PEGPH20, Gemicitabine and Nab-Paclitaxel for Pancreatic Ductal Adenocarcinoma

We will be conducting a Phase II study investigating PEGPH20 in combination with gemcitabine and nab-paclitaxel in patients with borderline resectable pancreatic ductal adenocarcinoma (PDAC) at the Helen Diller Family Comprehensive Cancer Center at University of California, San Francisco (UCSF). There are multiple definitions of borderline resectable PDAC including the MD Anderson definition and the criteria developed during the Consensus Conference sponsored by the American Hepato-Pancreato-Biliary Association, Society of Surgical Oncology, and Society for Surgery of the Alimentary Tract. Borderline resectable PDAC cases will be identified per the definition developed in the currently running inter-group pilot trial for borderline resectable pancreatic cancer (NCT01821612). Per this trial, borderline resectable PDAC is defined as "presence of any one or more of the following on CT:

* An interface between the primary tumor and the superior mesenteric vein or portal vein (SMV-PV) measuring ≥ 180° of the circumference of the vessel wall
* Short-segment occlusion of the SMV-PV with normal vein above and below the level of obstruction that is amenable to resection and venous reconstruction
* Short segment interface (of any degree) between tumor and hepatic artery with normal artery proximal and distal to the interface that is amenable to resection and reconstruction.
* An interface between the tumor, and Superior mesenteric artery (SMA) measuring \< 180º of the circumference of the vessel wall.

This trial will be conducted in two parts. In Part I, pre-treatment endoscopic ultrasound (EUS)-guided core biopsies of the pancreatic tumor, CA 19-9 levels and functional MRIs including Dynamic contrast-enhanced (DCE)-MRI and Diffusion-weighted magnetic resonance imaging (DWI-MRI) will be obtained for the first fifteen patients enrolled. After a 1-week run-in period with PEGPH20 on days 1 and 4, patients will have repeat EUS-guided core biopsies, functional MRI, CA 19-9 level and baseline CT chest, abdomen and pelvis. Subsequently, patients will be started on treatment with PEGPH20, gemcitabine and nab-paclitaxel given weekly for 3 weeks, every 28 days. To evaluate the disease response to treatment, CA 19-9 levels will be checked monthly and restaging CT chest, abdomen and pelvis will be obtained every 8 weeks. If there is disease progression at any point in the study, patients will be taken off of study and alternative treatments will be offered. At the completion of 4 cycles of therapy, restaging CT scans will be obtained to determine resectability. If the patients are found to have resectable disease, an additional functional MRI will be obtained to evaluate the PDAC stroma. If the patients are able to have successful surgeries, tissue analyses will be performed on the resected pancreatic tumor. These patients will then proceed to get 2 cycles of adjuvant chemotherapy with gemcitabine and nab-paclitaxel. If the patients are deemed to be surgical candidates but are found to have unresectable disease in the operating room, an intraoperative core biopsy of the pancreatic tumor will be obtained for tissue analyses. At the time of initiation of therapy with PEGPH20, patients will be started on prophylactic dose of enoxaparin 1 mg/kg subcutaneous daily. This will be continued throughout the study participation.

In Part II, an additional 21 patients will be enrolled, and will begin neoadjuvant therapy with PEGPH20, gemcitabine and nab-paclitaxel without the 1 week run-in of PEGPH20-only or the pre- and post-run-in EUS-guided biopsies.

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; Hyaluronic Acid (HA) binding); (2) fixed in Optimal Cutting Temperature (OTC) 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 magnetic resonance (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 apparent diffusion coefficient (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.

Eligibility Criteria:
Inclusion Criteria:

* Greater than or equal to 18 years old
* Histologically confirmed pancreatic adenocarcinoma
* Borderline resectable disease
* Performance status of Eastern Cooperative Oncology Group (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: Absolute Neutrophil Count (ANC) ≥1500/mm3, platelets ≥100,000/mm3 and hemoglobin ≥ 9 g/dL
* Hepatic: Serum total bilirubin ≤1.5 x upper limit of normal (ULN), alanine aminotransferase (ALT)/ serum glutamic-pyruvic transaminase (SGPT) and aspartate aminotransferase (AST)/ serum glutamic-oxaloacetic transaminase (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 ≤ 2 times the 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 low molecular weight heparin (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.