Immune Checkpoint Inhibitor M7824 and the Immunocytokine M9241 in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Advanced Pancreas Cancer

* INCLUSION CRITERIA:
* Histologically or cytologically proven pancreatic adenocarcinoma (subjects with endocrine or acinar pancreatic carcinoma are not eligible).
* Patients must have stage III or IV pancreatic cancer (Cohort 1) or locally advanced pancreas cancer (LAPC), either borderline resectable pancreas cancer or locally advanced, unresectable pancreas cancer (Cohorts 2 and 3).
* Patient must be eligible to undergo stereotactic body radiation therapy (SBRT) and have fiducial markers placed (any metal biliary stents are an acceptable alternative) (Cohorts 2-3).
* Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of bintrafusp alfa (M7824) and NHS-IL12 (M9241) in patients \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
* Must have measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
* Adequate hematological function defined by:

  * white blood cell (WBC) count greater than or equal to 3 times 10\^9/L
  * with absolute neutrophil count (ANC) greater than or equal to 1.0 times 10\^9/L,
  * lymphocyte count greater than or equal to 0.5 times 10\^9/L,
  * platelet count greater than or equal to 100 times 10\^9/L, and
  * Hemoglobin (Hgb) greater than or equal to 9 g/dL (in absence of blood transfusion)
* Adequate renal function defined by:

  * Creatinine OR Measured or calculated creatinine clearance (CrCl) (estimated glomerular filtration rate (eGFR) may also be used in place of CrCl)

    * \< 1.75 x institution upper limit of normal OR
    * greater than or equal to 45 mL/min/1.73 m\^2 for participant with creatinine levels greater than or equal to 1.75 X institutional upper limit of normal (ULN)
  * Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard
* Adequate hepatic function defined by:

  * a total bilirubin level less than or equal to 3 times ULN,
  * an aspartate aminotransferase (AST) level less than or equal to 5 times ULN,
  * alanine aminotransferase (ALT) level less than or equal to 5 times ULN
* Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
* Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.
* The effects of the study treatment on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) at the study entry, for the duration of study treatment and up to 120 days after the last dose of the drug for males and up to 60 days for females. 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.
* Patient must be able to understand and willing to sign a written informed consent document.

EXCLUSION CRITERIA:

* Treatment with any investigational agent within 28 days before treatment initiation.
* Prior therapy with any antibody / drug targeting T cell coregulatory proteins (immune checkpoints) such as anti-Programmed cell death protein 1 (PD-1), anti-Programmed death-ligand 1 (PD-L1), or anti-cluster of differentiation 152 (CTLA-4) antibody.
* Anticancer treatment within designated period before treatment initiation including:

  * major surgical procedure (such as laparotomy) within 28 days
  * minor surgical procedure (such as biliary stenting) within 7 days
  * chemotherapy with published half-life known to be 72 hours within 7 days
  * chemotherapy with unpublished or half-life greater than 72 hours within 28 days
* Receipt of any organ transplantation, including allogeneic stem-cell transplantation, except of transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant)
* Significant acute or chronic infections including tuberculosis (history of exposure or history of positive tuberculosis test; plus, presence of clinical symptoms, physical or radiographic findings)
* Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent with the exceptions:

  * diabetes type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible;
  * subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses less than or equal to 10 mg of prednisone or equivalent per day;
  * administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation.
* Known severe hypersensitivity reactions to monoclonal antibodies (Grade greater than or equal to 3 National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v5.0, any history of anaphylaxis or history of uncontrolled asthma.
* Known alcohol or drug abuse.
* Clinically significant cardiovascular / cerebrovascular disease as follows: cerebral vascular accident / stroke (\< 6 months prior to treatment initiation), myocardial infarction (\< 6 months prior to treatment initiation), unstable angina, congestive heart failure (New York Heart Association Classification Class greater than or equal to II), or serious cardiac arrhythmia.
* Administration of live vaccines within 30 days prior to treatment initiation.
* Human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV) patients on antiviral drugs are excluded due to the absence of previous experience on combination of antiviral and this trial drugs and possible interaction.
* Subjects with a history of serious intercurrent chronic or acute illness, such as cardiac or pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3 months) clinically significant bleeding events, or other illness considered by the Investigator as high risk for investigational drug treatment.
* Subjects unwilling to accept blood products as medically indicated.
* Female patients who are pregnant or breastfeeding. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M7824 or M9241, breastfeeding should be discontinued.