A Study of PEGylated Recombinant Human Hyaluronidase in Combination With Nab-Paclitaxel Plus Gemcitabine Compared With Placebo Plus Nab-Paclitaxel and Gemcitabine in Participants With Hyaluronan-High Stage IV Previously Untreated Pancreatic Ductal Adenocarcinoma

The purpose of this study is to compare the efficacy and safety of PEGylated Recombinant Human Hyaluronidase (PEGPH20) combined with nab-paclitaxel plus gemcitabine (PAG treatment), compared with placebo combined with nab-paclitaxel plus gemcitabine (AG treatment), in participants with hyaluronan (HA)-high Stage IV previously untreated pancreatic ductal adenocarcinoma (PDA).

Participants will be randomized in a 2:1 ratio to PAG or AG treatment.

Eligibility Criteria:
Inclusion criteria:

Participants must satisfy all the following inclusion criteria to be enrolled in the study:

1. Signed, written Institutional Review Board/Ethics Committee-approved Informed Consent Form (ICF).
2. Stage IV PDA with histological or cytological confirmation of PDA.
3. Participants must be determined to be HA-high based on archived or fresh tumor core biopsy or sample obtained after the participant has documented metastatic disease. Biopsies/samples must meet the following requirements:

   1. Pancreas tumor biopsies/samples obtained on or after the date that metastatic disease is documented or tumor biopsies/samples from a metastatic lesion are acceptable.
   2. Tumor biopsies or samples must meet the requirements provided in the Study Laboratory Manual with regard to tumor tissue architecture. Note: cytology samples from fine needle aspirates without maintained tissue architecture or brushing biopsies are not acceptable.
   3. Tumor tissue (formalin-fixed paraffin-embedded \[FFPE\] block preferred) must include enough tumor to make a minimum of 5-10 unstained, consecutive FFPE slides (10 slides are preferred) of 1 archival block that meet specific tissue sample requirements.
4. Radiographic confirmation of Stage IV PDA with at least 1 tumor metastasis measurable on computed tomography (CT) scan or magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria, excluding the primary pancreatic lesion.
5. If a participant has had adjuvant/neoadjuvant therapy and/or therapy for locally advanced disease (chemotherapy for non-metastatic pancreatic cancer in combination with or without radiation therapy), tumor recurrence or disease progression must have occurred no sooner than 6 months after completing the last dose of the aforementioned therapies, provided all toxicities have returned to baseline or less than or equal to (≤) Grade 1.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
7. Life expectancy greater than or equal to (≥) 3 months.
8. Age ≥18 years.
9. A negative urine or serum pregnancy test within 7 days before Cycle 1, Day 1 (C1D1; first dose of study medication) if female participant is of childbearing potential.
10. Screening clinical laboratory values as follows:

    1. Total bilirubin ≤1.5 times upper limit of normal (ULN) (participants with Gilbert syndrome are eligible independent of bilirubin levels).
    2. Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine aminotransferase (serum glutamic pyruvate transaminase) ≤2.5 times ULN, (if liver metastases are present, then ≤5 times ULN is allowed).
    3. Serum creatinine ≤2.0 milligrams/deciliter (mg/dL) or calculated creatinine clearance ≥40 milliliters/minute (mL/min).
    4. Serum albumin ≥2.5 grams/deciliter (g/dL).
    5. Prothrombin time or international normalized ratio (INR) within normal limits (±15%), unless participant takes warfarin, in which case prothrombin time or INR result must be within therapeutic range.
    6. Partial thromboplastin time (PTT) within normal limits (±15%).
    7. Hemoglobin ≥9 g/dL (transfusion and erythropoietic agents allowed).
    8. Absolute neutrophil count ≥1,500 cells/cubic millimeter (cells/mm\^3).
    9. Platelet count ≥100,000/mm\^3.
11. For women of childbearing potential (WOCBP) and for men, agreement to use a highly effective contraceptive method from the time of screening throughout the study until 1 month (WOCBP) or 6 months (men) after administration of the last dose of any study medication. Highly effective contraceptive methods consist of prior sterilization, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), oral or injectable contraceptives, barrier methods, and/or true sexual abstinence.

Exclusion criteria:

Participants are ineligible for enrollment if they meet any of the following exclusion criteria:

1. Clinical evidence of deep vein thrombosis (DVT), pulmonary embolism (PE) or other known thromboembolic (TE) event present during the screening period.

   1. Participants with superficial vein thrombosis are eligible.
   2. Participants with visceral/splanchnic vein thrombosis are still eligible if, in the opinion of the Investigator, the visceral/splanchnic vein thrombosis is primarily associated with the anatomic location of the underlying disease of metastatic pancreatic cancer (there must be primary or metastatic disease in reasonable proximity to the thrombosis, and the Investigator determines that the thrombosis is due to a local tumor event and not a coagulation issue).
2. Previous radiotherapy, surgery, chemotherapy, or investigational therapy for the treatment of metastatic disease.

   a. Palliative radiotherapy for pain control of metastatic bone lesions is allowed.
3. Known central nervous system involvement or brain metastases.
4. New York Heart Association Class III or IV cardiac disease or myocardial infarction within the past 12 months.
5. History of cerebrovascular accident or transient ischemic attack.
6. Clinically significant pre-existing carotid artery disease.
7. Known infection with human immunodeficiency virus, or active infection with hepatitis B or hepatitis C within the past 12 months.
8. Known allergy to hyaluronidase.
9. Current use of megestrol acetate or megestrol acetate-containing drugs (use within 10 days of Day 1).
10. Contraindication to heparin as per institutional guidelines.
11. Women currently pregnant or breastfeeding.
12. Intolerance to dexamethasone.
13. History of another primary cancer within the last 3 years with the exception of non-melanoma skin cancer, early-stage prostate cancer, or curatively treated cervical carcinoma in-situ.
14. Any other disease, active, uncontrolled bacterial, viral or fungal infection requiring systemic therapy, 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, or that may affect the interpretation of the results, or that may render the participant at high risk for treatment complications.
15. Immunization with a live vaccine up to 2 weeks prior to Day 1.
16. Hypersensitivity to the active substance or ingredients of PEGPH20, gemcitabine, and nab-paclitaxel.
17. Inability to comply with study and follow-up procedures as judged by the Investigator.