This is an open-label, phase 1 clinical trial to evaluate the safety and preliminary efficacy of neoadjuvant chemoimmunotherapy (NAI, sotevtamab, and zabadinostat in combination with gemcitabine and nab-paclitaxel) followed by resection and adjuvant immunotherapy for participants with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC). Eligible participants will undergo endoscopic ultrasound (EUS)-guided biopsies of the primary pancreatic tumor within 7 days of enrollment and prior to study day 1. EUS-guided biopsies will be used for histopathological examination to give clinical diagnostic information (as SoC) and will be stored in an ethically approved tissue bank.

Inclusion Criteria:

1. Age ≥ 18 years old.
2. Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines.
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
4. Histologically or cytologically confirmed PDAC that is confined to the pancreas.
5. Borderline resectable (surgical resection possible but challenging) or locally advanced (surgical resection not possible) PDAC, as determined by the local investigator based onlocal institutional guidelines.
6. Measurable tumor lesions according to RECIST v1.1. (within 90 days prior to first dose of study treatment).
7. Have not received prior anticancer therapy for pancreatic cancer.
8. Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
9. Agreement to practice effective contraception for female participants of child-bearing potential and non-sterile males. Female participants of child-bearing potential must agree to use effective contraception for up to 7 months after completion of therapy, and nonsterile male participants must agree to use a condom for up to 7 months after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), orals, injectables, 2 forms of barrier methods (eg, condom, diaphragm) used with spermicide, intrauterine devices (IUDs), and hormonal therapy.

Exclusion Criteria:

1. Resectable PDAC, meeting the following criteria upon CT/MRI: (a)No superior mesenteric vein (SMV) or portal vein (PV) distortion; (b) Clear fat planes around superior mesenteric artery (SMA), celiac artery (CA), and common hepatic artery (CHA).
2. Participants for whom an operation is not considered in the participant's best interest (eg, due to comorbidity).
3. Histologically or cytologically confirmed pancreatic tumor that is not adenocarcinoma.
4. CA19-9 > 1,000 U/mL.
5. QTc interval using Fridericia's formula (QTcF) > 470 ms.
6. If participants have had major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
7. Have received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed.
8. Have known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
9. Inadequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to baseline: (a) Absolute neutrophil count (ANC) < 1,500 cells/μL without granulocyte colonystimulating factor support, (b) Lymphocyte count < 500/μL, (c) platelet count < 100,000/μL without transfusion (d) Hemoglobin < 8.0 g/dL Note: Participants may be transfused to meet this criterion, (e) International Normalized Ratio (INR) or aPTT activated partial thromboplastin time (aPTT) < 1.5 × upper limit of normal (ULN) Note: This applies only to participants who are not receiving therapeutic anticoagulation; participants receiving therapeutic anticoagulation should be on a stable dose. (f) Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase > 2.5 × ULN, with the following exception: Participants with documented liver metastases: AST and/or ALT > 5 × ULN. (g) Serum bilirubin ≤ 3 × ULN (h) Creatinine clearance ≤ 60 mL/min (calculated using the Cockcroft-Gault formula), (i) Serum albumin ≤ 3.0 g/dL. (j) Urine dipstick for proteinuria > 2+ (within 7 days prior to initiation of study treatment). Participants with ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate < 1 g of protein in 24 hours.
10. Significant cardiovascular disease (such as New York Heart Association cardiac disease class II or greater), myocardial infarction within 3 months prior to baseline, unstable arrhythmias, or unstable angina.
11. Severe infections at the time of enrollment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
12. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Participants receiving prophylactic antibiotics (eg, to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
13. Prior allogeneic bone marrow transplantation or solid organ transplant.
14. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high risk for treatment complications.
15. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
16. Treatment with systemic immunosuppressive medications (including, but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to initiation of study treatment, or anticipation of the need for systemic immunosuppressive medication during study treatment, with the following exceptions: (a) A. Participants who have received acute, low-dose, systemic immunosuppressant medications (eg, a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the Medical Monitor, (b)B. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (eg, fludrocortisone) for participants with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
17. Participation in an investigational drug study or history of receiving any investigational treatment within 30 days prior to the start of treatment on this study.
18. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.
19. Pregnant and nursing women.