Pembrolizumab and CXCR4 Antagonist BL-8040 in Treating Patients With Metastatic Pancreatic Cancer

Inclusion Criteria:

* Have histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma based on pathology report
* Be willing and able to provide written informed consent for the trial
* Have measurable disease based on RECIST 1.1; target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
* Have documented objective radiographic progression after stopping treatment with first-line therapy; Note: the same image acquisition and processing parameters should be used throughout the study for a given subject
* Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion from a metastatic site; newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on day 1; subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from Merck; the specimen must be from a biopsy site that would be accessible for at least one subsequent biopsy after initiation on the trial
* Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
* Have a predicted life expectancy of greater than 3 months
* Absolute neutrophil count (ANC) \>= 1,000 /mcL (performed within 10 days of treatment initiation)
* Platelets \>=100,000 /mcL (performed within 10 days of treatment initiation)
* Hemoglobin \>= 9 g/dL or \>= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 14 days of assessment) (performed within 10 days of treatment initiation)
* Serum creatinine OR measured or calculated creatinine clearance (should be calculated per institutional standard) (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) =\< 1.5 X upper limit of normal (ULN) OR \>= 60 mL/min for subject with creatinine levels =\< 1.5 X institutional ULN (performed within 10 days of treatment initiation)
* Serum total bilirubin =\< ULN OR direct bilirubin =\< ULN for subjects with total bilirubin levels \> ULN (performed within 10 days of treatment initiation)
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase \[SGPT\]) =\< 1.5 X ULN (performed within 10 days of treatment initiation)
* Albumin \>= 3.3 mg/dL in the absence of dehydration (performed within 10 days of treatment initiation)
* International normalized ratio (INR) or prothrombin time (PT) =\< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 10 days of treatment initiation)
* Activated partial thromboplastin time (aPTT) =\< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 10 days of treatment initiation)
* Have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication (cycle 1, day 1) (female subjects of childbearing potential); if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Female subjects of childbearing potential must be willing to use an adequate method of contraception; contraception, for the course of the trial through 120 days after the last dose of trial drug; note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject; male subjects of childbearing potential must agree to use an adequate method of contraception; contraception, starting with the first dose of trial therapy through 120 days after the last dose of trial therapy

Exclusion Criteria:

* Has pancreatic tumor other than adenocarcinoma, including: acinar cell carcinoma, pancreaticoblastoma, malignant cystic neoplasms, endocrine neoplasms, squamous cell carcinoma; vater and periampullary duodenal or common bile duct malignancies
* Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy, herbal/complementary oral or IV medicine, or used an investigation device within 4 weeks of the first dose of treatment
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
* Had a solid organ or hematologic transplant
* Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
* Has a diagnosed additional malignancy within 1 year prior to first dose of study treatment with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cervical and/or breast cancers
* Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system (CNS) metastases and/or carcinomatous meningitis as assessed by principal investigator (PI) and radiology review
* Subjects excluded if there is a history of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease, or active, non-infectious pneumonitis
* Has an active infection requiring systemic therapy
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator, including dialysis
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment
* Has received prior immunotherapy with agents that target PD-1, PD-L1, PD-L2, CTLA-4, OX-40, or CD-137 agents, or if the subject has previously participated in Merck pembrolizumab clinical trials
* Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
* Has known hepatitis B or hepatitis C
* Has received a live vaccine within 30 days of planned start of study therapy (cycle 1, day 1); Note: the killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
* Has a known history of active TB (Bacillus tuberculosis)
* Unable to tolerate a contrast enhanced computed tomography (CT) or magnetic resonance imaging (MRI) for staging/restaging purposes
* Hypersensitivity to pembrolizumab or any of its excipients
* Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to such agents administered more than 4 weeks earlier
* Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to a previously administered small molecule agent; a. Note: subjects with =\< grade 2 neuropathy or alopecia are an exception to this criterion and may qualify for the study; b. Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
* Patients requiring beta blockade are disqualified from participating in this study
* Patients who, in the estimation of the treating physician or primary investigator, have had a clinical deterioration of their ECOG performance within the month prior to enrollment
* The use of natural or synthetic cannabinoids
* Patients with unstable angina, new onset angina within the last 3 months, myocardial infarction within the last 6 months, and current congestive heart failure New York Heart Association class III or higher