The purpose of this clinical trial is to determine whether using chemotherapy followed by stereotactic ablative body radiation therapy (SABR) and tumor treating fields (TTF) will slow tumor growth in people with locally advanced pancreas cancer. All participants will receive SABR therapy once per day for five days and use the TTF system for at least 18 hours per day starting on the first day of SABR until the tumor progresses or severe toxicity develops.

Inclusion Criteria:

• Histologically or cytologically confirmed locally advanced adenocarcinoma of the pancreas. Locally advanced pancreas cancer as per National Comprehensive Cancer Network (NCCN) Guidelines.

• Regional lymph node involvement is permitted if able to be treated with radiation therapy.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• At least 3 months of prior FOLFIRINOX, modified FOLFIRINOX, and/or gemcitabine/nab-paclitaxel delivered for pancreas cancer without evidence of distant progression on restaging radiographic studies.

• Carbohydrate antigen 19-9 (CA 19-9) ≤500 U/mL on most recent assessment prior to study enrollment.

• Adequate normal organ and marrow function as defined below:

  i. Hemoglobin ≥8.0 g/dL that may be achieved with transfusion ii. Absolute neutrophil count (ANC) ≥1500 per mm^3 iii. Platelet count ≥60,000 per mm^3 iv. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN) v. AST (SGOT)/ALT (SGPT) ≤3 x institutional ULN

• People of childbearing potential 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. Should a participant become pregnant or suspect they are pregnant while participating in this study, they must inform the treating physician immediately.

• Able to operate the tumor treating field (NovoTTF-100L) system independently or with assistance.

• All participants must sign written informed consent.

Exclusion Criteria:

• Distant metastasis from pancreas cancer.

• Contraindication to having a magnetic resonance imaging (MRI) scan.

• Prior abdominal radiation therapy.

• History of any primary malignancy with the exception of:

  1. Malignancy treated with curative intent and with no known active disease for at least 3 years before enrollment on this study.
  2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  3. Adequately treated carcinoma in situ without evidence of disease (i.e., cervical carcinoma in situ; superficial bladder cancer).

• Any unresolved toxicity (Common Terminology Criteria for Adverse Events version 5.0 > grade 2) from previous anti-cancer therapy. Participants with irreversible toxicity that is not reasonably expected to worsen by treatment on this study are permitted to enroll on this study.

• History of inflammatory bowel disease (i.e., Crohn's disease, ulcerative colitis).

• Any condition in the opinion of the investigator that would interfere with evaluation of study treatment or interpretation of patient safety or study results.

• Participants who are pregnant or breastfeeding. Patients with an electrical implantable device in the torso. Examples of electrical implanted medical devices include spinal cord stimulators, vagus nerve stimulators, pacemakers, and defibrillators.

• History of significant uncontrolled cardiovascular disease. Significant cardiac disease includes second/third degree heart block; significant ischemic heart disease; poorly controlled hypertension; congestive heart failure of the New York Heart Association (NYHA) Class II or worse.

• History of arrhythmia that is symptomatic or requires treatment. Patients with atrial fibrillation or flutter controlled by medication are not excluded from participation in the trial.

• Known allergy to medical adhesives or conductive hydrogel [gel used on electrocardiogram (ECG) stickers or transcutaneous electrical nerve stimulation (TENS) electrodes].