The main purposes of this study are to learn how effective the study drug combinations are in treating patients with metastatic pancreatic adenocarcinoma. The drug combinations are APX005M+Nivolumab+Gemcitabine+nab-Paclitaxel, or APX005M+Gemcitabine+nab-Paclitaxel.

Inclusion Criteria:

1. Subject has histologically or cytologically documented diagnosis of pancreatic adenocarcinoma with metastatic disease. Locally advanced subjects are not eligible.

2. Subject must have measureable disease by RECIST 1.1.

3. Subjects must be age 18 years or older.

4. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

5. Subjects must have the following laboratory values at screening within 2 weeks of the first dose of investigational agents:

   • Absolute neutrophil count (ANC) ≥1.5 x 109/L (in absence of growth factor support)
   • Platelet count ≥150 x 109/L
   • Hemoglobin ≥9 g/dL(without transfusion support)
   • Serum creatinine ≤1.5 mg/dL, and creatinine clearance ≥ 50 ml/min as measured by Cockcroft and Gault formula
   • Aspartate aminotransferase (AST) and ALT ≤2.5 x upper limit of normal (ULN)
   • Total bilirubin ≤1.5 x ULN, except in subjects with documented Gilbert's Syndrome, who must have a total bilirubin ≤3 x ULN

6. Women of childbearing potential (WOCBP) must have a negative pregnancy test (serum or urine) within the 7 days prior to study drug administration, and within the 3 days before the first study drug administration, or a negative pregnancy test within the 24 hours before the first study drug administration.

7. WOCBP and male subjects who are sexually active with WOCBP must agree to use 2 highly effective methods of contraception (including a physical barrier) before the first dose of study drugs, during the study, and for 5 months for women and 7 months for men following the last dose of study drug.

8. Subjects must have the ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

1. Subject must not have received any prior treatment, including chemotherapy, biological therapy, or targeted therapy for metastatic pancreatic adenocarcinoma, with the following exceptions and notes:

   1. Subjects who have received prior adjuvant therapy for pancreatic adenocarcinoma are eligible if neoadjuvant and adjuvant therapy (including chemotherapy and/or radiotherapy) was fully completed more than 4 months before the start of study treatment. In this case, prior Gem and/or NP is allowable
   2. Prior resection surgery is allowable.
   3. Patients initially diagnosed with locally advanced pancreatic cancer who have undergone chemotherapy then resection and were with no evidence of disease are eligible if metastatic relapse of disease has occurred and if the last dose of chemotherapy was more than 4 months before the data of study entry.

2. Subjects must not have another active invasive malignancy, with the following exceptions and notes:

   1. History of a non-invasive malignancy, such as cervical cancer in situ, non-melanomatous carcinoma of the skin, in situ melanoma, or ductal carcinoma in situ of the breast, is allowed.
   2. History of malignancy that is in complete remission after treatment with curative intent is allowed.
   3. No current or history of a hematologic malignancy is allowed, including subjects who have undergone a bone marrow transplant.

3. History of clinically significant sensitivity or allergy to monoclonal antibodies, their excipients, or intravenous gamma globulin

4. Previous exposure to CD40, PD-1, PD-L1, CTLA-4 antibodies or any other immunomodulatory agent

5. History of (non-infectious) pneumonitis that required corticosteroids or current pneumonitis, or history of interstitial lung disease

6. Subjects must not have a known or suspected history of an autoimmune disorder, including but not limited to inflammatory bowel disease, celiac disease, Wegner syndrome, Hashimoto syndrome, systemic lupus erythematosus, scleroderma, sarcoidosis, or autoimmune hepatitis, within 3 years of the first dose of investigational agent, except for the following.

   a. Subjects with Type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders such as vitiligo, or alopecia not requiring systemic therapy, or conditions not expected to recur in the absence of an external trigger are eligible.

7. Subjects must not have an uncontrolled intercurrent illness, including an ongoing or active infection, current pneumonitis, symptomatic congestive heart failure (New York Heart Association class III or IV), unstable angina, uncontrolled hypertension, cardiac arrhythmia, interstitial lung disease, active coagulopathy, or uncontrolled diabetes.

8. Subjects must not have a history of myocardial infarction within 6 months or a history of arterial thromboembolic event within 3 months of the first dose of investigational agent.

9. Subjects must not have a history of human immunodeficiency virus, hepatitis B, or hepatitis C, except for the following:

   1. subjects with anti-hepatitis B core antibody but with undetectable HBV DNA and negative for HBsAg
   2. subjects with resolved or treated HCV (i.e. HCV antibody positive but undetectable HCV RNA)

10. Subjects must not have a history of primary immunodeficiency.

11. Subjects must not receive concurrent or prior use of an immunosuppressive agent within 14 days of the first dose of investigational agent, with the following exceptions and notes:

    1. Systemic steroids at physiologic doses (equivalent to dose of oral prednisone 10 mg) are permitted. Steroids as anti-emetics for chemotherapy are not allowed.
    2. Intranasal, inhaled, topical, intra-articular, and ocular corticosteroids with minimal systemic absorption are permitted.
    3. Subjects with a condition with anticipated use of systemic steroids above the equivalent of 10 mg prednisone are excluded.

12. Subjects must not have a history of clinically manifested central nervous system (CNS) metastases.

    a. Subjects with known or suspected leptomeningeal disease or cord compression are not eligible.

13. Subjects must not have had major surgery as determined by the PI within 4 weeks before the first dose of investigational agent.

14. Subjects must not have received another investigational agent within the shorter of 4 weeks or 5 half-lives before the first dose of investigational agent.

15. Subjects must not have received a live attenuated vaccine within 28 days before the first dose of investigational agent, and subjects, if enrolled, should not receive live vaccines during the study or for 180 days after the last dose of investigational agent.

16. Females who are pregnant or lactating or who intend to become pregnant during participation in the study are not eligible to participate.

17. Subjects who are of reproductive potential who refuse to use effective methods of birth control during the course of participation of the study and within 5 month for women and 7 months for men of the last dose of investigational agent are ineligible to participate in the study.

18. Subjects who have any clinically significant psychiatric, social, or medical condition that, in the opinion of the investigator, could increase the subject's risk, interfere with protocol adherence, or affect the subject's ability to give informed consent are ineligible to participate in the study.