Second-line Study of PEGPH20 and Pembro for HA High Metastatic PDAC

Combination strategies geared towards blocking the PD1/PD-L1 inhibitory pathway, such as with
pembrolizumab, concurrent with stroma depletion (PEGPH20) may induce synergistic anti-cancer
activity and immune responses in pancreatic cancer. Effective harnessing of the immune system
and rational combinations with stroma-targeting biological agents (PEGPH20) is a novel field
that needs to be explored in pancreatic cancer. This phase II trial will determine the
efficacy of pembrolizumab plus PEGPH20 in metastatic pancreatic cancer patients who have
HA-high tumor expression. Stroma and immune-related biomarkers will be tested prospectively
in blood and tumor biopsies at baseline, after 6 weeks of therapy, and at time of cancer
progression. A phase I study with pembrolizumab and PEGPH20 is ongoing in lung and gastric
cancer patients (NCT02563548), and demonstrated safety and tolerability of this combination
at the doses administered in this study (Halozyme data).

Immunotherapies have the potential to induce durable therapeutic responses although this
typically occurs in a small fraction of patients. Biomarker-guided patient selection can, in
principle, identify those patients most likely to benefit. The investigators hypothesize that
stroma remodeling with PEGPH20 will potentiate effector CD8 T cell lymphocyte infiltration
and sensitize pancreatic cancer to immune therapy, and that immunologic, and/or genomic
biomarkers will identify patient subsets most likely to benefit. As examples, MSI-high status
and high tumor mutational burden (hypermutation) have been linked to sensitivity to immune
checkpoint inhibitors (Le et al. 2015, Le et al. 2016).

Assays may include but are not limited to: Immunohistochemical analysis, profiling of the
immune transcriptome, circulating cytokine analyses, flow cytometric analyses of peripheral
and intratumoral immune response.

This is an open label non-randomized Phase II trial for patients with previously treated
metastatic ductal pancreatic adenocarcinoma with HA-high expression, to assess the
progression-free survival rate (PFS) of patients treated with this combination therapy.
Secondary endpoints will assess safety and tolerability, overall response rate (ORR), disease
control rate (DCR= CR+PR+SD), duration of response and stable disease (DOR), and overall
survival (OS).

There will be an estimated 35 patients enrolled into the study, using 5 centers in the U.S.

Overall response rates as well as individual categories of response (CR, PR, SD, and PD) will
be determined using RECIST 1.1. Time-to-event endpoints, including PFS and OS will be
assessed using the Kaplan-Meier method. Toxicity (adverse events) will be recorded using the
NCI CTCAE, version 5.0 (published Nov 2017, Appendix B).

All patients will start treatment with PEGPH20 3 microgram/kg IV weekly x 3, and
pembrolizumab 200 mg IV every 3 weeks, in 3-week cycles.

Patients may remain on treatment with PEGPH20 in combination with pembrolizumab as long as
they are receiving clinical benefit, until disease progression per RECIST 1.1 criteria, or
until untolerable toxicity develops, whichever comes first. If no disease progression,
patients will be allowed to remain on study treatment for up to 24 months. If no disease
progression, but with unacceptable toxicity from PEGPH20, patients will be allowed to
continue on pembrolizumab alone for up to 24 months if deemed appropriate by the
investigator. If pembrolizumab needs to be discontinued for toxicity, patients may continue
treatment with PEGPH20 alone.

The estimated duration for accrual is anticipated to be 12 months. Patients will be followed
up for a minimum of 6 months. The overall study duration is estimated at approximately 18
months.

Inclusion Criteria:

1. Be willing and able to provide written informed consent/assent for the trial.

2. Histologically confirmed metastatic pancreatic ductal adenocarcinoma, via archived or
fresh core biopsy of either primary tumor or metastatic site.

3. Available tumor tissue (formalin-fixed paraffin-embedded [FFPE] block preferred) with
enough tumor to make a minimum of 5-10 unstained, consecutive FFPE slides (10 slides
are preferred) of 1 archival block that meets specific tissue sample requirements.
Archived or fresh tissue from the primary lesion or a metastatic lesion is required.
Note: Fine needle aspirates or brushing biopsies will not be acceptable. This tumor
tissue requirement is for the determination of the HA-high or -low expression status.

4. Subjects must be determined to be HA-high based on archival or fresh tumor biopsy that
meets the requirements noted in the previous inclusion criterion.

5. 18 years of age on day of signing informed consent.

6. Have measurable metastatic disease based on RECIST 1.1.

7. Life expectancy ≥ 12 weeks.

8. Have a performance status of 0 or 1 on the ECOG Performance Scale.

9. Received no more than 2 prior lines of systemic therapy for metastatic disease (1 or 2
prior lines of therapy for metastatic disease are allowed)

10. Be willing to provide tumor tissue from newly obtained tumor cores or excisional
biopsy for research purposes. Newly-obtained is defined as a specimen obtained within
2 weeks (14 days) prior to initiation of treatment on Day 1.

11. Be willing to provide tumor tissue from tumor biopsy after 6 weeks of treatment
(mandatory, if safe and feasible), and at the time of tumor progression (optional, if
safe and feasible). Note: Fine needle aspirates or brushing biopsies will not be
acceptable.

12. Demonstrate adequate organ function, all screening labs should be performed within 14
days of treatment initiation.

13. Female subjects of childbearing potential should have a negative urine or serum
pregnancy within 72 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.

14. Female subjects of childbearing potential must be willing to use an adequate method of
contraception for the course of the study through 120 days after the last dose of
study medication.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.

15. Male subjects of childbearing potential must agree to use an adequate method of
contraception starting with the first dose of study therapy through 120 days after the
last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.

16. No history of acute DVT/PE or CVA/TIA (new within 4 weeks of study registration) or
clinical significant carotid artery disease.

17. If prior history of DVT/PE the patient needs to be on stable doses of anticoagulation
with low molecular weight heparins.

- Patients should have all eligibility criteria met, before undergoing the baseline
research biopsy.

Exclusion Criteria:

1. Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 2 weeks of the first dose of treatment.

2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy
(equivalent of > 20 mg of hydrocortisone per day) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

3. Has a known history of active tuberculosis (TB).

4. Hypersensitivity to pembrolizumab or any of its excipients.

5. Known allergy to PEGPH20 (hyaluronidase).

6. Current use of megestrol acetate (use within 10 days of Day 1).

7. Contraindication to heparin as per institutional guidelines.

8. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
due to agents administered more than 2 weeks earlier.

9. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent.

- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.

- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
therapy.

10. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.

11. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.

12. Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs), or documented history of clinically severe autoimmune disease (e.g., colitis,
Crohns' disease)*. Replacement therapy (eg, thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
not considered a form of systemic treatment.

*Any relevant diseases that are not listed as examples of exclusionary diseases are to
be discussed with the Sponsor-Investigator.

13. Has known history of, or any evidence of active, non-infectious pneumonitis.

14. Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.

15. Has known hepatobiliary diseases (e.g., primary biliary cholangitis, primary
sclerosing cholangitis, immune mediated cholangitis); patients with cholangitis
attributed to infectious etiology (e.g., ascending cholangitis, bacterial cholangitis)
are eligible if the infection has been fully recovered prior to the screening visit.

16. Has known history of drug-induced hepatobiliary toxicities

17. Has an active infection requiring systemic therapy.

18. 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.

19. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

20. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.

21. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or any
other immune checkpoint inhibitors.

22. Has received prior therapy with PEGPH20, or has participated in the Halozyme HALO 301
phase III study.

23. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

24. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).

25. Has received a live vaccine within 30 days of planned start of study therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.