The purpose of this study is to test any good and bad effects of the study drug called PEGPH20. PEGPH20 alone is considered investigational. The Food and Drug Administration (FDA) has not approved the marketing or sale of PEGPH20, but have authorized its use in research studies with humans. PEGPH20 could shrink the cancer but it also can cause side effects. PEGPH20 is an enzyme that breaks down a specific tissue component called hyaluronan produced by some tumors. Pancreatic tumors often have a large amount of hyaluronan. The removal of hyaluronan from tumors may decrease tumor growth.

Inclusion Criteria:

• Signed, written Institutional Review Board (IRB)-approved Informed Consent Form (ICF).

• Histologically confirmed locally advanced unresectable (Stage III) or Stage IV PDAC.

• Measurable or evaluable disease on computed tomography (CT) or magnetic resonance imaging (MRI) scan per RECIST v1.1.

• For patients with locally advanced disease, no previous radiotherapy, surgery, chemotherapy, or investigational therapy for the treatment of PDAC is permitted. For patients with metastatic disease, prior treatment for non-metastatic disease with 5-FU or gemictabine administered as radiation sensitizer, or as a cytotoxic therapy, in the adjuvant setting is allowed, provided at least 6 months have elapsed since completion of the last dose and no ≥ Grade 2 treatment-related toxicities are present.

• Karnofsky Performance Status ≥70%.

• Life expectancy ≥3 months.

• Age ≥18 years.

• A negative serum pregnancy test, if female of reproductive potential.

• Screening clinical laboratory values as follows, performed within 14 days prior to day 1:

  • Total bilirubin ≤1.5 times upper limit of normal (ULN).
  • Aspartate aminotransferase ([AST]; serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase ([ALT]; serum glutamic pyruvate transaminase [SGPT]) ≤2.5 times ULN, (if liver metastases are present, then ≤5 times ULN is allowed).
  • Serum creatinine ≤2.0 mg/dL or calculated creatinine clearance ≥60 mL/min.
  • Serum albumin ≥3.0 g/dL.
  • Absolute neutrophil count (ANC) ≥1,500 cells/mm3.
  • Platelet count ≥100,000 plt/mm3.
  • Hemoglobin ≥9 g/dL
  • Prothrombin time (PT)/international normalized ratio (INR) within normal limits (±15%) or within therapeutic range if on warfarin.
  • Partial thromboplastin time (PTT) within normal limits (±15%).

• For men and women of reproductive potential, agreement to use an effective contraceptive method from the time of screening and throughout their time on study. Effective contraceptive methods consist of prior sterilization, intra-uterine device, oral or injectable contraceptives, and/or barrier methods. Abstinence alone is not considered an adequate contraceptive measure for the purposes of this study.

Exclusion Criteria:

• Known central nervous system involvement or brain metastases.
• New York Heart Association Class III or IV cardiac disease or myocardial infarction within the past 12 months.
• Known, clinically significant carotid artery disease.
• Known, increased risk of bleeding.
• Patients with TE event occurring > 6months prior to enrollment and receiving active anticoagulation.
• Patients with any prior history of arterial thrombosis or symptomatic pulmonary embolism.
• Patients with current use of megestrol acetate (use with 10 days of Day 1) will be excluded.
• Active, uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.
• Known active infection with human immunodeficiency virus, hepatitis B, or hepatitis C.
• Known allergy to hyaluronidase.
• Patients with prosthetic heart valves
• Women currently pregnant or breastfeeding.
• Intolerance of dexamethasone.
• History of another primary cancer within the last 3 years with the exception of non-melanoma skin cancer or curatively-treated cervical carcinoma in-situ.
• History of transient ischemic attack (TIA) or cerebrovascular accident (CVA).
• Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding that leads to reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or that may render the subject at high risk for treatment complications.
• Other unspecified reasons that, in the opinion of the Investigator, make the subject unsuitable for the study.
• Inability to comply with study and follow-up procedures as judged by the Investigator.