Inclusion Criteria:
* Participant has definitive histologically or cytologically confirmed adenocarcinoma of the pancreas. The definitive diagnosis of metastatic pancreatic adenocarcinoma will be made by integrating the histopathological data within the context of the clinical and radiographic data. Participants with islet cell neoplasms are excluded
* Patient has one or more metastatic tumors measurable by computed tomography (CT) scan (or magnetic resonance imaging \[MRI\], if patient is allergic to CT contrast media or if the tumor is difficult to delineate on CT scan) as defined by RECIST 1.1 criteria
* Non-pregnant and non-lactating
* If a female patient is of child-bearing potential, as evidenced by regular menstrual periods, she must have a negative serum pregnancy test beta-human chorionic gonadotropin (beta-hCG) documented 72 hours prior to the first administration of study drug
* The patient must agree to use a method of contraception considered highly effective by the investigator during the period of administration of study drug and after the end of treatment for an additional 3 months. Adequate birth control methods are defined below
* Women will be considered of childbearing potential unless surgically sterilized by hysterectomy or bilateral tubal ligation/salpingectomy, or if they are post-menopausal (defined as absence of menses for at least 1 year). Sexually active men and women of childbearing potential who are sexually active and not willing to use a highly effective method of birth control during the trial and for at least three months after will be considered ineligible for the trial. A highly effective method of birth control is defined as one which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized partner. In the event that local regulations require additional restrictions to the above definition, the patient information will specify the acceptable contraceptive methods
* Patients must have received no previous chemotherapy or investigational therapy for the treatment of metastatic pancreatic cancer. Prior adjuvant treatment is allowed as long as the last chemotherapy was \> 6 months ago. Prior use of 5-fluorouracil (5-FU) or gemcitabine administered as a radiation sensitizer or in the adjuvant setting is allowed, provided at least 2 month have elapsed since completion of the last dose and no lingering significant toxicities are present. Prior radiation is allowed as long as the planned lesion(s) to be measured were not previously radiated
* Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L (obtained =\< 14 days prior to randomization)
* Platelet count \>= 100,000/mm\^3 (100 x 10\^9/L) (obtained =\< 14 days prior to randomization)
* Hemoglobin (Hgb) \>= 9 g/dL (obtained =\< 14 days prior to randomization)
* Aspartate transaminase (AST), serum glutamic-oxaloacetic transaminase (SGOT), alanine transaminase (ALT) serum glutamic-pyruvic transaminase (SGPT) =\< 2.5 x upper limit of normal range (ULN), unless liver metastases are clearly present, then =\< 5 x ULN is allowed (obtained =\< 14 days prior to randomization)
* Total bilirubin =\< 2 x ULN (obtained =\< 14 days prior to randomization)
* Patient has Karnofsky performance status (KPS) \>= 60 or Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Patient has been informed about the nature of the study, has agreed to participate in the study, and signed the informed consent form (ICF) prior to participation in any study-related activities
Exclusion Criteria:
* Patient has known brain metastases, unless previously treated and well-controlled for at least 3 months (defined as clinically stable, no edema, no steroids and stable in 2 scans at least 4 weeks apart)
* Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy
* Patient has known active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* Patient has a history of allergy or hypersensitivity to any of the study drugs or any of their excipients
* Patient has serious medical risk factors involving any of the major organ systems, or serious psychiatric disorders, which could compromise the patient's safety or the study data integrity based on the assessment of the enrolling physician
* Patient is unwilling or unable to comply with study procedures
