Outcomes of Ablation of Unresectable Pancreatic Cancer Using the NanoKnife Irreversible Electroporation (IRE) System

The prognosis for pancreatic cancer is dismal, with a five-year survival rate of 4.9%.
Current treatment options include surgical resection, chemotherapy and radiation. Only 15%
percent of pancreatic cancers are considered resectable at the time of diagnosis. Current
chemotherapeutic options are limited, as pancreatic adenocarcinoma is poorly responsive to
chemotherapy. Radiofrequency ablation of the pancreas in the setting of locally advanced
unresectable disease has been described in a few case series1-6, but implementation of that
technology is limited by concerns over thermal injury to adjacent organs and vessels. With
42,470 new cases of pancreatic cancer diagnosed annually in the US and given that pancreatic
cancer is expected to claim 35,240 lives this year in the US7, it is the fourth leading cause
of cancer death in the Unites States. This information supports the notion that there is an
unquestionable need for novel therapeutic strategies for the treatment of this disease.

Irreversible electroporation (IRE) has the potential to dramatically widen the treatment
options for patients with pancreatic cancer. It provides a minimally invasive procedure that
could potentially avoid radical surgery for smaller lesions, and it could potentially offer
palliation of symptoms such as pain, gastric outlet obstruction and jaundice in patients with
locally advanced unresectable disease. Preliminary studies of IRE in the liver and prostate
have demonstrated that structures such as bile ducts, ejaculatory ducts, neurovascular
bundles, blood vessels, and the urethra heal normally after ablation, suggesting that vessels
and ducts within and around the pancreas may also be heal normally. Collagen matrix during
treatment with IRE is not destroyed thus allowing for a structure to heal normally. There is
no evidence that nerve ganglion are damaged.

Heat based ablative therapy in the pancreas has the potential for unique complications.
Pancreatic necrosis is believed to play a role in creating a potentially life-threatening
systemic inflammatory response in patients with severe acute pancreatitis8, 9 and the
presence of free active pancreatic enzymes is believed to contribute to the inflammatory
cascade of acute pancreatitis. Irreversible electroporation could potentially cause both
pancreatic necrosis and the release of active pancreatic enzymes. Additionally, the pancreas
surrounds or abuts several vital structures, including the common bile duct, the pancreatic
duct, the superior mesenteric artery and vein (SMA and SMV), the portal vein, the stomach,
and the duodenum. IRE as a non-thermic ablative modality has the potential to achieve
pancreatic ablation with respect of the surrounding vascular and ductal structures.

Electroporation is a technique that increases cell membrane permeability by momentarily
changing the transmembrane potential and subsequently disrupting the lipid bi-layer integrity
to allow transportation of molecules across the cell membrane via nano-size pores. This
process - when used in a reversible fashion - has been used in research for drug or gene
delivery into cells.

Irreversible electroporation (IRE) is a method to induce irreversible disruption of cell
membrane integrity (loss of cell homeostasis) resulting in cell death without the need for
additional pharmacological injury. Because IRE is a non-thermal technique, changes associated
with perfusion-mediated tissue cooling (or heating) are not relevant. While cells in the
ablation region are destroyed, the underlying extracellular matrix is not damaged thus
allowing tissues in the ablation zone to heal normally.

IRE is administered under general anesthesia with administration of atracurium,
cis-atracurium, pancuronium or an equivalent neuromuscular blocking agent. This is mandatory
to prevent undesirable muscle contraction.

Inclusion Criteria:

- Male or female

- 18 years of age

- Must be found to have locally advanced unresectable disease following standard
chemotherapy ± radiotherapy as demonstrated with either CT/MRI imaging and surgical
evaluation, and not have taken any chemotherapy/radiotherapy within 5 weeks of
treatment with the NanoKnife IRE System

- Must have an INR < 1.5

- Are willing and able to comply with the protocol requirements

- Are able to comprehend and willing to sign an informed consent form

Exclusion Criteria:

- A baseline creatinine reported as > 2.0 mg/dL

- Have any reported baseline lab values with a grade 3 or 4 toxicity as defined by the
CTCAE Version 3.0

- Inability to stop antiplatelet and coumadin therapy for 7 days prior to and 7 days
post treatment with the NanoKnife System

- Tumor size not measurable

- Known history of contrast allergy that cannot be medically managed

- Known hypersensitivity to the metal in the electrodes (stainless steel 304L) that
cannot be medically managed

- Unable to be treated with a muscle blockade agent (e.g. pancuronium bromide,
atracurium, cisatracurium, etc.)

- Women who are pregnant or currently breast feeding

- Women of childbearing potential who are not utilizing an acceptable method of
contraception

- Have taken an investigational agent within 30 days of visit 1

- Have implanted cardiac pacemakers or defibrillators

- Have implanted electronic devices or implants with metal parts in the immediate
vicinity of a lesion

- Have a history of epilepsy or cardiac arrhythmia (atrial or ventricular fibrillation)

- Have a recent history of myocardial infarction (within the past 2 months)

- Have Q-T intervals greater than 550 ms unless treated with an Accysync Model 72
synchronization system controlling the NanoKnife system's output pulses

- Evidence of distant metastases of stage IV

- Have taken any chemotherapeutic agent within 5 weeks of treatment with the NanoKnife
Irreversible Electroporation (IRE) System

- Receive non-conventional fractionation schedules, such as stereotactic radiation (5
fractions or less) or received higher than 54 Gray (Gy) delivered conventionally