upper limit of normal (ULN) or =< 5.0 times the ULN in the setting of liver metastases
• Absolute neutrophil count (ANC) >= 1500/uL
• Hemoglobin >= 9 g/dL (5.58 mmol/L)
• Platelets >= 100,000/uL
• Serum creatinine =< 1.5 x upper limit of normal (ULN)
• Creatinine clearance (measured via 24-hour urine collection) >= 40 mL/minute (that is, if serum creatinine is > 1.5 x ULN, a 24-hour urine collection to calculate creatinine clearance must be performed)
• Patients whose urinary protein is =< 1+ on a dipstick or routine urinalysis (UA); if routine analysis is > 2+, a 24-hour urine collection for protein must demonstrate < 1000 mg of protein in 24 hours to allow participation in this protocol)
• International normalized ratio (INR) =< 1.5, and a partial thromboplastin time (PTT) =< 5 seconds above the ULN (unless receiving anticoagulation therapy); patients receiving warfarin must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy
• Patients, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods)
• Female patients of childbearing potential must have a negative serum pregnancy test within 7 days of study entry

Exclusion Criteria

• Patients who have uncontrolled or poorly-controlled hypertension (> 139 mmHg systolic or > 89 mmHg diastolic for > 4 weeks) despite standard medical management
• Patients receiving any concurrent anticancer therapy or investigational agents with the intention of treating gastric/GEJ cancer; previously received trastuzumab as part of a regimen in the metastatic setting with evidence of progression; 89Zr-trastuzumab use as imaging agent for 89Zr-trastuzumab PET permitted
• Patients having: * 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
• Active or clinically significant cardiac disease including: * Congestive heart failure - New York Heart Association (NYHA) > class II * Active coronary artery disease * Left ventricular function < 50% * Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin * Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomization * Patients who 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 * Patients who are receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents; once-daily aspirin (maximum dose 325 mg/day) is permitted
• Evidence or history of bleeding diathesis or coagulopathy
• Patients who have experienced any grade 3-4 gastrointestinal (GI) bleeding within 3 months prior to first dose of protocol therapy
• Unwillingness to give written informed consent, unwillingness to participate, or inability to comply with the protocol for the duration of the study
• Patients with prior trastuzumab treatment
• Patients with known active brain or central nervous system metastases, including leptomeningeal disease; patients with treated and asymptomatic brain metastases may be eligible after discussion with PI
• Patients who are pregnant or breast-feeding
• Patients with a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to enrollment
• The patient has undergone major surgery within 28 days prior to first dose of protocol therapy
• Patients who have elective or planned major surgery to be performed during the course of the clinical trial; minor surgery/subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy is permitted
• Patients may not have had radiation within 28 days prior to first dose
• Patients may not have any other medical condition or reason, in that investigator's opinion, makes the patient unstable to participate in a clinical trial
• The patient has 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
• Patients may not have a prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors of perforation