Safety and Efficacy of APX005M With Gemcitabine and Nab-Paclitaxel With or Without Nivolumab in Patients With Previously Untreated Metastatic Pancreatic Adenocarcinoma

Inclusion Criteria

• Subject has histologically or cytologically documented diagnosis of pancreatic adenocarcinoma with metastatic disease. Locally advanced subjects are not eligible.
• Subject must have measureable disease by RECIST 1.1.
• Subjects must be age 18 years or older.
• Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• 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
• 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.
• 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.
• Subjects must have the ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria

• 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:
• 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
• Prior resection surgery is allowable.
• 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.
• Subjects must not have another active invasive malignancy, with the following exceptions and notes:
• 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.
• History of malignancy that is in complete remission after treatment with curative intent is allowed.
• No current or history of a hematologic malignancy is allowed, including subjects who have undergone a bone marrow transplant.
• History of clinically significant sensitivity or allergy to monoclonal antibodies, their excipients, or intravenous gamma globulin
• Previous exposure to CD40, PD-1, PD-L1, CTLA-4 antibodies or any other immunomodulatory agent
• History of (non-infectious) pneumonitis that required corticosteroids or current pneumonitis, or history of interstitial lung disease
• 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