Pembrolizumab and PEGPH20 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. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research. * Have at least one measurable lesion and one lesion available for biopsy (not the primary pancreatic lesion) 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 had prior treatment with first-line therapy for metastatic disease for at least 4 months, and have had a radiologic response or stable disease at the most recent imaging. Adjuvant therapy for resected disease will not count as first-line therapy. Therapies that are derivative of others (e.g. fluorouracil/leucovorin calcium/oxaliplatin \[FOLFOX\] vis-a-vis fuorouracil/irinotecan/leucovorin/oxaliplatin \[FOLFIRINOX\]) will be counted as a single line of treatment for the purpose of determining the number of prior therapies * Be willing to undergo a core biopsy or excisional biopsy of tumor from a metastatic site. Note that the biopsy itself will be done only after the patient has been found to meet all other inclusion/exclusion criteria and the patient is otherwise prepared to start therapy * Be willing to provide (and have available) archival tissue from a surgical or biopsy specimen obtained PRIOR to the most recent chemotherapy * Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale * Demonstrate adequate organ function. Specimens must be collected within 10 days prior to the start of trial treatment * Female subjects of childbearing potential must have a negative urine or serum pregnancy test at screening (prior to biopsy) and again within 24 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Male and female subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of trial therapy through 120 days after the last dose of trial therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Acceptable methods of contraception are as follows: * Single method (1 of the following is acceptable): intrauterine device (IUD), vasectomy of a female subject's male partner, contraceptive rod implanted into the skin * Combination method (requires use of 2 of the following): diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide), cervical cap with spermicide (nulliparous women only), contraceptive sponge (nulliparous women only), male condom or female condom (cannot be used together), hormonal contraceptive: oral contraceptive pill (estrogen/ progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous (SC) contraceptive injection Exclusion Criteria: * Has pancreatic tumor other than adenocarcinoma, including: acinar cell carcinoma, pancreaticoblastoma, malignant cystic neoplasms, endocrine neoplasms, squamous cell carcinoma, ampulla of Vater, periampullary, duodenal, or common bile duct malignancies * Has had more than one line of systemic chemotherapy for metastatic disease * Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment * Has had prior treatment with PEGPH20 * Has received prior systemic anti-cancer therapy that includes investigational agents within 2 weeks prior to treatment * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) 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 3 months (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Patients with autoimmune colitis (eg Crohn's disease) will be excluded. Any relevant diseases not listed here are to be discussed with the study supporters. Replacement hormone therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed * 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 tumors of low invasive potential (e.g. in situ cervical and/or breast cancers) * Has a history of central nervous system (CNS) metastases and/or carcinomatous meningitis * Has a history of (non-infectious) pneumonitis that required oral or IV steroids or currently has pneumonitis * Has an active infection requiring systemic therapy * Chronic use of steroids for pain or emesis management * 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 including anti-PD-1, anti-PD-L1, or anti-PD-L2 agents, or with an agent directed to another stimulatory or co-inhibitory T cell receptor (eg, CTLA-4, OX-40, CD137), or has previously participated in Merck pembrolizumab or PEGPH20 clinical trials * Has a known history of human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies) (HIV testing is required during screening) * Has a history of the following liver diseases: hepatitis B (defined as hepatitis B surface antigen \[HBsAg\] reactive), hepatitis C (defined as detectable hepatitis C virus \[HCV\] ribonucleic acid \[RNA\]), primary biliary cholangitis, primary sclerosing cholangitis, history of immune mediated cholangitis. Of note, patients with a history of bacterial cholangitis are eligible if the infection has been fully resolved prior to the screening visit. An exception is made for hepatitis C patients who have undergone treatment and who have negative serologic testing for at least one year * Has received a live vaccine within 30 days prior to the first dose of trial drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist) are live attenuated vaccines and are not allowed * Has a known history of active TB (Bacillus tuberculosis) * Is unable to tolerate a contrast enhanced computed tomography (CT) or magnetic resonance imaging (MRI) for staging/restaging purposes * Has not recovered (i.e., grade 1 or at baseline) from adverse events (AEs) due to chemotherapy (neuropathy and alopecia are excluded) * Has clinical evidence of a deep vein thrombosis (DVT), pulmonary embolism (PE), or other known thrombotic event present during the screening period. Of note - this does not apply to splanchnic vein (eg portal / superior mesenteric vein) thrombosis that, in the opinion of the primary investigator, are primarily associated with the anatomic location of the underlying disease * Requires Megace (medroxyprogesterone acetate) * 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 * 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 * Has 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. Additionally, subjects with myocardial infarction or atrial fibrillation within the past 12 months are excluded * Has a history of a cerebrovascular accident or transient ischemic attack * Known clinically significant pre-existing carotid artery disease * Has a history of active bleeding requiring transfusion within a 3 month period prior to screening * Known allergy/intolerance to hyaluronidase or dexamethasone * Has severe hypersensitivity (\>= grade 3) to pembrolizumab and/or any of its excipients * Contraindication to heparin or non-steroidal anti-inflammatory drugs (NSAIDs) * Known cases of drug-induced hepatobiliary toxicities (other than a radiological finding of fatty liver)