Safety

This is a single arm phase II trial assessing the potential activity of combination PEGPH20 plus Gemcitabine with radiotherapy in ten patients with localized, unresectable pancreatic adenocarcinoma.

This is a pilot trial evaluating the safety and potential efficacy of PEGylated Recombinant Human Hyaluronidase (PEGPH20) plus concurrent Gemcitabine and radiotherapy. Recognizing that PEGPH20 has not been previously delivered with radiotherapy but is unlikely to contribute to increased toxicities, this trial will have an abbreviated sequential dose escalation schema for the first three patients. PEGPH20 will be given twice per week for the first 28 days and then weekly for another 2 weeks during radiotherapy. Gemcitabine will be delivered weekly at the first day of radiotherapy and continued weekly, per published literature. Patients will remain on study for three months. The duration of active treatment with PEGPH20 and Gemcitabine plus radiotherapy will continue for 5-6 weeks. Efficacy outcome will occur 6-8 weeks after the completion of radiotherapy.

Inclusion Criteria:

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 Form;
2. 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;
3. Patients with previously untreated localized, unresectable histologically confirmed pancreatic adenocarcinoma (unresectable will be defined as locally advanced disease or when patients cannot have or refuse surgery);
4. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L;
5. Platelets ≥ 100 x 109/L;
6. Hgb ≥ 9 g/dL;
7. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 x [Upper Limit of Normal (ULN)];
8. Bilirubin ≤ 1.5 x ULN;
9. GFR ≥ 30 mL/min;
10. Patient has no clinically significant abnormalities in urinalysis results;
11. Patient has acceptable coagulation status as indicated by a Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) within 15% of normal limits;
12. Eastern Cooperative Oncology Group (ECOG) ≤ 2

Exclusion Criteria:

Subjects 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;
2. Any prior history of cerebrovascular accident, transient ischemic attack, or pre-existing carotid artery disease.
3. Known allergy to hyaluronidase;
4. Current use of megestrol acetate (use within 10 days of Day 1);
5. Contraindication to heparin including prior heparin induced thrombocytopenia (HIT), recent CNS bleed; intracranial or spinal lesion at high risk for bleeding; severe platelet dysfunction; recent major operation at high risk for bleeding; underlying hemorrhagic coagulopathy; high risk for falls; potential need for spinal anesthesia/lumbar puncture; active bleeding;
6. Women currently pregnant or breastfeeding;
7. Intolerance to dexamethasone;
8. Inability to comply with study and follow-up procedures as judged by the Investigator;
9. Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy;
10. Patient has known infection with HIV, hepatitis B, or hepatitis C;
11. Patient has a history of allergy or hypersensitivity to any of the agents they are supposed to receive (or to any of the excipients for those agents);
12. Patient has serious medical risk factors involving any of the major organ systems such that the investigator considers it unsafe for the patient to receive an experimental research drug, these can include New York Heart Association Functional Class ≥ 3, myocardial infarction within the past 12 months before screening, pre-existing atrial fibrillation, symptomatic COPD.
13. Patient is unwilling or unable to comply with study procedures.