Safety and Effectiveness Study of Chemotherapy and Ziv-aflibercept to Treat Metastatic Colorectal Cancer

Inclusion Criteria: * The Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1. * There must be histologic confirmation of a diagnosis of colorectal adenocarcinoma. * There must be documentation by PET/CT scan, CT scan, or MRI, that the patient has evidence of measurable metastatic disease per RECIST 1.1. * Prior adjuvant therapy is allowed if the last administration was greater than or equal to 6 months prior to randomization into this study including prior adjuvant oxaliplatin. * Patients who have received prior oxaliplatin therapy must have neuropathy recovery greater than or equal to grade 1 according to CTCAE v4.0 * At the time of study entry, blood counts performed within 4 weeks prior to study entry must meet the following criteria: absolute neutrophil count (ANC) must be greater than or equal to 1200/mm3; Platelet count must be greater than or equal to 100,000/mm3; and Hemoglobin must be greater than or equal to 9 g/dL. * The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to study entry must be met: Total bilirubin must be less than or equal to 1.0 x upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be less than or equal to 2.5 x ULN for the lab or less than or equal to 5 x ULN if liver metastasis; Alkaline phosphatase must be less than or equal to 3 x ULN for the lab or less than or equal to 5 x ULN if liver metastasis * Serum creatinine performed within 4 weeks prior to study entry must be less than or equal to 1.5 x ULN for the lab. (If creatinine 1.0-1.5 x ULN, the creatinine clearance should be 60 mL/mn per Cockcroft-Gault formula.) * A urine sample must be tested for proteinuria by dipstick method. Eligibility must be based on the most recent test result performed within 4 weeks prior to randomization. Urine dipstick must indicate 0-1+ protein and negative blood. If dipstick reading is greater than or equal to 1+ protein and greater than or equal to trace hematuria or greater than or equal to 2+ protein, a 24 hour urine specimen must be collected and must demonstrate less than or equal to 500 mg of protein. * Patients with reproductive potential (male/female) must agree to use accepted and effective methods of contraception while receiving study therapy, and for at least 6 months after the completion of study therapy. (The definition of effective method of contraception will be based on the investigator's judgment.) Exclusion Criteria * Diagnosis of anal or small bowel carcinoma. * Colorectal cancer other than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid. * Previous therapy with ziv-aflibercept or other angiogenesis inhibitors for any malignancy. * Previous chemotherapy or any other systemic therapy for metastatic colorectal cancer. * Prior radiotherapy less than or equal to 28 days from study entry. * Patients with initially resectable liver-only disease. * Active hepatitis B or hepatitis C with abnormal liver function tests. * History of brain metastases, uncontrolled spinal cord compression, carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. * Intrinsic lung disease resulting in dyspnea. * Active infection or chronic infection requiring chronic suppressive antibiotics. * Persistent CTCAE v4.0 greater than or equal to grade 2 diarrhea regardless of etiology. * Uncontrolled high blood pressure defined as systolic BP greater than or equal to 150 mmHg or diastolic BP greater than or equal to 100 mmHg with or without anti-hypertensive medication. Patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria. * Chronic daily treatment with corticosteroids with a dose of greater than or equal to 10 mg/day methylprednisolone equivalent (excluding inhaled steroids). * CTCAE v4.0 grade 3 or 4 anorexia or nausea related to metastatic disease. * History of hypertensive crisis or hypertensive encephalopathy. * CTCAE v4.0 greater than or equal to grade 2 vomiting related to metastatic disease. * Any of the following cardiac conditions: Documented New York Heart Association (NYHA) Class III or IV congestive heart failure; Myocardial infarction within 6 months prior to study entry; Unstable angina within 6 months prior to study entry; Symptomatic arrhythmia * Serious or non-healing wound, skin ulcer, or bone fracture. * Known bleeding diathesis or coagulopathy, or requirement of therapeutic dose of coumadin. * History of transient ischemic attack (TIA) or cerebral vascular accident (CVA) within 180 days prior to randomization. * History of symptomatic peripheral ischemia. * History of arterial thrombotic event within 180 days prior to randomization. * Gastroduodenal ulcer(s), erosive esophagitis, or gastritis determined by endoscopy to be active within 90 days prior to randomization. * Infectious or inflammatory bowel disease or diverticulitis. * History of GI perforation within 180 days prior to randomization. * Symptomatic interstitial lung disease or definitive evidence of interstitial lung disease described on CT scan, MRI, or chest x-ray in asymptomatic patients; dyspnea at rest requiring current continuous oxygen therapy. * Any significant bleeding (greater than or equal to grade 3 CTCAE v4.0) not related to the primary colorectal cancer (CRC) tumor within 180 days prior to randomization. * Major surgical procedure, open biopsy, or significant traumatic injury within 42 days prior to randomization. * Other malignancies unless the patient is considered to be disease-free and has completed therapy for the malignancy greater than or equal to 12 months prior to study entry. Patients with the following cancers are eligible if diagnosed and treated within the past 12 months: carcinoma in situ of the cervix, colorectal carcinoma in situ, melanoma in situ, and basal cell and squamous cell carcinoma of the skin. * Acquired immunodeficiency syndrome (AIDS-related illnesses) or known human immunodeficiency virus (HIV) disease requiring antiretroviral treatment. * Patients with known Gilberts syndrome. * History of hypersensitivity to fluoropyrimidines, or folic acid derivatives. * Known dihydropyrimidine dehydrogenase deficiency. * Symptomatic peripheral sensory neuropathy greater than or equal to grade 2 (CTCAE v 4.0) in patients with no prior oxaliplatin therapy. * Previous serious hypersensitivity reaction to monoclonal antibodies. (Determination of "serious" hypersensitivity reaction is at the investigator's discretion.) * Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements, or interfere with interpretation of study results. * Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing should be performed within 14 days prior to study entry according to institutional standards for women of childbearing potential.) * Use of any investigational agent within 4 weeks prior to study entry.