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.
Subjects must satisfy all the following inclusion criteria to be enrolled in the study:
1. Signed, written Institutional Review Board/Ethics Committee-approved Informed Consent
2. Stage IV pancreatic ductal adenocarcinoma (PDA) with histological or cytological
confirmation of PDA.
3. Subjects must be determined to be HA-high based on archived or fresh tumor core biopsy
or sample obtained after the subject 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
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 (see Study Laboratory Manual).
4. Radiographic confirmation of Stage IV PDA with at least 1 tumor metastasis measurable
on computed tomography (CT) scan and/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 subject 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 ≤ Grade 1.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
7. Life expectancy ≥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 subject is of childbearing potential.
10. Screening clinical laboratory values as follows:
1. Total bilirubin ≤1.5 times upper limit of normal (ULN) (subjects 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 mg/dL or calculated creatinine clearance ≥40 mL/min.
4. Serum albumin ≥2.5 g/dL.
5. Prothrombin time or international normalized ratio (INR) within normal limits
(±15%), unless subject 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/mm3.
9. Platelet count ≥100,000/mm3.
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.
Subjects are ineligible for enrollment if they meet any of the following exclusion
1. Clinical evidence of deep vein thrombosis (DVT), pulmonary embolism (PE) or other
known TE event present during the screening period.
1. Subjects with superficial vein thrombosis are eligible.
2. Subjects 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
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 (Appendix C) 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
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 subject at high risk for
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
17. Inability to comply with study and follow-up procedures as judged by the Investigator.