Irreversible Electroporation and Pembrolizumab Immunotherapy for Treatment in Patients with Locally Advanced or Unresectable Pancreatic Cancer

Inclusion Criteria

• Histologically or cytologically-confirmed pancreatic ductal adenocarcinoma (PDAC) meeting the American Joint Committee on Cancer (AJCC) 8th edition staging criteria of stage 3 disease.
• Tumor(s) is/are locally advanced and unresectable pursuant to National Comprehensive Cancer Network (NCCN) guidelines.
• Radiologically measurable disease per iRECIST version 1.1 or based on exploratory surgery.
• Prior to Total Cancer Care (TCC) registration, participants must have no prior therapy for PDAC and fall under treatment NCCN pancreatic adenocarcinoma guides (version 1.2022) for locally advanced disease. Prior to study consent, participant must have had standard of care first-line therapy consisting of 12 weeks of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) (at least 6 cycles), followed by 50 gray (Gy) of A-SMART, delivered in five 10 Gy fractions. Participant must show no evidence of disease progression after first-line treatment, based on NCCN guidelines.
• Age 18–74 years at diagnosis.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• The maximum axial and anterior to posterior tumor dimension must be ≤ 3.5 cm after "first strike" standard of care treatment.
• Absolute neutrophil count (ANC) ≥ 1,000/uL (within 14 days prior to IRE).
• Platelets ≥ 100,000/uL (within 14 days prior to IRE).
• Hemoglobin ≥ 8 g/dL (within 14 days prior to IRE).
• Total bilirubin ≤ 1.5 mg/dL (within 14 days prior to IRE).
• Aspartate aminotransferase (AST)((serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) ≤ 3 x institutional upper limit normal (ULN) or ≤ 5 x ULN (for subjects with documented metastatic disease to the liver) (within 14 days prior to IRE).
• Calculated creatinine clearance > 30 mL/min (within 14 days prior to IRE).
• Albumin ≥ 2.5 g/dL (within 14 days prior to IRE).
• Coagulation prothrombin time (PT) time and international normalised ratio (INR) within normal limits (+/- 15%). Partial thromboplastin time (PTT) within normal limits (+/-15%) (within 14 days prior to IRE)
• Hemoglobin A1c (glycosylated hemoglobin; HbA1c) ≤ 8% (within 14 days prior to IRE)
• Life expectancy ≥ 3 months.
• Accessible tumor for two on-study repeated tumor biopsies (following the initial pre-study biopsy that occurred, pursuant to TCC consent).
• Resolved acute effects of any prior therapy to baseline or grade ≤ 1 severity.
• If a participant requires anticoagulation, treatment must be modified to enoxaparin.
• At screening, all female participants of child-bearing age will undergo a urine pregnancy test. If the urine test is positive or inconclusive, a serum test will be performed. Regardless of whether urine or serum, female participants of child-bearing age must have a negative pregnancy test prior to enrollment to be eligible.
• The study drug can harm the developing human fetus. For this reason and because the pre-study SoC chemotherapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. In addition, women of childbearing potential (WOCBP) must agree to continue using adequate contraception for 4 months after pembrolizumab administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. If a woman is breastfeeding, she should stop study drug.
• Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, biopsies when required, and other procedures.
• The patient must be enrolled in the Moffitt Cancer Center (MCC) TCC protocol for tissue and blood banking prior to full study enrollment in order to be eligible for this study and must have their initial biopsy tissue available.
• Ability to understand and the willingness to sign a written informed consent document.
• Patients must be eligible for standard of care (SoC) NanoKnife therapy.
• Human immunodeficiency virus (HIV)-infected participants must be receiving an effective anti-retroviral therapy for the past 6 months with undetectable viral load and normal CD4 count.
• Participants with a history of chronic hepatitis B virus (HBV) infection must have an undetectable HBV viral load on suppressive therapy, if indicated.
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they must have an undetectable HCV viral load.

Exclusion Criteria

• Clinical evidence of deep vein thrombosis (DVT) or pulmonary embolism (PE), prior history of cerebrovascular accident (CVA) or history of transient ischemic attack (TIA) within 12 months, or other known treatment-emergent (TE) event present during the screening period.
• Clinically significant (i.e., active) cardiovascular disease: myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), serious cardiac arrhythmia requiring medication.
• Patients who have implanted cardiac pacemakers, defibrillators or implanted devices with bare metal parts in the thoracic cavity, abdomen, and/or retroperitoneum.
• Currently receiving treatment with medication that has a known risk to prolong the QT interval or to induce Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study treatment.
• Patient has other concurrent severe and/or uncontrolled medical conditions that would, in the investigator’s judgment, contraindicate patient participation in the clinical study.
• Contraindication to heparin as per institutional guidelines.
• Another primary cancer within the last 3 years requiring systemic therapy.
• Patient has had major surgery within 14 days prior to starting study treatment or has not recovered from major side effects.
• Patient is currently receiving increasing or chronic treatment (> 5 days) with corticosteroids or another immunosuppressive agent within 2 weeks of study participation or has an active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent.
• Patient is being treated at start of study treatment with any of the following drugs: * Drugs known to be strong or moderate inhibitors or inducers of isoenzyme cytochrome P450 3A4 (CYP3A4) including herbal medications. * Drugs with a known risk of inducing Torsades de Pointes. * Note: The patient must have discontinued strong inducers for at least 1 week and must have discontinued strong inhibitors before the treatment is initiated. Switching to a different medication prior to starting study treatment is allowed.
• Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.
• Known prior severe hypersensitivity to investigational product, hyaluronidase, or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4.03 grade ≥ 3).
• Patient has a medically documented poorly controlled psychiatric disorder(s), alcohol abuse, or drug abuse as defined according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-V).
• Gastrointestinal arteriovenous malformations.
• Local gastrointestinal organ (e.g., stomach, duodenum) invasion by tumor.
• Patient is unable to undergo magnetic resonance imaging (MRI) due to incompatible implanted device, body habitus, and/or phobia unamenable to anxiolytic therapy.
• Patient needs concurrent bypass bile duct surgery or bypass gastric outlet obstruction surgery.
• Clinical evidence of chronic obstructive pulmonary disease (COPD), emphysema, recurrent pneumonia within 6 months, or heavy tobacco use.
• Patient has any recent risk of active infection or poor wound healing.
• Any unusual arterial or venous anatomy which increased risk for bleeding or formation of pseudoaneurysm.
• Patients with a history of autoimmune disease are excluded.
• Patients with prior interstitial lung disease are excluded.
• Patients who have had any live vaccines within 30 days, are excluded.
• Patients with pancreas cancers with microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors are excluded.