PEGPH20, Gemicitabine and Nab-Paclitaxel for Pancreatic Ductal Adenocarcinoma

For Specific Aim 1, we will be monitoring the post-operative complication of clinically
relevant pancreatic fistula within one week of surgery per the standard clinical guidelines
as noted above. Common clinical presentations of pancreatic fistula include abdominal pain,
leukocytosis and fever (temperature >100.4 degrees). Diagnostic work-up of pancreatic
fistula will be with CT abdomen with contrast, which has a sensitivity of 63% and
specificity of 83% for detecting pancreatic fistula. The pancreatic fistulas will be
categorized into grades A, B or C as previously reported. Our study will be investigating
only clinically relevant pancreatic fistulas, i.e. grades B or C. Depending on the grade of
pancreatic fistula, patients will be treated as indicated with conservative treatment
options including bowel rest, antibiotics, somatostatin analogues and percutaneous drainage
or surgical re-exploration. We will also track other relevant post-operative complications
such as delayed wound healing, development of wound dehiscence or wound infection.

The tissue analyses will include review of the immunohistochemical (IHC) stains for actin,
hyaluronic acid staining with binding protein probe, proliferation as measured by ki-67% and
Phospho-histone H3 (Ph-H3); cell apoptosis as evaluated by IHC stain for cleaved caspase 3
(CC3) and Tunel. If limited tissue sample is obtained via the core biopsies, the priority of
tissue analysis will be as follows: (1) fixed in formalin for H&E and IHC (Ph-H3; CC3/Tunel;
HA binding); (2) fixed in OCT such that IHC with difficult antibodies can be done (to
potentially obtain mRNA or DNA). The IHC studies will be done at the UCSF Helen Diller
Family Comprehensive Cancer Center Immunohistochemistry and Molecular Pathology Core. The
tissue analyses of the biopsy and surgical specimens will be done by study pathologist.

The CT and MR imaging analyses will be performed at the Abdominal Imaging at UCSF. To
decrease the impact that metal stents may have on the functional MRI results, we will
include only patients who have plastic stents in our study. In addition, to reduce
variability in results, the DCE-MRI and DWI-MRI will be obtained on the same MR machine at a
similar time of day as the baseline scan. The DCE-MRI images will be analyzed by calculating
Ktrans and DWI-MRI images will be analyzed by calculating ADC as described elsewhere. We
will scan patients in a torso coil on a 3T clinical MR scanner. Imaging will include MR
diffusion with b-values of 0, 125, and 500 for estimates of perfusion and tumor, and dynamic
contrast-enhanced MR imaging (DCE-MRI) for measurement of Ktrans, blood volume, and blood
flow. The region of tumor will be determined by MR imaging in reference to the baseline CT
scans. The native T1 of the pancreas and liver will be calculated from a series of four, 3D,
spoiled gradient recalled echo (SPGR) sequences with different flip angles. The conventional
DCE-MRI will be acquired as a 3D, fast spoiled gradient echo sequence, covering the targeted
areas of the pancreas or liver, at a temporal resolution of 5 sec over 6 minutes after the
administration of 0.1 mmol/kg gadobenate dimeglumine. DCE-MRI images will be post-processed
using MIStar software (Apollo Medical Imaging, Melbourne, Australia), which allows for
motion correction to account for any shifts in data. Datasets with artifacts will be
eliminated before further post processing. After contrast delivery, the new T1 is calculated
and is presumed to change with the Gd concentration such that [Gd] = (1/T1-1/T10)/R1 where
R1 is assumed to be 4.5 sec-1 mmol/L-1 at 3T.

Run-in Period with PEGPH20

- Days 1, 4

PEGPH20 3 ug/kg Dexamethasone 8mg PO 1-2 hours pre-PEGPH20 and PO 8-to-12 hours post-PEGPH20

*Start enoxaparin 1 mg/kg subcutaneous daily on day 1 (to be continued throughout the trial)

- On day 8 of run-in period with PEGPH20, EUS-directed core biopsy, CA 19-9, functional MRI
and CT chest, abdomen (pancreatic protocol) and pelvis will be obtained.

