This is a phase II, multicenter, double-blinded, randomized, 2-arm trial evaluating the efficacy and safety of mFOLFIRINOX plus ramucirumab (Arm A) vs. mFOLFIRINOX plus placebo (Arm B) in 94 subjects with advanced pancreatic cancer, not amenable to curative treatment. Both arms will continue treatment until disease progression or unacceptable toxicity.

OUTLINE: This is a multi-center study.

EXPERIMENTAL ARM A:

• Oxaliplatin 85 mg/m^2 over 2-4 hours
• Irinotecan 165 mg/m^2 over 90 minutes
• 5-FU 2,400 mg/m^2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia.
• Arm A will receive ramucirumab (RAM) administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks.

CONTROL ARM B :

• Oxaliplatin 85 mg/m2 over 2-4 hours
• Irinotecan 165 mg/m2 over 90 minutes
• 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia.
• Arm B will receive a placebo infusion every 2 weeks. Due to the double-blinded nature of this study, the volume of placebo will be calculated as if it were RAM.

In order to demonstrate adequate organ function, all screening labs must be obtained within 7 days prior to registration:

Hematological:

• Hemoglobin ≥ 9 g/dL
• Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3
• Platelet Count (PLT) ≥ 100,000/mm^3

Renal:

• Creatinine ≤ 1.5 mg/dL or Creatinine clearance^1 ≥ 40 mL/min
• Albumin ≥ 2.5 g/dL

Hepatic:

• Bilirubin ≤ 1.5 mg/dL
• Aspartate aminotransferase (AST) ≤ 3 × ULN or < 5 xULN in the setting of liver metastases
• Alanine aminotransferase (ALT) ≤ 3 × ULN or < 5 xULN in the setting of liver metastases

Coagulation:

• International Normalized Ratio (INR) (Patients receiving warfarin must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy) ≤1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) < 1.5 x ULN

Inclusion Criteria:

• Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information. .
• Age ≥ 18 years at the time of consent.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 within 7 days prior to registration.
• Histologic or cytological diagnosis of recurrent or metastatic pancreas adenocarcinoma (PCA) who present for first line chemotherapy treatment.
• No prior first line systemic treatment (prior adjuvant or neoadjuvant treatment is permitted). Subjects whose disease has progressed after 6 months of last systemic chemotherapy or chemo-radiation in the adjuvant or neoadjuvant setting are eligible.
• Measurable disease determined using guidelines of Response Evaluation Criteria In Solid Tumors (RECIST 1.1). Baseline tumor assessment should be performed using high resolution computed tomography (CT) scans or magnetic resonance imaging (MRI).
• Urine protein < 1+ on dipstick test or routine urinalysis. If the proteinuria on these tests is ≥2+, then a 24-hour urine test must be collected and must demonstrate < 1g proteins in 24 hours to allow participation.
• Estimated life expectancy of >12 weeks, as assessed by the site investigator.
• If sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods) due to unknown risk of teratogenicity of ramucirumab

Exclusion Criteria:

• Subjects with histology other than adenocarcinoma; Examples include: neuroendocrine tumors, acinar cell cancer, sarcoma or lymphoma of the pancreas.
• Ongoing or active infection.
• Symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia. Symptomatic heart failure per New York Heart Association (NYHA) Class II-IV.
• Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management.
• Acute or sub-acute intestinal obstruction.
• Interstitial pneumonia or interstitial fibrosis of the lung, which in the opinion of the site investigator could compromise the subject or the study.
• Pleural effusion or ascites that causes > grade 1 dyspnea.
• Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) with a history of hepatic encephalopathy or clinical meaningful ascites resulting from cirrhosis; clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis.
• Grade 3 or higher bleeding event ≤ 3 months prior to randomization.
• Experience of any arterial thrombotic or arterial thromboembolic events, including, but not limited to myocardial infarction, transient ischemic attack, or cerebrovascular accident, ≤ 6 months prior to randomization.
• History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to randomization.
• Documented and/or symptomatic or known brain or leptomeningeal metastases.
• GI perforation/fistula
• Documented and/or symptomatic or known brain or leptomeningeal metastases.
• Severely immune-compromised (other than being on steroids), including known HIV infection.
• Concurrent active malignancy other than adequately treated non-melanoma skin cancer, other noninvasive carcinoma, or in situ neoplasm. A subject with previous history of malignancy is eligible, provided that he/she has been disease free for > 3 years.
• Breast-feeding or pregnant.
• Prior autologous or allogeneic organ or tissue transplantation.
• Known allergy to any of the treatment components.
• Major surgery within 28 days prior to the first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 2 days prior to first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial.
• Any condition that does not permit compliance with the study schedule including psychological, geographical or medical.
• Receiving medications that can effect clotting ability: warfarin, aspirin (once-daily aspirin use- maximum dose 325 mg/day is permitted), nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. .
• Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy.

All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.

Site pharmacy staff will be unblinded to the study treatment. Subjects, site investigators, site analysis teams, and other site personnel will be blinded to the study treatment.