PEGPH20, Gemicitabine and Nab-Paclitaxel for Pancreatic Ductal Adenocarcinoma
Condition: Adenocarcinoma
MeSH terms: Adenocarcinoma
Intervention: PEGPH20; Gemcitabine; Nab-paclitaxel
Intervention MeSH terms: Paclitaxel; Gemcitabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Pancreatic

Summary:

      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.
    

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.