Cycle 1 and onward

-Day 1, 8, 15

PEGPH20 3 ug/kg + Gemcitabine 1000mg/m2 + nab-Paclitaxel 125mg/m2 Dexamethasone 8mg PO 1-2
hours pre-PEGPH20 and PO 8-to-12 hours post-PEGPH20

- Gemcitabine and nab-paclitaxel will be administered 2-4 hours post-PEGPH20.

- Neoadjuvant therapy will be four 28-day cycles with CT chest, abdomen and pelvis scans
and CA 19-9 measurements every 8 weeks. Patients will be taken off of the study if
there is any evidence of disease progression.

- After four cycles of neoadjuvant therapy, patients will be evaluated for surgical
resection depending on the CT scan findings obtained on cycle 4, day 21.

- If they have resectable disease, they will have a functional MRI following the
restaging CT scan. If patients have successful resection, they will receive 2
additional cycles of gemcitabine and nab-paclitaxel. If they are found to have
unresectable disease in the operating room, an intra-operative core biopsy will be
obtained.

- If they have unresectable disease on the restaging scans following 4 cycles of therapy,
they will be taken off of the study.

Inclusion Criteria:

- Greater than or equal to 18 years old

- Histologically confirmed pancreatic adenocarcinoma

- Borderline resectable disease

- Performance status of ECOG of 0-1

- Therapy naïve

- Evaluable disease with either:

- RECIST-defined measurable disease

- An elevated serum CA19-9 >100 u/ml

- Adequate organ function including:

- Bone marrow: ANC ≥1500/mm3, platelets ≥100,000/mm3 and hemoglobin ≥ 9 g/dL

- Hepatic: Serum total bilirubin ≤1.5 x upper limit of normal (ULN), ALT

- (SGPT) and AST (SGOT) ≤ 2.5 x ULN.

- Renal: Serum creatinine (sCr) ≤ 1.5 x ULN, or creatinine clearance (Ccr) ≥ 40 mL/min
as calculated by the Modified Cockcroft-Gault formula.

- Peripheral neuropathy < grade 2

- Alkaline phosphatase ≤ 2X ULN unless bone metastasis is present in the absence of
liver metastasis

Exclusion Criteria:

- Age younger than 18 years old

- Locally advanced or metastatic disease

- Known allergy to hyaluronidase

- Contraindications to prophylactic dose LMWH, including

- Patients with recent gastrointestinal bleeding

- History of heparin induce thrombocytopenia on LMWH

- Subjects with previous severe hemorrhagic events on LMWH

- Known contraindications to heparin including:

- Recent central nervous system bleed, intracranial or spinal lesion at high risk for
bleeding

- Active bleeding (major): more than 2 units transfused in 24 hours

- Spinal anesthesia/lumbar puncture within the past month

- Chronic, clinically significant measurable bleeding > 48 hours

- Severe platelet dysfunction (uremia, medications, dysplastic hematopoiesis)

- Recent major operation at high risk for bleeding

- Underlying hemorrhagic coagulopathy High risk for falls (head trauma)

- Presence of metal biliary stents (plastic biliary stents are not an exclusion)

- Known status of HIV which is not well-controlled at the time of study eligibility

- Untreated Hepatitis B infection

- Active infection or antibiotics within 48 hours prior to study

- Currently active second primary malignancy or history of malignancy less than 5 years
prior to the time of study eligibility (Patients with history of skin cancers
excluding melanoma will be eligible for participation).

- Serious medical comorbidities such as New York Heart Association Class III/IV cardiac
disease, uncontrolled cardiac arrhythmias, myocardial infarction over the past 12
months.

- Patients with aneurysm clips, ear implants, spinal nerve stimulators, pacemaker,
shrapnel or any other metal in their body (contraindication for MRI scans)

- Known, existing uncontrolled coagulopathy. Patients who have had a venous
thromboembolic event (e.g., pulmonary embolism or deep vein thrombosis) requiring
anticoagulation are eligible IF: they are appropriately anticoagulated and have not
had a Grade 2 or greater bleeding episode in the 3 weeks before Day 1.

- Current use of warfarin (patients will be eligible if warfarin is discontinued and
low-molecular weight heparin is used instead).

- Intolerance to dexamethasone

- Prior history of cerebrovascular accident or transient ischemic attack, or
pre-existing carotid artery disease.

- Known pregnancy, nursing women or positive pregnancy test.

- Any condition that would preclude informed consent, consistent follow-up and
compliance for the study participation.